Small Animal Toxicology Essentials

Second Edition

Edited by

Tina Wismer, DVM, MS, DABVT, DABT

ASPCA Animal Poison Control Center
Champaign, IL, USA

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Library of Congress Cataloging‐in‐Publication Data

Names: Wismer, Tina, editor.
Title: Small animal toxicology essentials / [edited by] Tina Wismer.
Description: Second edition. | Hoboken, New Jersey : John Wiley & Sons, Inc., [2025] | Includes bibliographical references and index.
Identifiers: LCCN 2024058683 (print) | LCCN 2024058684 (ebook) | ISBN 9781394180110 (paperback) | ISBN 9781394180127 (adobe pdf) | ISBN 9781394180134 (epub)
Subjects: MESH: Poisoning–veterinary | Poisoning–therapy | Pets
Classification: LCC SF757.5 (print) | LCC SF757.5 (ebook) | NLM SF 757.5 | DDC 636.089/59–dc23/eng/20250213
LC record available at https://lccn.loc.gov/2024058683
LC ebook record available at https://lccn.loc.gov/2024058684

Cover Design: Wiley
Cover Images: Courtesy of Tina Wismer, Tamara Foss, and Tim Williams

Dedication

To Tim Williams, my long‐suffering husband and biggest fan. Thank you for all of the support for this project and others. I would also like to dedicate this edition to all of my colleagues that have a passion for veterinary toxicology. It has been a pleasure to see you all grow and flourish.

Contributors

Elisha Argo, CVT
ASPCA Animal Poison Control Center
Champaign, IL, USA

Jeff Backus, CVT, RVT, VTS (ECC)
ASPCA Animal Poison Control Center
Champaign, IL, USA

Brandee Bean, CVT
ASPCA Animal Poison Control Center
Champaign, IL, USA

Lisa Bunnell, CVT
ASPCA Animal Poison Control Center
Champaign, IL, USA

Rhian Cope, BVSc, BSc, PhD, DABT
ERMA New Zealand
New Zealand

Devon Davis, CVT
ASPCA Animal Poison Control Center
Champaign, IL, USA

Frank Davis, CVT
Multi‐site Hospital Manager
Urbana, IL, USA

Eric Dunayer, DVM, MS, DABVT, DABT
ASPCA Animal Poison Control Center
Champaign, IL, USA

Catherine Dzienisiewski, VMD, MLAS, DABT
ASPCA Animal Poison Control Center
Champaign, IL, USA

Tamara Foss, CVT
ASPCA Animal Poison Control Center
Champaign, IL, USA

Erin Freed, CVT
ASPCA Animal Poison Control Center
Champaign, IL, USA

Sharon Gwaltney‐Brant, DVM, PhD, DABVT, DABT
Veterinary Information Network
Mahomet, IL, USA

Jennifer Hopkins, DVM, DABT
ASPCA Animal Poison Control Center
Champaign, IL, USA

Jennifer Kendall, DVM, DABT, DABVT
ASPCA Animal Poison Control Center
Champaign, IL, USA

Safdar A. Khan, DVM, PhD, DABVT (retired)
Urbana, IL, USA

Carrie Lohmeyer‐Mauzy, CVT
ASPCA Animal Poison Control Center
Champaign, IL, USA

Kristi D. Long, CVT, LVT, AAT
ASPCA Animal Poison Control Center
Champaign, IL, USA

Charlotte Means, DVM, MLIS, DABVT, DABT
ASPCA Animal Poison Control Center
Champaign, IL, USA

Lisa Murphy, DVM, DABT
University of Pennsylvania
Kennett Square, PA

Brittany Parsons, DVM, DABT
ASPCA Animal Poison Control Center
Champaign, IL, USA

Mindy Perez, CVT, MBA
ASPCA Animal Poison Control Center
Champaign, IL, USA

Jenny Schuett, CVT
ASPCA Animal Poison Control Center
Champaign, IL, USA

Karla R. Smith, DVM
ASPCA Animal Poison Control Center
Champaign, IL, USA

Lizzy Stone‐Lawrence, RVT, VTS (ECC)
ASPCA Animal Poison Control Center
Champaign, IL, USA

Ginger Watts Brown, DVM, DABT, DABVT
ASPCA Animal Poison Control Center
Champaign, IL, USA

Tina Wismer, DVM, MS, DABVT, DABT
ASPCA Animal Poison Control Center
Champaign, IL, USA

Preface

The second edition of Small Animal Toxicology Essentials expands on the first and has updated information. It has also added more color photographs. The book is still divided into three sections. The first section is fundamentals and has self‐study questions. The second section covers body systems and what happens to them when exposed to toxins and what toxins can affect them. Section three covers specific toxicants divided by their type. The appendices contain drug dosages and lists of toxic and nontoxic plants.

Acknowledgement

I would like to acknowledge the hard work done by Sharon Gwaltney‐Brant, Robert Poppenga, and all the previous authors in the first edition. It gave me an easy outline to follow.

Section 1
Fundamentals of Veterinary Clinical Toxicology

1
General Toxicologic Principles

Sharon Gwaltney‐Brant

INTRODUCTION

Toxicology is the study of the nature, effects, and detection of poisons and the treatment of poisoning. For the purposes of this textbook, we define clinical toxicology as the diagnosis and treatment of the poisoned patient. Many of the basic principles of toxicology, such as the inherent toxicity of various forms of a chemical, variations in dose–response curves, different mechanisms of toxic action, variations in individual and species sensitivities to chemicals, and how differences in kinetics of chemicals (sometimes referred to as “toxicokinetics”) need to be applied to the successful diagnosis and treatment of poisoning. In clinical toxicology there is a need for the application of good critical care and medical practices (e.g., stabilizing, monitoring, and treating a patient) to achieve a successful outcome.

DEFINITIONS

All special areas of study have unique terminology that is important to master to fully appreciate the discipline. The following definitions provide some needed terminology in order to more effectively utilize this textbook.

Toxicant

A poison or poisonous agent; an intoxicant; any solid, liquid or gas that, when introduced into or applied to the body, can interfere with the life processes of cells or the organism by its own inherent qualities (toxicity) without acting mechanically and irrespective of temperature.

Toxin

A poisonous material that is synthesized or derived from an animal or plant; also referred to as a biotoxin. Zootoxins, bacterial toxins, and phyto (or plant) toxins are subcategories of toxins.

Toxicity

The poisonous characteristics of a substance; the degree to which something is poisonous. Perhaps the best known measure of toxicity of a chemical is its lethal dose or LD₅₀ (Table 1.1).

Acute Toxicity

Intoxication that results from the effects of a single dose or multiple doses of a toxicant given during a 24‐hour period (e.g., a dog got into a box of chocolates or a cat was left in a room contaminated by chemical fumes overnight). The LD₅₀ of a chemical is most often determined during acute exposure studies in which a single dose of a chemical is given.

Subacute Toxicity

Exposure to multiple doses of a toxin or toxicant given for greater than 24 hours but no longer than 30 days (e.g., an animal owner administers ibuprofen to dog for a week).

Subchronic Toxicity

Repeated or continuous exposures to toxicants for a duration of 1–3 months (e.g., a patient on weekly chemotherapy for cancer).

Table 1.1. Classification scheme for relative toxicity

Classification | Toxicity (LD₅₀ in mg/kg body weight)
Extremely toxic | <1 mg/kg
Highly toxic | 1–50 mg/kg
Moderately toxic | 50–500 mg/kg
Slightly toxic | 0.5–5.0 g/kg
Practically nontoxic | 5–15 g/kg
Relatively harmless | >15 g/kg

Chronic Toxicity

Intoxication that results from prolonged exposure, with the duration of exposure being 3 months or longer (e.g., repeated exposure of a cat to low levels of lead as a result of environmental contamination and grooming of contaminated paws or hair).

Dose

The quantity of drug or toxicant administered at one time irrespective of body weight.

Dosage

The regimen governing the size, amount, frequency, and number of doses of a therapeutic agent to be administered to a patient; most commonly measured in milligrams per kilogram (mg/kg), milligrams per pound (mg/lb), or milligrams per square meter of body surface area (mg/m²).

Lethal Dosage (LD)

The lowest dosage that causes death. An LD can be expressed as a percentage of individuals dying (e.g., an LD₁₀ means 10% of individuals will die from this dosage).

Median Lethal Dosage (LD₅₀)

The quantity of an agent that will kill 50% of the test subjects to which it is administered. Note that the LD₅₀ is a fairly rough estimate of overall toxicity and will not tell us at what dosage the first individual will develop signs of toxicosis (minimum toxic dosage or MTD) or die (minimum lethal dosage or MLD).

Parts per Million (ppm)

A weight‐for‐weight (w/w) concentration equal to 1 mg/kg or 1 g/ton (tonne). Used most commonly to express the concentration of toxicants or trace elements in water, feeds, solvents, and tissues. Note that mg/kg can refer to either a concentration in a material or a dosage in a patient; its meaning is dependent on the context of its use.

Parts per million (ppm), parts per billion (ppb), and parts per trillion (ppt) are the most commonly used terms to describe very small amounts of contaminants in our environment. They are measures of concentration or the amount of one material in a larger amount of another material; for example, the weight of a toxic chemical in a certain weight of food. The following example might help conceptually. If you divide a pie equally into 10 pieces, each piece would be one part per 10 or one‐tenth of the total pie. If, instead, you cut this pie into a million pieces, each piece would be very small and would represent a millionth of the total pie or one part per million of the original pie. If you cut each of these million pieces into a thousand little pieces, each of these new pieces would be one part per billion of the original pie. To give you an idea of how little this would be, a pinch of salt in 10 tons of potato chips is also one part (salt) per billion parts (chips). In the pie example, the pieces of the pie are made up of the same material as the whole. However, if there were a contaminant in the pie at a level of one part per billion, one of these invisible pieces of pie would be made up of the contaminant and the other 999,999,999 pieces would be pure pie. Similarly, one part per billion of an impurity in a biological or environmental sample represents a tiny fraction of the total amount of the sample (e.g., water, food, whole blood, urine, or tissue).

Hazard (Risk)

The likelihood that a chemical will cause harm under certain conditions. The hazard can vary for the same chemical. For example, the hazard or risk of intoxication is greater if a potentially toxic product or chemical is not stored properly and thereby the chance for accidental exposure is increased due to greater accessibility. Or the risk of intoxication of a compound may be low if the compound comes in contact with the skin but high if it is ingested.

CLASSIFICATION OF TOXICANTS

Toxins and toxicants are classified in a variety of ways; no one way is better than another and a combination of classification schemes is used in this textbook. Poisons can be classified based on the organ systems that are primarily affected (e.g., hepatotoxicants, neurotoxicants, nephrotoxicants, etc.). The limitation to this scheme is that many toxins or toxicants affect more than one organ system. Alternatively, poisons can be classified based on their chemical structure. For example, alkaloids are cyclic compounds that contain a nitrogen molecule within the ring. Toxic alkaloids are common in plants (e.g., nicotine in Nicotiana spp. or coniine in Conium maculatum). A third classification scheme categorizes poisons according to their use or location. For example, pesticides are subcategorized into rodenticides, insecticides, herbicides, fungicides, avicides, parasiticides, etc. based on the type of target organism for which they were developed. Poison categories based on location might include those found in homes, yards, or industrial sites. Within each of these categories are chemically diverse compounds with quite distinct target organs or mechanisms of toxic action. Finally, poisons can also be categorized according to their mechanism of toxic action. For example, some poisons cause damage via free radical formation or lipid peroxidation of cellular membranes and others inhibit protein synthesis.

SPECTRUM OF UNDESIRED EFFECTS

Toxicants cause damage through a variety of mechanisms, including altering cell and organelle membrane integrity, altering cell energy production, inhibiting protein synthesis or enzyme activity, or damaging DNA (Osweiler 1996). Other undesired effects that need to be considered are discussed below.

Idiosyncratic Reactions

Idiosyncratic reactions to chemicals are defined as genetically determined abnormal reactivity to a chemical (Aleksunes and Eaton 2019). Most commonly, this is caused by an acquired or congenital enzyme deficiency that prevents a toxicant from being processed properly. In some cases, the reason for an idiosyncratic reaction is unknown. See the discussion on genetic polymorphisms below.

Immediate vs. Delayed Reactions

Immediate effects can be defined as those that occur rapidly after a single exposure to a chemical. In contrast, delayed toxic effects are those that occur after some period of time (often, but not always, following repeated exposures). For example, many chemicals can induce cancer, but only after a long latency period of years (Aleksunes and Eaton 2019; Osweiler 1996). The focus of this textbook is on immediate adverse effects.

Reversible vs. Irreversible Damage

If a chemical damages a tissue, the ability of that tissue to regenerate largely determines whether the effect is reversible or irreversible. Tissues such as the gastrointestinal tract and the liver, which have high regenerative capabilities, are less likely to suffer irreversible damage than other tissues, such as nervous tissue, which has much more limited regenerative capacity. However, even highly regenerative tissues such as the liver can suffer irreversible damage, particularly as a result of fibrosis in response to chemically induced damage.

Local vs. Systemic Effects

Local effects of a chemical are those that typically occur at the site of first contact between the biological system and the chemical. Good examples of chemicals with primarily local effects include acid and alkali corrosives. Systemic effects require the absorption and distribution of a chemical to a distant site where damage occurs. Most chemicals discussed in this textbook have systemic effects. It is possible for some chemicals to have both local and systemic effects. A good example of this occurs following exposure to iron salts. The reactivity of iron damages mucosal cells along the gastrointestinal tract; systemic absorption of iron results in more widespread damage to multiple organs.

INTERACTION OF CHEMICALS

Because animals and people are exposed to multiple chemicals at any given time, it is necessary to consider how different chemicals might interact with each other to modify toxic responses. Chemical interactions occur by a number of mechanisms that can include alterations of absorption, biotransformation (metabolism), protein binding, or elimination (Aleksunes and Eaton 2019). An example of two chemicals interacting to affect toxicity of one involves the combination of piperonyl butoxide and pyrethrin/pyrethroid insecticides. Piperonyl butoxide interferes with the metabolism, and therefore the detoxification, of the insecticides (Volmer 2004).

In general, types of interactions between chemicals that can influence the toxicity of one or more of the chemicals are classified as additive, synergistic, or antagonistic (Table 1.2). Additive interaction means the effect of two chemicals is equal to the sum of the effect of the two chemicals taken separately (e.g., 2 + 3 = 5). This is usually due to the two chemicals acting on the body in the same way. An example of additive toxicity would be exposure to two different organophosphorus insecticides at the same time. Both have the same mechanism of toxic action (i.e., inhibition of acetylcholinesterase activity). Synergistic interaction means that the effect of two chemicals taken together is greater than the sum of their separate effects at the same dosages (e.g., 2 + 2 = 20). One example of synergism is simultaneous exposure to the hepatotoxicants ethanol and carbon tetrachloride. In this case the damage to the liver is greater than that expected from summing the toxicities of each individual chemical. Antagonistic interaction means that the effect of two chemicals is less than the sum of the effect of the individual chemicals (e.g., 4 + 6 = 8). This can be due to the second chemical increasing the excretion of the first or perhaps as a result of the first directly blocking the toxic actions of the second. Antagonism forms the basis for many antidotal drugs. For example, atropine blocks cholinergic receptors that are stimulated following exposure to organophosphorus or carbamate insecticides.

Table 1.2. Interactions of toxicants: when multiple chemical exposures occur, a variety of interactions may occur between those chemicals

Additive 2 + 2 = 4 | Exposure to two or more toxicants results in the sum of the expected individual responses
Synergistic 2 + 2 = 10 | Exposure of two or more toxicants results in response in great excess than the sum of their individual responses
Antagonistic 2 + 2 = 1 | Exposure to two toxicants results in effects that are less than the sum of their individual responses
Potentiated 0 + 2 = 4 | Exposure to a normally nontoxic agent in combination with a toxicant results in enhanced toxicity of the toxicant

One other term, potentiation, is used to describe chemical interactions. Potentiation occurs when one substance does not have a toxic effect on a certain organ or system but, when added to another chemical, makes the second chemical much more toxic (Aleksunes and Eaton 2019). For example, isopropanol is not hepatotoxic. However, when combined with carbon tetrachloride, the hepatoxicity of carbon tetrachloride is greatly enhanced.

Finally, tolerance is another term worth noting. It is defined as the state of decreased responsiveness to the toxic effect of a chemical as a result of prior exposure to that chemical or to a structurally related chemical (Aleksunes and Eaton 2019). Tolerance can occur either as a result of a decreased amount of a chemical reaching its site of toxic action or as a result of reduced responsiveness of a target to the chemical. The former can occur, for example, when exposure to a chemical increases the levels of metabolic enzymes in the liver, resulting in enhanced metabolism and detoxification of that chemical with subsequent exposures. The latter can occur as a result of down‐regulation of receptor numbers for chemicals that cause adverse effects due to receptor stimulation.

CHARACTERISTICS OF EXPOSURE

Every day, animals (including humans) are exposed to poisons in the air they breathe, the food they eat, and the water they drink. Even agents necessary for life such as oxygen, water, and sodium can be toxic under certain circumstances. The fact that we don't all develop signs of poisoning on a daily basis underscores the basic concept of toxicology: the dose makes the poison. However, many factors are involved in determining whether a sufficient dose of a poison reaches its site of action in order to invoke a toxicosis. Agent factors to consider include the toxicant, its physical properties (i.e., liquid vs. solid vs. gas, pH, etc.), its chemical structure, and its stability or reactivity. Host factors to consider include species and/or breed, age, weight, and general health status of the animal. The most important factors that must be considered in determining whether a toxicosis will develop are those surrounding the introduction of toxicant to host: the exposure. Without exposure to a poison, there will be no poisoning, so it is important to understand the characteristics of exposures to toxicants that help to determine whether a toxicosis will develop.

Route and Site of Exposure

In veterinary medicine most exposures to toxicants occur via ingestion (gastrointestinal tract). However, exposures to toxicants can occur via other routes, including inhalation (lungs), transdermal (skin), injection, ocular, and other minor parenteral routes (intramammary, etc.). Toxicants injected intravenously produce the most rapid response, with inhalation, intraperitoneal, subcutaneous, intramuscular, intradermal, oral, and dermal following in descending order of speed of response (Aleksunes and Eaton 2019). Not all poisons are toxic by all routes of exposure; in fact, most toxicants have a narrow range of routes by which they can gain access to the body. For instance, elemental mercury (quicksilver) is virtually nontoxic by dermal or oral routes; however, inhalation of the vapors can result in respiratory irritation as well as systemic absorption of mercury vapors via the lungs, which can, over time, result in central nervous system dysfunction from mercury toxicosis (Tchounwou et al. 2023).

Duration and Frequency of Exposure

Some toxicants can cause clinical effects with single exposures, but others may require repeated exposures over time before a toxicosis develops; the clinical syndromes of each of these types of exposures may be quite different. In small animal medicine, most toxicoses that present to the veterinary hospital are acute because they are most often due to a single exposure to a toxicant.

There can be significant differences between clinical syndromes demonstrated by patients, depending on whether the exposure was acute or chronic. For example, acute arsenic toxicosis causes severe gastrointestinal hemorrhage, shock, and, often, death in dogs, whereas sub‐acute to chronic exposure is expected to cause renal failure.

The frequency of exposure also can dictate the degree and severity of a toxicosis. For instance, a cat given 10 mg/kg of aspirin on a daily basis will quickly develop a toxicosis, but if the same dose is given every third day, toxicosis is unlikely.

DOSE–RESPONSE RELATIONSHIP

The basic concept in toxicology is “the dose makes the poison.” This concept is essential in assessing the risks of exposures to toxicants, and it is often overlooked by the lay public, who typically perceive substances as either “toxic” or “nontoxic.” Virtually any substance can be toxic under the appropriate circumstances. A veterinary technician who understands and is able to apply the basic concepts of toxicology to clinical situations will be able to provide objective and rational input into the development of risk assessments for patient exposures to potential toxicants.

The dose–response relationship is the correlation of the exposure characteristics with the spectrum of toxic effects that a particular toxicant can produce. Knowing the dose–response relationship allows us to predict what type of reaction might be expected from an exposure. For example, methylxanthines in chocolate can cause serious clinical effects if sufficient amounts are ingested (Gwaltney‐Brant 2001). A canine patient ingesting chocolate equal to 5 mg/kg of methylxanthines is not expected to have any serious clinical problems, but a dosage of 50 mg/kg could put the dog at risk for serious cardiovascular effects.

There are two components to the dose–response relationship: the population component and the individual component. Most dose–response relationships are made by grouping the responses of individuals to develop a population dose–response curve. As with all statistical studies of populations, the curve is bell‐shaped, and the majority of individuals (the “normal” population) fall under the middle area of the curve. However, there are always individuals on the lower or upper limits of the curve (i.e., outliers), meaning they are more or less sensitive, respectively, to the toxicant and they will respond at lower or higher levels than the “normal” population (Figure 1.1). For instance, most dogs ingesting 20–30 mg/kg of methylxanthines from chocolate will develop agitation, restlessness, polydipsia, and gastrointestinal upset (Gwaltney‐Brant 2001). However, at this dose, some dogs will show none of these clinical effects and appear clinically normal (less sensitive), while other dogs may develop signs at doses below 20 mg/kg (more sensitive). So, while knowing the dose–response relationship for a toxicant, it is important to also realize that there will be occasions when an individual patient fails to “read the same book” as the rest of us and responds differently than the norm. Some potential reasons for these individual variations will be discussed later in the chapter.

Figure 1.1. Illustration of dose–response curve. The majority of responders fall into the “Normal” range, but a small percentage of “Sensitive” individuals will respond at lower doses and another small percentage of “Resistant” individuals will not respond until the dose is much higher.

Therapeutic Index

Medications provide an excellent example of the dose–response relationship. If too small a dose of medication is taken, it will not have the desired therapeutic effect, and if too high a dose is taken, signs of toxicosis may be seen. The goal is to find a dose that is effective and yet carries a low risk of intoxication. When comparing the relative safety of two similar drugs, a measurement called the therapeutic index is often used. This index is a ratio of the dose known to produce a toxic effect in 50% of the population (TD₅₀) to the dose known to produce a desirable therapeutic dose in 50% of the population (ED₅₀) (Aleksunes and Eaton 2019). The larger the ratio, the greater the relative safety.

Figure 1.2. The margin of safety is the ratio of the lethal dose to 1% of the population to the effective dose to 99% of the population. It is used to measure drug safety. Bigger is better.

Another parameter that also compares a toxic dose (TD₁; the dose at which 1% will experience toxic effect) with an effective dose (ED₉₉; dose that is effective in 99% of the population) is the margin of safety. A drug with a wide margin of safety will have low risk of adverse effects in the vast majority of patients (Figure 1.2).

Variation in Toxic Responses

In discussing dose–response, one must keep in mind that there will always be individuals who do not respond in the same fashion as the majority of the population. An individual may show a higher or lower sensitivity to toxicosis than expected or may not show a therapeutic effect from a medication. Some reasons for these individual variations have been elucidated, but others still remain to be discovered (see idiosyncratic definition above).

Species Differences

Response to toxicants can vary tremendously between different species, with compounds that are relatively nontoxic to one species being quite toxic in a different species. These species differences can be the result of differences in physiology or toxicant absorption, metabolism, and/or elimination. For instance, cats evolved as true carnivores that did not need to metabolize plant‐derived compounds such as phenols, and they therefore did not evolve the necessary enzymes required to eliminate phenolic compounds from the feline body. As a result, cats have diminished ability to metabolize certain phenolic compounds, making them more susceptible to toxicosis from xenobiotics (such as acetaminophen) that contain phenols. Cats are also highly susceptible to developing methemoglobinemia and Heinz body anemia because their hemoglobin molecules contain eight reactive sulfhydryl groups (compared to four in dogs and two in humans), which can bind to oxidative agents, such as disulfides found in onions and other Allium spp., that can denature hemoglobin. Additionally, a relative deficiency of methemoglobin reductase enzymes in their red blood cells makes it difficult for them to reverse the hemoglobin damage (Osweiler 2013). Because species differences are common and many are not fully elucidated, care must be taken when attempting to extrapolate toxicity data from one species and apply it to another.

Genetic Polymorphisms

The influence of genetics on an individual's response to xenobiotics is the subject of much study in the human pharmaceutical world. Genetic polymorphism is the term for hereditary differences in a single gene that occur in more than 1% of the population (Aleksunes and Eaton 2019). Genetic polymorphisms are significant causes of individual variation in response to toxicants. Although a large number of genetic polymorphisms relating to xenobiotics have been identified in humans, less study has been done in companion animals. Perhaps the best known toxicology‐related genetic polymorphism in the veterinary world is the sensitivity of some dogs to macrolide antiparasitic agents (e.g., ivermectin, moxidectin, etc.). Individuals within certain genetic lines of collies, Shetland sheepdogs, Old English sheep dogs, and several related breeds carry an autosomal recessive defect in a gene that codes for a blood–brain barrier P‐glycoprotein (Lanusse et al. 2018; Mealey et al. 2023). This defect results in a faulty “pump” that normally excludes certain xenobiotics (including macrolides) from entering the central nervous system (CNS). As a result, macrolide agents are able to enter the CNS and cause clinical signs of intoxication at dosages that are not toxic to dogs without this defect. Likewise, other drugs that are normally excluded from the CNS by this pump but can gain access to the CNS in P‐glycoprotein‐defective dogs include digoxin, doxorubicin, and vincristine (Mealey et al. 2023). Similar P‐glycoprotein defects and macrolide sensitivities have been identified in cats, resulting from different P‐glycoprotein gene mutations than those found in dogs (Mealey et al. 2023).

Age

Age‐related responses to toxicants must be considered when dealing with pediatric and geriatric patients because behavioral, physiological, and pathological differences in these special populations can have a profound influence on sensitivity to toxicants. When assessing the risk of an exposure to a toxicant, pediatric and geriatric animals should be considered at increased risk, and treatment should be considered at lower levels of exposure than would occur with a young adult animal.

Pediatric Patients

Nursing puppies and kittens may be exposed to toxicants not only through ingestion or inhalation of toxicants in their environments but by exposure to toxicants that the nursing dam may have ingested if these toxicants are passed through the milk (Peterson 2013). By their inquisitive nature, young animals are more inclined to be exposed to toxicants in their environment that adult animals have learned to avoid (e.g., skunk spray). Younger animals have a variety of physiological differences making them more susceptible to toxicosis, including:

increased intestinal permeability to some toxicants (e.g., lead)

increased gastric pH, which enhances the absorption of some toxicants

decreased intestinal motility, which allows toxicants to stay in the gastrointestinal tract longer and provides more opportunity for absorption of toxicants

decreased plasma protein concentrations to bind toxicants, allowing more free toxicant in the blood to reach target tissues

less body fat to sequester lipid soluble toxicants

decreased glomerular filtration rate, which results in decreased excretion of toxicants and their metabolites

decreased hepatic function and metabolic enzymes to detoxify toxicants.

Geriatric Patients

As animals age, they experience physiological and metabolic changes that can alter the way that they respond to toxicants. Additionally, these animals may be on medications for degenerative disorders typical of elderly animals (e.g., arthritis), and interaction between the medication and toxicant may occur. Aging results in decreased kidney and liver function. Because these two organ systems are the predominant means of toxicant elimination, the aging animal has a decreased capacity to efficiently remove toxicants from the body. Geriatric animals share some of the same metabolic derangements seen in pediatric animals, including decreased intestinal motility, decreased plasma protein production, decreased glomerular filtration rate, and decreased hepatic function. Additionally, elderly animals may have decreased cardiovascular function, making them less able to handle the stresses of intoxication. Concurrent disease processes are more common in older patients and may increase the susceptibility to organ damage by toxicants (e.g., preexisting renal dysfunction may make a patient more susceptible to the toxic effects of nonsteroidal anti‐inflammatory drugs) or compromise the animal's ability to respond to a toxicant. The behavior of a geriatric patient on some medications might be altered such that there is an increased risk for toxicant exposure (e.g., dogs on corticosteroid therapy often experience polyphagia and may ingest something they normally would avoid).

DEVELOPMENTAL AND REPRODUCTIVE TOXICITY

Pregnant animals exposed to toxic agents represent a special case when doing a risk assessment. Not only do the immediate needs of the patient need to be considered, but the potential effects of the toxicant (and any agents used to treat the dam) on the fetuses must be taken into account before a treatment plan is initiated. Pregnancy itself can cause some physiological changes in the dam, including decreased intestinal motility, decreased plasma protein concentrations, and alterations in renal and hepatic function (Kutzler 2013). These changes can impact the absorption, distribution, metabolism, and elimination of toxic compounds, making the dam more or less susceptible to a particular toxicant. Pregnant animals may spontaneously abort their pregnancies due to stress, direct effects of toxicants on the reproductive organs, or fetal death from hypoxia secondary to hypotension or other hemodynamic aberrations.

Toxicants may have minimal effect on the pregnant female but result in significant harm to the fetuses. Whether a toxicant has a direct effect on the fetuses will depend on several factors. Most importantly, in order for a toxicant circulating in the blood to directly impact the fetus, it will need to cross the placenta in sufficient quantities to cause fetal damage. Whether a toxicant can pass the placenta will depend on the physical and biochemical properties of the toxicant as well as the structure of the placenta, which varies according to species. Toxicants reaching the fetuses can result in fetal death, fetal malformation (teratogenesis), or functional abnormalities (e.g., behavioral abnormalities), depending on the toxicant, species involved, and stage of gestation when the exposure occurs. Throughout gestation, there are peak times of susceptibility for organ malformation, generally coinciding with organogenesis. Organ‐specific teratogens that are introduced prior to or after organogenesis may have little or no impact on the developing fetus (Rogers 2019). Toxicants administered during gestation may cause a wide range of fetal defects. For example, feeding carbaryl (a carbamate insecticide) to dogs during gestation resulted in abdominal‐thoracic fissures, intestinal agenesis, brachygnathia, and a variety of appendicular skeletal abnormalities (Smalley et al. 1968).

Unfortunately, the potential effects of many toxicants on pregnant animals or their offspring are not known. When presented with a pregnant patient who has been exposed to a potential toxicant, it is always safest to err on the side of caution and attempt decontamination when it can be performed safely.

TOXICOKINETICS

Toxicokinetics refers to the movement of a toxicant through the body. The principles of toxicokinetics are the same as pharmacokinetics (the movement of drugs in the body) with the exception that the agent moving through the body is considered a toxicant rather than a therapeutic agent. The ultimate disposition of a toxicant in the body depends on the four components of toxicokinetics: absorption, distribution, metabolism (also called biotransformation), and elimination (Evans 2013). These components are often abbreviated as ADME for ease of use. The ADME characteristics will vary with the toxic agent, species, and individual.

Absorption

Other than caustic and corrosive agents that inflict their damage locally, most toxicants must enter the body to exert their effects (Evans 2013). Absorption is the process by which toxicants pass through the various barriers to enter the systemic circulation. The degree and extent to which a toxicant will be absorbed is dependent on the physical and chemical characteristics of the toxicant (molecular weight, pH, lipid solubility, etc.), the route of exposure, and species of animal. With the exception of intravenous injection, it is unlikely that 100% of a toxicant to which an animal is exposed will be absorbed. Bioavailability is a term that refers to the fraction of a toxicant that is actually absorbed.

The passage of toxicants into the body requires transport across cellular membranes to reach the general circulation; this transport can be passive (e.g., simple diffusion) or active, requiring energy to facilitate absorption (Evans 2013). Passive transport mechanisms do not require energy expenditure and include simple diffusion and filtration across membranes. Both of these processes require a concentration gradient for the toxicant to move along. The rate of toxicant movement is determined by the degree of difference in concentration between the two sides of the membrane, i.e., the larger the concentration differential, the faster the rate of movement. Simple diffusion is the primary means of toxicant passage across cell membranes, and it is most effective with small, lipid‐soluble, nonionized molecules. Filtration is the movement of molecules through pores in cellular membranes and is dependent on the size of the pores and size of the toxicant molecule. Facilitated diffusion is mediated by carrier molecules, which assist in carrying molecules across membranes. Active transport processes are energy‐dependent and do not depend on a concentration gradient; in fact, most active transport mechanisms work against concentration gradients (i.e., take a molecule from an area of low concentration to an area of high concentration). Examples of active transport “pumps” include the Na⁺−K⁺ ATPase transporter in nerve cell membranes and the P‐glycoprotein‐dependent multidrug‐resistant “pumps” in the blood–brain barrier.

Absorption can be influenced by a variety of factors, including route of exposure and the chemical and physical properties of the toxicant. The route of exposure plays a major role in determining how and to what extent a toxicant will be absorbed. In the gastrointestinal tract, the majority of molecules are absorbed by passive diffusion or carrier‐mediated processes (Slitt 2019). Gastrointestinal absorption is highly dependent on the pH of the toxicant, with weak acids being better absorbed in the stomach and weak bases being better absorbed in the proximal small intestine. Absorption of toxicants across the skin requires that the toxicant pass through the lipophilic stratum corneum (the major barrier to absorption of toxicants via the skin) and then through the hydrophilic dermis to reach the bloodstream. Solvents such as dimethyl sulfoxide (DMSO) greatly enhance absorption of topically applied agents by increasing the permeability of the stratum corneum. Absorption of toxicants (primarily gases, vapors, and aerosols) via the lungs is second only to intravenous injection in regard to the speed and efficiency of absorption. Toxicants reaching the alveoli have only a thin wall to pass through in order to reach the systemic circulation. Fortunately, the structure of the respiratory tract can filter out many toxicants and prevent them from reaching the alveoli.

Some toxicants undergo what is termed a first‐pass effect whereby toxicants absorbed from the gastrointestinal tract are taken via portal circulation to the liver, where a fraction of toxicant is removed from the blood prior to reaching the systemic circulation. The first pass effect can dramatically decrease the bioavailability of toxicants. For example, a dog ingesting its owner's sublingual nitroglycerine tablets will be at low risk of toxicosis as long as the dog swallows all of the tablets. The nitroglycerine absorbed from the stomach will be largely removed by the liver and will not enter the systemic circulation. However, if the dog has one or more tablets that remain in the oral cavity (e.g., adhered to the oral mucosa), absorption across the oral mucosa will allow the nitroglycerine to enter the systemic circulation and the dog will develop signs of hypotension because compounds absorbed from the oral cavity do not enter the portal circulation.

Distribution

Once a toxicant enters the body it may remain within the systemic circulation, or it may distribute to organs and tissues. Distribution is the translocation of the toxicant to various organs and tissues throughout the body. The degree and extent to which a particular toxicant will distribute to tissues is dependent on a variety of toxicant properties, including lipid solubility, molecular weight, and the affinity of the toxicant for various tissues (Evans 2013; Slitt 2019). The body has several physiologic barriers that may limit the distribution of certain xenobiotics, such as the blood–brain barrier, which excludes a large number of molecules from the central nervous system. The distribution characteristics of a toxicant are important in determining the clinical effects that a toxicant will produce. For example, the herbicide paraquat selectively concentrates in the lungs, where it is converted into toxic metabolites that induce severe lung damage and fibrosis. A related compound, diquat, has a similar mechanism of action, but does not selectively locate to the lung and therefore does not cause the pulmonary lesions that are seen with paraquat.

The storage of some toxicants within the body can actually aid in decreasing the acute toxicity of the compound. Some common storage depots for toxicants include bone (e.g., lead, cadmium), fat (e.g., organochlorine pesticides such as DDT), liver (e.g., copper), and kidney (e.g., cadmium). The toxicants in these storage depots are in equilibrium with the plasma, but certain metabolic situations can sometimes disrupt the equilibrium. For example, in chronic, low‐level exposure to lead, much of the lead is stored in the bones, which may protect the animal from manifestations of acute toxicosis; blood lead concentrations may be only slightly above the normal range in these cases. However, any condition that causes an increase in bone remodeling (e.g., lactation, fracture) may result in a sudden release of lead from the storage depot and precipitate acute lead toxicosis, even in a patient that is no longer exposed to lead from its environment.

Plasma proteins are a special storage depot for toxicants and are important in determining the toxicity of an agent. There are a large number of proteins in the blood that can bind toxicants, but albumin is the major protein responsible for the binding of xenobiotics (drugs and toxicants). Because only a free (unbound) toxicant can reach its site of action, plasma proteins essentially “bind up” the toxicant, preventing it from exerting its toxic effect. Toxicants that are highly protein‐bound have a lower level of toxicity than similar toxicants, which have poor protein binding. Species differences in types and amounts of plasma proteins are one reason for species differences in toxicity of various toxicants. An important consideration when dealing with a highly protein‐bound compound is the potential interaction that may occur with other highly protein‐bound agents. For instance, a dog that is on carprofen (a highly protein‐bound drug) for arthritis is exposed to a warfarin‐based rodenticide. Because warfarin is also highly protein‐bound, the two xenobiotics are in competition for plasma proteins, resulting in higher unbound concentrations of both, which may result in clinical signs of warfarin toxicosis at doses lower than those normally associated with warfarin. Additionally, there also might be increased risk of adverse effects from the carprofen (i.e., gastrointestinal upset or bleeding).

Metabolism

Metabolism refers to the fate of a toxicant within the body and is often used synonymously with the term biotransformation, which more correctly refers to the metabolic processes involved in creating a more water‐soluble form of xenobiotics (Evans 2013). In order to prepare toxicants for elimination from the body, they must be converted into forms that are excretable. In most circumstances, this entails making the toxicant more water‐soluble so that it can be eliminated by the kidneys; less commonly, compounds are made more lipid‐soluble and eliminated via the bile into the feces. The body has a limited range of metabolic enzymes that can act on a wide range of substrates. These enzymes are present in most tissues but are most concentrated in organs with highest exposure to xenobiotics, including the liver, gastrointestinal tract, kidneys, and lung.

There are two levels of biotransformation, termed phase I and phase II reactions, used to make toxicants more excretable. Not all toxicants undergo both reactions; some toxicants are eliminated with little or no metabolism, and others undergo one of the two reactions. Phase I reactions generally involve hydrolysis, oxidation, or reduction and are designed to make a compound more water‐soluble and/or expose a functional group for a subsequent phase II reaction. Phase I reactions include the oxidation reactions mediated by cytochrome P450 enzymes, which are the basis for much of the individual variation in susceptibility to adverse drug reactions (Parkinson et al. 2019). Phase II reactions involve attachment (conjugation) of a functional group (sulfate, glucuronide, amino acid, glutathione, methyl group, acetyl group) to a parent compound or one of its metabolites that results in a compound that has greatly increased water solubility. Species differences in phase II reactions include the defective glucuronidation in cats that makes them sensitive to phenolic compounds such as acetaminophen.

Bioactivation

Although biotransformation is generally thought of as a detoxifying process, allowing the body to eliminate potential toxicants, in some instances reactions might result in a compound that is more toxic than the parent compound. This conversion of a low or nontoxic parent compound to a toxic metabolite is termed bioactivation. Examples include the conversion of ethylene glycol to metabolites that induce acidosis and renal failure, and the conversion of acetaminophen to a highly reactive intermediate that causes liver damage.

Elimination

Elimination is the process of removing toxicants and their metabolites from the body. As has been mentioned, most biotransformation reactions are geared toward making toxicants more water‐soluble so that they can be excreted via the kidneys. Renal excretion is the most common means by which the body eliminates waste. Other elimination pathways include fecal (via bile), exhalation (via lungs), saliva, sweat, and milk. Toxicants and their metabolites can be eliminated by more than one route (e.g., fecal and urinary).

The elimination half‐life of a toxicant is the amount of time it takes for the original absorbed dose to be reduced by one‐half. Compounds with shorter half‐lives will be eliminated from the body more quickly than those with longer half‐lives. Two processes that can prolong the half‐life of a toxicant include enterohepatic recirculation and saturation of metabolic enzymes. Enterohepatic recirculation is the repeated cycling of a toxicant between the liver and the gastrointestinal tract. The toxicant passes from the systemic circulation into the liver, where it is excreted via the bile duct into the small intestine, from where it is reabsorbed to reenter the systemic circulation. This continued cycling can greatly prolong the amount of time that a toxicant stays in circulation. For example, in dogs, the nonsteroidal anti‐inflammatory drug naproxen undergoes extensive enterohepatic recirculation and has a half‐life of 74 hours, whereas in humans naproxen does not undergo enterohepatic recirculation, is eliminated primarily via the urine, and has a half‐life of only 6 hours (Frey and Rieh 1981; Lees 2018; Talcott and Gwaltney‐Brant 2013).

Toxicants that must be metabolized through enzyme‐mediated processes can have their half‐lives increased if the dose of toxicant exceeds the capacity of the enzyme system to catalyze the conversion of toxicant to metabolite. In these situations, the toxicant “backs up” as the enzyme system becomes saturated with substrate. For toxicants that can be eliminated as parent compound as well as metabolites (e.g., ethanol), saturation may only mildly affect half‐life, but for compounds that cannot be eliminated without first being converted to metabolites, the half‐life can be significantly impacted. An example is aspirin, which requires glucuronidation for elimination. In cats, the half‐life of aspirin ranges from 22 to 45 hours depending on the dose administered. As the dose increases, the half‐life increases due to saturation of the cat's defective glucuronidation system. This is why the dosing interval of aspirin for cats is every 48–72 hours compared to every 8–12 hours for dogs.

CHAPTER 1 STUDY QUESTIONS

Banjo, a 2‐year‐old, 25‐pound, neutered male dachshund mix ingested a 25‐mg propranolol tablet that his owner accidentally dropped on the floor. When researching this drug, which of the following information would be LEAST helpful to you in determining whether Banjo is at risk for serious clinical effects?

The minimum toxic dose for dogs

The maximum tolerated dose for dogs

The LD₅₀ for dogs

The minimum lethal dose for dogs

The therapeutic index for dogs

Ranger, a 3‐year‐old golden retriever, was just prescribed phenobarbital to control his epilepsy. Ranger's owner called later that day to say that Ranger was acting groggy and wants to know whether this is expected with the phenobarbital. Ranger's veterinarian tells you to relay to the owner that this is an expected event and that Ranger should adapt to his medication after several days. A call back to the owner a week later finds that Ranger is no longer acting groggy after receiving his phenobarbital. Ranger's decreased sensitivity to the sedative effects of phenobarbital over time is an example of

Potentiation

Tolerance

Synergism

Antagonism

Additivity

The fundamental principle of toxicology is “the dose makes the poison.” When determining whether the dose of a particular compound poses a risk of toxicosis to an animal, which of the following must be taken into account?

Physical properties of the compound (e.g., physical state, pH, reactivity, etc.)

Species exposed to the compound

Route of exposure

Age, sex, and weight of the patient

All of the above must be considered.

In general, the most rapid response to a toxicant will occur if it is administered

Intravenously

Intradermally

Orally

Intramuscularly

Subcutaneously

The dose–response curve represents the characteristics of a xenobiotic within a ______________, but _________________ variation can result in increased or decreased response at a particular dose.

Species, normal

Population, individual

Species, individual

Population, normal

Class, statistical

When compared to humans, the increased susceptibility of cats to acetaminophen toxicosis is related primarily to species differences in which of the following:

Absorption of acetaminophen

Distribution of acetaminophen

Metabolism of acetaminophen

Elimination of acetaminophen

Bioavailability of acetaminophen

Some Doberman pinschers have an increased susceptibility to liver injury when they receive sulfonamide antibiotics at therapeutic doses. Because this susceptibility in Doberman pinschers is familial (i.e., runs in families), it is suspected that this trait is inherited. If so, this would be an example of

Species difference

Genetic polymorphism

Age‐related response

Gender difference

Fetal toxicity

In cats, organogenesis is complete in the first trimester (first 3 weeks) of pregnancy. At week 8 of pregnancy, a queen was exposed to a medication known to adversely affect fetuses. Which of the following would NOT be an expected outcome of this exposure?

Anencephaly

Abortion

Stillborn kittens

Mummified fetuses

Premature parturition

The percentage of an ingested toxicant that is absorbed into the circulation is a measure of its

Toxicity

Distribution

Metabolism

Teratogenesis

Bioavailability

Select the incorrect statement.

Distribution refers to the movement of xenobiotics throughout the body and includes binding of xenobiotics to plasma proteins and storage of xenobiotics in various tissues, including the bone, liver, and kidney.

The “first pass effect” refers to the inability of some toxicants to cross the gastrointestinal mucosal barrier and enter the systemic circulation.

Metabolic activity that results in a metabolite that is more toxic than the parent compound is referred to as bioactivation.

The predominant goal of metabolism is to make xenobiotics more water‐soluble so that they can be more easily excreted via the urine.

Enterohepatic recirculation of a xenobiotic can result in prolongation of the xenobiotic's half‐life.

ANSWERS

1. c. The LD₅₀ identifies the dose at which 50% of dogs will die but does not give an indication of the dose at which dogs can tolerate propranolol without showing clinical signs (maximum tolerated dose), the dose at which clinical signs may be expected to develop (minimum toxic dose), or the lowest dose at which death might be possible (minimum lethal dose). All of these parameters are far more helpful in determining the risk following an acute exposure than the LD₅₀.

2. b. Tolerance is the reduced responsiveness to a chemical due to prior exposure to that chemical (or a similar chemical). In the case of phenobarbital, the enzymes that metabolize the drug are induced in the liver, resulting in an increase in phenobarbital metabolism, lower blood levels, and decreased adverse effect.

3. e. All of these factors are important in determining the risk of toxicosis from a toxicant.

4. a. Intravenous administration will produce the most rapid distribution of a toxicant to its site of action in the body.

5. b. The dose–response curve represents the characteristics of a xenobiotic within a population, but individual variation can result in increased or decreased response at a particular dose.

6. c. Cats lack essential enzymes for metabolizing acetaminophen into nontoxic compounds and instead produce metabolites that are highly reactive, resulting in toxicosis at relatively low doses of acetaminophen.

7. b. Genetic polymorphisms are inherited traits that result in differences in response to xenobiotics.

8. a. Anencephaly (absence of brain) would not occur because the exposure occurred after the brain had formed (i.e., after completion of organogenesis).

9. e. Bioavailability

10. b. The first pass effect refers to the hepatic removal of a fraction of a xenobiotic that has been absorbed into the portal circulation before the xenobiotic can reach the systemic circulation.

REFERENCES

Aleksunes, Lauren M and Eaton, David L. 2019. Principles of toxicology. In Casarett and Doull's Toxicology, the Basic Science of Poisons, 9th ed., edited by Curtis D Klaasen, pp. 25–64. New York: McGraw‐Hill Medical.

Evans, Tim J. 2013. Toxicokinetics and toxicodynamics. In Small Animal Toxicology, 3rd ed., edited by Michael E Peterson and Patricia A Talcott, pp. 13–20. St. Louis: Saunders.

Frey, Hans‐Hasso and Rieh, B. 1981. Pharmacokinetics of naproxen in the dog. American Journal of Veterinary Research 42(9):1615–1617.

Gwaltney‐Brant, Sharon M. 2001. Chocolate intoxication. Veterinary Medicine 96(2):108–110.

Kutzler, Michelle A. 2013. Considerations in pregnant or lactating patients. In Small Animal Toxicology, 3rd ed., edited by Michael E Peterson and Patricia A Talcott, pp. 203–214. St. Louis: Saunders.

Lanusse, Carlos E, Imperiale, Fernanda A, and Lifschitz, Adrian L. 2018. Macrocyclic lactones: endectocide compounds. In Veterinary Pharmacology and Therapeutics, 10th ed., edited by Jim E Riviere and Mark G Papich, pp. 1102–1127. Hoboken, NJ: John Wiley and Sons, Inc.

Lees, Peter. 2018. Analgesic, antiinflammatory, antipyretic drugs. In Veterinary Pharmacology and Therapeutics, 10th ed., edited by Jim E Riviere and Mark G Papich, pp. 467–500. Hoboken, NJ: John Wiley and Sons, Inc.

Mealey, Katrina L, Owens, Jane G, and Freeman, Elaine. 2023. Canine and feline P‐glycoprotein deficiency: What we know and where we need to go. Journal of Veterinary Pharmacology and Therapeutics 46(1):1–16.

Osweiler, Gary D. 1996. Philadelphia: Williams and Wilkins.

Osweiler, Gary D. 2013. General toxicological principles for clinicians. In Small Animal Toxicology, 3rd ed., edited by Michael E Peterson and Patricia A Talcott, pp. 1–12. St. Louis: Saunders.

Parkinson, Andrew, Ogilvie, Brian W, Buckley, David B, Kazmi, F, and Oliver, Parkinson. 2019. Biotransformation of xenobiotics. In Casarett and Doull's Toxicology, the Basic Science of Poisons, 9th ed., edited by Curtis D Klaasen, pp. 193–399. New York: McGraw‐Hill Medical.

Peterson, Michael E. 2013. Toxicologic considerations in the pediatric patients. In Small Animal Toxicology, 3rd ed., edited by Michael E Peterson and Patricia A Talcott, pp. 215–222. St. Louis: Saunders.

Rogers, John M. 2019. Developmental toxicology. In Casarett and Doull's Toxicology, the Basic Science of Poisons, 9th ed., edited by Curtis D Klaasen, pp. 547–590. New York: McGraw‐Hill Medical.

Slitt, Angela L. 2019. Absorption, distribution, and excretion of toxicants. In Casarett and Doull's Toxicology, the Basic Science of Poisons, 9th ed., edited by Curtis D Klaasen, pp. 159–192. New York: McGraw‐Hill Medical.

Smalley, Harry E, Curtis, Jack M, and Earl, Francis L. 1968. Teratogenic action of carbaryl in beagle dogs. Toxicology and Applied Pharmacology 13(3):392–403.

Talcott, Patricia A and Gwaltney‐Brant, Sharon M. 2013. Nonsteroidal antiinflammatories. In Small Animal Toxicology, 3rd ed., edited by Michael E Peterson and Patricia A Talcott, pp. 687–708. St. Louis: Saunders.

Tchounwou, Paul B, Landolph, Jr JR, Joseph, R, and Hulla, Janis E. 2023. Metals. In Principles and Methods of Toxicology, 7th ed., edited by A Wallace Hayes, pp. 995–1062. Boca Raton, FL: CRC Press.

Volmer, Petra A. 2004. Pyrethrins and pyrethroids. In Clinical Veterinary Toxicology, edited by Konnie H Plumlee, pp. 188–190. St. Louis: Mosby.

2
Incidence of Poisoning in Small Animals

Ginger Watts Brown

INTRODUCTION

Small animals are frequently exposed to potentially harmful substances, but the incidence of those exposures leading to severe signs or death is much lower than the incidence of other diseases, illnesses, or trauma in our companion animal patients. After confirming the patient is stable, the details of the exposure should be reviewed along with the patient's pertinent medical history. Proficient history‐taking is a foundational skill and a vital component of successfully managing clinical toxicology cases. Comparing the basic properties of the substance in question (e.g., such as kinetics and mechanism of action) with history details (e.g., onset and duration of symptoms after potential exposure, clinical progression) aids in the diagnosis and case management of clinical toxicology cases. Worried pet parents may incorrectly connect symptoms with substances that are coincidentally in the home, which is why a comprehensive history, coupled with a complete physical examination, plays a critical role in determining if the signs present are indeed from poisoning or if further diagnostic evaluation is warranted.

Potential toxins (natural in origin) and toxicants (man‐made in origin) are ubiquitous in our daily lives, but not all exposures will yield significant symptoms. Consider the axiom for which Paracelsus, the “Father of Toxicology,” is credited that holds true today: “What is there that is not poison? All things are poison, and nothing is without poison. Solely the dose determines that a thing is not a poison” (Grandjean 2016). Any substance, even water, has the potential to lead to toxicosis, given the right dose. The exposure dose that results in poisoning is dependent on many factors, including the substance, concentration, contact time, and route, as well as the size, health, and species of animal. For example, young, elderly, small, and/or debilitated animals may be more sensitive and have significant signs at lower doses, and prolonged contact time with concentrated detergents carries a higher risk for corrosive injury compared to dilute or ready‐to‐use products. A commonly encountered example of species sensitivity is cats with true lily flowers. Dogs that ingest Lilium sp. and Hemerocallis sp. tend to only have mild gastrointestinal upset, while any exposure to the same plant material, pollen, or even vase water carries a risk for acute kidney injury in cats. Given the infinite amount of potentially harmful substances and the numerous risk variables in our veterinary patients, careful collection and thoughtful consideration of the exposure history are needed to appropriately estimate risk and establish a case management plan.

Human and animal poison centers across the United States answer animal exposure calls each day, but with no centralized reporting agency or database for the animal call information, the actual incidence of animal poisoning is unknown. Additionally, the total number of calls between the poison centers would likely be an underestimate of incidence as veterinary hospitals and clinics may manage poisoning cases without calling for assistance or for reporting purposes. Fortunately, human and animal poison control centers often share animal call data voluntarily to help identify current trends and highlight commonalities in animal cases.

DEMOGRAPHICS

The call data provided by human and animal poison centers demonstrate that the vast majority of animal exposure calls involve dogs and cats (ASPCA 2023; Gummin et al. 2023; Pet Poison Helpline 2023). This demographic information is not surprising, with pet populations estimated to be over 83 million dogs and over 60 million cats in the United States (American Veterinary Medical Association 2022). Most American pets live indoors and are considered to be part of the family (American Veterinary Medical Association 2022), leading to easy access to medications, chemicals, detergents, and even foods that may present a potential risk.

Animal exposures tend to occur in the home, by accident. Malicious poisonings are quite rare and account for less than 1% of all exposures (Gwaltney‐Brant 2018). Dogs account for 88–89% of call center animal exposure cases, while calls involving cat exposures made up 8–11%; cases involving other species such as birds, rabbits, ferrets, rodents, and livestock make up only a small portion of the total calls taken (ASPCA 2023; Gummin et al. 2023; Pet Poison Helpline 2023). This is in contrast to historical data from animal poison control centers where small animals were in the minority and livestock were in the majority (Trammel et al. 1985).

Gwaltney‐Brant's (2018) demographic review demonstrates that young dogs and cats less than 1 year of age appear to be most often involved in potential poisonings, with males and females being equally represented across both species. Given their curious nature and tendency to explore the unknown with their mouths, it seems only logical that the oral exposure route is at the top of the list for both dogs and cats. While dermal exposures are a close second to oral, other routes, including inhalation, ocular, and parental, are far less commonly reported. Although the calls coming in for cats are far fewer than for dogs, cats may be more frequently exposed via both oral and dermal routes as they fastidiously groom substances off their fur (Gwaltney‐Brant 2018).

The American Society for the Prevention of Cruelty to Animals (ASPCA) Animal Poison Control Center 2022 data demonstrate that over 77% of cat breeds were identified as domestic short‐hair, domestic long‐hair, or domestic medium‐hair. Purebred cats represent a very small percentage of feline calls. Siamese, Maine Coon, Ragdoll, Bengal, and Siberian are the five most commonly reported, only accounting for 6.6% of feline calls collectively. Labrador Retrievers are the number one most common purebred canine reported, accounting for 11.7% of dog calls. The rest of the top five purebred canines reported include Golden Retriever (6.4%), American Pitbull Terrier (4.3%), Chihuahua (3.9%), and German Shepherd (3.5%). Breed identifiers feline unspecified (11.2% of feline calls) and canine unspecified (11% of canine calls) are frequently utilized as well (ASPCA 2023). This term is used to denote a mixed breed but may also be used when the breed is unknown. The popularity of adoption (American Veterinary Medical Association 2022) and growing support of animal rescue efforts may explain the upward trend in mixed breed and unspecified dog and cat breed numbers over purebred numbers.

The Labrador Retriever was the number one most popular dog breed in America from 1991 to 2021 (Haid 2023), and they have historically been the most commonly reported breed of dog involved in potential poisoning cases (Gwaltney‐Brant 2018). These facts lead one to wonder if Labradors are truly more likely to be involved in toxin exposure, or are they just overrepresented in the pet population? A comparison of the five most common American Kennel Club (AKC) breed registrations to the five most common breeds reported to the ASPCA Animal Poison Control Center (Table 2.1) reveals multiple similarities. With the 2022 AKC registration listing the French Bulldog in the number one spot, outpacing the Labrador Retriever for the first time (Haid 2023), the poison center data may be starting to demonstrate that some dog breeds have personalities more susceptible to shenanigans.

Table 2.1. Comparison of most common dog breeds registered with AKC vs. reported to the ASPCA Animal Poison Control Center

Most common dog breed AKC registrations (2022) | Most common dog breeds reported to the ASPCA animal poison control center (2022)
1. French Bulldog | 1. Labrador Retriever
2. Labrador Retriever | 2. Golden Retriever
3. Golden Retriever | 3. American Pitbull Terrier
4. German Shepherd Dog | 4. Chihuahua
5. Poodle | 5. German Shepherd Dog

AKC, American Kennel Club; ASPCA, American Society for the Prevention of Cruelty to Animals.

Source: ASPCA (2023) and Haid (2023).

AGENTS

Although exposures of animals to potentially toxic agents occur steadily throughout the year, the call volume to an animal poison control center reflects a significant jump in frequency for the summer months and during the fall and winter holiday seasons (ASPCA 2023). The list of potential exposures available is vast, and the availability of the agents involved can vary based on location, season, species, and lifestyle. On review of call information from the ASPCA Animal Poison Control Center, common patterns tend to emerge each year.

With the return of warmer weather in the springtime, garden and yard work will lead to increased opportunities for exposure to fertilizers, yard lime, weed prevention, plants, and other lawn‐care products. Spring religious celebrations bring increased exposure to lilies (Lilium spp.), special desserts such as raisin or chocolate babkas, and palm ceremonies using sago or cycad fronds. In March, calls on Shamrock plants (Oxalis spp.) increase. Summertime calls frequently involve pool chemicals, herbicides, and insecticides. Patriotic summer holidays bring calls involving picnic foods, glow sticks, fireworks, and even anxiety medication administration mistakes. As back‐to‐school season begins, pets are left alone more, increasing separation anxiety and leading to pantry and garbage raids. Autumn's chilly weather seems to inspire baking and bring calls involving baked goods with ingredients including raisins, nuts, chocolate, and xylitol. In addition to the influx of candy calls during the fall, calls involving rodenticides and lawn‐care products exposure increase as preparations for winter increase. Calls involving antifreeze, ice melts, and rodenticides increase during winter months. Winter holiday celebrations bring exposures to party foods, alcohol, desserts, candy, as well as tree preserver chemicals and mistletoe (see Figure 2.1).

While chocolate ingestions occur all year round, a spike in the number of chocolate exposure calls answered corresponds with each of the holidays commercially celebrated with chocolate candy and chocolate baked goods. Holidays with a significant increase in chocolate exposures include St. Valentine's Day, Easter, Halloween, and Christmas (ASPCA 2023). While holiday celebrations for Dia de Los Muertos, Diwali, Hanukkah, and Kwanzaa may include chocolate exchange and indulgence, their effect on chocolate call volume is often absorbed within the Halloween and Christmas seasonal impacts.

Figure 2.1. Seasonal pet dangers.

Buttke et al. (2012) reviewed human poison center call center data on animal calls made from 2000 to 2010, and reported the highest number of animal calls were made in the summer months, with the majority of the potential exposures to pesticides and human prescription medications. The ASPCA Animal Poison Control Center 2022 call information revealed that the agent trends have changed (see Figure 2.2). The most commonly reported agent categories are over‐the‐counter medications (e.g., ibuprofen and acetaminophen), human food items (e.g., xylitol and grapes/raisins), human prescription medications, chocolate, and plants. Once the most common category, pesticides have fallen to eighth place, with rodenticides right behind in ninth. The rest of the 10 most common categories include household toxins (such as detergents and disinfecting wipes) in sixth and veterinary products seventh. Recreational drugs (most commonly marijuana) represent the 10th most common toxin agent category based on call data from the ASPCA Animal Poison Control Center (ASPCA 2023).

Figure 2.2. American Society for the Prevention of Cruelty to Animals top 10 for 2022.

SIGNS AND OUTCOMES

Toxicology education in the veterinary community and increased visibility to families with pets have led to growing use of animal poison centers over recent years. Calls involving animals to human poison centers had been declining since 2005, but in 2022 over 50,381 animal exposure calls were received (Gummin et al. 2023). While final outcomes are not available for all calls to animal poison centers, Gwaltney‐Brant (2018) reports that most exposures to potential toxicants resulted in either no symptoms or only mild symptoms due successful decontamination and/or insufficient dose involvement. Mild symptoms were those which would likely resolve on their own with little to no treatment; Moderate signs developed in roughly 7–8% of known outcome calls and are described as signs that are more pronounced or prolonged and would require veterinary intervention. Gwaltney‐Brant (2018) also revealed that major signs, those with the potential to be life‐threatening, occurred in approximately 1% and death occurred in 2–3% of calls where the outcome was known (Gwaltney‐Brant 2018).

Of the ASPCA Animal Poison Control Center 2022 cases with known outcomes, the 10 most common agents resulting in death were bromethalin rodenticides, antimetabolite antineoplastic human medications (e.g., 5‐fluorouracil), nonsteroidal anti‐inflammatory medications (including human and veterinary use), anthelmintic agents (e.g., avermectins), xanthine derivatives (e.g., caffeine, theobromine, and methylxanthines), cholecalciferol, polyalcohols (e.g., xylitol), cardiac glycoside plants (e.g., Convallaria majalis, Nerium oleander, and Digitalis spp.), gamma‐aminobutyric acid derivative skeletal muscle relaxants (e.g., baclofen), and glycols (e.g., ethylene glycol). Common agent categories resulting in tremors include foods with xylitol, pyrethrin insecticides (e.g., permethrin, bifenthrin), isoxazoline insecticides (e.g., sarolaner), xanthine derivatives, and anthelmintics (ASPCA 2023).

CONCLUSION

Veterinary professionals commonly encounter small animal toxicosis during their daily work as it remains a significant cause of morbidity and mortality in canine and feline medicine. In recent years, increased awareness, along with access to and use of animal poison centers have allowed deeper insight into the incidence of animal poisoning. Reviewing call center data can help provide opportunities for education, reduce future incidence of poisoning, demonstrate the effectiveness of treatment modalities, measure risk, and monitor outcomes, as well as aid in the discovery of new toxic substances.

CHAPTER 2 STUDY QUESTIONS

True or false: Most poisonings are malicious.

Which of the following species is most commonly poisoned in the home?

Dog

Cat

Bird

Rabbit

True or false: Poisonings are seasonal in nature.

Which route of exposure to potential toxins is most common?

Dermal

Ocular

Oral

Rectal

True or false: The type of toxins pets are exposed to has changed over the years.

ANSWERS

1. False. Malicious poisonings are rare (<1%). Most are accidental.

2. a. Dogs account for almost 90% of household poisonings.

3. True. For example, exposures to gardening products peak during the summer and chocolate exposures peak around holidays.

4. c. Oral exposures are most common as pets explore their world with their mouths.

5. True. Insecticides were much more common years ago and there has been an increase recently in over‐the‐counter supplements and vitamins.

REFERENCES

American Veterinary Medical Association. 2022. 2022 AVMA Pet Ownership and Demographics Sourcebook. https://ebusiness.avma.org/files/ProductDownloads/eco‐pet‐demographic‐report‐22‐low‐res.pdf (accessed April 15, 2023).

ASPCA (American Society for the Prevention of Cruelty to Animals) 2023. Animal Poison Control Center AnTox Database. Unpublished data (accessed April 15, 2023).

ASPCA (Animal Poison Control Center). 2023. Pet Poison Prevention Infographics and Resources. https://www.aspcapro.org/resource/pet‐poison‐prevention‐infographics‐and‐resources (accessed April 15, 2023).

Buttke, Danielle E, Schier, Joshua G, Bronstein, Alvin C, and Chang, Arthur. 2012. Characterization of animal exposure calls captured by the National Poison Data System, 2000–2010. Clinical Toxicology 2(1):117.

Grandjean, Phillipe. 2016. Paracelsus revisited: the dose concept in a complex world. Basic and Clinical Pharmacology and Toxicology 119(2):132.

Gummin, David D, Mowry, James B, Beuhler, Michael C et al. 2023. 2022 Annual Report of the National Poison Data System© (NPDS) from America's Poison Centers: 40th Annual Report. Clinical Toxicology 61(10):717–939.

Gwaltney‐Brant, Sharon M. 2018. Epidemiology of animal poisonings. In Veterinary Toxicology: Basic and Clinical Principles, 3rd ed., edited by Ramesh C Gupta, pp. 37–44. London: Elsevier.

Haid, Melanie. 2023. 2022 Most Popular Dog Breeds. www.akc.org (accessed April 15, 2023).

Pet Poison Helpline. 2023. Toxin Trends. https://www.petpoisonhelpline.com/toxin‐trends (accessed April 15, 2023).

Trammel, Harold, Buck, William, and Beasley, Val. 1985. National Animal Poison Control Center: Seven years of service. Annual Proceedings of the American Association of Veterinary Laboratory Diagnosticians 29:183–191.

3
Toxicology Information Resources

Lisa Bunnell

INTRODUCTION

In the past several years, the amount of toxicology information has grown tremendously, as has the ability to access this information, whether through peer‐reviewed publications, textbooks, computer‐based resources, or virtual consultations with veterinary professionals. The primary challenge is determining which sources provide the most up‐to‐date, accurate, and reliable information. Additionally, diagnostic laboratories and poison control centers can provide invaluable information when dealing with a toxicological problem, and easier access to veterinary advice through virtual consultation can allow for faster evaluation and treatment recommendations for toxic exposures. This chapter provides an overview of toxicology information resources that are available to assist in dealing with toxicology questions.

EVALUATION OF RESOURCES

When choosing a toxicology information resource, it is important that the veterinary technician be aware of any potential issues regarding the quality or bias of the information (McNally et al. 2013). In general, peer‐reviewed resources (e.g., veterinary journals) that outline the methods by which conclusions are reached are more reliable than non‐peer‐reviewed resources (lay journals, nonfiction literature, the Internet), which tend to summarize data, often adding opinion to, or in place of, scientific theory or facts. Even peer‐reviewed resources may show some bias because the research may have been sponsored by a corporation or group with an agenda. It is wise to check the institutions from which the author(s) came to determine whether there might be some conflict of interest. That is not to imply that all research funded by industry or other interest groups is suspect; the reader should keep an open mind while reading the material critically.

Computer‐based resources, such as bibliography searches (e.g., MedlinePlus or PubMed, offered by the National Library of Medicine) can be extremely valuable and reliable, whereas personal or corporate web pages may be fraught with inaccurate, outdated, biased, or outright damaging information, depending on the agenda of the page owner. Because anyone can post a well‐designed website full of misinformation, scrutiny of the source of the information is imperative. In general, sites sponsored by reputable governmental, educational, and institutional agencies will contain information that is up to date, accurate, and tends to provide balanced views, even on controversial subjects. Sites that engage in polarized, emotional, or dogmatic discourse should be read with skepticism; in these cases, attempting to verify the statements made on these sites through other independent resources is highly recommended.

Items to consider in evaluating the information available on websites include:

the author's credentials and institutional affiliations

the date the material was posted

the clarity and comprehensiveness of the information provided

the relevance of hyperlinks to other sites

the inclusion of clear references, preferably peer‐reviewed.

“Internet rumors” are reports with little to no basis in fact, often with outrageously exaggerated claims, and they have the unfortunate tendency to become widely disseminated, usually via email or social media, in a very short period. Not surprisingly, many of these rumors involve poisonings of humans or pets, often by seemingly innocuous agents, such as shampoos, household cleaners, and the like. An example of an Internet rumor that has had wide dissemination (and several resurrections over the years) is the 2004 rumor that Swiffer WetJet cleaning solution poses a hazard to dogs because it contains an ingredient that is “one molecule away from antifreeze” and has caused liver failure in dogs and deaths in cats. The ingredient in question, propylene glycol n‐propyl ether, is of low toxicity, especially at the concentrations present in cleaning agents (it is present in many common household cleaners), and it will not cause liver injury. The rumor has been discredited by a variety of sources, but it still crops up every now and then (Oehme and Hare 2009). In general, a good rule of thumb is to treat unsolicited warnings received via email or social media with skepticism until further research can be done to verify their authenticity. The Urban Legends References Page (www.snopes.com) is a good first stop in the search for the truth of a particular story. This website has compiled and researched thousands of rumors, internet or otherwise, and rates them on their veracity as true, false, or undetermined.

TYPES OF RESOURCES

Peer‐Reviewed Journals

Peer‐reviewed journals provide detailed accounts of recent studies being done in a variety of specialized areas. They have the advantage of providing the most up‐to‐date information as well as describing the study in detail, allowing the reader to assess the conclusions drawn from the work. One disadvantage to this type of resource is that the information is new and may be revised over time based on the results of subsequent studies or scientific review.

There are no veterinary toxicology journals currently being published; however, animal toxicology information may be found in a variety of human toxicology journals as well as select veterinary journals. See Table 3.1 for a listing of some journals that publish clinically relevant toxicology articles.

Textbooks

In the past several years, the number of available veterinary toxicology texts and toxicology‐related chapters in veterinary medical texts has expanded greatly. In general, these resources focus on the most encountered toxicology issues, making them useful and convenient for those in clinical practice who lack the time to do detailed searches on individual topics. Textbooks are an economical and effective means of having toxicology information readily available. On the downside, texts may present abbreviated information due to limited space, some information may be outdated by the time the text is published, and newer discoveries must await the publication of newer editions. Table 3.2 provides a short list of some currently available toxicology textbooks applicable to small animal veterinary medicine.

Table 3.1. Journals with veterinary toxicology articles

American Journal of Veterinary Research

Canadian Journal of Veterinary Research

Canadian Veterinary Journal

Clinical Techniques in Small Animal Practice

Compendium: Continuing Education for Veterinarians

Journal of the American Animal Hospital Association

Journal of the American Association of Veterinary Laboratory Diagnosticians

Journal of the American Veterinary Medical Association

Journal of Medical Toxicology

Journal of Small Animal Practice

Journal of Veterinary Emergency and Critical Care

Journal of Veterinary Internal Medicine

Journal of Veterinary Pharmacology and Therapeutics

Journal of Zoo and Wildlife Medicine

North American Veterinary Conference Clinician's Brief

Preventive Veterinary Medicine

Veterinary Clinics of North America, Small Animal Practice; Exotic Animal Practice

Veterinary Journal

Veterinary Medicine

Veterinary Pathology

Veterinary Quarterly

Veterinary Record

Computer Databases and Internet Sites

Many computer databases exist that can provide quick access to a wide variety of toxicology information. Some of these are more geared toward human toxicology, but there often will be some animal information included. At the very least they can give the reader a rough estimate of potential for toxicity based on how hazardous some products are for humans. Proprietary databases such as Poisindex® or Tomes® (both by Micromedex) are available by subscription and would be of minimal availability to those working in veterinary practice. However, Poisindex is used by all US poison control centers, so the information would be available through a regional poison control center.

Table 3.2. Veterinary toxicology textbooks

Title, author/editor, year | Publisher
Blackwell's Five‐Minute Veterinary Consult Clinical Companion: Small Animal Toxicology, 3rd ed., Hovda, Brutlag, Poppenga, Epstein, 2024 | Wiley‐Blackwell
Clinical Veterinary Toxicology, Plumlee, 2003 | Mosby
Concepts and Applications in Veterinary Toxicology, Gupta, 2019 | Springer
Field Guide to Common Animal Poisons, Murphy, 1996 | Iowa State Press
Handbook of Small Animal Toxicology and Poisonings, 2nd ed., Gfeller and Messonnier, 2003 | Mosby
Natural Toxicants in Feeds, Forages, and Poisonous Plants, 2nd ed., Cheeke, 1998 | Interstate Publishers
Small Animal Toxicology, 3rd ed., Peterson and Talcott, 2012 | Saunders
Small Animal Toxicology Essentials, Wismer, 2024 | Wiley‐Blackwell
Toxicology (National Veterinary Medical Series), Osweiler, 1996 | Williams & Wilkins
Toxic Plants of North America, Burrows & Tyrl, 2012 | Wiley Blackwell
Veterinarian's Handbook of Toxic Plants of North America, Burrows and Tyrl, 2006 |
Veterinary Toxicology, Roder, 2001 | Butterworth‐Heinemann
Veterinary Toxicology Basic and Clinical Principles, 3rd ed., Gupta, 2018 | Elsevier

Other accurate and up‐to‐date databases are accessible via the internet, and many of these are provided for low to no cost. Other websites maintained by government agencies, academia, and organizations can provide a wealth of toxicology information, and most are available at no cost to the web surfer. As stated earlier, the veracity of the information available on websites can be in question, so some degree of healthy skepticism is merited when browsing information on websites maintained by individuals or organizations that may have underlying agendas (e.g., selling a product). Table 3.3 includes some websites providing reliable toxicology information.

Veterinary Diagnostic Laboratories

Veterinary diagnostic laboratories are invaluable tools in dealing with animal poisonings (Talcott 2013). Most states have their own veterinary diagnostic laboratories, often associated with veterinary colleges. Many are staffed with veterinary toxicologists, who can assist in case management (treatment, prognosis, etc.) as well as offer suggestions on which tests to perform and samples to submit to obtain a diagnosis of toxicant exposure or intoxication. Even if the diagnostic laboratory within a particular state is unable to perform a specific toxicologic analysis, samples often can be sent to other state laboratories for testing. Typically, there are fees that are charged for such analytical tests, but in general they are relatively modest compared to the actual expense to the diagnostic laboratory performing the test.

Contrary to popular belief, there is no one “poison screen” that will test for all known toxic agents. Because there are a variety of tests available to detect various toxicants, it is important that the most appropriate test be selected to minimize the time and cost associated with testing. When presented with a sample for testing, the toxicologist will weigh all the available information, including history, clinical signs, and any physical characteristics of the agent in question to determine which analysis is most appropriate. For this reason, the more information provided to the toxicologist the more likely it will be that he/she will be able to determine the most appropriate testing for that case. The veterinary technician can assist in this regard by ensuring that the submission forms are filled out as completely and legibly as possible.

Table 3.3. Internet websites with toxicology information

Name
URL
Description

Toxicology Information

American Academy of Clinical Toxicology (AACT)
www.clintox.org
Multidisciplinary organization uniting scientists and clinicians in the advancement of research, education, prevention, and treatment of diseases caused by chemicals, drugs, and toxins

American Association of Poison Control Centers (AAPCC)
www.aapcc.org
www.poisoncenters.org
Provides oversight and coordination of US poison control centers

American Board of Veterinary Toxicologists (ABVT)
www.abvt.org/public/index.html
Certifying body for veterinary toxicologists

American Board of Toxicologists (ABT)
www.abtox.org
Certifying board for general toxicology

Agency for Toxic Substances & Disease Registry (ATSDR)
www.atsdr.cdc.gov
Health agency of the US Department of Health and Human Services (USDHHS), providing public health information on science related to toxic substances

National Toxicology Program (NTP)
ntp‐server.niehs.nih.gov
Division of the National Institutes of Health that evaluates agents of public health concern and provides free reports to be used by the public and government agencies

Veterinary/Medical Information

Centers for Disease Control and Prevention (CDC)
www.cdc.gov
Primary US federal agency for conducting and supporting public health activities within the US

PubMed
http://pubmed.ncbi.nlm.nih.gov
Search engine for biomedical literature from MEDLINE, life science journals, and online books

Veterinary Information Network (VIN)
www.vin.com
Online community of veterinarians with board‐certified specialist consultants, diagnostic tools, and research materials

Veterinary Support Personnel Network (VSPN)
www.vspn.org
Online community for veterinary support staff providing expert consultants and continuing education

World Health Organization (WHO)
www.who.int
Directing and coordinating authority for health within the United Nations System

Pesticide Information

Extension Toxicology Network (ExToxNet)
extoxnet.orst.edu
Collaborative effort by several US universities to provide objective, science‐based information about pesticides, written for nonexperts

National Pesticide Information Center (NPIC)
npic.orst.edu
Provides objective, science‐based information about pesticides and pesticide‐related topics; operates toll‐free telephone service for questions related to pesticides

US Environmental Protection Agency
www.epa.gov
US agency charged to protect human health and the environment by working for a cleaner, healthier environment

Food/Drug Information

Food Animal Residue Avoidance Databank (FARAD)
www.farad.org
Computer‐based decision system designed to provide information on avoiding drug, pesticide, and environmental contaminant residue problems in food animals

Internet Drug Index (RxList)
www.rxlist.com
Provides information on prescription drugs

US Food and Drug Administration
www.fda.gov
USHHS agency charged with overseeing safety of food, drugs, and medical devices

FDA Safety Portal
www.safetyreporting.hhs.gov
Portal for reporting safety issues regarding foods (human or pet), animal drugs, or NIH gene‐transfer research

Dietary Supplements Labels Database
Drugs.com
www.fda.gov/food/dietary‐supplements/information‐select‐dietary‐supplement‐ingredients‐and‐other‐substances
www.drugs.com/pill_identification.html
Offers information about ingredients in dietary supplements
Database of various medications identified by shape, size and imprints/markings

Plant/Mushroom Information

ASPCA Animal Poison Control
www.aspca.org/pet‐care/animal‐poison‐control/toxic‐and‐non‐toxic‐plants
Searchable site that outlines plants that are toxic and nontoxic to animals

Center plant list MushroomExpert.Com
www.mushroomexpert.com
Website listing information on toxic and nontoxic mushrooms

Poisons Help; Emergency Identification for Mushrooms and Plant
https://www.facebook.com/groups/144798092849300/?ref=share
Facebook group offering emergency identification of mushrooms and plants for known ingestions only

Poison Control Centers

There are approximately 55 poison centers in the United States that provide 24‐hour assistance to the public and healthcare providers in cases of human exposures to potentially toxic agents (poisoncenters.org). These centers are generally staffed by nurses and pharmacists, many with specialized training in toxicology (Specialists in Poison Information or SPIs) and are funded through tax dollars. Most are members of the American Association of Poison Control Centers, an organization that oversees the education and training of poison control specialists and provides public education by promoting awareness of the importance of poison prevention. Individuals can reach their regional poison control center by calling 1‐800‐222‐1222 from anywhere in the United States; callers will automatically be routed to the appropriate poison control center for their region.

Human poison control centers can be of assistance to veterinary staff in helping to identify unknown human medications through their database of imprint codes. Although some centers permit their staff to manage animal cases, most lack the information and financial resources to be primary resources for veterinary patients. Extrapolation of information from the human poison database to animals can sometimes result in erroneous treatment recommendations and is not generally recommended.

The American Society for the Prevention of Cruelty to Animals (ASPCA) Animal Poison Control Center (APCC) was the first animal‐oriented poison control center in the United States. The center provides 24‐hour assistance and is staffed by over 100 veterinary technicians and assistants and 65 veterinarians, 22 of whom have achieved specialty‐board certification in general and/or veterinary toxicology. In addition to their extensive experience in dealing with animal toxicology emergencies, the veterinary staff at the APCC has access to a database that incorporates 45 years of cases of animal poisonings to assist them in managing animal toxicoses. The APCC is a member of the American Association of Poison Control Centers and works with human poison control centers, governmental agencies, zoos, and other organizations to provide accurate and up‐to‐date information on newly discovered hazards to animals. The ASPCA APCC can be contacted by telephone at 1‐888‐426‐4435; in most cases a per‐case consultation fee will apply, including unlimited follow‐up for owners and veterinary clinics.

Pet Poison Helpline is another 24‐hour animal poison control center in North America. This poison control center is staffed by a large group of veterinarians, some of whom are board certified in veterinary toxicology (ABVT) and internal medicine (ACVIM). Pet Poison Helpline is operated by SafetyCall International, the world's largest industry poison control center providing poison control services to consumers of veterinary and human pharmaceuticals, household goods, pesticides, personal care products, agricultural products, and dietary supplements; it is also affiliated with the University of Minnesota. The Pet Poison Helpline can be consulted by telephone at 1‐800‐213‐6680. A consultation fee may apply; this consultation fee includes unlimited follow‐up.

Veterinary Telemedicine

Telemedicine, or medical consultation using electronic communication (videoconferencing, text, email, and instant messaging services), has become increasingly popular and accessible in recent years, including in veterinary medicine (sometimes referred to as “televet”). Many clinics offer appointments via phone and internet, and can be utilized effectively in managing a variety of veterinary needs, including toxicology. Other veterinary organizations, such as pet insurance and microchip companies, offer on‐call veterinary consultations, such as hotlines to assess and triage emergent conditions in companion animals. It must be noted that the qualifications of veterinary personnel providing services are not uniform from one provider to the next; staffing may include veterinary assistants, credentialed veterinary technicians, and/or veterinarians. The ability for assistants and technicians to consult with a veterinarian may vary from service to service, as well.

It is important to note the difference between telemedicine and tele‐triage. A vet–client–patient relationship (VCPR) is required before a veterinarian may diagnose or prescribe medication for an animal. There is variation from state to state regarding the establishment of VCPRs, but most states require in‐person VCPRs. This may create restrictions on an owner's ability to access telemedicine by requiring their pet to be an established patient with a veterinarian prior to any virtual assessments or treatment. Tele‐triage services, however, do not require a VCPR, and are generally utilized to help owners determine if they need to pursue in‐person evaluation and treatment for their pet, such as a trip to an emergency room versus making an appointment with their primary care provider the next day. Most telemedicine and tele‐triage services require an existing VCPR or membership/account‐holding with the provider and may charge a fee for service.

Telemedicine/triage is a useful tool for both owners and care providers, however, it is essential to understand the limitations of these services. Assessment and diagnosis generally rely more heavily on owner observations and descriptions to characterize the status of the animal's health and condition, and physical examinations or diagnostics are not possible during these types of consultations. These limitations extend to toxic exposures just as any other disease process or injury a pet might sustain, and owners may still be referred to other services specializing in toxicology.

SUMMARY

A wide range of toxicology information resources is available to assist veterinary staff in the identification, diagnosis, and management of animal poisonings. Judicious care should be taken to confirm the reliability of information sources, particularly those found in lay literature or on the internet.

ACKNOWLEDGEMENTS

The author would like to acknowledge Sharon Gwaltney‐Brant for her contributions to the previous version of this chapter.

CHAPTER 3 STUDY QUESTIONS

A dog owner calls to say that Sarge, her 70‐lb German shepherd dog, has just ingested an herbal supplement containing valerian. Which of the following would be the LEAST desirable source of information on this supplement?

Peer‐reviewed veterinary journal article on valerian uses in dogs

Veterinary herbal medicine textbook

Animal poison control center

Internet website selling valerian for use in dogs

Veterinary diagnostic laboratory toxicologist

Which of the following would be the least reliable source of information on potential toxicants for pets?

US Environmental Protection Agency website

US Food and Drug Administration website

Medline literature search

University website

Pet owner's personal website

Poison control centers can provide vital, life‐saving information in cases of animal poisonings. Which of the following is false regarding the use of poison control centers by veterinary professionals?

In the US there are currently two animal poison control centers staffed by veterinary professionals on a 24‐hour/7‐day basis.

Human poison control centers are just as capable of managing animal poisonings because both animal and human poison control centers employ veterinary professionals and use information from the same databases.

Poison control centers can assist in the identification of unknown medication through their database of imprint codes.

The National Poison Control Hotline number is 1‐800‐222‐1222 and will route land line callers to their appropriate regional poison control center.

ANSWERS

1. d. Internet websites selling products may overstate benefits and downplay risks in order to sell a product. In addition, such sites rarely have information on accidental exposure or overdose.

2. e.

3. b. Human poison control centers rarely employ veterinary professionals and use a human‐oriented database; animal poison control centers employ veterinarians and veterinary technicians and use their own animal‐oriented databases.

REFERENCES

McNally, Jude, Boesen, Keith, and Boesen, Kelly Green. 2013. Toxicological information resources. In Small Animal Toxicology, 3rd ed., edited by Michael E Peterson and Patricia A Talcott, pp. 21–26. St. Louis: Saunders.

Oehme, Fred W and Hare, William R. 2009. Urban legends of toxicology: facts and fiction. In Current Veterinary Therapy XIV, edited by John D Bonagura, pp. 109–111. St. Louis: Elsevier Saunders.

Talcott, Patricia A. 2013. Effective use of a diagnostic laboratory. In Small Animal Toxicology, 3rd ed., edited by Michael E Peterson and Patricia A Talcott, pp. 125–132. St. Louis: Saunders.

4
Taking a Toxicologic History

Carrie Lohmeyer‐Mauzy

INTRODUCTION

Obtaining a thorough history is critical in effectively treating patients that have been exposed to a toxic agent. The history‐taking process begins from the moment the client walks through the front door of the veterinary hospital, calls in on the telephone, or reaches out through an on‐line platform. It is the veterinary technician's responsibility to gather a reliable and accurate history to prevent the loss of money, time, energy, and resources in the hospital setting. The most important reason for obtaining a thorough history though is to provide the safest and most appropriate care for the patient (Fitzgerald 2013). This chapter offers guidelines to assist veterinary technicians and hospital staff in developing the skills necessary to be successful in obtaining a toxicological history.

PATIENT PRESENTATION

Depending on the circumstances, the technician may not know the patient has been exposed to a toxic agent on its presentation to the veterinary hospital. When dealing with toxic exposures the case will reflect one of four situations: the agent is known and the patient is asymptomatic, the agent is known and the patient is symptomatic, the agent is not known and the patient is symptomatic (aka “mystery poisoning”), the agent is not known and the patient is asymptomatic. The history‐taking process will generally be the same for all four situations but adjustment may be needed depending on the circumstances.

As with any medical emergency, it is important to be prepared and organized in the event of a toxicology case. Developing a protocol for toxicological cases will aid in stabilizing and treating patients effectively and efficiently. Some toxicants can cause a sudden onset of clinical signs; therefore, time plays a key role in establishing a plan of care. Patients presenting with clinical signs should be assessed and stabilized as needed. While the patient is being stabilized, a second staff member can obtain a preliminary history. Identifying ahead of time which staff member will assist in emergent patient care and which will obtain the historical information can save time and prevent confusion when a known or suspected toxicological case presents.

MEDICAL RECORD

The medical record for a toxicology case is composed of seven sets of required data: client information, patient information, clinical status, environment information, agent information, exposure information, and implemented treatments. The first three categories are usually a component of any history‐taking process, whether a poisoning is involved or not. Environmental information, agent information, exposure information, and implemented treatments are going to be additional elements. A written protocol can be very helpful in guiding veterinary technicians and assistants through the history‐taking process to avoid overlooking important information relating to a toxicological exposure. Each protocol is going to vary from one veterinary hospital to another due to individual preferences, but the seven key components of a toxicological history should be incorporated into the protocol and documented in the medical record. Once a written protocol is developed, it should be readily available to everyone in the hospital setting; this will prevent miscommunication when a toxicity case develops (see Figure 4.1).

Figure 4.1. Toxin triage sheet.

Client Information

The first component of any medical record is the client information. This should include the name of the client, a billing address, e‐mail address, and a telephone number where the client can be reached. If the client is not the owner of the patient (e.g., extended family, friend, foster, or pet sitter), the contact information for both parties should be obtained. When obtaining contact information, it is important to ensure that the record includes all possible means of contacting the client to assure that veterinary staff will be able to communicate changes in clinical status in a timely fashion.

Patient Information

Patient information is the second component of the medical history. The patient's name, species, breed, age, reproductive status, and weight should all be noted in the medical record as part of the patient signalment. The vaccination status, date of last veterinary visit, current medications and supplements (including dosage), diet, and preexisting health conditions should also be included. Each item of patient signalment has a purpose. Breed identification is important because some breeds can be more or less sensitive to certain agents. A dose of ivermectin considered nontoxic for a Labrador retriever could potentially be problematic for a collie because some collies possess a defective P‐glycoprotein in the blood–brain barrier that makes them more sensitive to ivermectin. Similarly, the age of the patient is going to play a role in determining toxicity and recommended treatments. Very young or very old patients may have limited organ function, which can influence absorption, metabolism, and elimination of toxicants (Fitzgerald 2013). For instance, a dog that is 14 years old may be at higher risk of developing kidney failure from an overdose of naproxen than a healthy 3‐year‐old dog ingesting the same dose. The reproductive status of a patient is also an essential element in a toxicological history. Pregnant or lactating females exposed to toxic agents may require additional or alternative treatment than males or nonpregnant, nonlactating females. The potential effects of the toxicant, as well as any drugs used to treat the toxicosis, on the fetuses must be considered when the case involves a pregnant animal. Some toxicants (e.g., some anticoagulant rodenticides, certain medications) can be passed to offspring through the milk; an important consideration when dealing with lactating animals is whether they have nursed their young subsequent to being exposed to the toxic agent.

A current, accurate weight of the patient is critical for calculating doses of active ingredients of toxicants as well as for calculating appropriate medication dosages. The basic tenet of toxicology is “the dose makes the poison,” meaning that some exposures will result in no toxic consequences because a toxic dose is not achieved. For instance, a 2‐oz bar of a 70% dark chocolate will not pose a serious toxic hazard for an 80‐lb dog, but the same bar ingested by a 10‐lb dog has potential to cause marked central nervous system (CNS) and cardiovascular stimulation if treatment is not implemented.

The patient's vaccination status, date of last veterinary visit, current medications and supplements, diet, and preexisting health conditions can be grouped into the general category of overall health. Knowing the vaccination status may aid in ruling in or out infectious causes of a patient's clinical signs. For example, a 5‐month‐old, unvaccinated puppy presents to the veterinary hospital with severe vomiting and diarrhea. A toxicological history was obtained, but the vaccination status of the patient was not asked. According to the owners, the dog ingested a few crystals from a silica gel packet that came out of a shoebox a few hours before the signs began. Silica gel is a minimally toxic agent that may, at worst, cause mild and self‐limiting stomach upset. Without knowing that silica gel exposures do not cause serious toxicosis, the assumption may be made that the puppy's signs are related to the ingestion of the silica gel while overlooking a more serious potential cause, such as parvoviral enteritis.

The date of the patient's last veterinary visit also provides information on the patient's prior healthcare. The prior health of patients that have not been examined by veterinarians for many years is going to be relatively unknown compared to patients that receive regular veterinary care. The results of any prior clinical pathology evaluations may be useful to determine whether any significant changes have occurred that may be attributable to the current exposure. Conversely, the lack of prior clinical pathology information may make it difficult to determine whether, for example, an elevation in liver enzyme values is due to the patient's current issue or whether preexisting liver disease is present.

Current medications and preexisting health conditions are two other components of a toxicological history that should not be overlooked. Medications that the patient is taking can influence a toxicology case in several ways (Fitzgerald 2013). Some medications may increase sensitivity to certain toxicants. For instance, a dog that is being treated with a nonsteroidal anti‐inflammatory drug for arthritis pain and then ingests ibuprofen may be at a higher risk for the development of gastrointestinal ulcers and acute renal failure. Medications may also influence the treatment plan for a given case because possible interaction of the medication with a drug in a treatment protocol may result in the need to alter the protocol for that patient. Although less common, it is also possible that the patient's clinical signs in a “mystery poisoning” are due to an adverse reaction to a prescribed medication. Preexisting health conditions also come into play when deciding what treatment to implement. A patient that has a heart murmur, megaesophagus, or seizure disorder may require different or additional treatment and monitoring than a healthy patient. Decontamination is indicated in many exposures to toxicants; however, emesis may be contraindicated in a patient that has a history of seizures, heart problems, or megaesophagus. Patients with histories of prior organ dysfunction may be at increased risk from toxicants affecting those organs, and may therefore require more aggressive treatment at lower dosages than would healthy animals.

Clinical Status

The clinical status of a patient will fall into one of two categories. The patient will either be asymptomatic on presentation or symptomatic. The clinical status of the patient will determine the first line of care implemented. For patients who are asymptomatic, it is important to determine whether clinical signs were observed by the client prior to presentation. Mindful questioning of the client can help identify the signs the patient developed, when the signs began, and their severity. For example, a 10‐lb dog ingested 3 oz of semisweet chocolate approximately 1.5 hours prior to presentation to the veterinary hospital. On presentation the dog is bright, alert, and responsive (BAR) and the physical examination is unremarkable. Since the dog is asymptomatic, the veterinary staff wish to initiate treatment by administering a dose of apomorphine to induce emesis. However, the history indicates that the patient had already vomited five times at home, recovering a large amount of chocolate. Since the patient has already spontaneously vomited, induction of emesis is not indicated because additional vomiting is unlikely to result in significant further decontamination. For patients who are symptomatic on arrival at the veterinary hospital, it is important to note what the client observed at home in addition to what is being observed at the clinic.

Environmental Information

The environment in which the patient lives is important when identifying possible contributing causes of clinical signs a patient has developed (Lee 2013). A domestic animal that is indoor/outdoor or strictly outdoors will have additional opportunities to be exposed to toxic substances, infectious agents, trauma, and other hazards when compared to patients that live strictly indoors. Environmental information is especially essential in determining the cause of a patient's clinical signs when dealing with an unknown toxicant. For example, a previously healthy 2‐year‐old German shepherd presents to a veterinary hospital with severe vomiting and lethargy. Diagnostic testing indicates that the dog is in liver failure. The owner is unaware of any toxic exposure that may have occurred and is certain that the dog was not exposed to anything inside the home. When questioned more thoroughly, the owner remembers that the dog was unattended in the yard for approximately 6 hours on the previous day. The owner has a wide variety of plants in the yard as well as occasional mushrooms growing in the grass. The plant varieties in the yard include juniper, sago palm, daffodils, rosebushes, and tulips. From this information, the possibility that the sago palm or a hepatotoxic mushroom may be the cause of the dog's signs must be considered. Without questioning the owner about possible exposures that may have occurred outside the home, the potential exposure to sago palm or mushrooms would have been overlooked.

For indoor animals, information that may be useful includes the areas of the house to which the animal has access, including recent access to areas the pet does not normally go (e.g., attic, basement, garage, or crawlspace). The types of medications/herbal products (human and veterinary, prescription, illicit and over‐the‐counter) in the household, and whether there have been recent visitors who may have dropped medication are important queries to make. It is best to ask for a list of all medications/herbals that are in the household, even if the client is sure that the patient did not have access to it. The types of houseplants in the home should be listed; and it is best to try to obtain the scientific name of the plant whenever possible because many different plants share common names. For example, Peruvian lilies, Easter lilies, and calla lilies are common plants felines are exposed to. Although all three plants have lily in their common name, all three are in different genus of plants and have varying degrees of toxicity. Peruvian lilies and calla lilies have a low risk of toxicity for felines when compared to Easter lilies, which can cause in acute kidney failure even with minimal exposures. The presence of children or teenagers in the household is important to know because items may have been left in the pet's reach or pets may have been allowed access to a toxicant; sometimes children on medication will feed the medication to a pet to avoid taking it themselves. The presence of rodenticides or insecticides in the home is an important piece of historical information. Recent redecorating or renovation may expose toxicants (e.g., old bags of rodenticide, lead in paint chips or flakes) that were not previously accessible to the animal. The presence of other pets and whether the other pets in the house appear normal should also be ascertained.

For outdoor animals confined by fences or other means, identification of potentially toxic agents in outbuildings, garages, barns, or sheds to which the pet may have access is important. Other potential hazards found in yards include compost piles, plants, mushrooms, yard treatments (especially some systemic insecticides and crabgrass killers), and pest‐control applications. For free‐roaming animals, the challenge is much greater because the number of potentially toxic agents available is quite large. Determining whether the animal is in an urban, suburban, or a rural environment and identifying the nature of the animal's immediate surroundings (e.g., wooded areas vs. parks and lawns) may help in narrowing down the agents to which the roaming animal may have been exposed. The presence of livestock in the pet's environment should stimulate questioning to determine the pet's access to the barns or feed bins, whether medicated feeds, fly baits, or feeds with growth promoters (e.g., ionophores) in them are present, whether the livestock have recently been medicated or dewormed, or whether any livestock have recently been euthanized and buried on the property.

Agent Information

The next data set required for the toxicological medical record is the toxic agent, if known. The trade name of the product or medication, active and inactive ingredients, ingredient concentrations, scents or flavors, EPA registration numbers, and manufacturer contact information should all be documented in the medical record. This information is easy to obtain if the packaging (prescription bottles, containers, boxes, etc.) is brought to the veterinary hospital with the patient. In many cases, clients may not have that information with them because the package may have been ingested, discarded, or destroyed or may never have been available. In some cases, it may be necessary to send clients back home or to the store where the agent was purchased to obtain package information. Imprint codes from individual medication tablets or capsules can be used to identify a drug in cases where prescription bottles are not available. Rodenticide exposures provide excellent examples of why ingredient information is essential. There are three main types of commonly used rodenticides, and each has a different level of toxicity and treatment protocol. Bromethalin, anticoagulants, and cholecalciferol exposures will not be managed in the same manner because these rodenticides have different mechanisms of action and toxic dosages (bromethalin affects the central nervous system, anticoagulants inhibit the normal blood coagulation process, and cholecalciferol results in hypercalcemia and kidney failure). Knowing the brand name of the product is often not sufficient to determine the active ingredient because products with the same brand name may have different active ingredients. Rodenticide pellets and bars come in a variety of colors, but, unfortunately, there is no way to identify the active ingredient by the bait's physical appearance alone. There can be blocks and pellets of rodenticides that look identical, but contain different active ingredients. When questioning the owner about what type of bait is involved, it is important to note whether information was obtained from an internet search, from a third party, or directly from the package itself.

Exposure Information

Once the identity of an agent has been confirmed, the next step in the history‐taking process is to obtain a detailed account of events surrounding the exposure. Knowing only the name of the agent, or the active ingredients, may not provide sufficient information to determine whether an exposure is likely to result in problems for the patient. The veterinary staff needs to have an accurate picture of what occurred before, during, and after the exposure. Information to be documented in the medical record includes the amount of the agent ingested (count, volume, or weight), the physical form of the agent, calculated doses of active ingredients in mg/kg body weight, the route, time, and location of the exposure, the location of the owner when the exposure occurred, the reason that the agent was administered (if applicable), the original source of the agent, the person(s) responsible for administering the agent (if applicable), and the potential for other animals to be exposed. Many clients may initially feel they have “no idea” as to the amount of toxicant to which the patient may have been exposed, but patient questioning can sometimes help to get an approximation. For medication, if the original prescription amount is known, remaining pills (if any) can be counted out and subtracted from the original prescribed amount; calculating the dose taken and the number of days from the time that the prescription was filled may enable the veterinary technician to estimate the maximum number of pills that may be missing. For other products (e.g., rodenticide pellets, granulated material, liquids, etc.), information can be obtained by asking how much might be missing from the original and subtracting out a worst‐case‐scenario amount: “Complete this question: I know it could not have been more than (blank).” Narrowing down the amount with questions (i.e., “Was it as much as a tablespoon? Less? How about a teaspoon? More? Maybe two teaspoons?”) can sometimes help to get an idea of how much might have been ingested. When estimating in this way it is important to err on the side of caution, so slightly overestimating the amount is better than underestimating.

Other questions to consider for “mystery poisonings” include:

How long has it been since the last time the animal appeared normal?

Was the onset of signs gradual or sudden?

What was the location of the animal in the last few hours prior to the development of clinical signs?

Is there any history of administration of medications/herbal products/flea or tick control products to this animal or other animals in the household in the past 24 hours?

The answers to these questions may assist in narrowing down the possible toxicants to which the patient might have been exposed.

Implemented Treatment

Once the where, how, and why of the exposure is known, the next step for the history‐taker is to determine whether the owner had already implemented any treatment at home before calling the veterinary hospital or bringing the patient into the hospital setting. Implemented treatment may include induction of emesis, bathing the patient for dermal exposures, or giving over‐the‐counter medications to help prevent the development of signs or to treat current signs. Some owners will be knowledgeable about treatment that can be implemented at home, such as inducing emesis. If an owner has already been successful at inducing vomiting, this is an important piece of information to note in the medical record. What the owner gave to induce vomiting, how much, when it was given in relation to time of exposure, and the results (including what was observed in the vomitus) also need to be documented. In certain instances, treatments implemented at home can result in unintended consequences by the owner. Salt and syrup of ipecac are sometimes used to induce vomiting at home. Administration of salt can cause serious electrolyte abnormalities, and large doses of syrup of ipecac can cause prolonged gastrointestinal upset and possible cardiac effects. Furthermore, breed disposition, clinical signs the pet is displaying, and overdoses of hydrogen peroxide can further complicate cases. For example, a 20‐lb Boston terrier chewed into a container of tetrahydrocannabinol (THC) edible gummies and ingested several of the gummies. The owner was only away from the home for 30 minutes, but the dog was already ataxic, sedate, and hyperesthetic when the owner arrived home. In an attempt to recover some of gummies, the owner decided to induce emesis with 3% hydrogen peroxide solution. The dog was given half a cup of peroxide using a syringe. The dog vomited six times at home. No clear evidence of gummies was recovered. On presentation to the clinic the dog was still vomiting, showing marked CNS depression, and was having dyspnea. An examination and radiographs showed the pet's respiratory difficulty was consistent with aspiration pneumonia. Emesis would have been contraindicated in this case due to the dog's brachycephalic breed and the symptoms the pet was already displaying. Additionally, the amount of peroxide administered was not appropriate for this size pet, resulting in more than mild vomiting and gastritis.

TELEPHONE TRIAGE

Some clients may call seeking advice about a toxicological exposure before bringing the patient into the veterinary hospital. In these cases, having a telephone questionnaire for obtaining a toxicological history may help to determine which patients need to be treated at a veterinary hospital and which patients can be monitored at home. The largest disadvantage to taking a history over the phone is that the clinical status of the patient may be unknown or inaccurate. Unlike when a patient is presented to the hospital, the components of a physical examination cannot be implemented over the phone. To the owner, the patient may look normal, and subtle clinical signs such as mydriasis or abnormal mucous membrane color can be overlooked. Heart rate, blood pressure, temperature, and respirations are generally unavailable, as many animal owners are unaware of or lack the equipment to accurately obtain these vital statistics. Always ask about how the patient is doing. If the patient is bleeding, unconscious, dyspneic or seizuring, the animal should be brought immediately to the veterinary hospital (Lee 2013).

Another disadvantage to taking a history over the phone is determining the reliability of the owner; indeed, this can often be a challenge when dealing with clients in person. When speaking with a client over the phone, the veterinary technician has to rely solely on verbal communication. Observing a client's body language can at times provide more information about a particular situation than what is communicated verbally. Reliability can be poor due to a number of reasons. Clients may purposely withhold pertinent information as a result of feeling ashamed or embarrassed that their animal was exposed to a potentially toxic agent, whether by accident or simply due to a lack of knowledge as to what might be toxic. Clients may also feel they might be reprimanded by veterinary professionals for applying a product incorrectly or by attempting to treat a condition at home by giving over‐the‐counter human medications to their animal. Clients sometimes withhold information merely to avoid having to bring their patients into a veterinary hospital due to finances or inconvenience. When illicit substances are involved, clients may be reluctant to provide information due to fear of being “turned in” to law enforcement by veterinary staff. Tactful questioning and reassurance that the primary concern of the veterinary staff is the well‐being of the patient can sometimes help to elicit truthful answers. A gentle reminder that knowing what the toxicant is will allow the patient to be treated much more effectively and less expensively because knowing the toxicant may well reduce the number of diagnostic tests that may need to be performed. Veterinary technicians should be aware of reasons client information may be less than accurate and use their common sense and instinct to try to determine whether the historical information provided does not seem to fit the circumstances. Telephone triage may be the first interaction veterinary staff have with the client and there is generally a very short window of time to establish trust between client and veterinary professional. It is important to be mindful that judgment can result in a breakdown of communication with the client and may lead owners to withhold information, or worse be untruthful with their answers, resulting in an inaccurate picture of what is occurring with the patient. Being empathetic and caring, while obtaining pertinent information, will aid in establishing confidence with clients.

CONCLUSION

When managing a toxicologic case, it is the veterinary technician's responsibility to provide an accurate history to their veterinarians to ensure the most appropriate treatment is implemented for the patient. Taking an accurate history requires patience, attention to detail, and empathy. In situations where aggressive patient care is required, it is sometimes tempting to skip parts of the history‐taking process. However, if details in the history are overlooked, the patient's overall welfare could be compromised, and that key piece of information that could be vital to the case may be overlooked.

CHAPTER 4 STUDY QUESTIONS

The veterinary medical record is composed of basic data sets, including client information, patient signalment, and clinical status of the patient. When dealing with a suspected poisoning case, additional data that should be obtained for the medical record include which of the following?

Agent information

Exposure history

Implemented treatments

Environment

All of the above

Patient signalment includes all of the following except:

Breed

Age

Reproductive status

Vaccination history

Weight

Give three reasons why the patient's age and prior health history are important information to obtain when dealing with a poisoning case.

Sparky, a 5‐year‐old, neutered, male, 12‐lb Jack Russell terrier presents to the emergency clinic with a history of vomiting. According to the owner, Sparky has a habit of “eating everything within reach,” but was not witnessed ingesting anything out of the ordinary by the owner. In spite of his history of dietary indiscretion, the owner reports that Sparky has never been ill and is current on his vaccination and heartworm status. What questions should be asked about Sparky's clinical status?

Referring to the patient in Question 4, what questions should be asked about Sparky's environment?

ANSWERS

1. e. All of the listed data should be obtained for the medical record.

2. d. Signalment includes all of the “personal” information on the patient but does not include medical history.

3. Prior medical conditions may affect how the patient is managed (e.g., whether emesis is induced); patients may be more or less susceptible to toxicosis due to age‐related differences in response to certain toxicants; medications that the patient is currently taking may alter how the toxicant affects the patient.

4. How long has Sparky been vomiting? Have there been any other clinical signs that are not currently apparent? How many times has Sparky vomited and what did the vomitus contain?

5. Can you please outline Sparky’s activities over the 24‐hour period before he became ill? What is Sparky’s normal diet and have there been any recent changes? Have there been any major household changes in the past few days (visitors, renovation, etc.)? Is Sparky on any medications, supplements, or herbal products? Is Sparky an indoor or outdoor dog? To what areas of the house, yard, and neighborhood does Sparky have access? Has he been allowed access to any areas that he normally doesn’t go? Has Sparky traveled or been boarded in the past week? What type of plants are in Sparky’s environment? Have any new weeds or mushrooms been noted in the yard? What type of medications, over‐the‐counter products, and herbals/supplements are in use in the house? Are there any children in the house; if so, do they have any medications/supplements, paintballs, sugarfree gums, or candies, etc.? Are there other pets in the household; if so, are any of them acting abnormally? Does Sparky have access to animals other than household cohorts? Are any rodenticides or insecticides used in the house or yard?

REFERENCES

Fitzgerald, Kevin T. 2013. Taking a toxicological history. 2013. In Small Animal Toxicology, 3rd ed., edited by Michael E Peterson and Patricia A Talcott, pp. 39–44. St. Louis: Saunders.

Lee, Justine A. 2013. Emergency management and treatment of the poisoned small animal patient. Veterinary Clinics of North America Small Animal Practice 43(4):757–771.

5
Essential Calculations

Jennifer Kendall

INTRODUCTION

Mathematics is integral to the field of toxicology. A substantial portion of our knowledge regarding toxins and how they affect the body can be attributed to mathematical modeling. We can use these models to help determine what amount will cause adverse clinical signs, how quickly it will enter the body, and how it will be distributed and eliminated. Perhaps the most fundamental mathematical parameter we use in clinical toxicology is the “dose” at which something becomes a toxin.

Paracelsus, known as the “Father of Toxicology”, can be credited with coining the phrase “Solely the dose determines that a thing is not a poison” (Grandjean 2016). The purpose of this chapter is to learn how to calculate at what point something becomes a poison. Many other factors come into play, including stage of development, species, and even genetics (Grandjean 2016). We know that the same parameters for toxicity will not hold true in all cases; for instance, guinea pigs are relatively resistant to the neurotoxic rodenticide bromethalin because they cannot metabolize it to its toxic form, desmethylbromethalin (Murthy et al. 2022). Japanese dog breeds are more sensitive to the effects of Allium spp. (garlic, onions) than other breeds, and cats are more sensitive to the effects of Allium than dogs (Cope 2005). Ivermectin is another excellent example. When used at therapeutic dosages, it is an excellent and safe anthelmintic. However, in overdose situations, severe clinical signs can result. Further, we know that dogs with the genetic variant ABCB1 have defective P‐glycoproteins and may exhibit much more severe clinical signs than a dog without this defect receiving the same dosage (Mealey 2008). All these factors play a part in determining if a thing is indeed a “poison”.

TERMINOLOGY

Before we move forward, it is important that we recognize the difference between dose and dosage. The dose is the total amount of toxicant that is received per animal, whereas the dosage is the amount of toxicant per unit of body mass (Osweiler 2013). This is commonly expressed as milligrams per kilogram, or mg/kg. Why is this important? If you were to give a 50‐ and a 5‐kg dog each a 200‐mg dose of carprofen, the dosage would be 4 and 40 mg/kg, respectively. Carprofen is generally prescribed in dogs at 2.2 mg/kg twice daily or 4.4 mg/kg once daily. Dosages above 20 mg/kg can result in gastrointestinal ulceration, and dosages above 40 mg/kg can result in acute kidney injury (Mensching and Vollmer 2009). While both animals received the same amount of drug, the first dog received a therapeutic dosage, but the second dog would be at risk for developing gastrointestinal ulceration and acute kidney injury.

Using the example above, we can also define toxic and toxicity. Dosage allows us to describe the toxicity of carprofen, since toxicity is the dosage of a poison that will produce a defined effect. To say that something is toxic is to describe the effects of the toxicant (Osweiler 2013). In the above example, the toxic effects of carprofen can include gastrointestinal ulceration and acute kidney injury. Toxicity for gastrointestinal ulceration and acute kidney injury is seen at dosages above 20 and 40 mg/kg, respectively.

Other terms you may encounter frequently are the LD₅₀ (median lethal dosage) and the NOAEL (no observed adverse effect level). These descriptors can be used to compare the relative toxicity of one substance to another or to give you a quick idea of how toxic a dosage may be. The median lethal dosage is the dosage that was lethal to 50% of animal exposed. The NOAEL is the largest dose studied that did not result in measurable or observable changes (i.e., the highest measured nontoxic dose of that substance) (Osweiler 2013). Always keep in mind that these values are derived from studied dosages – the true NOAEL could be higher than studied if there were large jumps in dosages studied.

ESSENTIAL QUESTIONS: TAKING A HISTORY

Before you determine if a pet was exposed to enough of a toxicant to be of concern, make sure to have all pertinent details of the exposure. Start with the patient's signalment: age, weight, breed, sex, and reproductive status. See Chapter 4 for more details.

Are there any pre‐existing health conditions?

Is the pet currently taking any medications?

Were there any recent surgeries or procedures?

Is the pet up to date on vaccinations?

As previously discussed, there are age and breed sensitivities that may impact toxicity. It is also important to know what medications the pet is on in case there are interactions between those medications and the toxicant. Something may be harmless to a bitch but hazardous to her unborn or nursing puppies. Recent medical procedures may affect what treatments are pursued moving forward, and diseases such as parvovirus, leptospirosis, or rabies may need to be considered as the actual cause for signs in an unvaccinated pet.

Next, determine the circumstances of the exposure:

What was the product the pet was exposed to?

In some cases, containers may be illegible if they are chewed. Is it a herbicide, rodenticide, or insecticide? If so, perhaps the owner can provide the EPA Registration number (EPA – REG) from the package to look up exact product information on www.epa.gov. If it was placed by a pest control company, perhaps the owner can call and ask what was used at their address. Is the product a prescription medication? If so, perhaps the owner can call the pharmacy for information on the medication, strength, and quantity in the container.

How was the pet exposed to the product?

Many times, pets get into products or medications accidentally – they were left on the counter or otherwise in reach. Other times, exposures can occur because the pet was given the wrong oral medication or the wrong topical flea preventative.

You may also find out during history taking that there was no known exposure – the pet has symptoms and the owner is concerned a substance may be the cause for signs. It is important not to get tunnel vision and remember that intoxicated pets comprise a small percentage of sick pets. Keep things such as systemic disease or dysfunction in mind. Examples that come to mind are dogs with first‐time seizures or cats with urethral obstructions – signs are abrupt and extreme, and owners will try to rationalize the symptoms occurring from a specific cause, such as a plant in the house or a medication the pet recently received.

How much was the pet exposed to?

Sometimes, we know the exact amount – the pet was accidentally given 1 dose of another pet's medication, or the pet ate a 3‐oz 70% cacao chocolate bar. Other times, we must work backwards. If the owner comes home to find that their dog ripped apart a 100‐count container of vitamin D tablets, and now they can only find 15, we should assume the dog ate the 85 missing tablets. If an owner comes home to find a 12‐oz bag of chocolate chips ripped open, but they have a kitchen scale that confirms the bag still weighs 8 oz, we can assume the pet(s) ate 4 oz.

There will be times when you will be unable to determine an exact exposure. It may be that a pet got into a bottle of medication (liquid or tablets) that was previously opened and used, and the owner does not know how many had been used. When this occurs, we err on the side of caution and assume a worst‐case scenario. Let's say, for example, an owner finds an empty 25‐count ibuprofen bottle on the floor. They have had the container for years and know it was not full. Unfortunately, they can only confidently say they've taken two tablets from the bottle. We must assume the pet may have ingested 23 tablets, with the understanding that the bottle may have been nearly empty.

Similarly, let's assume a dog bites into a used bottle of liquid cold medication and it is now empty. The owner knows it was no more than half full, and there is liquid soaked into the carpet. We still must assume the dog may have consumed all the missing liquid because we cannot quantify how much is soaked into the carpet.

When was the pet exposed?

Knowing when an exposure occurred is important for determining if and when decontamination is appropriate. It also helps us determine what monitoring and treatment is necessary. Laboratory findings, treatment options, and prognosis for a dog exposed to ethylene glycol 1 hour ago are very different than options for a dog exposed to it 12 hours ago.

Lastly, ask if anything was done by the owner to try to treat the exposure. It is not uncommon for people to try to make pets vomit by sticking a finger down their throat or giving them problematic substances, such as salt or excessive amounts of hydrogen peroxide. You may find you have an additional toxicosis to address.

ESSENTIAL CONVERSIONS

Units of Mass

Once you have established the details of an exposure, make sure the information you have is usable to determine a dosage. Since dosages are typically expressed in metric units (mg/kg), you may need to convert from the imperial units commonly used in the United States or from percentages and parts per million (ppm)/parts per billion (ppb) (see Table 5.1).

A Note on Density

Be very careful with using cups, tablespoons, and teaspoons to quantify a solid substance. For most liquids, there will be a 1:1 conversion (i.e. 1 ml of the liquid will weigh 1 g). However, with solids in particular, 1 tablespoon will not always weigh 15 g. This is because the density may be higher or lower than that of water, which is 1 g/ml. For instance, some cocoa powders weigh 91 g/cup or 5.7 g/tablespoon. If you were told the pet ate 1 tbsp of cocoa powder and assumed this meant it ingested 15 g, you would be incorrect. For baking products, the nutrition facts can be a good source of information on weight per volume (it may say a serving size is 1 tbsp, or 5.7 g). For products such as slug baits or rodenticides, the Safety Data Sheet (SDS) is a great source for density or specific gravity information. When available, the specific gravity is a great conversion factor because it is the density of the substance in question divided by the specific gravity of water (1 mg/ml) and is unitless. This only needs to be used when you are given a volume of a substance with a different density than water, and you need the mass of the substance to do your calculations. This will be demonstrated in Example 5.4.

Table 5.1. Common conversions

Given measurement
Conversion equivalent

1 mcg
1000 ng

1 mg
1000 mcg

1 g
1000 mg

1 kg
1000 g

1 L
1000 ml

1 mg/kg
1 mcg/g, 1 mg/La, 1 mcg/mla
1 ppm
1000 ppb

1 mcg/kg
1 ng/g
1 ppb

1%
10,000 ppm
10 mg/g, 10,000 mcg/g
10,000 mg/kg
10 mg/ml, 10,000 mcg/ml

Imperial to metric conversion of solids

1 oz
28.35 g

1 lb (16 oz)
453.6 g

2.2 lb
1 kg

Imperial to metric conversion of liquids

1 cup
8 oz or 227 ml

1 quart
32 oz or 946 ml

1 gallon
4 qt or 3.785 L

1 teaspoon (tsp)
5 ml or 5 ga

1 tablespoon (tbsp)
3 tsp or 15 ml or 15 ga

a Only if the density of the product is equal to the density of water (1 g/ml or 1 g/cc).

Example 5.1

Janet gave her 12‐lb dog, Jax, 2 tbsp of children's acetaminophen liquid because he was limping. You confirmed the product is 160 mg/5 ml and that there are no other active ingredients or xylitol. What dosage did Jax receive?

Convert tablespoons into milliliters:

Determine the total dose of medication given:

Convert the dog's weight to kilograms:

Thus, the dosage is 960 mg/5.45 kg or 176 mg/kg acetaminophen.

Example 5.2

Daniel came home to find that his 40‐lb puppy, George, got into a 4‐oz bag of rat bait. You were able to confirm by the EPA‐REG number on the package that it is 0.005% diphacinone, an anticoagulant. You were also able to confirm that each block in the bag is 1 oz. Daniel found one of the blocks, but the other three are missing. Daniel can't remember if he had used any of the blocks prior to George getting into the bag. What is George's dosage of diphacinone?

Convert ounces to grams (notice we assume all missing blocks were ingested):

Next, you will need to determine the milligrams of diphacinone in the product. There are a few ways to accomplish this (see practice section for additional examples). A simple approach is to remember that percentages are unitless, so you can turn them into fractions as long as you are consistent with your units and appropriately move your decimal place (it is per cent, i.e. per 100):

Convert the dog's weight to kilograms:

Thus, the dosage is 4.275 mg/18.18 kg or 0.24 mg/kg diphacinone.

Example 5.3

Lisa made a 5% salt (NaCl) solution in water for a foot soak. She left one quart of it sitting out and her 95‐lb Labrador, Gunner, drank all of it. How much salt was ingested and what is his dosage?

Determine the volume ingested:

Determine the concentration of salt (NaCl) in the product in mg/ml:

Determine the milligrams of NaCl ingested:

Convert the dog's weight to kilograms:

Thus, the dosage is 47,300 mg/43.2 kg or 1094.9 mg/kg NaCl.

In Examples 5.2 and 5.3, a 0.005% bait converted to 0.05 mg/g, and a 5% solution converted to 50 mg/ml. While it is important to understand how it is converted, a shortcut is to move the decimal place one place to the right. So, a 20% solution of lidocaine is 200 mg/ml and a 0.075% cholecalciferol bait is 0.75 mg/g product. Percentages are only used when 1 g = 1 ml (the specific gravity of water), so it is simply a matter of whether the product is a liquid or solid on whether you use “per gram” or “per milliliter.”

Iron

Products containing iron often do not list the amount of elemental iron in the product, although this is more common in newer vitamins and supplements. However, pets may ingest various other products that include iron, such as slug baits, and the label often provides the amount of the iron salt rather than elemental iron. When this is the case, it needs to be converted to elemental iron to obtain a proper dosage. See Table 5.2 for common iron salts.

Example 5.4

Mr. Grier has had a problem with snails eating the vegetables in his garden. He bought a 3.5‐lb bag of Corry's Slug & Snail Killer® and sprinkled half the box's contents around the garden. He caught his 37‐lb (16.8‐kg) beagle, Sarah, eating it along with some soil about 30 minutes ago. Mr. Grier estimates no more than 2 tbsp of the bait could have been eaten by Sarah. The active ingredient is listed as sodium ferric EDTA 5.0% by weight. The owner also read off the EPA REG 67702‐33‐8119 so that you could confirm the product on www.epa.gov. You also found a specific gravity on the SDS of – 0.79 ± 0.03. What is the worst‐case scenario dosage of iron for Sarah?

As you can see, the specific gravity for this bait is less than that of water, so using 15 g/tablespoon would overestimate the amount of iron ingested. We can start with this calculation and move to a more specific calculation afterwards – if the overestimate is not enough to be concerning, than neither is the lower actual amount using the correct specific gravity.

Assuming 30 g ingested at 5.0% by weight:

Divide by the dog's weight in kilograms:

Now that we have the amount of sodium ferric EDTA, let's determine the amount of elemental iron ingested using our conversion from Table 5.2:

Now, let's get more specific with our calculation. We know that the specific gravity of this bait is at most 0.82, or 82% of the weight of an equal amount of water. Since 2 tbsp holds 30 g of water, we know that the mass of bait ingested is:

Repeating the calculation with the appropriate amount of bait gives us:

Table 5.2. Percentage of elemental iron in common iron salts

Source: Osweiler (2013).

Salt | % Elemental iron
Iron (as ferric or ferrous salt) | 100
Ferric ammonium citrate | 15
Ferric chloride | 34
Ferric EDTA | 13
Ferric hydroxide | 63
Ferric phosphate | 37
Ferric pyrophosphate | 30
Ferriglycine sulfate | 16
Ferrous fumarate | 33
Ferrous carbonate | 48
Ferrous gluconate | 12
Ferrous lactate | 24
Ferrous sulfate (anhydrous) | 37
Ferrous sulfate (hydrate) | 20
Peptonized iron | 16

Salicylates

The most well‐known salicylate is aspirin. However, there are numerous salicylate compounds in products (such as bismuth subsalicylate in Pepto Bismol®) that cause the same symptoms as aspirin if enough is ingested. Since we typically determine salicylate toxicity in terms of aspirin, you can convert these other salicylates to their aspirin equivalents (see Table 5.3).

Example 5.5

Johnny gave his cat, Pepper, 30 ml of Pepto Bismol mixed into his food because he was having diarrhea. Pepper weighs 14 lbs (6.36 kg). The label states that 15 ml of Pepto‐Bismol contains 262 mg of the active ingredient bismuth subsalicylate. What aspirin equivalent dosage did Pepper receive?

Determine how many milligrams of bismuth subsalicylate Pepper was given:

Use the aspirin conversion factor to determine the aspirin equivalent dose of bismuth subsalicylate:

Table 5.3. Aspirin equivalents of common salicylates

Source: Adapted from Vandenberg et al. (1989).

Salicylate | Aspirin conversion factor
Acetaminosalol | 0.8290
Aloxipirin | 0.8333
Aluminum aspirin | 0.8956
Ammonium salicylate | 1.1611
Antipyrine salicylate | 0.5520
Aspirin | 1.000
Benorylate | 0.5750
Benzyl salicylate | 0.9246
Bismuth subsalicylate | 0.4975
Bromosalicylic acid acetate | 0.6954
Calcium carbaspirin | 0.3930
Carbamoyl‐phenoxyaceic acid | 0.9229
Choline salicylate | 0.7466
Diethylamine salicylate | 0.8526
Ethyl salicylate | 1.2244
Fendosal | 0.4723
Glycol salicylate | 0.9889
Homosalate | 0.7154
Lithium salicylate | 1.2512
Magnesium salicylate | 1.2068
Menthyl salicylate | 0.6792
Octyl salicylate | 0.7303
Phenazone salicylate | 0.5519
Phenyl salicylate | 0.7469
Physostigmine salicylate | 0.4360
Potassium salicylate | 1.0224
Salicylic acid | 1.3043
Salsalate | 1.3953
Silver salicylate | 0.7354
Sodium salicylate | 1.1252
Sodium thiosalicylate | 1.0226
Thurfyl salicylate | 0.8108
Triethanolamine salicylate | 0.6292

Vitamins

Vitamins may be found in multiple products, both prescription and over the counter, but they are often given in International Units rather than in grams and must be converted (see Table 5.4).

Table 5.4. Conversions for common vitamins

Vitamin | Micrograms (mcg) per IU
A | 0.3
D₃ | 0.025
E | 670

Example 5.6

Penny's owner dropped a 50,000 IU prescription strength vitamin D₃ tablet on the floor, and Penny ate it. Penny weighed 22 kg at her last visit to her veterinarian. What dosage of vitamin D did Penny ingest?

Convert IU to mg:

Divide by Penny's weight:

Chocolate

Chocolate products are made with varying amounts of unsweetened baking chocolate or chocolate liquor. These products, unsweetened, have approximately 400 mg/oz of methylxanthines (Shively and Tarka 1984). When products list a “% cacao” or “% cocoa”, they are listing the percentage of this unsweetened baking chocolate in the product. Thus, 100% cocoa would be 400 mg/oz methylxanthines, while 60% cacao would be 400 × 0.60 = 240 mg/oz of methylxanthines, etc.

Example 5.7

Katie is a 26‐kg cocker spaniel that ate approximately 50% of her owner's chocolate bar. Per the label, the bar is 2.89 oz and 88% cacao. What dosage of methylxanthines did Katie ingest?

Convert to amount ingested:

Determine methylxanthine amount:

Divide by weight:

ESSENTIAL SOLUTIONS

Mathematics is not only an integral part of determining if a toxicant may cause clinical signs; it is also essential to the treatment of many toxicities. Often, treatments involve the use of medications or products that require dilution. This often means making a solution, which is defined as a homogenous mixture of two or more substances, consisting of one or multiple solutes, and a solvent. The solute is the minor component of a solution. It is what is dissolved in the solvent. The solute may be a solution as well. For instance, you may use a stock 50% dextrose solution to make a 5% solution of dextrose in a pet's intravenous fluids. While the 50% dextrose is a solution (it is 500 mg/ml dextrose in water), you are using it as a solute. A solvent is simply a liquid capable of and used for dissolving other substances. Water is the most common solvent. In medicine, products such as Normosol‐R or 0.9% saline are common solvents, but they can also be considered solutions.

Simple examples of solutes:

sodium chloride

dextrose

medications that require reconstitution or dilution before use (cephazolin, ampicillin/sulbactam, N‐acetylcysteine, some antivenins).

Simple examples of solutions:

saline: the solvent is H₂O and the solute is NaCl

D5W: the solvent is H₂O and the solute is dextrose

Normosol‐R: this is more complicated, but the solutes are sodium chloride, sodium gluconate, potassium chloride, magnesium chloride, and sodium acetate.

To make a simple solution, commit this equation to memory:

where C stands for concentration, V stands for volume, 1 denotes the initial concentration and volume, and 2 denotes the final concentration and volume. When using this equation, you must be consistent with your units (all concentrations should be expressed the same, and all volumes should be expressed the same). Usually, we are solving for V₁ (the volume of solute you need to put into the solvent):

Example 5.8

Benny the golden retriever was just hospitalized after eating a large volume of xylitol‐containing gum. You have been asked to start him on 2.5% dextrose fluids. How much 50% dextrose do you need to add to a 1‐L bag of fluids to create a 2.5% solution?

V ₁ = volume of dextrose needed (unknown)

C ₁ = concentration of dextrose you are using in the bag (50%)

V ₂ = final volume of your solution (1 L)

C ₂ = desired final concentration of your dextrose solution (2.5%)

upper V 1 equals StartFraction left-parenthesis 2.5 percent-sign d e x t r o s e right-parenthesis left-parenthesis 1 normal upper L right-parenthesis Over 50 percent-sign d e x t r o s e EndFraction = StartFraction 2.5 left-parenthesis 1 normal upper L right-parenthesis Over 50 EndFraction = StartFraction 2.5 Over 50 EndFraction equals 0.05 normal upper L Baseline 50 percent-sign d e x t r o s e

In this example, we were able to cancel out the % for dextrose, even though % is not technically a unit (it is just a ratio). It is very important to carry your units and keep track of them during the calculation. With percentages, you can either cross out the % or convert it to number form (i.e. 50% = 0.50 = 500 mg/ml dextrose).

You can use the original equation (C₁V₁ = C₂V₂) to check your calculations by plugging in your numbers and confirming both sides are equal:

Now, how do we make this solution? Remember that the final volume needs to be 1000 ml. Since you are adding 50 ml to the bag, you first need to remove 50 ml from the bag (otherwise, your final volume will be 1050 ml and your calculation will not be correct).

Example 5.9

A 9‐kg domestic cat was just admitted after ingesting 23 mg/kg acetaminophen 1 hour ago. You need to start its loading dose of N‐acetylcysteine (NAC, 140 mg/kg) after diluting it in saline to 5%. The NAC comes as a 20% solution.

First, determine what we need to know:

V₁ = volume of NAC needed (we need to solve for this first)

C₁ = concentration of undiluted NAC (20% or 200 mg/ml)

V₂ = final volume of your solution (unknown)

C₂ = desired final concentration of NAC (5%)

Next, solve for V₁:

Now you can solve for V₂:

So, to make your solution, you will add 6.3 ml of NAC to (25.2–6.3 = 18.9 ml) of saline.

Now, check your work:

CHAPTER 5 STUDY QUESTIONS

Gonzo the 7‐kg chihuahua found his owner's melatonin supplement container and chewed it open. Each dissolving tablet contained 3 mg of melatonin and 200 mg of xylitol. His owner knows there were originally 30 tablets in the container, but she has had it for a few months and only uses it once in a while and can only confirm she has taken three of them. She found five tablets in the bottle, but Gonzo vomited and had a seizure, so she left the house to go to the veterinarian before counting how many tablets were still on the floor.

What is the possible dosage of xylitol and melatonin ingested?

Determine how many tablets Gonzo would need to eat to cause hypoglycemia, assuming we can see hypoglycemia at 100 mg/kg xylitol.

If xylitol can cause liver injury at 500 mg/kg, is this a possible risk for Gonzo?

Mr. Jones left a tube of arthritis pain cream sitting on the coffee table. He returned to the room 30 minutes later to find his 90‐lb pitbull, George, chewing on the 100 g tube. The active ingredient is 1% diclofenac. Mr. Jones estimates half the contents of the tube are missing. Henry, a 26‐lb French bulldog, was also in the room, but he doesn't usually eat things.

What possible dosage of diclofenac did George ingest?

What about Henry?

Princess is a 4‐lb pomeranian. Her pet sitter accidentally gave her an iron tablet instead of oclacitinib. The label states that each tablet contains 325 mg ferrous sulfate hydrate. What dosage of elemental iron did Princess receive?

Dino is a naughty, 42‐kg golden retriever who got into his owner's pill minder. The pill minder contained seven tablets of 500 mg salsalate. What is the aspirin‐equivalent dosage ingested?

Charity is a 63‐lb husky who got into an unopened bottle of Vitamin D₃ gummies. All 60 gummies are now missing. The label states that each three‐gummy serving contains 2000 IU vitamin D₃. What dosage of vitamin D was ingested?

Jax, a 12‐lb Jack Russell terrier, was caught chewing on a 14‐g bait pack. The owner placed the pack this morning and confirmed from the packaging that the active ingredient is 0.075% cholecalciferol. The owner also has a kitchen scale and weighed the remaining bait as 11 g. Assuming 0.1 mg/kg could lead to hypercalcemia and requires treatment, does Jax need to go to the veterinary clinic?

A patient is hypoglycemic and hypokalemic after ingesting xylitol. You need to add 2.5% dextrose and 40 mEq/L potassium chloride (KCl) to its 1‐L bag of Norm‐R. Your stock cabinet has 50% dextrose and 2 mEq/ml KCl for injection. How do you make this solution?

You need to treat a dog for antifreeze toxicity. Your clinic does not have the antidote, 4‐4‐methylpyrazole, but you do have 80 proof (40%) vodka. You need to administer a loading dose of ethanol at 600 mg/kg, followed by a constant rate infusion (CRI) of 100 mg/kg/h ethanol. The ethanol must be diluted to 7% and the dog is 34 kg.

How much vodka is needed for the loading dose, and what is the total volume of the loading dose?

How many hours will a 1‐L bag last for the CRI? (Hint: 80 proof = 40% ethanol.)

A 15‐kg dog presented to your clinic 30 minutes after ingesting an unknown number of caffeine tablets. You have given a 0.50 mg/kg bolus of esmolol which normalized the heart rate, but it is coming up again, so you decide to start a constant rate infusion at 50 mcg/kg/minute. You have 10 mg/ml injectable esmolol at your clinic. What rate (ml/h) will you need to set the syringe pump to in order to deliver the proper dosage?

Jake, a 12‐lb toy poodle, ate 75% of a chocolate bar 1 hour ago. The label lists 68% cacao and the bar initially weighed 3 oz. What is Jake's methylxanthine dosage?

ANSWERS

1. Since only eight of the 30 tablets are accounted for, we must assume Gonzo ingested 23 tablets.

a. StartLayout 1st Row upper M e l a t o n i n colon 23 normal t a b l e t s times StartFraction 3 m g normal Over t a b l e t normal EndFraction 2nd Row equals 69 m g m e l a t o n i n EndLayout

Since Gonzo is 7 kg, this is 9.9 mg/kg melatonin and 657.1 mg/kg xylitol.

b. To be at a level of concern for hypoglycemia, Gonzo needs to ingest:

Gonzo only needs to ingest 3.5 tablets to be at risk for hypoglycemia.

c. Hepatotoxicity is seen at 500 mg/kg and Gonzo could have eaten 657.1 mg/kg so there is a risk for liver injury.

2. Since half the contents of the 100‐g tube are missing, we must calculate how may milligrams of 1% diclofenac was ingested, assuming 50‐g was consumed.

1% = 10 mg/g diclofenac

a. George's weight is 90 l b times StartFraction 1 k g Over 2.2 l b EndFraction equals 40.9 k g, so his dosage is 12.2 mg/kg.

b. Even though the owner does not suspect Henry, he was in the room and no one witnessed the ingestion. We must assume he participated, making his possible dosage 42.4 mg/kg.

3. Ferrous sulfate hydrate is 20% elemental iron (see Table 5.2). Thus, 325 × 0.20 = 65 mg elemental iron was ingested. The dosage for a 4‐lb (1.8 kg) dog would be 36.1 mg/kg.

4. A total of 7 × 500 mg = 3500 mg salsalate was ingested. Multiply by the conversion factor (see Table 5.3) to get the aspirin equivalent:

5. Each 2000 IU (see Table 5.4) serving is three gummies, so Charity ingested 60/3 = 20 servings:

6. While we can assume Jax ingested 3 g, use the associated dosage with caution because there can be variation in the production of products and in the accuracy of scales. As you can see below, Jax would be at a level of concern for signs if even a quarter of the missing material were ingested:

7. For this question, tackle each additive separately.

Determine the amount of dextrose needed:

C ₁ = 50% dextrose

C ₂ = 2.5% dextrose

V ₁ = unknown volume of 50% dextrose

V ₂ = 1 L (1000 ml)

Determine the amount of KCl needed:

C ₁ = 2.0 StartFraction m upper E q Over m l EndFraction

C₂ =40 StartFraction m upper E q Over normal upper L EndFraction equals StartFraction 40 m upper E q Over 1000 m l EndFraction equals StartFraction 0.04 m upper E q Over m l EndFraction

V₁ = unknown volume of 2.0 StartFraction m upper E q Over m l EndFraction upper K upper C l

V ₂ = 1 L (1000 ml)

To make the solution, you need to remove 50 + 20 = 70 ml from the 1‐L bag, otherwise your final volume would be 1070 ml. Then, add 50 ml of 50% dextrose and 20 ml of 2 mEq/ml KCl to the bag.

8. We need to dilute an initial concentration of 40% ethanol to a final concentration of 7% ethanol. To determine the final volume of our loading dose, we need to know the initial volume of undiluted ethanol to provide 600 mg/kg ethanol:

a. Now that we have V₁, we can solve for V₂:

b. We know that the dog needs a 100 mg/kg/h constant rate infusion of a 7% solution, and we want to know how long 1 L of solution will last. We need 100 mg × 34 kg = 3400 mg ethanol per hour, so let's determine what volume of 7% solution this equates to:

Thus, 1000ml will last approximately

9. First, we need to convert mcg/kg/min to mg/h:

Next, convert to ml/h:

10. Jake ingested 0.75 × 3 oz = 2.25 oz of chocolate. At 68% cacao, the bar contains 0.68 × 400 mg/oz = 272 mg/oz methylxanthines. Thus, he ingested:

REFERENCES

Cope, Rhian B. 2005. Allium species poisoning in dogs and cats. Veterinary Medicine 100(8):562–566.

Grandjean, Philippe. 2016. Paracelsus revisited: the dose concept in a complex world. Basic & Clinical Pharmacology & Toxicology 119(2):126–132.

Mealey, Katrina L. 2008. Canine ABCB1 and macrocyclic lactones: heartworm prevention and pharmacogenetics. Veterinary Parasitology 158(3):215–222.

Mensching, Donna and Vollmer, Petra. 2009. Toxicology brief: managing acute carprofen toxicosis in dogs and cats. Veterinary Medicine 104(7):325–333.

Murthy, Vishal D, McLarty, Ehren, Woolard, Kevin D et al. 2022. Case report: MRI, clinical, and pathological correlates of bromethalin toxicosis in three dogs. Frontiers in Veterinary Science 26(9):879007.

Osweiler, Gary D. 2013. General toxicologic principles for clinicians. In Small Animal Toxicology, 3rd ed., edited by Michael E Peterson and Patricia A Talcott, pp. 1–12. St. Louis: Saunders.

Shively, Carol A and Tarka, Stanley M Jr. 1984. Methylxanthine composition and consumption patterns of cocoa and chocolate products. Progress in Clinical and Biological Research 158:149–178.

Vandenberg, Sharon A, Smolinske, Susan C, Spoerke, David G, and Rumack, Barry H. 1989. Non‐aspirin salicylates: conversion factors for estimating aspirin equivalency. Veterinary and Human Toxicology 31(1):49–50.

6
Initial Management of Acute Intoxications

Brittany Parsons

TELEPHONE TRIAGE

Oftentimes, the initial contact with a patient's owner is over the phone. It is imperative that the appropriate questions are asked to better instruct the client on the next steps to be taken. One of the first steps is to obtain the animal's signalment: species, breed, age, and approximate body weight. It is important to then obtain information regarding the patient's status (i.e., alert, unresponsive) and any current clinical signs the patient may be experiencing (i.e., vomiting, trembling, difficulty breathing, seizures, etc.) (Lee 2013). It is challenging to fully determine the condition of a patient over the phone, however it is important to try to establish if they may be experiencing any life‐threatening signs (i.e., dyspnea, seizures, level of consciousness). If so, an owner should be instructed to seek immediate veterinary care.

If a toxic substance is known or suspected, a patient owner or veterinary staff can be instructed to contact a poison control center to seek further guidance. The American Society for the Prevention of Cruelty to Animals (ASPCA) Animal Poison Control Center (888‐426‐4435) or the Pet Poison Helpline (800‐213‐6680) are both staffed with veterinary toxicologists and specially trained veterinarians that can provide assistance in regards to treatments and diagnostics. Both poison control centers charge a consultation fee.

HOSPITAL PRESENTATION

Triage

On presentation to the hospital, a member of the medical team should triage the patient. Triage is described as the preliminary assessment of casualties to determine the urgency of their need for treatment. The goal of triage is to determine whether the patient can be categorized as stable or unstable, allowing appropriate prioritization of care. This should take approximately 5 minutes and includes a brief assessment of the patient's neurologic, cardiovascular, and respiratory status, and a condensed history. The basic principles of emergency patient assessment should also be applied, even in the poisoned patient (Lee 2013).

The initial history should include the patient's signalment, primary complaint, duration of the problem, and current medications. Information specific to toxic exposure may include, if this is a known or possible exposure, the type and amount of toxin, and a brief establishment of a timeline of events. It is not uncommon for owners to be unaware that their pet was exposed to a toxin. A more detailed history is an important part of the patient's assessment, but can be obtained later, after initial evaluation.

Initial Assessment and Stabilization

The ABCs (airway, breathing, circulation) should be addressed first. The initial assessment includes a brief assessment of those organ systems and vital signs, obtaining vascular access, possibly an initial database followed by development of the emergency plan. The respiratory, cardiovascular, and neurologic systems should be assessed to determine the patient's stability. Vitals, including temperature, heart rate, respiratory rate, mucous membrane color, and capillary refill time should be obtained. Normal vitals (Table 6.1) are based on the species, breed, and size of patient .(Lee 2013). If the patient is showing life‐threatening clinical signs or abnormal vitals, then the patient would be deemed unstable and would require immediate attention by a veterinarian, no matter the cause of the clinical signs.

Table 6.1. Normal vital signs

Species | Temperature (degrees Fahrenheit, °F) | Heart rate (beats per minute) | Respiratory rate (respirations per minute) | Mucous membrane color | Capillary refill time (seconds)
Canine | 99.5–102.5 | 60–120 | 15–30 | Pink | <2
Feline | 100.0–102.5 | 130–140 | 20–30 | Pink | <2

Respiratory System

The first system to be evaluated should be the respiratory system. A normal respiratory rate in dogs and cats can range from 12 to 32 respirations per minute. Apparent and clear breath sounds should be auscultated with a stethoscope. If a pet appears obtunded or is in severe respiratory distress, they should be evaluated immediately to determine if intubation or oxygen is needed. Distress can be indicated if an upper airway noise is present or tachypnea (increased respiratory rate) is seen. A patient can also show signs of slow, prolonged breathing (bradypnea) or apnea (no breathing). Other abnormal findings can include labored inspiration or expiration or paradoxical respiration (chest wall and abdominal wall do not move synchronously). Some toxins, such as fumes from bleach or formaldehyde, can be inhaled causing respiratory irritation. Other toxins, including anticoagulant rodenticides or aspirin, can cause secondary changes to the respiratory system by bleeding into the lungs or causing an acidosis respectively (Mellema 2013).

Cardiovascular System

Assessment of the cardiovascular system includes auscultating the heart and assessing perfusion parameters. Perfusion parameters include heart rate, mucous membrane color, capillary refill time, and pulse quality. A normal resting heart rate in a canine can range from 60 to 120 beats per minute (bpm). For felines, a normal resting heart rate can range from 130 to 140 bpm. When assessing heart rate, it is important to consider the patient's mental status, as excitement or anxiety in the clinic may increase the heart rate of a patient. Tachycardia is described as >120 bpm in a canine and >140 bpm in a feline. Bradycardia is described as <60 bpm in a canine and <130 bpm in a feline. Cardiovascular function can be affected by a wide variety of toxins, including methylxanthines, illicit substances, cardiac glycoside plants, or therapeutic medication overdoses (Lee 2013).

The pulse quality should be strong and synchronous with the heart rate. Both femoral and digital pulses should be palpated. A weak or absent pulse indicates poor perfusion or hypotension. A bounding or tall and narrow pulse suggests hypertension or a possible state of shock. Dropped beats indicate an arrhythmia is present.

A normal, healthy mucous membrane color should be pink. Areas to assess mucous membrane color include the gingiva or conjunctiva. Cyanosis or blue mucous membranes can indicate severe hypoxemia. Pale or white suggests anemia or shock. A muddy or grey color suggests poor perfusion. Icteric or yellow mucous membranes can indicate hepatic dysfunction or hemolysis. Brown mucous membranes imply the possibility of methemoglobinemia, which can be seen with acetaminophen toxicosis. Hyperemic or bright red mucous membranes are seen when cardiac output is increased, or in hyperthermia, sepsis, or cyanide toxicity.

Central Nervous System

The central nervous system can initially be assessed by level of consciousness, mentation, pupil size and position, and gait. A patient can also experience muscle tremors, seizures, disorientation, or agitation related to toxin exposure. These neurologic abnormalities can occur with amphetamines, bromethalin rodenticide, metaldehyde, mycotoxins, as well as many other substances. A canine or feline that appears bright, alert, and responsive indicates a normal mentation. Stress or anxiety can sometimes alter the appearance of a pet's mental status. The following levels of consciousness can be observed:

Alert: Normal.

Depressed: Quiet, unwilling to perform normally; responds to environmental stimuli.

Obtunded: Minimally responsive to auditory or tactile stimuli.

Stuporous: Unresponsive to environmental stimuli; responds to painful stimuli.

Comatose: No response to environmental and painful stimuli.

Normal pupils in a canine should appear round and should constrict when exposed to a bright light. Felines have a more elliptical shaped pupil. Mydriasis, or dilated pupils, can indicate stress, toxin exposure (serotonergic medications, avermectins, etc.), blindness, or possible brain disorder. Miosis, or constricted pupils, can indicate opioid toxicosis, brain or ocular disorder. Other pupil abnormalities include nystagmus (involuntary motion of the eyes) or strabismus (misalignment of eyes).

Gait anomalies include ataxia (unsteadiness when walking), paresis, paralysis, or loss of motor function. Toxins affecting gait can include various substances, for example alcohol, benzodiazepines, opioids, marijuana, bromethalin, and centrally acting skeletal muscle relaxants (Lee 2013). Gait abnormalities should be accessed along with the level of alertness.

VASCULAR ACCESS

Intravenous access should be obtained in any critically ill patient for administration of fluids and medications. The most common vessels used for intravenous catheterization in dogs and cats are the cephalic or lateral saphenous veins. Central venous access via the medial femoral or jugular vein allows for a larger diameter catheter to be placed, which is ideal for allowing achievement of higher drug concentrations in the coronary vessels as well as rapid fluid administration. These vessels are not as accessible as the peripheral vessels. In neonates, the easiest and most expeditious way to obtain vascular access is via intraosseous catheter placement. Ideally, at this time a blood sample may be collected and stored for future toxicological analysis because some medications that may subsequently be administered may interfere with diagnostic tests. For example, propylene glycol in diazepam injectable solutions will cause a false positive on ethylene glycol tests (Dalefield 2004).

DIAGNOSTICS

Baseline Assessment

Most modern veterinary hospitals are well equipped and have the ability to provide in‐house diagnostics. Using these tools, rapid evaluation of the poisoned patient's metabolic and hydration status can be performed. This information will aid in the overall approach to and outcome for these patients. If the exact toxicant has already been determined, the direct effects and any secondary consequences of it can be predicted. In situations where the toxicant is not known, the diagnostic approach must be based on clinical signs, a thorough history, and response to symptomatic therapy.

Once the patient has been appropriately triaged and vital signs stabilized, a systematic approach to diagnostics should be taken. If possible, during venous access, blood samples should be collected. A serum chemistry/electrolytes and complete blood cell count (CBC) should be analyzed as a baseline assessment. Depending on the history and clinical signs, blood gas, electrocardiography (ECG), blood smear, coagulation panel, and urinalysis may also reveal further evidence of a toxicosis (Lee 2013). Other diagnostics that may provide useful information include radiographs or testing for specific substances.

The packed cell volume (PCV) and total solids (TS) are generally interpreted in conjunction with each other. The changes in the two parameters often parallel each other in situations of free water loss or hemorrhage. Decrease in both PCV and TS suggests hemorrhage. A decreased PCV with normal TS indicates red blood cell destruction, decreased red blood cell production, or anemia of chronic disease. The foremost clinical significance to a decreased PCV is reduced oxygen‐carrying capacity of the blood. Decreased total solids may occur due to loss from hemorrhage, protein loss into third spaces, or external loss through the intestines or kidneys. Hypoproteinemia results in decreased intravascular oncotic pressure. This may result in loss of fluid from the intravascular space and decreased ability to maintain vascular volume and blood pressure. Increases in both PCV and TS are most commonly due to dehydration.

CBC and peripheral blood smear analysis are useful tools in diagnosing hematological abnormalities. The CBC provides information regarding red blood cell parameters and white blood cell parameters. The red blood cell parameters can help further determine the oxygen‐carrying capacity of the blood, classify anemias (acute vs. chronic), and determine regeneration. The white blood cell parameters can help to characterize inflammatory or infectious mechanisms.

Peripheral blood smear analysis is performed to evaluate the appearance of the cellular components of the blood (red blood cells, white blood cells, platelets), identify the presence of hematologic infectious agents (e.g., Dirofilaria or Babesia) and identify any other changes that may assist in diagnosis. For example, the presence of Heinz bodies and methemoglobinemia can put acetaminophen or garlic/onion toxicosis on the list of differential diagnoses. During acute toxicosis, some changes may not be evident in the first 24–48 hours and it may be necessary to re‐evaluate a CBC and blood smear.

Serum chemistry and electrolyte panels are important to assess because some alterations in these measurements may be a direct result of the toxicant. Many toxicants affect renal function (i.e., ethylene glycol). If there is evidence of azotemia or acute renal failure, one then can move forward with diuresis and other appropriate therapy. Some toxicants (e.g., xylitol, acetaminophen, Cycas spp., blue green algae) may result in acute hepatic failure or necrosis, which will be reflected in the liver enzymes. Blood glucose, calcium, sodium, potassium, or chloride concentrations can also be altered by various toxicants, such as calcium channel blockers, albuterol, digitalis, or vitamin D‐based rodenticides. Evaluation of serum chemistry and electrolyte results can provide clues into the original cause of the abnormalities and provide feedback on response to therapy.

Blood glucose readings are an essential portion of the emergency database. Normal blood glucose ranges from 80 to 120 mg/dl (3.3–6.2 mmol/L), and severe aberrations (either elevations or depressions) can be life‐threatening to the patient. Hypoglycemia can occur due to conditions such as sepsis, liver dysfunction, neonatal/juvenile hypoglycemia, insulin or insulin‐like factor secreting tumors, xylitol ingestion (dogs), or alpha‐lipoic acid ingestion. A transient hyperglycemia can occur in overly stressed patients (particularly felines). True hyperglycemia is most commonly due to diabetes mellitus.

Urine should be collected for a baseline screening, especially in patients who have ingested or have been exposed to nephrotoxic substances such as ethylene glycol, lilium species, or certain doses of non‐steroidal anti‐inflammatory drugs. A complete urinalysis will provide useful information in determining the ability of the kidneys to concentrate urine. The presence of hemoglobinuria, glucosuria, proteinuria, cellular or granular casts, pigments, and crystals can aid in narrowing down the cause of renal dysfunction.

Additional Testing

During the course of patient management, additional testing may be indicated based on the clinical status of the patient or changes in historical information received from clients. Tests such as coagulation profiles, illicit drug screening, other drug or chemical screening, radiography, electrocardiography, and ultrasound can assist in identifying causes and measuring response to therapy.

Blood gas analysis is a great tool used to assess the patient's acid‐base status. Many intoxicated patients will present with a history of vomiting, diarrhea, respiratory distress, or seizures. Although these clinical signs may be secondary, patients will likely present with some degree of acid‐base derangement. The rapid evaluation of blood gas parameters is highly useful and can provide great insight to the patient's acid‐base status. Metabolic acidosis is characterized as a pH of <7.2 with a base excess of <4 (Rieser 2013). Many times these patients have severe gastrointestinal distress. Respiratory acidosis may be present in the intoxicated patient, which is characterized by a pH of <7.2 and PCO₂ of >45 (Rieser 2013). This can occur with substances that cause a respiratory depression resulting in hypoventilation (i.e., anticonvulsants or centrally acting skeletal muscle relaxant medications). Lactic acidosis is due to the large amounts of lactic acid produced in response to excessive muscle activity. This can occur with seizure activity or with toxicants causing tremorgenic activity such as pyrethroid insecticides or tremorgenic mycotoxin ingestion. This type of acidosis will generally resolve on its own once the seizures or tremors have been controlled. In other situations, hypoperfusion may result in lactic acidosis, requiring intravenous fluid therapy to resolve. A respiratory alkalosis is characterized by a PCO₂ of <35 mmHg and can be seen in patients with hypoxemia or from substances causing excitement or hyperventilation.

Coagulation profiles are used to detect changes in the clotting parameters of the blood, especially prolonged prothrombin time (PT) and partial thromboplastin time (aPTT). These profiles (or individual tests) are often performed at the clinic and are helpful in diagnosing coagulopathy from a variety of causes, including anticoagulant rodenticide toxicosis. Anticoagulant rodenticides interfere with recycling of vitamin K in the body, leading to depletion of clotting factors, which results in uncontrolled hemorrhage. Because most animals have a “reserve” of clotting factors, exposure to these rodenticides generally will not result in prolongation of PT or aPTT until 60–72 hours post ingestion.

Illicit drug screening has become an invaluable tool used in cases where illicit drug ingestion is suspected. There are several types of these tests available at most pharmacies, designed for home monitoring of drug use. The tests are easy to perform, inexpensive, require only a small amount of urine, and provide results within a matter of minutes. The kits can screen from one to 12 substances, including marijuana, amphetamines, barbiturates, benzodiazepines, cocaine, methadone, methamphetamine, nicotine, opiates, phencyclidine, and tricyclic antidepressants. Some of these substances may cross‐react with other drugs, for example amphetamine tests may cross‐react with sympathomimetic drugs such as pseudoephedrine or ma huang. This can sometimes be helpful if ingestion of these legal drugs is suspected. Based on clinical experience, in many kits the test for marijuana does not give consistent results (i.e., gives false negatives) due to differences in the metabolites excreted between humans and dogs. These tests have not been validated in nonhumans, meaning they would not stand up in a court of law, but they have great utility in assisting veterinary staff in diagnosis of suspected drug ingestion. Any positive result based on the use of a drug screening kit is not considered confirmatory, and false‐positive or ‐negative results can occur (see Figure 6.1). If someone wishes to pursue a case legally following a positive on an over‐the‐counter test kit (i.e., suspected malicious poisoning), blood and urine should subsequently be submitted to a validated diagnostic laboratory for analysis that will be acceptable in a court of law. Some clients may be reluctant to have the test performed for fear of police authority involvement. As an animal care provider, it is very important to reassure clients that the only concern is for appropriate therapy for their pet. The cooperation of the client and the ability to provide illicit drug screening allows for a targeted treatment plan that can greatly improve the overall outcome of these patients.

Ethylene glycol testing is used in detecting the presence of high serum concentrations of ethylene glycol (EG). EG is the major component found in many commercial antifreeze products. There are two common types of in‐house EG tests that can be found in most emergency clinics: the Kacey EG test (kaceydiagnostics.com) and the Catachem EG test (catachem.com). These tests are most accurate when performed within 1–12 hours post ingestion. Some substances, such as propylene glycol, ethanol, or xylitol, may cause false positives with these tests. Details of these issues can be found in the discussion on EG in Chapter 29.

Human hospital laboratories may be helpful in determining exposure to a variety of toxicants, including EG and acetaminophen. When in‐house EG testing is not available, or there is concern that the test result may be a false positive, a human hospital laboratory can run a quantitative analysis. For dogs, the level of concern is 50 mg/dl or greater and for cats the level of concern is 20 mg/dl or greater. Tests run in human hospitals for EG are very sensitive and specific. In some situations, there is concern that a cat or dog may have been exposed to acetaminophen. In these cases, human hospitals can analyze blood for acetaminophen levels, which can tell whether the animal was exposed; unfortunately, nomograms do not exist for dogs and cats to determine subtoxic doses from toxic doses, but this test can help determine if there was an exposure in dogs. The test is not sensitive enough for cats.

Figure 6.1. Potential false positives using illicit drug urine screens.

Radiography may be useful in providing evidence of a metallic foreign body. Common radiopaque materials include batteries, screws, galvanized metal, and coins. Some heavy metals can be highly toxic, such as zinc (pennies minted after 1982) and lead. If radiographs are diagnostic, an endoscopy or a gastrotomy may be required after patient stabilization.

ECG may help detect arrhythmias a patient may be experiencing. Many patients intoxicated with substances such as methylxanthines, amphetamines, cocaine, or albuterol will present with sinus tachycardia or ventricular tachyarrhythmias. Bradycardia and bradyarrhythmias may present in patients exposed to substances such as organophosphosphate insecticides, pharmaceuticals (e.g., beta‐adrenergic blockers), alcohol, or marijuana. Bradyarrhythmias can also occur in patients with severe electrolyte abnormalities (e.g., hyperkalemia) secondary to a toxicosis (e.g., digitalis toxicosis). The use of appropriate antiarrhythmic medication will be dictated by the veterinarian based on the type and severity of the abnormal rhythm. Continuous ECG monitoring is recommended when treating these patients.

INITIAL DECONTAMINATION

Decontamination is an important part of initial stabilization for the poisoned patient. The intent of decontamination is to inhibit further absorption of the toxin and enhance elimination from the body (Mellema 2013). When performed quickly and efficiently, this can greatly reduce the risks of the poison. These procedures may involve induction of emesis, administration of activated charcoal, or bathing the patient. It is important to ensure the stability of the patient prior to moving forward with any decontamination measure. For more information see Chapter 7.

Gastrointestinal Decontamination

When exposed to an oral substance, there are a variety of methods for decontamination, including dilution, inducing emesis, adsorbents, enemas, or endoscopy/gastrotomy. When deciding whether to pursue gastrointestinal decontamination, the patient's mental status and the type of substance should be considered. If a patient's mental status is altered, gastrointestinal decontamination techniques (i.e., inducing emesis, administering activated charcoal) could potentially prove harmful. Likewise, if a patient ingests a corrosive substance, inducing emesis may be contraindicated.

Ocular Decontamination

Damage to the eyes from an exposure can range from mild irritation to significant corrosive injury and possible blindness. If an ocular exposure occurs, the eyes should be flushed with either tepid water or a sterile saline solution for a minimum of 20–30 minutes (DeClementi 2018). Sedation may be needed to minimize stress on the patient. For smaller patients, an eyedropper can be utilized. For larger patients, a syringe, plastic bottle, or a cup can be used. After flushing, a fluorescein stain can help to determine if there is ulceration.

Dermal Decontamination

Substances such as corrosive materials or sticky substances have the potential to damage the skin. Topical medications (i.e., flea/tick medications, permethrin) can cause a dermal hypersensitivity or have the possibility to cause central nervous system signs. For these products, bathing in warm water with a mild liquid hand dish detergent will be most effective. After bathing, the patient should be rinsed thoroughly, towel dried, and kept in a warm environment until completely dry. When removing sticky substances, a small amount of vegetable oil, olive oil, or mayonnaise can be massaged into the fur to help break the substance down prior to bathing (DeClementi 2018). Solvents should not be used as these can be irritating to the patient.

CONCLUSION

There are a variety of reasons that animals may present to an emergency service, including infectious, inflammatory, metabolic, and toxic processes. In many circumstances involving poisoning, the cause of the animal's condition may not be known, particularly in cases where exposure to a toxicant was not witnessed. Having a systematic approach to these patients is paramount to identifying the major health issues present. Patient stabilization is essential to keeping the patient alive while the underlying problem is diagnosed and treated. Evaluation of the patient's clinical status and detailed historical information are often necessary to identify the inciting cause and provide prompt and appropriate treatment.

The author would like to thank the previous edition authors: Elisa Petrollini‐Rogers and Bridget McNally.

CHAPTER 6 STUDY QUESTIONS

Which of the following is NOT part of the signalment?

Reproductive status

Species

Breed

Vaccine status

Age

A cat with a heart rate greater than 200 beats per minute is considered:

Bradycardic

Tachycardic

Normal

Fibrillating

Which mucus membrane color is indicative of sepsis?

Blue

Grey

White

Yellow

Bright red

Which of the following can be found in a peripheral blood smear?

Babesia

Roundworms

Hookworms

Giardia

Tapeworms

Pseudoephedrine, found in cold medications, can give a false positive on urine drug screen for which type of drug class?

Amphetamines

Barbiturates

Cocaine

Marijuana

Opiates

ANSWERS

1. d

2. b

3. e

4. a

5. a

REFERENCES

Dalefield, Rosalind. 2004. Ethylene glycol. In Clinical Veterinary Toxicology, edited by KH Plumlee, pp. 150–154. St. Louis: Mosby.

DeClementi, Camille. 2018. Prevention and treatment of poisoning. In Veterinary Toxicology: Basic and Clinical Principles, 3rd ed., edited by Ramesh C Gupta, pp. 1141–1160. London: Elsevier.

Lee, Justine A. 2013. Emergency management and treatment of the poisoned small animal patient. The Veterinary Clinics of North America. Small Animal Practice 43(4):757–771.

Mellema, Matthew. 2013. Initial management of the poisoned patient. In Small Animal Toxicology, 3rd ed., edited by Michael E Peterson and Patricia A Talcott, pp. 63–71. St. Louis: Saunders.

Rieser, Teresa M. 2013. Arterial and venous blood gas analyses. Topics in Companion Animal Medicine 28(3):86–90.

7
Decontamination Procedures

Lisa Murphy

SOURCES

Companion animals may need to be decontaminated due to a variety of exposures to potentially harmful substances. The most common scenarios that may require decontamination and follow‐up veterinary care are oral, inhalation, dermal, and ocular exposures.

Oral exposures in the animal's environment may include consumption of contaminated food or water, ingesting dropped pills or other items, licking puddles of unknown liquids, grooming, and swallowing particles that are first inhaled then returned to the pharynx from the lower respiratory tract by the mucociliary apparatus (Gwaltney‐Brant et al. 2003).

Inhalation exposures can result from exposures to dusts, ash, gases, and toxic fumes (Gwaltney‐Brant et al. 2003). Gases and toxic fumes are most dangerous in enclosed spaces, so animals confined indoors may be at the greatest risk for dangerous levels of exposure. Animals can easily inhale dust, ash, and other particulates when displaced by either their own movement or that of people walking through a contaminated area with animals located nearby. Fires are another important source of inhaled smoke, toxic gases, and other hazardous substances.

Dermal exposures can occur in many ways, including direct application of sprays, drops, ointments, or other substances by the owner. In addition, animals may roll or walk in puddles, spills, or other sources of contamination that they find in their environment, or they may be exposed during intentional uses or accidental releases of various chemicals if the pet is in the vicinity and located down‐wind (Murphy et al. 2008). As mentioned previously, dermal exposures can become oral exposures as a result of grooming. It is also important to realize that animals may directly transfer potentially harmful substances from their feet and haircoat to any people, other animals, surfaces, and other objects they come in contact with prior to being decontaminated.

Ocular exposures can occur with liquids, solids, and gases. Solid objects and particles that are blown or rubbed into the eyes can cause corneal abrasions and other mechanical trauma. Liquids can enter the eyes through splashes, immersions, or instillation (accidental or intentional) by the owner. Depending on the compound involved, direct chemical effects and even systemic signs may be possible. Irritant gases may come in direct contact with the cornea and surrounding ocular structures and result in a variety of clinical signs.

CLINICAL EFFECTS

Clinical signs caused by toxic compounds will vary depending on the substance(s) involved, the animal's age and health history, the amount the animal comes in contact with, the duration of exposure, and sometimes the route of exposure as well (Poppenga 2004). Table 7.1 shows a variety of local and systemic effects that can result from exposures to hydrocarbons. Common hydrocarbons that companion animals may come into contact with include lighter fluid, furniture polish, kerosene, gasoline, other automotive fluids, and chemical solvents such as mineral spirits. Small exposures of short durations result in mild local irritant effects; larger exposures of longer durations may potentially result in life‐threatening systemic signs.

Table 7.1. Range of clinical effects associated with hydrocarbon exposures

Affected system | Possible syndromes
Skin | Dermatitis, skin eruptions, burns, epidermal necrosis
Eyes | Conjunctivitis, corneal irritation, corneal necrosis
Gastrointestinal tract | Nausea, vomiting, diarrhea, abdominal pain
Respiratory tract | Vascular endothelial damage, petechiation and hemorrhage, atelectasis, dyspnea
Central nervous system | Disorientation, seizures, coma

Signs

Animals exposed to toxicants may show no signs, immediate problems, or delayed clinical effects depending on the type and amount of substance involved. Signs may also be either local (e.g., confined to the footpads if an animal walks through a toxic substance) or systemic if significant absorption occurs.

Mild local effects associated with oral exposures to toxicants may be limited to drooling, gagging, and foaming (especially in cats), rubbing and pawing at the mouth, vomiting, and diarrhea. More severe signs, such as deep ulcerations and sloughing of the tongue and mucous membranes, can occur with ingestions of alkaline substances such as drain cleaners and electric dishwasher detergents. It is important to note that the development of these signs may be delayed following a significant exposure. In severe cases, potential sequelae include scarring or perforations of the esophagus or other structures of the gastrointestinal tract. Severe vomiting and gagging can also put animals at risk of aspiration and subsequent respiratory problems.

Inhalation of particulates and gases can result in immediate coughing, respiratory distress, and damage to the lining of the respiratory tract. Signs such as dyspnea secondary to pulmonary edema can be delayed up to 24 hours.

When small quantities of toxic or irritating substances come in contact with the skin, the only signs may be redness, itching, or mild transient hair loss. More extensive or prolonged exposures may result in deep chemical burns, scarring, and permanent hair loss, and put the animal at risk for infection and thermoregulatory problems.

As shown using the example of hydrocarbons in Table 7.1, ocular exposures may result in signs ranging from mild conjunctivitis, corneal irritation, tearing, and blepharospasm to corneal necrosis, perforation, and permanent blindness.

MANAGEMENT OF EXPOSURES

The goal of decontamination is to minimize exposures to potentially toxic substances. This can be accomplished by preventing or minimizing absorption or enhancing elimination.

Precautions

Proper safety measures should be taken before admitting a patient that is suspected to have been exposed to a toxic substance. Not only are human personnel potentially at risk, but other animals on the premises could also be harmed. The minimum personal protective equipment for veterinary personnel performing animal decontamination includes gloves, an apron or other water‐resistant clothing, and eye protection (Murphy et al. 2008). Specific substances such as pepper spray and other riot control agents also require the use of respiratory protection and adequate ventilation, preferably in an area of the hospital that is isolated from other staff members and patients.

Oral Decontamination

Induction of vomiting (emesis)

Induction of vomiting (emesis) is used to remove potentially harmful substances from the stomach. Complete stomach emptying is generally not possible, although the total amount of toxicant available for absorption can be significantly reduced. Emesis in companion animals is typically most useful within 30 to 90 minutes of the ingestion (see Figure 7.1).

There are certain circumstances under which emesis should not be induced (DeClementi 2018). Following ingestions of caustic substances or hydrocarbons, an animal could aspirate these substances into its respiratory tract if vomiting occurs. Animals that are already demonstrating clinical signs, such as dyspnea, disorientation, or seizure activity, could also aspirate or develop more severe problems if they are then also made to vomit. Vomiting can also cause an acute worsening of preexisting conditions in patients with a known history of cardiovascular or seizure disorders.

Hydrogen peroxide (3% US Pharmacopeia) can be safely and effectively used to induce vomiting (Khan et al. 2012). Acting by local irritation of the stomach, 3% hydrogen peroxide dissociates into nonharmful oxygen and water after it has finished foaming. Table 7.2 outlines general dosing recommendations for dogs. Hydrogen peroxide is not recommended in cats due to the high risk of severe hemorrhagic gastritis (Obr et al. 2017). If no vomiting occurs after 5–10 minutes a second oral dose may be administered. Hydrogen peroxide often works most effectively if given after a small soft meal such as bread or canned pet food. Potential adverse effects of the use of hydrogen peroxide include protracted vomiting, hematemesis, and gastritis; these effects are generally the result of overdosing of hydrogen peroxide.

Figure 7.1. Animals should be watched during emesis induction. Emesis should be on a hard surface so it can be examined for presence of the toxic agentn.

Photograph courtesy of Katrina Nolan.

Table 7.2 Hydrogen peroxide dosing recommendations for the induction of vomiting in dogs

Source: DeClementi (2018) / with permission of ELSEVIER.

Body weight | Volume of 3% hydrogen peroxide
<2.3 kg (<5 lb) | 5 ml (1 teaspoon)
2.3–4.5 kg (5–10 lb) | 10 ml (2 teaspoons)
4.5–9.1 kg (10–20 lb) | 20 ml (1.3 tablespoons)
9.1–13.6 kg (20–30 lb) | 30 ml (2 tablespoons)
13.6–18.2 kg (30–40 lb) | 40 ml (2.7 tablespoons)
>18.2 kg (> 40 lb) | 45 ml (3 tablespoons)

Apomorphine is a centrally acting emetic that is commonly used in dogs. Mild sedation and prolonged vomiting may occur as a side effect. These adverse effects can be minimized by instead instilling apomorphine into the conjunctival sac and then flushing it out with sterile saline solution when vomiting begins. Apomorphine does not work in cats due to their vomiting center being regulated by alpha receptors.

Ropinirole (Clevor®) eye drops have been developed as a safe emetic agent that can be easily administered to dogs in an emergency. It works on the same vomiting receptors as apomorphine. In a clinical study 95% of ropinirole‐treated dogs vomited within 30 minutes (Suokko et al. 2019). Metoclopramide (0.5 mg/kg subcutaneously) can be administered in the event of excessive vomiting or vomiting that lasts longer than 1 hour. Ropinirole does not work in cats.

The cat vomiting center is regulated by alpha receptors. Although xylazine will often cause vomiting in cats, its effects can be inconsistent and it can result in excessive sedation. Success rates in cats may be higher with dexmedetomidine hydrochloride (Thawley and Drobatz 2015). The sedation caused by xylazine and dexmedetomidine can be reversed with atipamezole.

Extra precautions should be taken and no unnecessary personnel should be allowed in the treatment area if it is suspected that the animal has ingested something especially noxious, such as zinc phosphide rodenticide. In these situations the resulting vomitus could lead to dangerous human exposures to the noxious material (e.g., phosphine gas in the case of zinc phosphide). Induction of emesis outdoors or in a well‐ventilated area is highly recommended in these cases.

Other substances that are not generally recommended for the induction of emesis include liquid dishwashing detergent, powdered mustard, syrup of ipecac, and salt. Detergents and mustard are not particularly effective in companion animals and can cause significant gastrointestinal irritation. Syrup of ipecac does not consistently induce vomiting in animals and has been associated with adverse cardiovascular effects in people; there is also a significant delay of up to 40 minutes for emesis to occur. Salt is another substance that also often fails to induce emesis after oral administration and if not vomited up can put the animal at risk for potentially life‐threatening sodium toxicosis. There are times when emesis is contraindicated. Emesis with hydrocarbons has a high risk of aspiration. Emesis should also not be induced with corrosive and caustic ingestions as there is an increased risk of damage to the esophagus.

If vomiting cannot be successfully induced following the ingestion of significant quantities of potentially harmful substances, other decontamination options include diluents, adsorbents, and cathartics.

Diluents

Dilution with fluids such as water works by making ingested compounds less irritating. Other diluents, such as milk and liquid antacids, can have the added benefit of soothing and coating damaged mucous membrane surfaces. For all diluents, only limited amounts should be offered to reduce the risk of excessive distention of the stomach and subsequent vomiting and possible aspiration. Volumes as found in Table 7.3 based on body weight can be safely offered or administered to otherwise stable and asymptomatic animals.

Activated Charcoal

Activated charcoal is an adsorbent that binds most organic compounds, reducing their absorption and facilitating their elimination in the feces. Available in powder, gel, or liquid formulations, the recommended oral dose for all species is 1–2 g/kg of body weight. It can be offered to some animals in a dish or administered with a large syringe or stomach tube. Repeated doses may be useful for minimizing the severity and duration of clinical signs associated with ingestions of compounds that undergo enterohepatic recirculation, such as barbiturates, bromethalin, and ivermectin.

Table 7.3. Dilution volume for milk or water

tsp, teaspoon (5 ml); tbsp, tablespoon (15 ml).

Weight | Volume to use
Under 5 lb | 1 tsp
5–9.9 lb | 1.5 tsp
10–14.9 lb | 2 tsp
15–19.9 lb | 2.5 tsp
20–24.9 lb | 1 tbsp
25–29.9 lb | 1.5 tbsp
30–39.9 lb | 2 tbsp
40–49.9 lb | 3 tbsp
50–69.9 lb | ¼ cup
70 + lb | 1/3 cup

Activated charcoal will not bind small molecules (xylitol, ethanol) or heavy metals (iron, zinc, lead). Activated charcoal can cause vomiting and potential aspiration pneumonia. Activated charcoal can also cause fluid shifts, pulling free water into the gastrointestinal tract and leading to hypernatremia. Benefits and risks should always be weighed before administering activated charcoal.

Cathartics

Cathartics enhance elimination of substances, including activated charcoal, by moving them through the gastrointestinal tract more quickly. Bulk cathartics such as psyllium (Metamucil), canned pumpkin, and wholegrain breads rely on high fiber content to retain water in the lower gastrointestinal tract and produce bulkier stools. Bulk cathartics can also be useful in facilitating the passage of ingested foreign bodies such as coins, rocks, and glass. Osmotic cathartics pull free body water into the gastrointestinal tract and decrease total gastrointestinal transit time. The most frequently used osmotic cathartic is 70% sorbitol and it is often combined with activated charcoal products. Saline cathartics such as sodium sulfate (Glauber's salts) and magnesium sulfate (Epsom salts) work by stimulating gastrointestinal motility and require careful monitoring to avoid harmful electrolyte disturbances. Cathartics should also not be administered to animals with preexisting dehydration, electrolyte imbalances, or diarrhea (DeClementi 2018).

Other Gastrointestinal Decontamination Techniques

Enemas, such as warm soapy water or dioctyl sodium sulfosuccinate, can be useful in eliminating toxicants from the lower gastrointestinal tract. Body temperature solutions are best. Phosphate enemas should be avoided, particularly in cats.

Gastric lavage requires general anesthesia and the use of a cuffed endotracheal tube, but may be necessary in cases of potentially life‐threatening oral exposures. The use of anesthesia also provides an extra measure of safety for animals that may unexpectedly begin to have a seizure or develop other neurologic signs as a symptom of intoxication. After the lavage has been completed and before the endotracheal tube is removed, activated charcoal can be instilled directly into the stomach. Gastric lavage should not be used to remove caustic substances or hydrocarbons due to the risk of aspiration and esophageal damage.

General anesthesia is also required for endoscopy. This technique can be extremely useful for the removal of coins, batteries, toys, and other small items before they can pass out of the stomach. Availability will vary depending on practice location.

Decontamination for Inhalation Exposures

The initial treatment for exposure to inhaled toxicants is removing the patient to fresh air. In the veterinary clinic, symptomatic and supportive care may include administration of supplemental oxygen, intravenous fluid therapy, and pain management if local injury has occurred. Monitoring may consist of blood gas measurements, pulse oximetry, and serial thoracic radiographs. Antidotal treatments and additional diagnostics may be needed for some specific chemical exposures.

Dermal Decontamination

Most dermal exposures are treated by washing the affected area or bathing the entire animal. Liquid dishwashing detergent, used for hand‐washing of dishes and distinct from highly alkaline electric dishwasher detergents, is very safe and effective for removing a variety of contaminants, especially greasy or oily substances (DeClementi 2018). It is readily available and relatively nonirritating to skin and mucous membranes. If an animal licks a small amount during bathing, brief drooling or gagging may be expected. Repeated baths may be needed for heavily contaminated animals or if the initial washing needs to be curtailed because the patient begins to shiver or appears stressed. An animal such as a cat that may be particularly fearful of a direct spray of water may be more easily wetted down for washing and subsequent rinsing by gently immersing it up to its neck in a bucket or other suitable container of warm water while carefully supporting its body. After bathing all animals should be carefully monitored in a draft‐free environment to prevent hypothermia.

Vacuuming or combing is helpful for removing powders and other dry compounds from the haircoats of animals that will tolerate it. This is especially useful for products that would otherwise become sticky or clumped with the addition of water. Shaving or clipping is appropriate for dried paint, tar, and other similar substances.

Oily substances such as mineral oil, vegetable oils, and peanut butter can be used to remove items such as glue traps, asphalt, and tree sap. After applying these to the contaminated skin or hair it can then be gently massaged to work the contaminant into small gummy balls that can then either be combed out or washed away with liquid dishwashing detergent.

Ocular Decontamination

Eyes should be flushed with sterile saline solution or clean room‐temperature water. Careful irrigation of the nostrils can also facilitate the removal of substances that may have entered the nasolacrimal ducts. Sterile eye wash solutions are available in small handheld bottles. Bagged or bottled intravenous solutions can also be used to flush eyes after removing the needle from the end of the intravenous drip set. Prolonged or especially dangerous ocular exposures may require the eyes to be flushed for as long as 20–30 minutes, but in many cases it may not be necessary for small splashes involving only mildly irritating chemicals. When more extensive decontamination is needed some animals may tolerate repeated flushings of short durations paired with rest periods in between.

Fluorescein staining should be performed after flushing if the patient history or physical examination suggests a significant ocular exposure or injury. Staining should then be repeated 12–24 hours later even if initial staining fails to detect any corneal defects. Instillation of lubricant ointments can then follow the fluorescein staining.

PROGNOSIS

The likelihood of a full recovery for otherwise healthy animals that are promptly decontaminated before significant clinical signs develop is generally excellent. Even animals that display adverse effects may still have a good prognosis if they are closely monitored and receive appropriate symptomatic and supportive care.

CHAPTER 7 STUDY QUESTIONS

Barney, a 75‐lb, 7‐year‐old neutered, male golden retriever presents within an hour of his owner finding Barney gobbling down the contents of a 2‐lb bag of semisweet chocolate morsels. What is the first step in managing this case?

Assess the patient.

Induce vomiting.

Administer intravenous fluids.

Radiograph the abdomen.

Administer oral activated charcoal.

Barney has melted chocolate smeared on his muzzle, but other than a bad case of “chocolate‐breath,” he is bright, alert, and responsive. His heart rate is 120 beats per minute, he is panting, and his body temperature is 102.5 °F. It is determined that it is safe to induce vomiting to try to retrieve some chocolate. Which of the following is/are NOT recommended as an emetic?

3% hydrogen peroxide

Apomorphine administered intravenously or via conjunctival sac

Syrup of ipecac

Salt

c and d

Which contaminant is correctly matched with the best means of removing it from the hair/skin of a dog or cat?

Motor oil: plain water

Latex paint: mineral oil

Latex paint: paint thinner

Glue‐based mouse trap: vegetable oil

Dried tar: soapy water

Smurf, a 6‐lb, 1‐year‐old, male Persian cat is boarding at a veterinary clinic. Smurf was being treated with a topical ophthalmic solution for a preexisting eye condition. By mistake, a staff member accidentally instilled an ear mite medication containing ivermectin into Smurf's eye. The ear mite medication insert indicates that the product may cause mild irritation if ocular exposure occurs. Which of the following is the best course of action?

Flush Smurf's eye with sterile saline for 1–2 minutes and monitor for redness or irritation.

Flush Smurf's eye with soapy water for 1–2 minutes and monitor for redness or irritation.

Flush Smurf's eye with soapy water for 10–20 minutes and then stain with fluorescein.

Flush Smurf's eye with sterile saline for 10–20 minutes and then stain with fluorescein.

Flush Smurf's eye with mineral oil for 10–20 minutes and then stain with fluorescein.

Which of the following will activated charcoal NOT bind to?

Chocolate

Ivermectin

Lead

Ibuprofen

Bromethalin

ANSWERS

1. a. Assess the patient.

2. e. Neither salt nor syrup of ipecac is considered a safe or consistently effective emetic for dogs.

3. d. Vegetable oil (or other oily compounds) can help to remove the adhesive properties of glues. Oily compounds are not removed effectively by water‐based compounds (and vice versa) unless a detergent is included to break up the oil, so answers a and b are incorrect. Paint thinner and other mineral spirits should never be used on dog or cat skin because chemical burns can develop; this fact and the fact that latex paint is water‐based and therefore would not effectively be removed by paint thinner makes answer c incorrect. Dried tar (answer e) will not be removed by soapy water; small amounts may respond to oily compounds, but often tar dried in a hair coat may need to be clipped off.

4. a. Sterile saline is the agent of choice for ocular decontamination. Because the product information indicated that only mild irritation was expected, a short period of flushing and monitoring is acceptable.

5. c. Activated charcoal does not bind to heavy metals. Lead is a heavy metal.

REFERENCES

DeClementi, Camille. 2018. Prevention and Treatment of Poisoning. In Veterinary Toxicology: Basic and Clinical Principles, 3rd ed., edited by Ramesh C Gupta, pp. 1141–1159. London: Elsevier.

Gwaltney‐Brant, Sharon M, Murphy, Lisa A, Wismer, Tina A, and Albretsen, Jay C. 2003. General toxicologic hazards and risks for search‐and‐rescue dogs responding to urban disasters. Journal of the American Veterinary Medical Association 222(3):292–295.

Khan, Safdar A, McLean, Mary Kay, Slater, Margaret, Hansen, Steven, and Zawistowski, Stephen. 2012. Effectiveness and adverse effects of the use of apomorphine and 3% hydrogen peroxide solution to induce emesis in dogs. Journal of the American Veterinary Medical Association 241(9):1179–1184.

Murphy, Lisa A, Slessman, Dawn, and Mauck, Bob. 2008. Decontamination of large animals. In Technical Large Animal Emergency Rescue, edited by Rebecca Gimenez, Tomas Gimenez, and Kimberly Anne May, pp. 293–310. Ames, Iowa: Wiley‐Blackwell.

Obr, Teresa D, Fry, Joanna K, Lee, Justine A, and Hottinger, Heidi A. 2017. Necroulcerative hemorrhagic gastritis in a cat secondary to the administration of 3% hydrogen peroxide as an emetic agent. Journal of Veterinary Emergency and Critical Care 27(5):605–608.

Poppenga, Robert. 2004. Treatment. In Clinical Veterinary Toxicology, edited by Konnie H Plumlee, pp. 13–21. St. Louis: Mosby.

Suokko, Minna, Saloranta, Lasse, Lamminen, Terttu, Laine, Tarmo, and Elliott, Jonathan. 2019. Ropinirole eye drops induce vomiting effectively in dogs: a randomised, double‐blind, placebo‐controlled clinical study. Veterinary Record 186:283–283.

Thawley, Vincent J and Drobatz, Kenneth J. 2015. Assessment of dexmedetomidine and other agents for emesis induction in cats. Journal of the American Veterinary Medical Association 247(12):1415–1418.

8
Antidotes

Tina Wismer

INTRODUCTION

Antidotes are remedies to counteract poisons. They can prevent, reverse, or decrease the action of a toxicant. While many clients “just want the antidote,” there are some very real obstacles to this in many situations (Post and Keller 1999). First, the vast majority of toxicants have no specific antidote, so treatment is symptomatic and supportive. Second, even in situations where an antidote exists, there are often obstacles to its use (cost, availability, etc.). Many manufacturers do not produce antidotes because there is little profit to be made. Third, antidotes themselves can cause intoxication or adverse reactions. Unfortunately, there is no universal antidote and choices must be made depending on the specific situation. Almost all antidotes are off‐label use in veterinary patients.

There are three major classifications of antidotes: chemical, pharmacological, and functional (Chacko and Peter 2019). The chemical antidotes include chelators, commercial antibodies, and enzyme inhibitors. Chemical antidotes act directly on a toxicant to decrease toxicity or to increase excretion. Pharmacological antidotes antagonize or compete with the toxicant at its receptor site or through other macromolecules. They can bind to the toxicant itself or to the target to prevent the toxicant from binding. Functional antidotes treat the symptoms caused by the toxicant (symptomatic care). Antidotes can be in different classification groups depending on which toxic substance they are treating.

CHEMICAL ANTIDOTES

Chelators

Chelators, from the Greek word for claw, bind toxicants (usually metals) in a ring structure to increase their water solubility and excretion (Chacko and Peter 2019). Chelators decrease levels of free toxicant in the blood, decrease tissue concentrations, and increase elimination. A chelator should be chosen that is resistant to biotransformation, is able to reach sites of toxicant storage, forms nontoxic complexes with toxic substances, has a low affinity for essential metals, and is easily excreted from the body. Unfortunately, no chelators can fulfill all of these requirements.

Calcium Disodium EDTA (Versenate®)

Calcium disodium EDTA (CaEDTA, sodium calcium edentate, calcium disodium edathamil, calcium disodium edetate, calcium disodium ethylenediaminetetra‐acetate, calcium disodium versenate, disodium calcium tetracemate) is used to chelate many heavy metals. It is used mostly in the treatment of lead and zinc toxicoses, but it can also chelate cadmium, copper, cobalt, iron, nickel, chromium, manganese, plutonium, thorium, uranium, yttrium, and possibly vanadium (Chisolm 1992). The divalent or trivalent metal displaces the calcium in CaEDTA to form a water‐soluble complex that is excreted in the urine.

All metal should be removed from the gastrointestinal (GI) tract before administration because CaEDTa will increase absorption of metal from the GI tract. It is recommended that CaEDTA is given slowly intravenously, because IM injections are very painful. Calcium disodium EDTA therapy is not benign. It can cause nephrotoxicity (renal tubular necrosis) and GI irritation. Maintaining hydration will help decrease renal toxicity. Calcium disodium EDTA can also chelate essential metals (e.g., zinc, iron), resulting in deficiency; this is especially problematic when chelation is required for an extended period of time (Kosnett 2017a). Chronic use of CaEDTA may lead to zinc and iron deficiency and supplementation should be implemented.

Monitor animals closely when starting CaEDTA therapy for lead because initially blood lead levels will increase due to removal from body stores; this may worsen clinical signs or precipitate signs in asymptomatic animals with high body burdens of lead. Do not use sodium EDTA (edentate disodium); it chelates calcium and can cause severe hypocalcemia (Kosnett 2017a).

Deferoxamine (Desferal®)

Deferoxamine (DFO, desferoxamine mesylate) is a chelating agent approved for use in humans for the treatment of acute and chronic iron poisoning and aluminum overload in patients on chronic dialysis (Westlin 1971). It has also been used to treat doxorubicin, paraquat, aminoglycoside, and acetaminophen poisonings. Deferoxamine has been used off‐label to treat iron toxicosis in animals.

Deferoxamine chelates free iron, which is then excreted in the urine and bile. Early administration, within the first 24 hours, is most effective. The dose is given IM every 4–8 hours. If using the intravenous (IV) route, the animal should be monitored for development of pulmonary edema and hypotension (Ioannides and Panisello 2000). Pink to orange‐red urine (“vin rose”) indicates excretion of chelated iron (Cantrell 2017). Excretion of deferoxamine can be increased by giving ascorbic acid after the gut has been cleared of iron. Therapy may be stopped if asymptomatic and the urine is clear. Deferoxamine will artificially depress serum iron levels, so this diagnostic parameter is not valid during treatment (Cantrell 2017).

One advantage of using deferoxamine includes the lack of chelation of other trace metals (except aluminum). Adverse effects include pain at the injection site, vomiting, and diarrhea; chronic high doses can cause hypocalcemia and thrombocytopenia. Animals treated with deferoxamine are at risk to develop certain infections as deferoxamine supplies the iron siderophore growth factor needed by both Yersinia bacteria and Rhizopus fungus to grow (Melby et al. 1982). Humans have reported cataracts, retinal abnormalities, night blindness, and hearing loss after treatment (Levine et al. 1997). Although these effects have not yet been reported in dogs and cats, the potential for their development should be taken into consideration when choosing this compound for use in companion animals.

Dimercaprol

Dimercaprol (BAL, British anti‐Lewisite, dimercaptopropanol, dithioglycerol) provides sulfhydryl groups to chelate heavy metals. It was originally developed during World War II as an antidote to the blistering agent Lewisite (Kosnett 2017b). Dimercaprol can be used to chelate lead, arsenic, gold, inorganic mercury, antimony, bismuth, chromium, nickel, copper, zinc, and tungsten (Kosnett 2017b). In veterinary medicine, BAL is most commonly used to treat arsenic toxicosis and occasionally lead, mercury, and gold intoxications. It should not be used with iron, cadmium, and selenium poisoning because the chelated complex is more toxic than the metal alone.

Dimercaprol can remove lead from the brain and red blood cells, and may be the recommended chelator in small animal cases where severe central nervous system (CNS) signs are present. Binding to dimercaprol is not irreversible and metals can dissociate in an acidic environment. Alkalinizing the urine will increase excretion and decrease renal toxicity. BAL is nephrotoxic and is extremely painful on injection. Hypertension, hyperpyrexia, tachycardia, vomiting, and seizures can occur with higher dosages (Kosnett 2017b). Calcium disodium EDTA and BAL may be used together in severe lead poisoning cases.

Intravenous Lipid Emulsion (Intralipid®, Lipsosyn®)

Intravenous lipid emulsions are intravenous fat solutions used to provide parenteral nutrition. These emulsions can be used to treat systemic drug toxicoses. Highly fat‐soluble drugs will bind to the lipids and be removed from the bloodstream in a similar way to chylomicrons (Fernandez et al. 2011). IV lipid solutions have been used to treat local anesthetics, bupropion, barbiturate, calcium channel blocker, marijuana, propranolol, verapamil, tricyclic antidepressants, and avermectin toxicoses (Fernandez et al. 2011).

D‐penicillamine (Cuprimine®)

D‐penicillamine is a hydrolytic product of penicillin, but has no antimicrobial action. It is used to chelate a variety of heavy metals, such as copper, cadmium, mercury, iron, and lead (Eidelman and Lowry 2017). D‐penicillamine is used most commonly in veterinary medicine to treat copper‐storage hepatopathies (dogs), but can also be used in lead poisoning.

D‐penicillamine is less effective than other chelating agents (CaEDTA or dimercaprol) for the treatment of severe lead poisoning, but it has the benefit of being given orally. Penicillamine should be given on an empty stomach because food decreases the bioavailability. Vomiting is a common side effect that may be minimized by splitting doses or pretreating with dimenhydrinate (Eidelman and Lowry 2017). Penicillamine should not be given if metal is still present in the GI tract because it will increase absorption. Penicillamine will also chelate essential metals, including zinc, cobalt, and manganese. Pyrexia, depression, anorexia, diarrhea, proteinuria, lymphadenopathy, immune‐complex glomerulonephropathy, and blood dyscrasias are rare but can be seen.

Protamine Sulfate

Protamine sulfate combines with acidic glycosaminoglycans and is used in the treatment of heparin overdosage. Protamine and heparin bind to form an inactive stable salt (Raschke and Curry 2017). Protamine can also be used in the treatment of low molecular weight heparins (dalteparin, enoxaparin), but it does not completely inhibit their activity (Raschke and Curry 2017). Protamine begins to neutralize heparin within 5 minutes after IV administration (Raschke and Curry 2017). Protamine should be given over 1–3 minutes because too rapid administration of protamine can cause hypotension, bradycardia, and dyspnea (Raschke and Curry 2017).

Succimer (Sanofi‐Synthelabs, Chemet®)

Succimer (DMSA, 2,3‐dimercaptosuccinic acid) is an oral heavy metal chelator used primarily in the treatment of childhood lead poisoning (Kosnett 2017c). It has also been used to treat arsenic and mercury poisoning in humans (Kosnett 2017c). Succimer is used off‐label to treat lead poisoning in dogs, cats, other small mammals, and birds. It can be given orally or per rectum if the animal is vomiting. Dosing for caged birds is critical because overdoses have caused death in cockatiels (Denver et al. 2000).

The advantages of succimer include less nephrotoxicity than BAL, oral administration, and lower incidence of GI upset, and it is also less likely than the others to induce zinc, iron, calcium, or magnesium deficiency. Unlike other chelators, succimer will not increase the absorption of lead from the GI tract, so it can be used in situations where the GI tract may not be free of metal. Succimer can be used alone or following CaEDTA or BAL. Concurrent use with other chelating agents is not recommended. Succimer can cause a sulfurous odor to the breath, saliva, feces, or urine (Kosnett 2017c).

Trientine (Syprine®)

Trientine (TETA, triethylenetetramine) is an oral copper chelator. It is used in the treatment of copper‐associated hepatopathies in dogs (Talbot et al. 2023). Trientine is more expensive than penicillamine and may need to be compounded into smaller dosages, but it has fewer adverse effects (vomiting). It does need to be administered in a capsule since topical exposure to trientine causes dermatitis. Trientine also chelates zinc and iron and so supplementation may be needed during treatment.

Commercial Antibodies

Commercial antibodies include antitoxin‐specific serum and monoclonal antibodies. These products decrease the free form of the toxicant, decrease tissue concentration, and increase elimination. Commercial antibodies are dosed depending on plasma concentrations of the agent to be removed, not the patient's body weight. Commercial antibodies also do not penetrate tissue so they need to be given early in the syndrome while there is still circulating toxicant. New technology employing Fab fragments has decreased the antigenicity (allergic reactions) seen with commercial antibodies, but it also increases their excretion. Fab fragment products may require a larger volume due to this short half‐life (Sevcik et al. 2007).

Antivenin, Black Widow (Lyovac®)

Black widow antivenin neutralizes Latrodectus mactans (black widow spider) venom. Antivenin is used only to treat patients with severe signs because most cases will recover with just supportive care. Antivenin administration is recommended if severe hypertension is present or if pain is not controlled (Clark et al. 1992). Antivenin will reverse muscle cramping, pain, central nervous system effects, and hypertension (Clark et al. 1992). With most veterinary patients, usually one vial is sufficient. As with any antivenin of equine origin, anaphylactic reactions may occur.

Antivenin, Crotalidae Polyvalent (Equine) (Boehringer Ingelheim)

Antivenin, Crotalidae Polyvalent is approved for use in dogs. It is used to neutralize the venom of crotalids (pit vipers) native to North, Central, and South America. It can be used to treat envenomations from Crotalus (diamondback rattlesnake, Cascabel), Bothrops (fer‐de‐lance), Agkistrodon (copperhead, cottonmouth), and Lachesis (bushmaster) (Carotenuto et al. 2021). Early use (within 4 hours) is recommended but if clinical signs are present, antivenin therapy can still be helpful. The antivenin should be reconstituted in sodium chloride or 5% dextrose and given intravenously. As this product is of equine origin, monitor closely for anaphylactic reactions.

Antivenin, Crotalidae Polyvalent (Equine) (Rattler Antivenin®)

Antivenin, Crotalidae Polyvalent (Equine) (Rattler Antivenin) is a whole immunoglobulin G (IgG) molecule antivenin approved for use in cats, dogs, and horses. It is sold as a frozen bag of plasma. The immunizing venoms include eastern diamondback (Crotalus adamanteus), western diamondback, prairie (Crotalus viridis), and Mojave rattlesnakes. It is effective again Mojave Type A toxin (Carotenuto et al. 2021).

Antivenin, Crotalidae Polyvalent Immune Fab (Ovine) (Protherics, CroFab®)

Antivenin, Crotalidae Polyvalent Immune Fab (Ovine) is approved in humans for the management of North American crotalid snake envenomation (Sevcik et al. 2007); animal use is off‐label. The antivenin can be used to treat envenomation by 10 different North American crotalid species (see Table 8.1). Early use (within 6 hours of snakebite) is best, but if coagulation abnormalities exist, administration of antivenin can still be beneficial after this time period. Crotalid Fab has good efficacy in dogs, although some did require more than one vial (average dosing was 1.25 vials) (Peterson et al. 2011). However, there are fewer reactions to this product when compared to the IgG antivenin. The biggest drawback to using this antivenin is the cost.

Antivenin, Crotalidae Polyvalent Immune F(ab)2 (Venom Vet®)

Antivenin, Crotalidae Polyvalent Immune F(ab)2 is an equine origin product approved for animal use. It is a liquid ready‐to‐use product. It treats hemotoxic, neurotoxic, and myotoxic effects of envenomations. It is effective against Mojave Type A toxin. As a F(ab)2 product it has two antigen binding sites per molecule and a longer half‐life (2–4 days) (Carotenuto et al. 2021). Since there is no Fc fragment there should be a reduction in hypersensitivity reactions when compared to whole IgG products.

Table 8.1. Cross‐reactivity of Crotalidae polyvalent immune Fab

Scientific name | Common name
Agkistrodon picivorus | Cottonmouth, water moccasin
Agkistrodon contortrix contortrix | Copperhead
Crotalus adamanteus | Eastern diamondback rattlesnake
Crotalus atrox | Western diamondback rattlesnake
Crotalus horridus atricaudatus | Canebrake rattlesnake
Crotalus horridus horridus | Timber rattlesnake
Crotalus molossus molossus | Northern blacktail rattlesnake
Crotalus scutulatus | Mojave rattlesnake
Crotalus viridis helleri | Southern Pacific rattlesnake
Sistrurus malarius barbouri | Pygmy rattlesnake

Antivenin, North American Coral Snake

North American coral snake antivenin neutralizes the venom of Eastern (Micurus fulvius fulvius) and Texas (Micrurus tener) coral snakes, fer‐de‐lance, and Central and South American rattlesnakes. This antivenin is NOT effective for Arizona or Sonoran coral snakes (Micruroides euryxanthus) envenomations. There are many factors involved in the potential seriousness of a coral snake bite (size of victim, bite site, number of bites, species of snake, etc.). Bites in which the snake “hangs on” and “chews” result in a higher venom exposure (Kitchens and Van Mierop 1987). Early administration of antivenin is recommended because once clinical signs appear it is not always possible to stop the progression. This antivenin is difficult to source for veterinary patients.

Digoxin Specific Antibody Fragments (Digibind®)

Digoxin‐immune Fab will bind directly to digoxin or digitoxin and inactivate it. Antidigitoxin Fab fragments can also be effective against bufotoxins from toads, lucibufagins from fireflies, and against cardiac glycosides from plants (see Table 8.2) (Megarbane 2017). Patients who fail to respond to supportive care should be given antidigitoxin Fab fragments, which are expensive but can be lifesaving (Ward et al. 1999). They can reverse severe ventricular arrhythmias (ventricular tachycardia, ventricular fibrillation), progressive bradyarrhythmias (severe sinus bradycardia), and second‐ or third‐degree heart block not responsive to atropine (Megarbane 2017). Monitor potassium closely because reactivation of ATPase may lead to hypokalemia (Megarbane 2017).

Table 8.2. Cross‐reactivity of antidigoxin Fab fragment with plant cardiac glycosides

Scientific name | Common name
Acokanthera oblongifolia |
Adenium sp. | Desert rose
Adonis microcarpa | Pheasant's eye
Asclepias sp. | Milkweed
Byrophyllum tubiflorum | Mother of millions
Calotropis procera | King's crown
Carissa laxiflora |
Cerbera manghas | Sea mango
Convallaria majalis | Lily of the valley
Crytostegia grandioflora | Rubber vine
Digitalis sp. | Foxglove
Helleboros sp. |
Nerium oleander | Oleander
Ornithogalum sp. | Star of Bethlehem
Scilla hyacinthoides | Scilla hyacinth
Strophanthus sp. | Corkscrew flower
Thevetia neriifolia, T. peruviana | Yellow oleander
Urginea maritima | Squill

Enzyme Inhibitors

Enzyme inhibitors inhibit the formation of toxic metabolites by either competitive inhibition or irreversible inhibition. They are used to treat substances that become toxic through in vivo metabolism by decreasing the amount of toxic metabolite. They may increase the time needed for elimination of the parent drug and need to be dosed before excessive toxic metabolites are produced (Dalefield 2004).

Ethanol

Ethanol (EtOH, ethyl alcohol, grain alcohol) may be used to treat ethylene glycol (EG; antifreeze) toxicosis. Ethanol is a competitive inhibitor of alcohol dehydrogenase. By competing for this enzyme, ethanol delays the breakdown of EG to its more toxic metabolites (Dalefield 2004; Mathews 2017). Ethylene glycol is then excreted in the urine unchanged. Ethanol sources include medical or laboratory grade alcohol or clear commercially available liquors (Everclear®, vodka).

Ethanol is well absorbed orally but is administered intravenously for management of EG toxicosis. Ethanol can be dosed in boluses or as a constant‐rate infusion (see Chapter 29 for more dosing information). Ethanol must be given very early after ingestion of EG for it to be effective. In dogs it should be given within the first 6–8 hours, in cats, before 3 hours (Connally et al. 2010). Ethanol is inexpensive and readily available, but it can worsen metabolic acidosis and CNS depression.

Fomepizole

Fomepizole (4‐MP, 4‐methylpyrazole) is used in the treatment of EG toxicity in dogs. It is a competitive inhibitor of alcohol dehydrogenase. By inhibiting this enzyme, EG is excreted unchanged in the urine, without being biotransformed into the more toxic metabolites responsible for metabolic acidosis and renal tubular necrosis. The benefits of using fomepizole rather than ethanol are that it does not induce CNS depression, hyperosmolality, or diuresis (Connally et al. 2010). While immediate treatment holds the best prognosis, dogs may be treated as late as 8 hours post ingestion and can still have a favorable prognosis. Fomepizole slows down the metabolism of EG and so serum EG levels may still be detectable at 72 hours after ingestion. Continue treatment if the EG test is still positive. Fomepizole is more expensive than ethanol. It is not labeled for use in cats but can be used off‐label at high doses (Connally et al. 2010). Cats will become ataxic and depressed at these high doses. With EG poisoned cats, therapy must be started within 3 hours or the prognosis is grave.

PHARMACOLOGICAL ANTIDOTES

Atipamezole (Antisedan®)

Atipamezole is an alpha‐2‐adrenergic antagonist approved for use in dogs as the reversal agent for dexmedetomidine (Dexdomitor®). It can also be used off‐label to treat several toxicoses. Atipamezole will reverse other alpha‐2‐adrenergic agonists (amitraz, xylazine, imidazoline decongestants, bromonidine, clonidine, and tizanidine) (Gwaltney‐Brant 2004). Atipamezole quickly reverses the sedation, hypotension, and bradycardia seen in these toxicoses. It can be given intramuscularly or intravenously. Atipamezole reversal lasts about 2–3 hours and may need to be repeated.

Atropine

Atropine (tropine tropate, dl‐tropyl tropate, dl‐hyoscyamine) may be used to treat the muscarinic signs caused by anticholinesterase pesticides (organophosphates, carbamates) (see Table 8.3), physostigmine excess, antimyasthenic agents, nerve gas agents (sarin, soman, tabun, venomous agent X), synthetic choline esters, cholinergic agonists, and clitocybe and inocybe mushrooms (French and Walter 2017). Atropine blocks the effects of accumulated acetylcholine at the synapse. Atropine is also used as an adjunct in treating bradyarrhythmias. Muscarinic signs include salivation, lacrimation, urination, defecation, dyspnea, and emesis (SLUDDE). Atropine sulfate does not control nicotinic signs (muscle tremors, muscle weakness).

Table 8.3. Selected common organophosphates and carbamates

Aldicarb | Carbaryl | Chlorpyrifos | Diazinon | Disulfoton
Fenthion | Malathion | Methiocarb | Methomyl | Parathion
Propoxur | Terbufos | Tetrachlorvinphos |  |

Atropine should be used to treat bradycardia and dry up excess bronchial secretions; patients not experiencing either of these signs do not require atropine. Atropine may be given intravenously, intramuscularly, subcutaneously, endotracheally, or intraosseous (Prete et al. 1987). Atropinization may need to be maintained for hours to days, depending on the toxicant. Overdoses of atropine can cause CNS stimulation, seizures, sinus tachycardia, hypertension, and ileus (French and Walter 2017).

Atropine can also be used as a diagnostic test for poisoning by cholinesterase inhibitors (e.g., organophosphorus or carbamate insecticides). The heart rate is measured before and after a preanesthetic dose of atropine is given. If the heart rate increases, it is not a cholinesterase inhibitor toxicosis because it takes about 10 times this amount to raise the heart rate in poisoned patients (Wismer and Means 2018).

Calcium Salts

Calcium salts (calcium chloride, calcium gluconate, calcium borogluconate, calcium lactate, calcium phosphate) can be used in veterinary toxicology for treating various toxicoses. Calcium salts can be used in treating fluoride, hydrofluoric acid, ethylene glycol, calcium channel blocker (verapamil, diltiazem, etc.), beta‐blocker, and nondepolarizing neuromuscular blocking agent poisonings (see Table 8.4) (el Saadi et al. 1989; Roder 2004). They can also be used to reverse hypocalcemia, hyperkalemia, hypermagnesemia, oxalic acid, and oxalate poisoning.

Table 8.4. Nondepolarizing neuromuscular blocking agents

Atracurium

Curare

Gallamine

Metocurine

Pancuronium bromide

Tubocurarine

Vecuronium

Folinic Acid (Leucovorin®)

Folinic acid (calcium folinate, citrovorum factor) is the reduced active form of folic acid. It is used to treat methotrexate, trimethoprim, pyrimethamine, and Gyromitra esculenta mushroom ingestions (Lambie and Johnson 1985; Leathem and Dorran 2007). These toxins stop conversion of folic acid to folinic acid (active form) by blocking the enzymes needed for this reaction. By administering the active form, these enzyme blockades are bypassed. Folinic acid should be given as soon as possible for the best results.

Flumazenil (Romazicon®)

Flumazenil (flumazepil) is a competitive blocker of benzodiazepines and reverses sedation within 1–2 minutes (DeClementi 2018). The dose may need to be repeated because the half‐life for flumazenil is about 1 hour. Flumazenil is usually limited to animals at risk of severe toxicosis. Flumazenil is contraindicated in animals with tricyclic antidepressant overdoses because it can cause seizures.

Glucagon

Glucagon is a hormone with glycemic and inotropic actions. It is used in beta‐adrenergic blockers, calcium channel blockers, and tricyclic antidepressant overdoses that produce severe bradycardia, atrioventricular block, or hypotension (Love and Howell 1997). Glucagon can also be used to treat hypoglycemia from insulin and oral hypoglycemic agents (sulfonylureas, etc.) because it stimulates hepatic glycogenolysis. Glucagon is administered as an IV bolus, followed by a constant rate infusion (CRI). Patients should be monitored for hyperglycemia with secondary hypokalemia.

Hydroxocobalamin (Cyanokit®)

Hydroxocobalamin (vitamin B12a, α‐cobione) is a vitamin B12 precursor. It is used to treat cyanide toxicosis. Hydroxocobalamin combines with cyanide to form cyanocobalamin (vitamin B12) (Bebarta 2017). Cyanocobalamin is eliminated through the urine. Cyanide poisoning can be seen secondary to nitroprusside, acetonitrile, cyanogenic glycoside plant (see Table 8.5) ingestion, and hydrogen sulfide inhalation. Hydroxocobalamin does not produce either methemoglobinemia or hypotension, as sodium nitrite does. Administration of hydroxocobalamin can interfere with aspartate transferase, total bilirubin, creatinine, magnesium, and iron measurements (Bebarta 2017).

Hyperbaric Oxygen

Hyperbaric oxygen therapy can be used in the treatment of carbon monoxide, methylene chloride, carbon tetrachloride, cyanide, and hydrogen sulfide toxicosis to increase oxygenation (Tomaszewski and Thom 1994). By delivering 100% oxygen at pressures greater than 1 atm, it displaces carbon monoxide (CO) and increases the elimination of other toxicants. Hyperbaric chambers may be available at larger veterinary referral centers.

Methylene Blue

Methylene blue (tetramethylthionine chloride trihydrate) is an oxidation–reduction agent that helps convert methemoglobin (Fe³⁺) to hemoglobin (Fe²⁺) (Rumbeiha et al. 1995). Methylene blue is used in small animal medicine to treat methemoglobinemia from aniline dyes, nitrites, nitrates, naphthalene, phenols, and local anesthetics (benzocaine, etc.) (Rumbeiha et al. 1995). It is given as a slow IV infusion. Methylene blue should not be given unless methemoglobinemia is evident, especially in cats, because methylene blue can induce methemoglobinemia in normal animals. It can also cause Heinz body anemia in cats (Schechter et al. 1973). The new methylene blue found in laboratory dyes can NOT be substituted for methylene blue because new methylene blue can be toxic if injected.

N‐acetylcysteine (Mucomyst®, Acetadote®)

N‐acetylcysteine (NAC, mercapturic acid) is a mucolytic that can also reduce the extent of liver injury and methemoglobinemia after ingestion of acetaminophen. NAC is a precursor of glutathione, provides organic sulfate needed for the sulfation pathway, and directly binds with acetaminophen metabolites to enhance elimination (Steenbergen 2003). NAC has been used in high doses to treat Amanita phalloides (death cap mushroom)‐poisoned people. It was effective in preventing permanent hepatic injury in 10 of 11 people (Montanini et al. 1999). NAC can also be used to treat white/yellow phosphorus, cyclophosphamide, and carbon tetrachloride toxicoses. NAC may be given orally (use a taste masking agent) or slowly intravenously. Oral administration can cause vomiting. When treating acetaminophen toxicosis, especially in cats, it is recommended that acetylcysteine be dosed before the activated charcoal.

Table 8.5. Cyanide‐containing plants

Scientific name | Common name
Acacia | Acacia
Alocasia | Elephant's ear
Amelanchier | Serviceberry, shadebush, Juneberry
Canavalia | Wonder bean
Cercocarpus | Mountain mahogany
Chenopodium | Goosefoot, wormseed
Contoneaster | Contoneaster
Cynodon | Stargrass, Bermudagrass
Drosera | Sundew
Eucalyptus | Eucalyptus
Glyceria | Mannagrass
Heteromeles | Christmas berry, California holly
Hydrangea | Hydrangea
Juncus | Rushes
Lotus | Bird's‐foot trefoil, Nevada deer vetch
Manihot | Cassava
Nandina | Bamboo
Panicum | Switchgrass, kleingrass, millet
Phalaris | Canarygrass
Prunus | Apricot, cherry, plum, chokecherry, peach, almond, mock orange
Pyracantha | Firethorn
Ranunculus | Buttercup
Rhodotypos | Jetbead
Sambucus | Elderberry
Sorghum | Sorghum, sudangrass
Sorghastrum | Indiangrass
Spirea | Spirea, bridal wreath
Suckleya | Suckleya
Stillingia | Stillingia
Trifolium | Clovers
Triglochin | Arrowgrass

Naloxone (Narcan®)

Naloxone (N‐allylnoroxymorphone hydrochloride) is an opioid antagonist that competes with and displaces narcotics from their receptor sites (mu, kappa, and sigma) (Lucyk and Nelson 2017). Naloxone is most commonly used to reverse opiates (buprenorphine, butorphanol, codeine, fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxycodone, oxymorphone, tramadol, etc.). It can also be used to reverse CNS depression associated with dextromethorphan, benzodiazepines, angiotensin‐converting enzyme inhibitors, alpha‐2 agonists, imidazoline decongestant overdoses, and ethanol (Jefferys and Volans 1983). Naloxone may be administered intravenously, intramuscularly, subcutaneously, intranasally, intraosseous, and even sublingually. Naloxone acts within minutes and has a duration of action of 45–90 minutes (Lucyk and Nelson 2017). When treating long‐acting substances, naloxone may need to be repeated.

Pralidoxime (Protopam®)

Pralidoxime (2‐PAM, 2‐pyridine aldoxime methylchloride, 2‐formyl‐1‐methylpyridinium chloride oxime) is an oxime used to control the nicotinic signs (muscle and diaphragmatic weakness, fasciculations, muscle cramps, etc.) seen in organophosphate toxicoses (Wismer and Means 2018). 2‐PAM is a cholinesterase reactivator that displaces the acetylcholinesterase enzyme from its receptor site. It binds with the insecticide and is excreted in the urine. 2‐PAM works best if administered as soon as possible; however, this can vary with some compounds (Vale 2017). Once the organophosphate receptor bond “ages,” oximes are no longer effective. Since “aging” varies with the compound, oximes may be effective even hours to days after exposure (Vale 2017). Oximes are generally not recommended for use in carbamate poisoning because of the lack of “aging” in these compounds (Vale 2017).

Pyridostigmine (Mestinon®)

Pyridostigmine is an anticholinesterase. Pyridostigmine competes with acetylcholine for binding to acetylcholinesterase, so acetylcholine accumulates in the synapse. It is used to treat nondepolarizing neuromuscular blocking agents (see Table 8.4) and botulism. It may also be used in the treatment of atropine, avermectin, coral (Micrurus) and cobra (Naja) snake bites, tetrodotoxins (porcupine fish [Diodon]), and anticholinergic alkaloid plants poisonings (see Table 8.6) (Martinez 2011). Other drugs in this group (neostigmine, edrophonium, physostigmine, etc.) can also be used to treat these toxicoses, but they have a much shorter duration of action.

Table 8.6. Anticholinergic alkaloid plants

Scientific name | Common name
Atropa | Belladonna
Cestrum | Jasmine
Datura | Jimsonweed
Hyoscyamus | Henbane
Lycium | Boxthorn
Lycopersicon | Tomato
Mandragora | Mandrake
Physalis | Ground cherry
Solanum | Nightshade, bittersweet Various mushrooms

Pyridoxine

Pyridoxine (vitamin B6) is used in the management of coma and seizures associated with overdoses of isoniazid, seizures due to Gyromitra mushroom (false morel) poisoning, penicillamine‐induced seizures, and as an adjunct therapy for EG toxicosis (Kennedy and Schaeffer 2017).

Silymarin

Silymarin (milk thistle) is a nutraceutical that can be used as a hepatoprotectant agent. It has been shown to be effective as an adjunct in the treatment of cyclopeptide mushroom (Amanita) and acetaminophen toxicoses (Jahn et al. 1980). Silymarin should be started within the first 48 hours and continued for several weeks. Oral silymarin can cause vomiting but is otherwise well tolerated. Because silymarin is considered a nutritional supplement by the United States Food and Drug Administration (FDA), quality and content can vary between different formulations. Choose a product that states the concentration (usually 70%–80%) of silymarin contained in the product. Injectable silymarin is not available in the USA and unfortunately the oral form has poor bioavailability.

Yohimbine

Yohimbine is an alpha‐2‐adrenergic antagonist approved as a reversal agent for xylazine in dogs, but it can also be used to treat other alpha‐2‐adrenergic agonist toxicoses (amitraz, clonidine, etc.). The onset of action is within minutes, and yohimbine has a short half‐life (1.5 to 2 hours) so repeated dosing may be required (Jernigan et al. 1988). Dogs receiving five times the recommended dose developed muscle tremors and seizures.

FUNCTIONAL ANTIDOTES

Acepromazine

Acepromazine (ace, acetylpromazine) is a neuroleptic phenothiazine. It is approved for use in dogs and cats. Acepromazine is used to decrease the CNS stimulation associated with amphetamine, methamphetamine, serotonergic drugs, 4‐methylimidazole, and metaldehyde toxicosis (Stern and Schell 2018). Intravenous injection will have the quickest onset, but acepromazine can be given intramuscularly, subcutaneously, or orally. Acepromazine can cause hypotension at high doses, and blood pressure should be monitored after administration.

Bicarbonate, Sodium

Sodium bicarbonate (sodium hydrogen carbonate, mono‐sodium carbonate, sodium acid carbonate, baking soda) has many uses in veterinary toxicology. It is a systemic alkalinizer, which can be used to correct metabolic acidosis, QRS prolongation, and rhabdomyolysis and to alkalinize urine in poisonings (Kolecki and Curry 1997). Administration of sodium bicarbonate to a serum pH of 7.45–7.55 will help decrease the cardiac toxicity of tricyclic antidepressants (amitriptyline, doxepin, imipramine, nortriptyline, etc.) and type 1 antidysrhythmics (quinidine) (Kolecki and Curry 1997).

Urinary alkalinization with sodium bicarbonate traps weak acids and enhances the elimination of salicylates, phenobarbital, chlorpropamide, and chlorophenoxy herbicides (Wax and Haynes 2019). Oral sodium bicarbonate may decrease the absorption of anticholinergics, histamine 2 blockers (cimetidine, ranitidine, etc.), iron, ketoconazole, and tetracyclines, but increase the amount of naproxen absorbed and reduce the efficacy of sucralfate. Urinary alkalinization will decrease excretion of some drugs (e.g., quinidine, amphetamines, ephedrine).

Chlorpromazine (Thorazine®)

Chlorpromazine is a phenothiazine used in the treatment of monoamine oxidase inhibitor, amphetamine, and metaldehyde toxicoses (Grantham et al. 1964). It is used to decrease the stimulatory signs. Chlorpromazine is less potent than acepromazine but has a longer duration of action. Chlorpromazine can be given orally, intravenously or intramuscularly. Do not use chlorpromazine with physostigmine or paraquat toxicoses because it may increase the toxicity.

Cyproheptadine (Periactin®)

Cyproheptadine has been used traditionally in veterinary medicine for its antihistaminic and appetite‐stimulant effects (cats) but is now being used to help treat serotonin syndrome (DeClementi 2018). Serotonin syndrome is caused by excess serotonin within the CNS and can be characterized by tremors, seizures, hyperthermia, ataxia, vomiting, diarrhea, abdominal pain, excitation or depression, and hyperesthesia. Serotonin syndrome is seen secondary to the ingestion of drugs that increase brain serotonin levels (selective serotonin reuptake inhibitors, amphetamines, tricyclic antidepressants, 5‐hydroxytryptophan, etc.) (DeClementi 2018). The dose may be given orally or per rectum (if vomiting or activated charcoal already given). Discontinue if no effect after the second dose (Gwaltney‐Brant et al. 2000).

Dantrolene

Dantrolene is used in veterinary toxicology to treat the malignant hyperthermia‐like syndrome seen in dogs after ingestion of hops (Humulus lupulus) (Duncan et al. 1997). It is a direct‐acting muscle relaxant that reverses muscle rigidity and associated hyperthermia. Dantrolene can be given orally or intravenously. Hepatotoxicity has been seen in humans with high dose chronic therapy. It is unknown if this occurs in animals.

Dextrose

Dextrose is used in the treatment of hypoglycemia, which may result directly from toxicants (α‐lipoic acid, biguanides, insulin, sulfonylureas, xylitol) or indirectly (clonidine, ethanol, salicylates, amanita mushrooms, organophosphates, ackee [Blighia], sneezeweed [Helenium], desert marigold [Baileya], paperflowers [Psilostrophe], sartwellia [Sart‐wellia], periwinkle [Catharanthus], balsam apple and pear [Momordica], castor bean [Ricinus], bitterweed, and rubberweed [Asteraceae]) (Browning et al. 1990). Multiple bolus doses or a CRI may be required.

Hyperbaric oxygen

Hyperbaric oxygen, if available, can be used to reduce circulating levels of carboxyhemoglobin seen secondary to CO intoxication. Hyperbaric oxygen can reduce the half‐life of CO in the bloodstream from 3 to 5 hours in room air to 20–30 minutes (Montalbano et al. 2021).

Methocarbamol (Robaxin®)

Methocarbamol (guaiphenesin carbamate) is approved in animals as a centrally acting skeletal muscle relaxant. It is used in toxicology to treat tremors associated with permethrin, bifenthrin, metaldehyde, strychnine, tetanus (Clostridium), white snakeroot (Ageratina), ergot alkaloids (Claviceps), Penicillium, and other tremorgenic mycotoxins (DeClementi 2018; Richardson 2000; Richardson et al. 2003; Schell 2000). Methocarbamol depresses pathways in the spinal cord without interfering with muscle function. It may be given intravenously, orally, or rectally (crush tablets in saline).

Nitroprusside

Nitroprusside is used for treatment of severe hypertension secondary to poisonings (phenylpropanolamine, etc.). It causes both peripheral arterial and venous vasodilation. Nitroprusside has an immediate onset and short duration of action, which allows accurate titration of blood pressure (Curry and Spyres 2017). Blood pressure should be monitored closely because it will return to pretreatment levels within 1–10 minutes once the CRI is stopped. Prolonged use may lead to potential cyanide toxicosis, especially in patients with hepatic or renal insufficiency. Metabolic acidosis and delirium are early signs of cyanogen toxicosis (Curry and Spyres 2017).

Norepinephrine (Levophed®)

Norepinephrine (noradrenalin) is an alpha‐adrenergic agonist used to reverse hypotension by increasing systolic and diastolic blood pressure through vasoconstriction. It is used to treat alpha‐adrenergic blockers (see Table 8.7) and other toxicants that cause acute hypotension (amanita mushrooms [Amantia], beta‐blockers, calcium channel blockers, ergot alkaloids, lily of the valley [Convallaria], periwinkle [Vinca], phenothiazines, quinine sulfate, tetrodotoxins, tricyclic antidepressants, yew [Taxus]) (Smith and Maani 2023). Norepinephrine must be given intravenously because extravasation causes severe necrosis.

Table 8.7. Alpha‐adrenergic blockers

Generic name | Trade name
Atipamezole | Antisedan®
Doxazosin | Cardura®
Phenoxybenzamine | Dibenzyline®
Phentolamine |
Prazosin | Minipress®
Tamsulosin | Flomax®
Terazosin | Hytrin®
Tolazoline | Tolazine®
Yohimbine | Yobine®

Octreotide

Octreotide is a synthetic somatostatin analogue. It is used in humans to treat acromegaly, neuroendocrine tumors, secretory diarrhea secondary to irritable bowel disease, and for suppressing insulin secretion. In pets it has been used in the treatment of hepatotoxic mushroom toxicosis (Goupil et al. 2021). Octreotide aids in decreasing liver necrosis by sequestering the amatoxins in the gall bladder by several mechanisms. It blocks the OATP1P3 protein needed for entry of amatoxins into hepatocytes, increases the tonicity of the sphincter of Oddi (valve surrounding the exit of the bile duct), and suppresses gallbladder emptying.

Pamidronate (Aredia®)

Pamidronate (ADP sodium) is a synthetic bisphosphonate that binds to the hydroxyapatite found in bone. It inhibits osteoclastic bone resorption and is used in veterinary toxicology to treat hypercalcemia secondary to vitamin D and its analogs (cholecalciferol, calcipotriene, calcitriol) (Pesillo et al. 2002). Pamidronate is administered as a slow IV infusion over 2–4 hours. It has long‐lasting effects and may need to be repeated once in 5–7 days. Pamidronate can cause hypomagnesemia, renal toxicity, and arrhythmias.

SAMe (Denosyl®, Zentonil®)

SAMe (S‐adenosyl‐methionine, ademetionine) is a nutraceutical used as a treatment for acetaminophen toxicity in small animals (Wallace et al. 2002). It has also been used for liver support in chronic hepatitis, hepatic lipidosis, cholangiohepatitis, feline triad disease, and osteoarthritis. SAMe is formed from the amino acid methionine and adenosine triphosphate (ATP). It plays an essential role in major biochemical pathways (transmethylation, transsulfuration, and aminopropylation). Through these pathways SAMe provides compounds (sulfur, glutathione) important in liver support.

SAMe should be given on an empty stomach because food will greatly reduce the amount of drug absorbed. SAMe is well tolerated and adverse effects are rare. Because SAMe is considered a nutritional supplement by the FDA, there are no standards for potency, purity, safety, or efficacy. Due to this lack of oversight, a well‐known brand name should be used.

Vitamin K1

Vitamin K1 (phytonadione, phylloquinone, phytomenadione) is used to treat anticoagulant rodenticides, coumarin, and sulfaquinoxaline toxicoses (Wang 2017). Vitamin K1 is needed for the regeneration of blood clotting factors II, VII, IX, and X. After administration it takes about 6–12 hours for new clotting factors to be synthesized. Vitamin K1 can be given orally, intramuscularly, or subcutaneously. IV use is not recommended due to a high incidence of anaphylactoid reactions. Giving vitamin K1 with a fatty meal will increase bioavailability. Because vitamin K1 does not accumulate in the liver and it may take several weeks to eliminate some of the anticoagulant rodenticides from the body, the drug must be dosed daily.

Zoledronic Acid (Zoledronate)

Zoledronic acid (zoledronate) is an injectable bisphosphonate used in human medicine to treat osteoporosis, hypercalcemia of malignancy, and other bone diseases. It is used off‐label in veterinary medicine for its ability to inhibit osteoclastic bone resorption. Zoledronic acid has been used to treat hypercalcemia secondary to vitamin D and its analogs. It is considered to be 50 times more potent than pamidronate. Dosage for both dogs and cats is given intravenously. Caution in using zoledronic acid with renal failure (Brewer et al. 2022).

CHAPTER 8 STUDY QUESTIONS

Functional antidotes differ from chemical or pharmacological antidotes in that

They increase the excretion of toxicant from the body.

They decrease the absorption of the toxicant from the gastrointestinal tract.

They treat the clinical signs caused by the toxicant.

They increase the metabolism of the toxicant.

They decrease the metabolism of the toxicant.

Which of the following best describes the mechanism of action of chelators?

They bind to target‐organ receptors to prevent the toxicant from binding.

They bind to a toxicant to increase the toxicant's water solubility and enhance excretion.

They enhance excretion of a toxicant by increasing toxicant metabolism.

They bind to a toxicant to decrease absorption of the toxicant from the gastrointestinal tract.

They bind to a toxicant and cause the toxicant to be sequestered with a specific organ (e.g., spleen).

When using chelators to treat heavy metal toxicoses, it is necessary that the gastrointestinal tract be free of any metal or the chelator will actually increase the further absorption of metal from the gastrointestinal tract into the bloodstream. This statement is true for all chelators and metals with which exception?

Use of calcium disodium EDTA to treat lead poisoning

Use of deferoxamine to treat iron poisoning

Use of dimercaprol to treat lead poisoning

Use of d‐penicillamine to treat lead poisoning

Use of succimer to treat lead poisoning

Antibodies have been developed to treat intoxication from all of the following except

Rattlesnake venom

Digitalis

Coral snake venom

Fire ant venom

Black widow spider venom

When treating ethylene glycol toxicosis, fomepizole has all of the following advantages over ethanol except that

Fomepizole does not cause significant CNS depression.

Fomepizole does not cause hyperosmolality and diuresis.

Fomepizole is less expensive than ethanol.

Fomepizole administration and monitoring are less labor‐intensive than ethanol.

Fomepizole is FDA‐approved for use in dogs.

ANSWERS

1. c. Functional antidotes help manage clinical signs caused by the toxicant but have no impact on the level of toxicant in the body.

2. b. Chelators bind toxicants to increase water solubility and enhance excretion.

3. e. Succimer does not enhance the absorption of lead from the gastrointestinal tract.

4. d. No antivenom exists to treat envenomation from fire ants.

5. c. Fomepizole is more expensive than ethanol to obtain; however, because ethanol requires more monitoring and constant administration of intravenous fluids, the cost of nursing care for ethanol may make the difference in cost much less significant.

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9
Most Deadly Toxins; Investigating Fatal Suspected Poisonings

Devon Davis and Safdar A. Khan

INTRODUCTION

While exposure to most toxicants yields a good outcome with treatment, there is a small subset of poisons that result in death in small animals despite treating aggressively. When faced with an acute, sudden or unattended death, it is necessary to add common deadly intoxications to our differential list.

Veterinary staff may encounter situations where they are asked to investigate the cause of death of a companion animal that was apparently healthy when observed last but was later found dead by the owner. In many such situations, the animal may have had clinical signs that went unnoticed by the owner, or the animal may not have been observed during the time of illness. Investigating sudden death in dogs and cats in the absence of clinical signs can be quite challenging. The definition of sudden death in terms of time may vary from person to person. For the sake of discussion in this chapter, sudden, unattended, or unexplained death is defined as death occurring in an apparently healthy animal within a 12‐ to 24‐hour period with no premonitory clinical signs or with minimal clinical signs of illness (Casteel and Johnson 2020). The purpose of this chapter is to outline the approach for investigation of sudden death and to provide some common toxicologic rule‐outs that should be included for investigating sudden acute unattended death in dogs and cats (Table 9.1).

CAUSES OF SUDDEN DEATH

A list of common causes of acute sudden death is available for large animals. However, for small animals, limited information is available on this topic. Animal poisoning (accidental or malicious) in dogs, according to one 10‐year retrospective study, is the second most cause of sudden death in dogs after heart diseases (Table 9.2) (Olsen and Allen 2000). In cats, however, poisoning has not been listed as a cause of acute sudden death (Table 9.3) (Olsen and Allen 2001).

Investigation of sudden death in a dog or a cat is no different than investigation of any other disease condition. Non‐toxicologic rule‐outs, including infectious, metabolic, nutritional, physical, and miscellaneous causes, must be considered along with poisoning when investigating sudden death in a pet.

It is important to realize that the effects of a toxicant on the body are generally dose dependent. Many of the toxicants listed in the rule‐out list from Table 9.1 may not be expected to cause acute sudden death with small exposures. However, the list includes the most common/likely toxicants that possess the potential to cause acute sudden death with the right amount (dose) of exposure. The reader is encouraged to review more detail about a particular topic or agent listed in this text once a reasonable cause of death has been narrowed down.

The most common causes of acute death in dogs and cats noted at the American Society for the Prevention of Cruelty to Animals (ASPCA) Animal Poison Control Center over the past 10 years are described in the following sections.

Baclofen

Baclofen is a centrally acting muscle relaxant (see Chapter 23 for more information). It is typically used for back and spinal pain or other diseases involving the spinal cord. While there are therapeutic doses for dogs, it has a narrow margin of safety. Signs seen with baclofen overdoses include ataxia, vomiting, hypersalivation, weakness, and vocalization. Signs can progress to respiratory depression as the diaphragm becomes involved. Recumbency, tremors, seizures, coma, and death can follow (Wismer 2004).

Table 9.1. Toxicants that can cause sudden death in dogs and cats

CNS, central nervous system.

Agent | Comments
5‐Flurouracil | Topically used anticancer medication; seizures, vomiting, cardiac arrhythmias; acute death possible with large ingestion
5‐hydroxytryptophan | Used as an over‐the‐counter sleep aid and antidepressant; seizures, hyperthermia; acute death with large ingestions possible
Acetaminophen | Death due to methemoglobinemia within hours with large ingestion; cats more sensitive
Albuterol | Prescription bronchodilator for asthma; acute death with large ingestion possible; cardiac arrhythmias, hypokalemia
Amphetamines | Recreational or human prescription; hyperthermia, hyperactivity, circling, hypertension, tachyarrhythmias; acute death with large ingestion possible
Anticoagulant rodenticides | Internal bleeding 3–5 days post ingestion; acute death due to pulmonary hemorrhage possible
Antidepressants | Common human prescription medications; acute death possible with large ingestion; CNS and cardiac effects
Arsenic | Toxicosis uncommon; watery bloody diarrhea, abdominal pain, shock, acute death possible
Baclofen | Prescription drug; coma, hypothermia, respiratory depression; death
Barbiturates | Common anticonvulsant, accidental ingestion of large doses; outside dogs eating flesh/carcass of animals euthanized by barbiturates; coma, hypothermia, death
Blue‐green algae | History of drinking from a lake/pond; algae on the muzzle; collapse, shock, seizures, liver failure, death
Botulism | Acute death rare; ingestion of preformed toxins from eating a carcass; progressive weakness, paralysis, death
Bread dough (raw yeast) | Seen in dogs; gastric dilation, alcohol toxicosis
Brunfelsia spp. ingestion | Strychnine‐like signs (seizures, rigidity); dogs attracted to fruit/seed pods/flowers; acute death possible with large ingestion
Caffeine | Ingestion of chocolate or caffeine pills; acute death with large ingestion possible; vomiting, CNS signs, cardiac arrhythmias
Carbon monoxide | Uncommon; bright red mucous membranes
Cardiac glycosides‐containing plants | Acute death uncommon; evidence of plant ingestion
Castor beans | Acute death unlikely; only possible if several seeds have been ingested
Cocaine | Acute death possible; cardiac arrhythmias, hypertension
Ethylene glycol | Acute death with large ingestions possible; cats more sensitive
Garbage poisoning | History of eating garbage; acute death possible with some Salmonella, E. coli toxins; vomiting, progressive shock and death
Hepatotoxic mushrooms | Vomiting, diarrhea, abdominal pain, shock, liver failure, death
Hops (used for beer flavoring) | Malignant hyperthermia‐like syndrome in dogs; acute death possible
Ionophores (e.g., monensin, lasalocid) | Eating cattle feed; farm dog; acute death with large ingestion possible
Iron | Multivitamins, fertilizer; large ingestions, acute death uncommon, vomiting, shock, liver damage
Isoniazid ingestion | Antituberculosis drug; seizures, acute death possible
Lidocaine and other local anesthetics | Uncommon toxicosis; CNS and cardiovascular effects
Metaldehyde | Used mostly as slug bait; seizures, hyperthermia, acute death with large ingestion possible
Moldy food ingestion (tremorgenic mycotoxins) | History of ingestion of moldy food; seizures, hyperthermia, vomiting, acute death possible
Nicotine | Acute death with large ingestion possible; gastrointestinal, CNS and cardiac effects
Organochlorine type pesticides | Lindane, eldrin, dieldrin; use not common anymore; cats more sensitive; seizures, tremors, and acute death
Organophosphates/carbamate insecticides | Some highly toxic organophosphates/carbamates like methomyl, aldicarb (tres pasitos), disulfoton; usually SLUDDE (salivation, lacrimation, urination, diarrhea, dyspnea, emesis) signs present; acute rapid death possible
Pseudoephedrine | Over‐the‐counter decongestant; amphetamine‐like signs; acute death with large overdose possible
Sago palm | Acute death unlikely; seizures, liver failure
Salt (sodium chloride) | Homemade play‐dough ingestion; some use for inducing emesis; seizures, hypernatremia, death possible
Smoke inhalation | History of pet trapped in the house during fire; pulmonary edema, death
Snake bite | Mohave rattle snake, eastern rattle snake; acute death possible
Strychnine | Rodenticide; rapid onset, seizures, hyperthermia, rigidity, death, rapid onset rigor mortis
Tetrodotoxins | Acute death rare; ingestion of dried puffer fish, pet salamander; paresis, respiratory failure, death
Water intoxication | History of being on the beach/swimming; hyponatremia, hypochloremia, polydipsia
Toads (Incilius alvarius, Rhinella marinus) | Acute collapse, salivation, cardiac arrhythmias, seizures, death
Xylitol ingestion | Acute death due to severe hypoglycemia possible; acute liver failure possible 1–3 days after ingestion
Zinc phosphide | Available as gopher bait; vomiting, CNS effects; acute death with large ingestion possible

Table 9.2. Underlying causes of sudden and unexpected deaths in 151 dogs as reported in the literature

Source: Olsen and Allen (2000) / National Library of Medicine / CC BY 4.0.

General cause of death | Number of cases | % of total
Heart disease | 33 | 21.9
Toxicosis | 25 | 16.6
Gastrointestinal disease | 20 | 13.2
Trauma | 19 | 12.6
Hemorrhage not associated with trauma | 10 | 6.6
Malnutrition or dehydration | 8 | 5.5
Respiratory disease | 6 | 4.0
Urogenital disease | 5 | 3.3
Central nervous system disease | 2 | 1.3
Peritonitis | 2 | 1.3
Pancreatic disease | 2 | 1.3
Undetermined | 19 | 12.6
Total | 151 | 100

Table 9.3. Underlying causes of sudden and unexpected deaths in 79 cats as reported in the literature

Source: Olsen and Allen (2000) / National Library of Medicine / CC BY 4.0.

General cause of death | Number of cases | % of total
Trauma | 31 | 39.2
Heart disease | 16 | 20.3
Intestinal disease | 6 | 7.6
Respiratory disease | 5 | 6.3
Urinary tract disease | 4 | 5.1
Feline leukemia virus‐related disease | 3 | 3.8
Menengioencephlitis | 1 | 1.3
Hepatic necrosis | 1 | 1.3
Sepsis | 1 | 1.3
Hemorrhage not associated with trauma | 1 | 1.3
Undetermined | 10 | 12.7
Total | 79 | 100.2a

aExceeds 100 due to rounding.

5‐Fluorouracil

5‐Fluorouracil is a chemotherapeutic agent most commonly found in topical preparations to treat skin cancer (see Chapter 23 for more information). It has an extremely narrow margin of safety, and significant signs can be seen with minute exposures. Animals can be exposed by getting into containers or licking the product off the owner. Signs seen with 5‐fluorouracil exposures include severe gastrointestinal signs, hemorrhagic gastroenteritis, ataxia, weakness, tremors, agitation and seizures. The seizures are difficult to control. Gastrointestinal and central nervous system (CNS) signs are seen rapidly after exposure, and bone marrow suppression can occur up to 1–3 weeks post exposure (Fry and Forman 2004).

5‐Hydroxytryptophan

5‐Hydroxytryptophan (5‐HTP) is an amino acid that can be found in many over‐the‐counter (OTC) supplements and is used to treat depression and sleep disorders in humans. Overdoses of 5‐HTP lead to serotonin syndrome, and patients may experience signs such as vomiting, hypersalivation, lethargy, ataxia, mental dullness, mydriasis, agitation, vocalization, tachycardia, hypertension, hyperthermia, tremors, seizures, and death. Signs are severe and have a rapid onset, 30–60 minutes after ingestion (Gwaltney‐Brant et al. 2000). Clinical signs may last as long as 48 hours (see Chapter 21 for more information).

Calcium Channel Blockers

Calcium channel blockers (diltiazem, amlodipine, etc.) are used in people and animals to treat high blood pressure and heart rhythm abnormalities (see Chapter 23 for more information). They have a narrow margin of safety and can cause lethargy, bradycardia, and severe hypotension. Death is due to cardiac failure (Hayes 2018).

Lamotrigine

Lamotrigine is an anticonvulsant medication in humans. Dogs are not prescribed lamotrigine as they produce a toxic metabolite. Fatal arrhythmias can occur. Signs are typically seen within 4 hours of exposure and can last up to 48 hours after onset (Hagley et al. 2020).

Hops

Hops (Humulus lupulus) are used as a bittering agent in brewing beer and can also be found in OTC supplements (see Chapter 20 for more information). The toxic principle is unknown. Hops can quickly cause life‐threatening hyperthermia in dogs, 30 minutes to 2 hours post exposure. Once animals become symptomatic their prognosis is guarded. Signs can last up to 48 hours after onset (Duncan et al. 1997).

Blue Green Algae

Blue green algae (cyanobacteria) can be found in natural bodies of water such as lakes, ponds, rivers, and also in fountains. Some cyanobacteria produce acute liver failure (microcystins) while others produce neurotoxins [anatoxin‐a, anatoxin‐a(s)]. The microcystins cause weakness, pallor, seizures, coma, shock (hemorrhagic and hypovolemic), and death from hepatic necrosis. Liver signs begin about 12 hours post exposure. In the cases that develop CNS signs, onset is seen within minutes and animals die from respiratory paralysis (Wild et al. 2015).

Metaldehyde

Metaldehyde is a molluscicide found in slug and snail baits (see Chapter 19 for more information). Clinical signs are often seen within 1–4 hours post exposure and can include hypersalivation, tremors, seizures, hyperthermia, and death. Most clinical signs will last for 1–3 days after onset (Buhl et al. 2013).

Methomyl

Methomyl is a carbamate insecticide, most commonly found in fly baits (see Chapter 18 for more information). It is rapidly absorbed after ingestion. Signs are often short‐lived compared to other organophosphates but can become life‐threatening quickly. Within minutes of an exposure, a patient can experience SLUDDE (salivation, lacrimation, urination, diarrhea, dyspnea, emesis) signs, bradycardia, weakness, ataxia, tremors, seizures and death (Gupta and Milatovic 2012).

DIAGNOSTIC APPROACH

History

The investigation of acute sudden death involves close cooperation between client, veterinary staff, and diagnostic laboratory personnel. A complete and thorough case history is essential for such investigations. A good case history can help expedite the process of putting together all the pieces and eliminate several unnecessary steps early. Obtaining a recent case history from the client may sometimes be difficult, especially in situations where the animal was unsupervised immediately prior to death. Clients may be too distraught to have good recollection of recent events, and it is not uncommon for them to focus on one particular event (e.g., a pesticide recently used in the pet's environment) as the potential cause of death. Patience and tactful questioning is paramount to getting a history that is as accurate as possible.

Important historical questions must include animal signalment (breed, sex, weight, and age); previous medical history, vaccination history, and any medications the pet was taking; information regarding other animals present in the household; timeline of death (i.e., when the pet was last seen alive, where and when the pet was found dead); where pet had been in the hours/days prior to death (e.g., traveling, beach, park, neighbors, pet sitter, party); evidence of clinical signs (e.g., vomiting, diarrhea, seizure); number of affected animals (i.e., any other sick animals in the household); information about the animal's environment (indoor vs. outdoor, free‐roaming vs. fenced), location (urban vs. rural), time of the year (summer vs. winter); recent renovations, construction or updates; availability of recreational drugs (amphetamines, cocaine) or human medications in the animal's environment (antidepressants, painkillers, stimulants, nutritional supplements, overnight visitors taking prescription medications); the presence of insecticides, flea/tick control products, herbicides, or rodenticides in the house or yard; recent visits by pest control or lawn care companies; and information about presence of indoor or outdoor plants and lawn/garden fertilizers or chemicals (Khan 2017). Information about disputes involving the neighbors, coworkers, family members, or others may help determine if the death could be malicious.

Sample Collection

The best way to investigate acute sudden death is by having a complete necropsy (gross and histopathologic examination) performed, preferably by a board‐certified veterinary pathologist (Volmer and Meerdink 2002). After obtaining an initial history, multiple digital pictures of the dead animal with any lesions (hemorrhage, mucous membrane color, broken skin/bones etc.) along with the incriminating agent (if any) and surrounding environment (plants, chewed‐up container, bait, feed, water, etc.) should be taken. Stringent written documentation and chain of custody protocols should be followed for all potential medicolegal cases. If necessary, contact local animal control or law enforcement for details on securing potential legal evidence. For shipment to a diagnostic laboratory, triple‐bag the dead animal and ship it to a diagnostic laboratory on ice or dry ice through express mail. Before shipping the samples, review the shipping/sample handling instructions provided on the diagnostic laboratory website or by calling them. Inform the diagnostic laboratory about the shipment (dates, types of samples being shipped, etc.) before shipping. Avoid shipping over the weekends or holidays. Talk to the shipping carrier before shipping the animal to discuss packaging and labeling requirements.

Unfortunately, in many situations the options for a complete necropsy may not be feasible due to economics, animal size, or shipment constraints. In such circumstances, appropriate postmortem samples should be obtained from the animal and the environment. Collection of inappropriate type or amount of samples, and inadequate preservation techniques are some of the most common errors that hinder investigation by diagnostic laboratories. To avoid cross‐contamination, all samples should be collected in separate containers, properly labeled with the patient's and owner's name, and dated. For histopathologic examination, a full set of tissues from all major organ systems should be cut 4–5 mm thick and placed in 10% formalin.

Most toxicologic analyses require frozen or refrigerated samples. Important samples for toxicologic investigations include liver, kidney, stomach contents, urine, abdominal fat, brain, heart clot blood and serum, hair, feed, water, or suspected bait (if available). The preferred anticoagulant for storage of whole blood is EDTA, although heparin is also acceptable in some cases. Whole blood, serum, or urine samples should be refrigerated or chilled until analyzed. The amount of samples should be reasonable. Generally, the larger the amount, the better it may be. You can always discard the excessive amount or extra samples later if not needed. Larger amounts can allow the toxicologist to repeat an analysis, test for additional potential toxicants, and confirm the results with a different method if necessary. An entire set of samples must be collected for toxicologic analysis even when the diagnosis may be obvious or apparent (Casteel and Johnson 2020; Volmer and Meerdink 2002).

Sample Submission

A concise history of events should be submitted to the diagnostic laboratory along with your request for analyses. For a complete necropsy or toxicologic analysis, an accredited diagnostic laboratory should be utilized whenever possible. Most laboratories now have websites that detail sample submission requirements. Discuss cost, turn‐around time, limitations of analytical methods if any, and interpretations of results with the diagnostic laboratory staff or toxicologist if needed. The latter is especially important because with modern analytical equipment, it is possible to detect a wide variety of compounds in body fluids/tissues at levels far below those that would have any clinical significance. The toxicologist can assist in determining whether the levels found in the submitted samples are consistent with the suspected toxicosis.

Common Non‐Toxicologic Rule‐Outs

Determining the cause of acute, sudden, unattended death or illness in dogs or cats must include investigation into both toxicologic and non‐toxicologic causes (Khan 2018). Reported incidences of poisoning or non‐poisoning‐related deaths in dogs or cats may vary significantly among various geographic areas due to several factors such as prevalence of infectious disease, variations in the types of animal population, or the diagnostic capability of a laboratory (instrumentation available, availability of trained staff). This can also become a limiting factor due to the amount of testing allowed by the animal owner. Having a thorough local knowledge, including current or previous incidences of infectious, non‐infectious, metabolic, or environmental disease patterns in various animal species can save time to help narrow down the etiology.

Tables 9.4 and 9.5 list recently reported incidences of acute death in dogs and cats. This, along with local disease knowledge, can be used as guidelines when investigating causes of acute death.

CONCLUSION

The sudden death of a companion animal can be an emotionally challenging time for animal owners and veterinary staff. It is important that the veterinary staff understand the steps that need to be taken to investigate the cause of death so that the right questions can be asked and answered, and the appropriate samples are collected.

Table 9.4. Leading toxicologic and non‐toxicologic causes of sudden unexpected deaths reported in the literature in dogs (n = 150)

Source: Adapted from Stalker (2019).

Causes of death | Number/percentage reported | Comment(s)
Underlying occult neoplasia | 42 cases (28%) | Majority were hemangiosarcoma cases (33) with pericardial, thoracic, or abdominal hemorrhaging
Cardiac diseases | 36 cases (24%) | Included various forms of cardiomyopathies and four cases of aortic stenosis
Respiratory diseases | 16 cases (11%) | Nine deaths were due to acute choking/asphyxiation/aspiration of food
Trauma | 14 cases (9%) | Nine deaths were motor vehicle accidents, one was predator attack
Gastrointestinal causes | 11 cases (7%) | Nine cases were due to gastric dilatation/volvulus, two were foreign body obstruction/perforation
Miscellaneous inflammatory diseases | 10 cases (7%) | Included cases of septicemia, pyelonephritis, hemolytic anemia, and hemorrhagic enteritis
Poisoning cases | 7 cases (5%) | Five cases of anticoagulant toxicosis, one case each of chocolate and bromethalin toxicosis

Table 9.5. Leading toxicologic and non‐toxicologic causes of sudden unexpected deaths reported in the literature in cats (n = 71)

Source: Adapted from Stalker (2019).

Cause of death | Number/percentage reported | Comments
Underlying cardiac diseases | 44 cases (62%) | Majority (42) were various forms of cardiomyopathies
Trauma | 6 cases (9%) | Includes predator attacks
Miscellaneous inflammatory conditions | 6 cases (9%) | Anaphylaxis, sepsis, hepatitis
Undetermined cause | 5 cases (8%) | No detectable lesions to determine the cause
Miscellaneous infection | 5 cases (8%) | Panleukopenia, Salmonella sepsis
Neoplasia | 2 cases (3%) | Only 3% of cases compared to 28% in dogs
Poisoning cases | 0 (0%) | No cases reported

CHAPTER 9 STUDY QUESTIONS

A client brings a dead adult male cat into the hospital. What is the first step in dealing with this case?

Collect samples for toxicology.

Perform a necropsy.

Obtain a history.

Take radiographs.

Draw some blood for a chemistry profile.

The client says that the cat was a stray that she and several neighbors had been feeding for several months. One neighbor had taken the cat to be neutered and vaccinated 2 months ago, and the cat appeared generally healthy. The client had fed the cat last night and he seemed fine; this morning he was lying dead on her porch. The client called the neighbors who were helping to feed the cat; no one saw anything out of the ordinary in the past 24 hours, and none had administered medication or flea control to the cat within the past week. The client is suspicious that the cat has been maliciously poisoned and wants to know why the cat died. A cursory external examination shows no lesions or evidence of why the cat may have died. What is the next step?

Collect samples for toxicology.

Perform a necropsy.

Take radiographs.

Draw some blood for a chemistry profile.

A necropsy is performed and samples are taken for histopathology. Additional samples are collected for toxicology but are kept at the clinic pending the results of the necropsy and histopathology. What is the preferred means of storage of these samples until they are ready to be submitted to the toxicology laboratory?

Frozen

Refrigerated

Fixed in 10% buffered formalin solution

a and b

a, b, and c

The necropsy and histopathology on the cat were highly suggestive of ethylene glycol (antifreeze) toxicosis. What is the next step?

Call the diagnostic laboratory to determine which sample(s) to submit for ethylene glycol.

Call animal control to report a malicious poisoning.

Call the neighbors to see whether they suspect anyone of poisoning the cat.

The toxicologic analysis of the submitted samples confirmed the presence of ethylene glycol in the cat's stomach contents, fat, and kidney. Is this proof that the cat was maliciously poisoned? Why or why not?

ANSWERS

1. c. Obtain a history to determine the most appropriate course of investigation.

2. b. A necropsy holds the best chance of determining why the cat died.

3. d. Samples for toxicology can be stored either refrigerated or frozen prior to submitting to the laboratory.

4. a. Determine which samples to submit and have them analyzed by the diagnostic laboratory.

5. No, without a witnessed exposure it is not possible to say for sure whether the exposure was malicious or accidental.

REFERENCES

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Casteel, Stan W and Johnson, Philip J. 2020. Collapse/sudden death. In Large Animal Internal Medicine, 6th ed., edited by Bradford P Smith, David C Van Metre, and Nicola Pusterla, pp. 227–235. St. Louis: Elsevier.

Duncan, Karen L, Hare, William R, and Buck, William B. 1997. Malignant hyperthermia‐like reaction secondary to ingestion of hops in five dogs. Journal of the American Veterinary Medical Association 210(1):51–54.

Fry, Michael M and Forman, Marnin A. 2004. 5‐Fluorouracil toxicity with severe bone marrow suppression in a dog. Veterinary and Human Toxicology 46(4):178–180.

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Olsen, Tammy F and Allen, Andrew L. 2001. Causes of sudden and unexpected death in cats: a 10‐year retrospective study. Canadian Veterinary Journal 42:61–62.

Stalker, Margaret. 2019. Causes of sudden unexpected death in dogs and cats – it's not the neighbor! Animal Health Laboratory Newsletter, University of Guelph, ON, Canada 23(4):16–17.

Volmer, Petra A and Meerdink, Gavin L. 2002. Diagnostic toxicology for the small animal practitioner. The Veterinary Clinics of North America. Small Animal Practice 32(2):357–365.

Wild, Margaret A, Wong, David, Buttke, Danielle, and Cheny, Cara. 2015. Freshwater harmful algal blooms and cyanotoxin poisoning in domestic dogs. Journal of the American Veterinary Medical Association 247(9):1004–1005.

Wismer, Tina. 2004. Baclofen overdose in dogs. Veterinary Medicine 99(5):406–408.

10
Toxicologic Testing and Using Diagnostic Laboratories

Lisa Murphy

SOURCES

Toxicologic testing may be available at many levels: in the veterinary clinic (e.g., ethylene glycol testing), at a local or regional commercial veterinary diagnostic laboratory, or at a veterinary diagnostic laboratory associated with a veterinary school or state department of agriculture. When selecting a diagnostic laboratory the following criteria should be considered: cost, turnaround time, experience with the sample type, available detection limits for the toxicant of concern, quality assurance and quality control programs, and assistance in the interpretation of results (Galey 2004).

The use of specialized instruments and highly trained personnel will often make toxicologic testing quite expensive compared to other diagnostic tests routinely performed for small animal patients. Many laboratories also charge additional fees for samples that are sent from another state, so be sure to ask about any additional fees that may apply.

Turnaround time refers to how long it will generally take to receive test results once samples arrive at the laboratory. Since some toxicologic tests may take several days or sometimes more than a week to complete, it will still be necessary to stabilize, decontaminate, and begin to treat the patient while waiting for results. Since some analyses can be completed more quickly, especially if the laboratory receives prior notice, it is important to contact the laboratory directly before submitting samples for critically ill patients.

Common sample types submitted for toxicologic testing in veterinary medicine include blood, plasma, serum, urine, stomach contents, tissues, food, baits, water, and plant material. Each distinct sample type may require its own specific processing and analysis to detect the same toxic substance. Not all sample types may be appropriate for obtaining reliable results for all toxicologic tests. Diagnostic laboratories should be able to recommend which sample types are best or preferred for specific toxicologic tests (Talcott 2013).

Detection limits refer to the minimum amount of a toxic substance that must be present to reliably produce a positive test result. Detection limits will often be listed on a diagnostic report as the MDL, the minimum detection limit or method detection limit. When a toxic substance is either not found in a sample or appears to be present at a very low level below the MDL that is not confirmable, the result may be reported as either “none detected” or less than the MDL. If a specific level of detection of a toxicant is needed for either diagnostic or treatment purposes, the veterinary toxicology laboratory should be contacted ahead of time to be sure that its method is able to adequately provide the desired information.

Quality assurance and quality control are the practices laboratories use to ensure that the results they report are consistent and accurate. This reliability is typically accomplished by the use of standard reference materials, standard data curves, spiked samples, regular use of check samples, and participation in multilaboratory proficiency tests. When using an unfamiliar laboratory for the first time, it may be prudent to inquire about its quality assurance and quality control program (Galey 2004; Talcott 2013).

Once a test has been completed, interpretation of the results by a trained professional, such as a veterinary toxicologist, can be critical in determining its significance to the case as a whole and may be used to direct additional patient care or diagnostic testing. To determine whether a patient's result is abnormal or diagnostically significant, something should be known about what “normal” results are expected to be for an animal of a particular species, age, or sex. As an example, anticoagulant rodenticides would not be expected to be present in the blood of an unexposed animal, while a low level of lead in the same animal's blood could be considered normal and not expected to be associated with signs of lead toxicity.

An experienced veterinary toxicology laboratory will be able to provide reliable, accurate, and useful results in a timely matter.

DIAGNOSTICS

The appropriate selection of diagnostic tests in cases of suspected intoxications will rely heavily on obtaining a good case history. Based on the historical information provided, a veterinary toxicology laboratory's professional staff should be able to assist veterinary clinics with questions about which tests should be selected for a given case, the best and appropriate sample types to submit, how samples should be collected and in what container type for storage and shipping, and the desirable sample quantities needed to run the requested analyses.

Environmental Samples

Many toxicants cannot be successfully detected in animal tissues or bodily fluids, so the collection and submission of environmental samples may be critical to identifying an animal's access to a potentially toxic substance. Common environmental samples that could represent sources of intoxication to small animals include foods, baits, plants, mushrooms, water, and other unidentified substances or medications. For a description of typical sample amounts and how they should be collected, stored, and submitted for toxicologic testing, see Table 10.1.

Antemortem

Common sample types that can be obtained from a live patient for toxicology testing include whole blood, serum, urine, vomitus, stomach contents, feces, biopsy specimens, and hair. Samples should be obtained preferably at the earliest feasible opportunity after the animal arrives at the clinic. If specimens cannot be collected before extensive medical treatments are instituted, any drugs administered or treatments given should be noted as part of the case history when submitting toxicology samples for testing. Suggested sample amounts and how they should be stored and transported are described in Table 10.2. The sample size that can be safely collected from tiny patients such as neonates and exotic species may be limited. Some form of toxicologic testing can still be performed in most cases, although the number and types of tests along with the ability to verify any positive results may be severely limited (Talcott 2013).

Table 10.1. Environmental sample types and amounts for toxicologic testing

Sample type | Amount | Collection/storage method
Human or animal foods | 500 g (approximately 2 cups) | Refrigerate or freeze in a well‐sealed plastic bag or container
Baits | Entire amount present up to 500 g (approximately 2 cups) | Refrigerate or freeze in a well‐sealed plastic bag or container
Plants | Whole green plant including the roots; a fresh tree or shrub branch with leaves (and flowers if present); entire nut, fruit, berry, or other characteristic part of the plant | Press or wrap in newspaper, place in a sealed plastic bag, and then send to the diagnostic laboratory either fresh or frozen
Mushrooms | Whole mushroom or as much as possible if the only remaining source is from the animal's vomitus or stomach contents | Keep relatively cold and dry in a paper bag to reduce moisture accumulation and subsequent spoilage
Water | 0.5–1 L (approximately 2–4 cups) | Ideally, collect into a new, unused, clean and dry glass container that is free of any detergent, chemical, food, or beverage residues
Other unidentified substances or medications | Representative amount of what is present up to 500 g (approximately 2 cups) | Refrigerate or freeze in a well‐sealed plastic bag or container

Postmortem

When patients have died as a result of a suspected toxicosis, it may be beneficial to refrigerate or freeze samples for potential toxicologic testing while awaiting results of other diagnostic tests such as complete blood counts, serum chemistries, gross autopsies, and histopathology. These results may provide valuable information about possible cause(s) of death and subsequently what specific toxicologic analyses should be pursued. One exception may be if other animals in the same household or neighborhood are sick or at risk. In these cases, toxicologic testing may be pursued more quickly when the history and clinical signs observed are strongly supportive of or suspicious for poisoning. Common postmortem sample types are described in Table 10.3. Rarely, collection of other postmortem sample types may be necessary for the detection of some compounds, such as lung tissue for paraquat. This kind of special testing information can be obtained by consulting with the toxicology laboratory.

Table 10.2. Suggested antemortem samples for toxicologic testing

Sample type | Amount | Collection/storage method
Whole blood | 2–4 ml | Refrigerate in calcium EDTA or heparin tube
Serum | 2–4 ml | Spin and refrigerate or freeze the serum in a plain glass or plastic blood tube to separate from the red blood cells
Use a special all‐plastic trace mineral tube for accurate zinc levels
Urine | At least 10–20 ml | Refrigerate or freeze in a clean, tightly sealed plastic container
Vomitus or stomach contents | At least 10–20 ml | Refrigerate or freeze in a clean, tightly sealed plastic bag or container
Feces | At least 100 g | Refrigerate or freeze in a clean, tightly sealed plastic bag or container
Biopsy specimens | At least 2–5 g | Refrigerate or freeze in a clean, tightly sealed plastic bag or container
Hair | 5–10 g | Place in a clean, tightly sealed plastic bag or container

Table 10.3. Postmortem samples for toxicologic testing

Sample type | Amount | Storage method
Stomach contents | At least 10–20 ml | Refrigerate or freeze in a clean, tightly sealed plastic bag or container
Liver | At least 5–10 g | Refrigerate or freeze in a clean, tightly sealed plastic bag or container
Kidney | At least 5–10 g | Refrigerate or freeze in a clean, tightly sealed plastic bag or container
Brain | Half of the brain | Cut in half sagittally, leaving the other half and the midline intact for histopathology
Refrigerate or freeze in a clean, tightly sealed plastic bag or container
Body fat | At least 5–10 g | Refrigerate or freeze in a clean, tightly sealed plastic bag or container
Eye | One globe | Refrigerate or freeze in a clean, tightly sealed plastic bag or container; allows testing of either ocular fluid or retina
Injection site | Surrounding tissue | Refrigerate or freeze in a clean, tightly sealed plastic bag or container

MANAGEMENT OF EXPOSURES

Diagnostic testing should not be substituted for general patient care and case management. All patients should be evaluated as individuals and life‐threatening signs such as respiratory distress, cardiovascular compromise, and central nervous system abnormalities such as seizures should be addressed first. Once the patient has been stabilized, diagnostic tests can be performed and specific care can be provided. Even if diagnostic toxicologic testing is not readily available, most intoxicated animals can recover if close monitoring, symptomatic treatment, and good nursing care are provided.

CHAPTER 10 STUDY QUESTIONS

Manny, a 6‐year‐old, 65‐lb, intact male German shepherd dog, presents to the veterinary hospital with a history of vomiting and muscle tremors that began about 2 hours ago. Prior to development of signs, Manny had been roaming free on the owner's farm. The owners are concerned that Manny may have got into the shed that houses the farm pesticides. They also noted that Manny was seen digging in the compost pile in the pasture. Besides blood or serum, list two other samples from Manny that might be helpful to aid in diagnosis.

For each of the two samples selected in Question 1, indicate the amount to collect and the best method of storage/handling of the sample for submission to a diagnostic laboratory.

Which of the following is not correct regarding diagnostic toxicology samples?

Freezing or refrigeration is an acceptable means of preserving samples prior to submission to the diagnostic laboratory.

Veterinary diagnostic laboratory personnel can assist the veterinary technician in determining the best test and sample for a particular suspected toxicology case.

When determining whether a laboratory result is clinically significant, the diagnostic toxicologist will compare the result with a range of “normal” values.

Toxicology testing should always be the first step in attempting to diagnose the cause of death in a suspected poisoning case.

Environmental samples that may be submitted in a suspected toxicology case include animal foods, plants, mushrooms, and water.

Which of the following is true regarding the MDL (minimum detection limit)?

Refers to the minimum amount of toxicant in an animal that will cause a toxicosis.

Refers to the highest amount of toxicant that the diagnostic test can detect in a sample.

Refers to the minimum amount of a toxic substance that must be present to reliably produce a positive test result.

Refers to the lowest level of toxicant that will be toxic to a particular animal.

Refers to the smallest amount of a nontoxicant (i.e., contaminant) that will give a false positive result.

The appropriate selection of diagnostic tests in cases of suspected intoxications will rely heavily on the diagnostic laboratory obtaining _____________.

An adequate blood sample

A good case history

A freshly dead animal

Frequent calls from the veterinary clinic asking for results

Payment in advance

ANSWERS

1. Urine, vomitus (stomach content), feces.

2. Urine, collect at least 10–20 ml and submit refrigerated or frozen in a clean, tightly sealed plastic container. Vomitus (stomach contents), collect at least 10–20 ml or grams and submit refrigerated or frozen in a clean, tightly sealed plastic container. Feces, submit at least 100 g and submit refrigerated or frozen in a clean, tightly sealed plastic container.

Urine, collect at least 10–20 ml and submit refrigerated or frozen in a clean, tightly sealed plastic container. Vomitus (stomach contents), collect at least 10–20 ml or grams and submit refrigerated or frozen in a clean, tightly sealed plastic container. Feces, submit at least 100 g and submit refrigerated or frozen in a clean, tightly sealed plastic container.

3. d. In most cases toxicology testing should be performed after other testing (necropsy, histopathology, clinical pathology) results are obtained in order to help narrow down the potential toxicants to analyze for.

4. c.

5. b. A good case history is essential in knowing what kind of testing would be most appropriate for a particular case.

REFERENCES

Galey, Frank D. 2004. Diagnostic toxicology. In Clinical Veterinary Toxicology, edited by Konnie H Plumlee, pp. 22–27. St. Louis: Mosby.

Talcott, Patricia A. 2013. Effective use of a diagnostic laboratory. In Small Animal Toxicology, 3rd ed., edited by Michael E Peterson and Patricia A Talcott, pp. 125–132. St. Louis: Saunders.

Section 2
A Systems-Affected Approach to Toxicology

11
Nervous System

Tina Wismer

INTRODUCTION

The nervous system is a target for an extremely large number of toxic agents, including drugs, environmental and industrial chemicals, and “natural” products such as bacterial toxins and animal venoms (Tables 11.1–11.4). Many of these agents are able to bypass the nervous system's protective blood–brain barrier and cause neurologic dysfunction. Many agents that affect the nervous system, especially psychotropic drugs, exert their effects through biochemical mechanisms that do not leave any telltale clinical pathologic changes or anatomic lesions to aid in diagnosis in animals experiencing a toxicosis. Because the nervous system has a limited number of responses to injury, the clinical effects of toxicoses affecting nervous system function will resemble effects from other causes of neurologic dysfunction such as infectious, metabolic, traumatic, and neoplastic injury. Definitive diagnosis of nervous system toxicosis can therefore be quite challenging.

ANATOMY AND PHYSIOLOGY

The nervous system encompasses both the central nervous system (CNS) and the peripheral nervous system (PNS). The CNS coordinates the activity of all parts of the body and consists of the brain and spinal cord. The PNS connects the CNS with the limbs and organs.

The basic functional unit of the nervous system is the neuron. Neurons initiate and conduct nerve stimuli. The basic structure of a neuron contains the body (soma), dendrites, and axons. The dendrites are short branches off the body that receive stimuli from other neurons and transmit it to the soma. The axon carries impulses away from the soma and is often covered by myelin, a fatlike substance that increases the speed of impulse conduction (Spencer 2000). Nervous impulses cross the synapses between neurons by the release of chemicals termed neurotransmitters (Moser et al. 2019). Neurotransmitters include acetylcholine, catecholamines (dopamine, norepinephrine, epinephrine), amino acid derivatives (serotonin, gamma amino butyric acid [GABA], glycine, histamine, aspartic acid, glutamic acid), and various other neuropeptides (substance P, orexins, endorphins, vasopressin, thyroid‐releasing hormone) (Spencer 2000).

Neurotransmitters can be excitatory and/or inhibitory. Excitatory neurotransmitters stimulate postsynaptic membranes, and inhibitory neurotransmitters decrease (or make less likely) the transmission of an impulse. Acetylcholine is both excitatory and inhibitory. It has inhibitory effects on the heart but stimulatory effects on other organs. The catecholamines are hormones that are released by the adrenal glands in reaction to stress. Epinephrine and norepinephrine are associated with the sympathetic nervous system (fight or flight response). Dopamine is found in the brain and affects muscle control and autonomic functions. GABA is the main inhibitory neurotransmitter. GABA regulates neuronal excitability throughout the nervous system. Glycine is also an inhibitory neurotransmitter found in the spinal cord, brainstem, and retina.

The major protective mechanism in the CNS is the blood–brain barrier. The blood–brain barrier forms a “wall” between capillaries in the brain and the nervous tissue. The tight junctions allow small molecules and lipid soluble molecules to enter easily, but keep other substances out of the brain. The PNS is not protected by the blood–brain barrier, leaving it exposed to toxicants.

Table 11.1. Pesticides

Toxicant | Possible effect on the nervous system
4‐aminopyridine (Avitrol®) | Stimulation, tremors, seizures
Amitraz | Depressant
Anticholinesterase insecticides (organophosphates, carbamates) | Seizures
Avermectins (ivermectin, moxidectin) | Weakness, ataxia, tremors, seizures, coma
Bromethalin | Stimulant at high doses; depressant at low doses
3‐chloro‐p‐toluidine hydrochloride (Starlicide®) | Depressant, weakness, paralysis
DEET (diethyltoluamide) | Seizures
Metaldehyde | Seizures, tremors
Organochlorine insecticides (lindane, DDT) | Seizures
Pyrethrins | Tremors
Sodium fluoroactate (1080) | Intermittent seizures, stimulation
Strychnine | Seizures
Zinc phosphide | Ataxia, seizures

Table 11.2. Biologic agents

Toxicant | Possible effect on the nervous system
Ageratina altissiama (white snakeroot) | Tremors, ataxia, stiff gait, weakness
Asclepias spp. (Milkweed) | Weakness, tremors, seizures
Atropa belladonna (deadly nightshade, belladonna) | Tremors, paralysis, hallucinations
Black widow spider envenomation | Flaccid paralysis, muscle cramping
Blue‐green algae (anatoxin‐a, anatoxin‐a[s]) | Tremors, seizures
Botulism | Flaccid paralysis
Brunfelsia spp. (yesterday, today, and tomorrow) | Tremors (can last for weeks), seizures
Calycanthus spp. (bubby bush) | Seizures
Cannabis sativa (marijuana) | Depressant, ataxia, coma; possible agitation
Cicuta spp. (water hemlock) | Seizures
Conium spp. (poison hemlock) | Initial stimulation, followed by depressive signs
Coral snake envenomation | Ataxia, tremors, paralysis
Datura spp. (jimsonweed, angel's trumpet) | Tremors, paralysis, hallucinations
Essential oils | Depressant, ataxia, weakness, tremors; seizures with large doses
Ipomoea spp. (morning glory) | Stimulation, hallucinations
Lobelia spp. (lobelia) | Initial stimulation, followed by depressive signs
Lupinus spp. (lupine) | Initial stimulation, followed by depressive signs
Macadamia nuts | Weakness, tremors (dogs only)
Mushrooms, isoxazole | Alternating CNS stimulation and depression
Mushrooms, monomethylhydrazines | Tremors, seizures, coma
Mushrooms, psychedelic | Ataxia, tremors, hallucinations
Nerium oleander (oleander) | Tremors, seizures
Nicotine (cigarettes, Nicotiana spp.) | Initial stimulation, followed by depressive signs
Tetanus | Muscle rigidity
Tick paralysis | Weakness, paralysis
Tremorgenic mycotoxins (Penitrem A, roquefortine) | Tremors, seizures
Valeriana officinalis (valerian) | Sedation

Table 11.3. Pharmaceuticals

Toxicant | Possible effect on the nervous system
Amphetamines (Ritalin®, Adderall®, crack, methamphetamine, MDMA) | Stimulation
Antihistamines (diphenhydramine, hydroxyzine, loratadine) | Stimulant at high doses; depressant at low doses
Atropine | Seizures with high doses
Barbiturates (phenobarbital) | Depressant
Benzodiazepines (diazepam, alprazolam) | Depressant, ataxia; rarely agitation
Bromide | Depressant, weakness, ataxia
Bupropion (Wellbutrin®) | Stimulant at high doses; depressant at low doses
Buspirone | Stimulant at high doses; depressant at low doses
Cocaine | Stimulation
Cyproheptadine | Stimulant at high doses; depressant at low doses
Decongestants (pseudoephedrine, phenylephrine, ma huang, ephedra) | Stimulation
5‐fluorouracil (Efudex®) | Seizures
General anesthetics (isoflurane, sevoflurane, halothane, propofol) | Depressant
Ibuprofen | Seizures, coma with high doses
Isoniazid | Seizures
Lithium | Seizures
Local anesthetics (lidocaine, benzocaine) | Seizures with high doses
LSD | Stimulation, hallucinations
MAO inhibitors (Anipryl®) | Stimulant at high doses; depressant at low doses
Melatonin | Depressant
Methylxanthines (caffeine, theobromine, theophylline) | Stimulation
Mirtazepine (Remeron®) | Stimulant at high doses; depressant at low doses
Nefazadone, trazodone | Stimulant at high doses; depressant at low doses
Opiates (hydrocodone, morphine, codeine, butorphanol, tramadol) | Depressant; rarely agitation and seizures
Phenothiazines (acepromazine, chlorpromazine) | Depressant
Piperazine | Ataxia, tremors
Salicylates | Seizures with high doses
Serotonergic drugs (Prozac®, Paxil®, 5‐hydroxytryptophan, Effexor®) | Stimulant at high doses; depressant at low doses
Tricyclic antidepressants (amitriptyline, clomipramine) | Stimulant at high doses; depressant at low doses

Table 11.4. Nonmedicinal agents

Toxicant | Possible effect on the nervous system
Alcohol | Depressant
Carbon monoxide | Depressant, weakness, ataxia
Ethylene glycol | Depressant effect, ataxia, tremors, seizures
Lead | Intermittent stimulation and depression
Liver toxicants | Secondary to hepatic encephalopathy
Organic alkyl mercury | Blindness, ataxia, paralysis, coma
Phenol | Tremors, seizures with large doses
Propylene glycol | Depressant effects, ataxia, seizures
Sodium | Tremors, seizures
Thiaminase (raw fish) | Depression, ataxia, paresis
Thallium | Tremors, weakness, seizures
Turpentine | Depressant, weakness, ataxia, coma

MECHANISMS OF TOXICOLOGIC INJURY

In small animal toxicology, most toxicants work directly on the neurons or affect the release and/or binding of neurotransmitters. Toxicant‐induced alteration of neurotransmitters can result in stimulation or inhibition of postsynaptic neurons, resulting in excitatory or depressive clinical effects depending on the type of neurotransmitter affected, type of postsynaptic neuron, and amount of neurotransmitter and receptors involved. For instance, CNS stimulation (manifested as hyperactivity, agitation, and/or seizures) may be caused by increasing the synaptic levels of an excitatory neurotransmitter (e.g., stimulation of acetylcholine release by organophosphorus insecticides) or by decreasing the synaptic levels of an inhibitory neurotransmitter (e.g., strychnine‐induced decrease in glycine neurotransmission).

The brain is very susceptible to injury because it requires a continually high level of oxygen. It has a high percentage of blood flow for an organ of relatively small mass. Hypoxia is a common cause of neuronal injury. It may be secondary to systemic hypotension, cerebral infarction, vascular injury, or oxygen deprivation. Respiratory compromise leading to hypoxia is the primary life‐threatening issue in many toxic exposures causing alterations of consciousness (Moser et al. 2019). Brain damage can also occur secondary to hypoglycemia. During periods of low blood sugar, neuronal damage to dentate and granule cells occurs. Hypoglycemia can result in either cerebral cortex or brainstem deficits. Other mechanisms of toxicologic injury to the nervous system include ion balance disruption (excessive intracellular accumulation of calcium), cytoskeleton damage, decreased protein synthesis (loss of rough endoplasmic reticulum), and glial cell damage (Moser et al. 2019). Disruption or dysfunction of the blood–brain barrier may result in normally excluded compounds entering the CNS, resulting in increased neurologic injury and/or dysfunction.

PATTERNS OF TOXICOLOGIC INJURY

Toxicological insults to the nervous system produce a wide range of clinical signs when compared to other organ systems. Toxicants can affect multiple areas of the nervous system depending on the dose, route of exposure, and species of animal. To make diagnosis more difficult, toxicants can cause a progression of clinical signs (e.g., initial CNS depression, followed by CNS stimulation).

Many neurotoxicants affect neurotransmission and leave no obvious lesions. Functional neurotoxicants can affect the CNS, PNS, and autonomic nervous system. They act by preventing synthesis, storage, release, binding, reuptake, or degradation of neurotransmitters. Functional neurotoxicants may also interfere with axonal transmission via sodium, potassium, chloride, or calcium channels, and alter action potentials (Spencer 2000).

There are a few structural changes caused by neurotoxicants. These include neuronopathy, axonopathy, and myelinopathy. In neuronopathy, neurotoxicants directly target the cell body, causing cell death and secondary axonal degeneration. The response to the loss of neurons is gliosis, proliferation of astrocytes, and/or microgilial cells (Moser et al. 2019). Neuronopathies can be selective or diffuse.

In axonopathy, in contrast to neuronopathy, the neuronal cell body remains intact, but the portion of the axon distal to the lesion degenerates (Wallerian degeneration) (Mandella 2014). Histologic changes can be seen in the Nissl substance. These changes include chromatolysis (dissolution of the Nissl substance) as well as movement of the nucleus to the periphery of the cell body. Neurons with axons of the greatest length are most susceptible to axonal damage.

Myelinopathy occurs when toxicants cause a loss of myelin (demyelination) or edema in the myelin sheath and subsequent separation of myelin layers. This slows down nerve transmission. Clinical signs include ataxia, incoordination, and paresis.

HEALING AND REPAIR

Damage to the nervous system is frequently irreversible because the adult neuron does not divide. With peripheral neuronopathies the prognosis for at least partial regeneration is good. However, this is not true in the CNS. Central neuronopathies, with few exceptions, are not reversible.

In axonopathies, glial cells debride the area. The cell body undergoes central chromatolysis, which may lead to cell death. If the cell body does not die, axonal regrowth may occur slowly (approximately 1 mm per day). Secondary demyelination can be seen with axonal injury (Mandella 2014). Remyelination can occur in some cases, more often in the PNS than in the CNS.

CHAPTER 11 STUDY QUESTIONS

Many psychotropic drugs alter nervous system function by changing the brain biochemistry through alterations of

Hormones

Neurotransmitters

Cytokines

Tight junctions

Glial cells

The functional unit of the nervous system is the _______, composed of ____________ that receive stimuli from other cells, _____________ that carry impulses away from the cell body, and the cell body, also known as the ____________.

Soma, dendrites, axons, neuron

Dendrites, soma, axons, neuron

Neuron, axons, dendrites, soma

Neuron, dendrites, axons, soma

Soma, axons, dendrites, neuron

GABA is an inhibitory neurotransmitter within the CNS. The most significant effect of inhibition of the action of GABA would be expected to be

CNS depression and coma

CNS stimulation and seizures

Fight or flight response

Corticosteroid release

Immunosuppression

The blood–brain barrier

Keeps all foreign compounds out of the CNS regardless of size

Protects the CNS and PNS from entry of potentially damaging compounds

Repels negatively charged compounds, keeping them from entering the nervous system

Is readily traversed by inflammatory cells

Is composed of tight junctions that allow the passage of small molecules and lipid‐soluble compounds but prevent passage of other substances

Which of the following is not a potential cause of brain injury?

Hypoglycemia

Hypoxia

Blood–brain barrier disruption

Disruption of ion balance

All of the above are potential causes of brain injury.

ANSWERS

1. b. Neurotransmitters

2. d. The neuron is composed of dendrites that receive stimuli, axons that transmit impulses, and the soma, or cell body.

3. b. Inhibition of CNS inhibitory neurotransmitters such as GABA and glycine commonly cause CNS stimulation and, potentially, seizures.

4. e.

5. e.

REFERENCES

Mandella, Rosemary C. 2014. Neurotoxicology. In Handbook of Toxicology, 3rd ed., edited by Michael J Derelanko and Carol S Auletta, pp. 303–324. Boca Raton: CRC Press.

Moser, Virginia C, Aschner, Michael, Richardson, Jason R, Bowman, Aaron B, and Richardson, Rudy J. 2019. Toxic responses of the nervous system. In Casarett and Doull's Toxicology, the Basic Science of Poisons, 9th ed., edited by Curtis D Klaasen, pp. 839–876. New York: McGraw‐Hill Medical.

Spencer, Peter S. 2000. Biological principles of chemical neurotoxicity. In Experimental and Clinical Neurotoxicology, 2nd ed., edited by Peter S Spencer, Herbert H Schaumburg, and Albert C Ludolph, pp. 3–54. New York: Oxford University Press.

12
Cardiovascular System

Karla R. Smith

INTRODUCTION

Cardiovascular toxicity can be broadly defined as adverse effects on the heart and blood vessels following exposure to toxic agents. These toxicants can produce direct or indirect effects on the heart and/or vascular system. Agents that affect the heart may increase the force of contraction (cardiotonic or positive inotropic effect), may increase the rate of contraction (positive chronotropic effect), or may have cardiac depressant effects (negative inotropic or chronotropic effects).

ANATOMY AND PHYSIOLOGY

The cardiovascular system can be divided into two categories: the heart and the blood vessels. The heart is made up of two large pumps; the right and left ventricle, which work in concert to pump blood through the blood vessels.

The right ventricle pumps blood through the lungs, where it is oxygenated. The left ventricle pumps blood through the systemic circulation. The smaller pumps, the right and left atria, move blood into their associated ventricles. The right atrium houses the sinoatrial (SA) node, which is responsible for initiating cardiac impulses.

Electrical impulses begin in the SA node and are transmitted throughout the atria, causing them to contract and force blood into the ventricles. When the electrical impulse reaches the atrioventricular (AV) node, there is a slight delay in conduction, which allows complete filling of the ventricles before the impulse is transmitted throughout the ventricles via the AV bundle and Purkinje fibers (Fox et al. 1999).

The cardiac muscle (myocardium) does the work of the heart. The myocardium is a type of involuntary striated muscle found only in the walls of the heart. It shares some similarities with skeletal muscle but is unique in many ways. The striations observed in cardiac muscle are due to alternating thick (myosin) and thin (actin) protein filaments. It is the sliding of actin filaments past myosin filaments that causes contraction of the myocardium. This action requires both adenosine triphosphate (ATP) and an adequate concentration of sodium and calcium (Kittleson and Kienle 2005).

The blood vessels make up the circulatory system, which transports blood throughout the body. The arteries transport blood away from the heart, the capillaries are small vessels that allow the exchange of oxygen and nutrients and connect the arterial and venous sides of the vascular system, and the veins transport blood back toward the heart. The blood vessels have limited ability to contribute to forward blood flow. Arteries can regulate their inner diameter by contraction or relaxation of the vascular smooth muscle layer. This vasoconstriction or vasodilation can be an important mechanism in cardiovascular toxicity, contributing to hypertension or hypotension. All blood vessels are lined with endothelial cells that interface between circulating blood and the vessel wall. The endothelial cells have multiple functions, including helping to control blood pressure and forming specialized barriers, such as the blood–brain barrier.

MECHANISMS OF TOXIC INJURY TO THE HEART

Toxicologic injury to the cardiovascular system may develop by either direct or indirect means (see Table 12.1). Direct toxins include those that have a primary effect on the functional or biomechanical properties of the heart and vascular system. An example would be the tricyclic antidepressant clomipramine, which inhibits myocardial sodium channels, leading to cardiac dysrhythmias. Indirect toxicity arises when the cardiovascular system is secondarily affected by toxicosis to another body system. For example, ingestion of bromadiolone, an anticoagulant rodenticide, can cause significant blood loss leading to hypovolemic shock. The fall in blood volume causes a drop in systemic blood pressure. Reflex vasoconstriction causes splenic contraction in an effort to increase the circulating blood volume, and the heart rate elevates as the heart attempts to move the remaining blood through the circulatory system more rapidly.

Table 12.1. Toxicants that injure the cardiovascular system

Toxicant | Mechanism
ACE inhibitors (lisinopril, benazepril) | Inhibition of angiotensin‐converting enzymes (vasodilation)
Albuterol | Stimulate beta‐2 (and beta‐1 in overdose situations) receptors
Alpha‐2‐adrenergic agonists (amitraz, dexmedetomidine, clonidine, tizanidine, imidazoline decongestants [oxymetazoline, naphazoline]) | Sympathetic depression (decreased catecholamines); vasoconstriction in vascular smooth muscle at high doses
Amphetamines (prescription attention deficit hyperactive disorder medications, methamphetamine) | Alpha‐ and beta‐agonist
Angiotensin II receptor antagonists (losartan, valsartan) | Prevents angiotensin from binding to vessel walls (vasodilation)
Antibiotic antineoplastics (doxorubicin) | Cardiomyopathy
Beta‐blockers | Inhibit catecholamine binding
Bronchodilators | Beta‐receptor agonist
Calcium channel blockers (diltiazem, amlodipine) | Conduction blockade; vasodilation
Cardiac glycosides (digoxin, lily‐of‐the‐valley, oleander, foxglove, toads, fireflies) | Inhibit Na⁺/K⁺ ATPase pumps
Cholecalciferol | Soft tissue mineralization
Direct vasodilators (hydralazine, nitroglycerine) | Vasodilation
Grayanotoxins (azalea, rhododendron, laurel) | Stabilize sodium channels
Ionophores | Increase ion transport across membrane
Methylxanthines (chocolate, caffeine) | Antagonism of adenosine receptors
Minoxidil | Stimulates ATP‐sensitive potassium channels (relaxation of vessels; vasodilation)
Phenylpropanolamine | Vasoconstriction (alpha‐2‐adrenergic agonist)
Pimobendan | Increases contractility; inhibits phosphodiesterase 3 (vasodilation)
Taxine alkaloids (yew) | Inhibit ion channels
Tricyclic antidepressants (amitriptyline, clomipramine) | Inhibition of myocardial sodium channels
Tropane alkaloids (atropine, cocaine, deadly nightshade, jimson weed) | Parasympathetic effects on heart

PATTERNS OF TOXIC INJURY TO THE HEART

Direct Myocardial Injury

Some toxicants can cause degeneration and necrosis of the myocardium, either by direct injury to the myocardial cells or by hemodynamic alterations resulting in ischemic injury. Depending on the toxicant, the pattern of injury on the heart can vary from small areas of necrosis to massive necrosis of the myocardium, resulting in congestive heart failure (CHF), cardiomyopathy, conduction disturbances, or death. Areas of myocardial necrosis will appear as pale spots or streaks in the heart muscle; older lesions may be more pronounced due to fibrosis or mineralization. Agents that can cause this type of myocardial injury in dogs and cats include doxorubicin, thallium, sodium fluoroacetate (a pesticide also known as 1080), and minoxidil (DeClementi et al. 2004).

Conduction Disturbances

It is important to recognize when specific cardiac arrhythmias and electrocardiogram findings may be related to exposure to a cardiotoxic agent. Three mechanisms contribute to production and maintenance of arrhythmias: (1) abnormal impulse initiation, (2) abnormal triggered rhythms, and (3) abnormal impulse conduction. Toxicants causing myocardial conduction disturbances leave few to no lesions in the heart unless significant cardiac ischemia occurs during the toxicosis, in which case areas of myocardial necrosis may be identifiable.

Abnormal impulse initiation may occur when there is increased automaticity of the atrial or ventricular myocardial cells unassociated with the SA or AV nodes. This area is generally referred to as an ectopic focus. If the firing rate of the ectopic focus is greater than the SA node, the ectopic focus will become the predominant pacemaker of the heart. The drugs digitoxin and digoxin are digitalis glycosides, which are used in both human and veterinary medicine to treat congestive heart failure and atrial fibrillation. They act by depressing the rate of cardiac impulses initiated by the SA node and increasing intracellular calcium, leading to slower and more forceful cardiac contraction. While they are effective drugs used in treating atrial fibrillation commonly seen with dilated cardiomyopathy, they have a narrow margin of safety, with both acute and chronic toxicity being observed. Toxic doses cause marked slowing of conduction through the AV node, potentially allowing an ectopic focus to take over as the prominent pacemaker of the heart. Increased intracellular calcium can also cause cardiac arrhythmias to develop. Clinical signs typically include ventricular tachycardia and preventricular contractions.

Abnormal triggered rhythms occur from either potassium channel blockade or intracellular calcium overload. Barium salts, which are used to create green colors in fireworks, cause intracellular trapping of potassium along with cardiac dysrhythmias, including preventricular contractions, ventricular tachycardia, or bradycardia.

Abnormal impulse conduction occurs when electrical impulses traveling through the myocardium reach an area that, due to ischemia, disease, or toxicant exposure, is not appropriately able to conduct these impulses. When these impulses are completely blocked, bradyarrhythmias may occur. Slow conduction may trigger a reentry circuit, causing either supraventricular or ventricular tachycardia. The sympathomimetic drug phenylpropanolamine has been shown to cause myocardial necrosis when ingested at toxic doses. This myocardial necrosis may be partially responsible for arrhythmias seen following toxicity (Pentel et al. 1987).

CARDIOTOXIC AGENTS

Many substances cause cardiac toxic responses directly or indirectly. However, the next section will focus on drugs that have primary cardiac toxicity.

Calcium Channel Blockers

There are several classes of calcium channel blocking drugs that are currently in use in both human and veterinary medicine. The formulations most likely to be encountered in a clinical veterinary medicine setting are verapamil, amlodipine, nifedipine, and diltiazem. These drugs are used to treat angina, supraventricular arrhythmias, and myocardial infarction in humans and supraventricular arrhythmias, hypertension, and hypertrophic cardiomyopathy in domestic pets (Hayes 2018). The calcium channel blockers affect both the myocardium and cardiac pacemaker cells. Ultimately there is slowing of impulse initiation by the SA node, conduction through the AV node, and decreased cardiac contractility. Clinical signs of overdose may include hypotension, bradycardia or tachycardia, heart block or other arrhythmias, electrolyte imbalances, vomiting, and lethargy. The calcium channel blockers are also natriuretic, acting directly on renal tubules to increase sodium excretion. Treatment for toxicity includes careful administration of intravenous fluids, as fluid overload must be avoided. If intravenous fluid therapy will not control hypotension then other treatments, such as calcium gluconate or vasopressors, may be needed. The use of intralipid (20% solution) has been shown to be very effective for the treatment of verapamil (log p 5.04) and other calcium channel blocker overdoses (Ozen et al. 2019).

Beta‐Adrenergic Blocking Agents

The beta‐blocking drugs act by inhibiting catecholamine binding to beta‐receptors in the heart, kidneys, and vascular smooth muscle. They are common drugs, used to treat hypertension, tachycardia, congestive heart failure, and glaucoma. Formulations include atenolol, esmolol, metoprolol, and propranolol. Overdose of a beta‐blocking agent is most likely to cause hypotension, bradycardia, and metabolic acidosis. Administration of intravenous fluids for blood pressure support is the most common treatment.

Angiotensin‐Converting Enzyme Inhibitors

The angiotensin‐converting enzyme (ACE) inhibitor enalapril is often one of the first drugs administered to dogs suffering from CHF, hypertension, or valvular disease. The ACE inhibitors work by blocking angiotensin II. Angiotensin II is a potent vasoconstrictor and mediator of sodium reabsorption in the kidneys. Ultimately, this leads to increased blood volume and blood pressure. By blocking angiotensin II, the ACE inhibitors lower blood pressure. In an overdose situation the primary concern is hypotension. The ACE inhibitors have a wide margin of safety in the dog and in many cases no clinical signs are noted.

Angiotensin II Antagonists

The angiotensin II antagonists are very similar to the ACE inhibitors but are not used in veterinary medicine. They are used to treat hypertension by blocking the vasoconstricting effects of angiotensin II. Clinical signs in small animal patients are not expected to be severe, but they may include hypotension and reflex tachycardia. The angiotensin II antagonists will also act synergistically with ACE inhibitors, calcium channel blockers, and beta‐blockers to cause hypotension.

Cardiac Glycosides

Digoxin is used in veterinary medicine to treat CHF, atrial fibrillation, and supraventricular tachycardias. The glycosides act by increasing intracellular calcium concentrations, leading to increased myocardial contractility. They also decrease conduction through the AV node, slowing the heart rate and allowing for more complete filling of the ventricles. Digoxin has a narrow therapeutic index, meaning that the therapeutic dose and toxic dose are very close together. In a clinical setting patients may be seen with either chronic or acute toxicity from these agents. Clinical signs may include those related to the cardiovascular system, such as heart block, tachycardia, or preventricular contractions. Other clinical signs may include gastrointestinal upset, depression, and electrolyte changes.

Pimobendan

Pimobendan is a selective phosphodiesterase III inhibitor currently approved to manage CHF in dogs. It has positive inotropic and vasodilator effects, leading to increased cardiac output and reduction in systemic vascular resistance. Pimobendan appears to have a wide margin of safety. At doses up to 3 mg/kg in dogs the most common clinical signs are hypotension, lethargy and tachycardia. Doses over 3 mg/kg may cause tachycardia and hypertension, likely due to the calcium sensitizing effects.

Sympathomimetics

Sympathomimetics have been available as a drug class since the 1st century AD when Pliny used ephedrine to treat bleeding. Sympathomimetics currently used in veterinary medicine include phenylpropanolamine, albuterol, dopamine, ketamine, and terbutaline. Pet owners may have sympathomimetics in their houses either legally in the form of methylphenidate (Ritalin®), dextroamphetamine (Adderall®), pseudoephedrine and phenylephrine or illegally in the form of cocaine or methamphetamine.

Sympathomimetics are defined as catecholamine‐like substances that have physiologic actions similar to those observed with activation of the sympathetic nervous system. They have an overall excitatory effect on the heart, and those formulations that cross the blood brain barrier cause CNS stimulation. In general, signs of overdose include mydriasis, tachycardia, hypertension, and agitation. In large overdoses, phenylpropanolamine may cause such significant hypertension that a reflex bradycardia may develop rather than the expected tachycardia (King et al. 2017). Phenylpropanolamine has also been shown to cause focal cardiac necrosis when administered to rats at doses greater than 4 mg/kg (Pentel et al. 1987).

Methylxanthines

Theophylline, caffeine, and theobromine are naturally occurring plant alkaloids. They are found in food (chocolate) and drinks (tea, coffee, colas) for human consumption, over‐the‐counter medications that promote wakefulness, and as therapeutic agents to treat asthma. Clinical signs of methylxanthine overdose may include tachycardia, premature ventricular contractions, and hypotension. Ingestion of medications containing both caffeine and ephedrine (a sympathomimetic) can cause hemorrhagic myocardial necrosis (Nyska et al. 2005).

MECHANISMS OF TOXIC INJURY TO THE VASCULAR SYSTEM

The potential for toxic injury to the vascular system may be underestimated in veterinary medicine when it is considered that all toxicants, following absorption, contact the vascular system. The vascular endothelial cells are frequently the immediate target of toxic agents, followed by the vascular smooth muscle cells. Both of these cell types are metabolically active, and systems present in these cells may bioactivate some toxicants. Oxygen‐derived free radicals formed during bioactivation may injure endothelial cells, leading to changes in permeability. Toxicants can also cause alterations in the structure of the vessels. Hypertonic intravenous solutions can cause the endothelial cells to shrink, leading to increased permeability (Weddle and Morgan 2004).

Cholecalciferol

Cholecalciferol or vitamin D₃ is the most common agent seen in veterinary medicine that does significant, lasting damage to the vascular system. Cholecalciferol (or its analogues) can be found in rodenticides, vitamins, and prescription creams for the treatment of psoriasis. Cholecalciferol overdose causes an increase in serum calcium and phosphorus levels due to increased renal tubular reabsorption of calcium, increased intestinal absorption of calcium, and increased release of calcium from bone. This excess calcium and phosphorus in the blood causes deposition of these minerals within the vascular wall. The vessel then becomes hard and rigid, and sudden death may result (Weddle and Morgan 2004).

Carbon Monoxide

Small animal patients may be exposed to carbon monoxide due to accidental exposures to automobile exhaust or household fires. Short‐term exposure to carbon monoxide can cause direct damage to vascular endothelial cells and smooth muscle cells. Carbon monoxide also causes a direct vasodilatory response on coronary circulation. The primary toxic effect of carbon monoxide is due to its reversible interaction with hemoglobin. It binds preferentially to hemoglobin, impairing oxygen delivery, which leads to cellular hypoxia (Ramos and Williams 2008). Clinical signs in the pet may include tachycardia, dyspnea, lethargy, and coma.

CONCLUSION

Ultimately any toxic exposure may cause some effect on the cardiovascular system, and an important aspect of managing toxicosis is providing support to the cardiovascular system. This typically includes intravenous fluid therapy and appropriate drugs to regulate heart rate and blood pressure.

CHAPTER 12 STUDY QUESTIONS

A cardiac drug that increases the rate of heart contraction and decreases the strength of heart contraction would be classified as

Negative chronotrope, positive inotrope

Negative chronotrope, negative inotrope

Positive chronotrope, positive inotrope

Positive chronotrope, negative inotrope

Cardiotonic

Cardiac electrical impulses stimulate the coordinated contraction of myocardial cells. These impulses are initiated by the

Interventricular node

Sinoatrial node

Submandibular node

Atrioventricular node

Popliteal node

Missy, a 12‐lb, 2‐year‐old, spayed female Maltese presents with lethargy, vomiting, and weakness. Her body temperature is 98 °F, her heart rate is 65 beats per minute, and her mean arterial blood pressure is 55 mmHg. Missy's condition is best described as

Hypothermic, bradycardic, hypotensive

Hyperthermic, bradycardic, hypertensive

Hypothermic, tachycardic, hypotensive

Hyperthermic, tachycardic, hypertensive

Hypothermic, tachycardic, normotensive

Missy's owner is concerned that the dog may have ingested one of the husband's heart medications. She is able to tell you the general class of drugs that her husband takes. Which of the following is LEAST likely to be responsible for Missy's condition?

Beta‐blocker

Calcium channel blocker

Cardiac glycoside

Sympathomimetic

ACE inhibitor

Cholecalciferol rodenticides affect the cardiovascular system by

Causing massive blood loss through disruption of normal blood coagulation.

Causing direct myocardial necrosis and fibrosis.

Causing mineralization within the walls of blood vessels.

Causing necrosis of pulmonary endothelial cells, resulting in pulmonary edema.

Causing dilation of peripheral vessels, resulting in hypotension.

ANSWERS

1. d. Chronotropy refers to heart rate and inotropy refers to force of contraction. Cardiotonic drugs increase the force of contraction (i.e., positive inotropes).

2. b. The sinoatrial (SA) node is responsible for initiation of myocardial contraction.

3. a. Missy's body temperature, blood pressure, and her heart rate are all below normal.

4. d. Sympathomimetics are cardiovascular stimulants, so they would be expected to cause hypertension and tachycardia.

5. c.

REFERENCES

DeClementi, Camille, Bailey, Keith L, Goldstein, Spencer C, and Orser, Michael S. 2004. Suspected toxicosis after topical administration of minoxidil in 2 cats. Journal of Veterinary Emergency and Critical Care 14(4):287–292.

Fox, Philip R, Sisson, David, and Moise, N Sydney (eds). 1999. Textbook of Canine and Feline Cardiology Principles and Clinical Practice, 2nd ed. Philadelphia: W.B. Saunders Company.

Hayes, Christine L. 2018. An update on calcium channel blocker toxicity in dogs and cats. Veterinary Clinics of North America: Small Animal Practice 48(6):943–957.

King, Andrew M, Malone, Eric R, and Aaron, Cynthia K. 2017. Sympathomimetic syndromes. In Critical Care Toxicology: Diagnosis and Management of the Critically Poisoned Patient, 2nd ed., edited by Jeffrey Brent, Keith Burkhart, Paul Dargan, Benjamin Hatten, Bruno Megarbane, Robert Palmer, and Julian White, pp. 549–567. New York: Springer.

Kittleson, Mark D and Kienle, Richard D. 2005. Normal physiology. In Small Animal Cardiovascular Medicine, edited by Mark D Kittleson and Richard D Kienle. St. Louis: Mosby https://www.vin.com/members/cms/project/defaultadv1.aspx?pId=5928&catId=8431&id=5496625&ind=9&objTypeID=10.

Nyska, Abraham, Murphy, Elizabeth, Foley, Julie F et al. 2005. Acute hemorrhagic myocardial necrosis and sudden death of rats exposed to a combination of ephedrine and caffeine. Toxicological Sciences 83(2):388–396.

Ozen, S Baltaci, Celebi, Hulya, Coskun, Demet, Gungor, Irfan, and Inan, Gozde. 2019. Effect of intralipid administration on calcium therapy in verapamil toxicity. Bratislavske Lekarske Listy 120(10):789–793.

Pentel, Paul R, Jentzen, Jeffrey, and Sievert, Jenny. 1987. Myocardial necrosis due to intraperitoneal administration of phenylpropanolamine in rats. Fundamental and Applied Toxicology 9(1):167–172.

Ramos, Kenneth S and Williams, E Spencer. 2008. Vascular toxicology: a cellular and molecular perspective. In Cardiovascular Toxicology, 4th ed., edited by D Acosta Jr, pp. 569–622. Boca Raton, FL: CRC Press.

Weddle, Diann L and Morgan, Sherry J. 2004. Cardiovascular system. In Clinical Veterinary Toxicology, edited by Konnie H Plumlee, pp. 48–54. St. Louis: Mosby.

13
Pulmonary System

Jeff Backus

INTRODUCTION

In toxicology terms, inhalation toxicology is used to describe the pulmonary route of exposure, while pulmonary toxicity is used to describe toxicity to the lung. Lung toxicity is often caused directly by inhaling airborne toxicants, but there are those which can enter the body via other routes and cause toxicity to the lung, such as the oral ingestion of paraquat. While the lung and alveoli are the final destinations for inhaled air, toxicity can occur in other areas of the respiratory system up to that point.

ANATOMY AND PHYSIOLOGY

Anatomy of the Respiratory Tract

Starting rostrally, the nares are the opening to the respiratory tract and open into the nasal cavity. The nasal cavity contains the nasal turbinate bones, which increase surface area within the cavity and also serve to moisten and warm inhaled air, while filtering out large particulate matter. Air that passes through the nasal cavity advances caudally through the nasopharynx. From there, the inspired air reaches the so‐called conducting airways, first passing through the trachea, then down through one of the mainstem bronchi and to smaller and smaller branches, or bronchioles, deep within the lungs. The most terminal portion of bronchioles lead to the alveoli, the functional unit of the lung and the site of exchange of inspired oxygen and the to be expired carbon dioxide. Smaller particulate matter that makes it deeper into the airways is filtered out by mucus produced by goblet cells, and is expelled via the ciliary escalator, which refers to the ciliated cells that line all parts of the respiratory tree minus alveoli, through coughing or swallowing. Much smaller particles may be removed by pulmonary macrophages. Anatomical variations amongst the veterinary species lead to variations in adverse effects (Morris et al. 1986), and variations within a species, such as the brachycephalic breeds of dogs, can lead to variations with a species (Krainer and Dupre 2022).

MECHANISMS AND PATTERNS OF RESPIRATORY TRACT INJURY

Most commonly, respiratory toxicants exert their effects directly on the respiratory tract in various ways (Woods and Wilson 2004). Gases such as methane, carbon dioxide or nitrogen displace oxygen, resulting in tissue hypoxia and hypoxemia. This is called displacement asphyxia. Other gases, such as carbon monoxide or cyanide, disrupt oxygen transport in the blood or oxygen delivery to tissues, resulting in asphyxia, even in the presence of a normal amount of environmental oxygen. Many toxicants, such as heptane, are direct irritants to the lining of the respiratory tract and can damage the epithelium therein, and can also result in loss of mucosal cells and breakdown of the ciliary escalator. These same irritants can also reach the alveoli and damage the alveolar lining, decreasing surfactant and resulting in atelectasis. Severe cases of this can result in necrosis and allow serum or blood to leak in the alveoli. When alveolar surface area is lost, gas exchange decreases and hypoxia results. Some toxicants can enter the lung from the bloodstream, damaging the alveolar capillaries, resulting in non‐cardiogenic pulmonary edema. While some toxicants may cause clinical signs rapidly, for others it may take several hours for symptoms to develop (Maddry 2017). See Table 13.1 for some common respiratory toxicants and their action on the respiratory tract.

Table 13.1. Respiratory toxicants

Source: Adapted from Woods and Wilson (2004).

Mechanism
Toxicant

Displacement asphyxiation
Carbon dioxide

Methane

Natural gas

Nitrogen gas

Oxygen transport asphyxiation
Carbon monoxide

Cyanide

Airway irritation
Ammonia

Chlorine

Phosphine (zinc/aluminum phosphide)

Increased bronchial secretions
Anticholinesterase insecticides

Muscarinic mushrooms (Clitocybe, Inocybe)

Pneumonia, aspiration
Hydrocarbons

Iatrogenic (e.g., barium, activated charcoal)

Pulmonary edema
Chlorine

Cisplatin (cats)
Heptanes

Paraquat

Phosphine (zinc/aluminum phosphide)

Pine oil

Sulfuryl fluoride (Vikane®)

Pulmonary fibrosis
Paraquat

Diagnostics and Treatment

In many cases, the first line of defense is to move the patient to fresh air and remove them from the source of the toxicant. If hypoxemia is present or suspected, supplemental oxygen may be of benefit. Hypoxemia is defined as partial pressure of oxygen in the arterial blood (PaO₂) <80 mmHg with severe hypoxemia being demonstrated with PaO₂ <60 mmHg (Heath et al. 2019). If the patient is not stable enough to perform arterial blood gas sampling, a pulse oximetry reading can be attempted, with hypoxemia being present with oxygen saturation (SpO₂) <90%. Additionally, if arterial blood gas analysis is performed, a P/F ratio (PaO₂/FiO₂ ratio, where FiO₂ is the fraction of inspired oxygen) can be evaluated to assess oxygenation. A normal P/F ratio is >500. If carbon monoxide poisoning is suspected, a CO‐oximetry evaluation is beneficial. CO‐oximetry can differentiate between oxygen‐carrying hemoglobin (oxyhemoglobin) and non‐oxygen‐carrying but normal hemoglobin (deoxyhemoglobin) from carboxyhemoglobin (COHb) and methemoglobinemia (MetHB) (Farry and Norkus 2019). With this device, a patient that has been exposed to carbon monoxide may have a normal SpO₂, but the CO‐oximeter may detect the presence of the carboxyhemoglobin.

When appropriate, thoracic radiography is indicated to assess the lungs and evaluate for the presence of pulmonary edema. Radiographic evidence of pulmonary edema can be delayed, so repeat radiographs may be indicated to evaluate for progression of disease. Aspiration or other types of pneumonia may also be noted.

Sedation is a mainstay of treatment for many of these patients. As respiratory distress progresses, patient stress increases, increasing oxygen demand and increasing respiratory rate. Mild sedating medications such as butorphanol may be beneficial in calming the patient enough to proceed with further diagnostics and treatment.

With many of the hydrocarbon agents, aspiration as a result of vomiting is of high concern due to the high volatility of these agents. Maropitant can be given for nausea or vomiting at a dose of 1 mg/kg. Monitoring for increased respiratory rate or respiratory effort after vomiting, along with signs of a new cough or wheezing, may indicate aspiration.

When indicated, furosemide may be given when pulmonary edema is present. Furosemide, 1–2 mg/kg, can be given intravenously or 1–2 mg/kg/h can be given as a constant rate infusion. It is important to monitor renal values and electrolytes with long‐term use. If bronchodilation is needed, beta‐2 adrenergic agonists such as terbutaline can be given at a dose of 0.01 mg/kg intravenously. If repeated dosing is needed, monitoring of electrolytes is recommended.

In some cases, high‐flow oxygen therapy or mechanical ventilation may be required if hypoxemia is persistent with supplemental oxygen is ineffective. If hypercapnia (PaCO₂ >60 mmHg) is present, if aspiration occurs, or if respiratory fatigue is seen, mechanical ventilation is often required. This is often associated with a worsening prognosis and considerable lengthening of treatment, while also greatly increasing the cost of treatment.

CHAPTER 13 STUDY QUESTIONS

The function of the mucociliary escalator of the respiratory tree is to

Filter out particulates to prevent them from entering deeper into the lung.

Move trapped particulates up the respiratory tree to the pharyngeal area, where they are coughed up or swallowed.

Move particulate matter deeper into the bronchi, where the particulates are engulfed by bronchiolar macrophages.

Move particulates to the rostral nasal area, where they are sneezed out.

Prevent aspiration pneumonia by moving inhaled ingesta out of the lungs.

Small particulates entering the pulmonary alveoli undergo which fate?

The particulates are moved up the respiratory tree via the mucociliary escalator.

The particulates cross the alveolar wall and enter the bloodstream.

The particulates are translocated to the alveolar interstitium, where they reside for the life of the animal.

The particulates are coughed up out of the lung to the pharyngeal area, where they are swallowed.

The particulates are engulfed by pulmonary macrophages.

Direct injury to the respiratory tissues can result in all of the following except

Loss of alveolar surfactant

Noncardiogenic pulmonary edema

Dysfunction of mucociliatory escalator

Displacement asphyxia

Atelectasis

Hypoxemia is defined as:

PaCO₂ >60 mmHg

P/F ratio >500

SpO₂ >90%

PaO₂ <80 mmHg

PaO₂ >60 mmHg

ANSWERS

1. b.

2. e.

3. d.

4. d.

REFERENCES

Farry, Trish A and Norkus, Christopher L. 2019. Monitoring the critical patient. In Veterinary Technician's Manual for Small Animal Emergency and Critical Care, 2nd ed., edited by Christopher L Norkus, pp. 45–64. Hoboken, NJ: Wiley Blackwell.

Heath, Dana J, Atkins, Lori B, and Norkus, Christopher L. 2019. Respiratory emergencies. In Veterinary Technician's Manual for Small Animal Emergency and Critical Care, 2nd ed., edited by Christopher L Norkus, pp. 111–131. Hoboken, NJ: Wiley Blackwell.

Krainer, Dorothee and Dupre, Giles P. 2022. Brachycephalic obstructive airway syndrome. Veterinary Clinics of North America Small Animal Practice 52(3):749–780.

Maddry, Joseph K. 2017. Irritant and toxic pulmonary injuries. In Critical Care Toxicology: Diagnosis and Management of the Critically Poisoned Patient, 2nd ed., edited by Jeffrey Brent, Keith Burkhart, Paul Dargan, Benjamin Hatten, Bruno Megarbane, Robert Palmer, and Julian White, pp. 1973–2002. New York: Springer.

Morris, John B, Clay, Richard J, and Cavanaugh, David G. 1986. Species differences in upper respiratory tract deposition of acetone and ethanol vapors. Fundamental and Applied Toxicology 7(4):671–680.

Woods, Leslie W and Wilson, Dennis W. 2004. The respiratory system. In Clinical Veterinary Toxicology, edited by KH Plumlee, pp. 80–88. St. Louis: Mosby.

14
Hepatobiliary System

Sharon Gwaltney‐Brant

INTRODUCTION

The liver plays a vital role in the metabolism and/or elimination of many toxicants. Through its biotransformation pathways, the liver decreases (or, less commonly, increases) the toxicity of hazardous compounds. Dysfunction from a variety of causes, including toxic insults, can limit the ability of the liver to adequately metabolize and eliminate toxicants and impair the ability of the liver to fulfill its physiologic role, resulting in a variety of metabolic derangements such as coagulopathies and hepatic encephalopathy.

ANATOMY AND PHYSIOLOGY

The liver is situated in the proximal‐most area of the peritoneal cavity, immediately distal to the diaphragm, and is divided into grossly distinguishable lobes. Closely associated with the ventral aspect of the liver in the dog and cat is the gall bladder. The liver plays a critical role in a variety of functions, including nutrient homeostasis, filtration of particulates, protein synthesis, bioactivation and detoxification, formation of bile, and biliary secretion (Roth et al. 2019). Hepatic injury due to chemicals and drugs is the most common cause of acute liver failure in humans in the United States and is the leading cause of regulatory action against drugs (Watkins and Seef 2006). Epidemiologic studies into the incidence of drug‐ and chemical‐induced liver injury in veterinary species is lacking, but as the number of pharmaceuticals, nutraceuticals, and “natural” remedies for our companion animals increases, it is likely that the incidence of drug‐induced liver injuries in companion animals will also increase.

Understanding the toxicologic changes that can occur in the liver requires an understanding of its structural and functional anatomy. When viewed microscopically, the liver appears to be composed of hexagonal lobules surrounding a central blood vessel (central vein) and bordered by six portal triads at the outer edge of each lobule; each portal triad consists of a branch from each of the hepatic artery, portal vein, and bile duct (Figure 14.1). Between the portal triads and central vein are single‐cell‐wide cords of hepatocytes arranged radially around the central vein. Between the hepatocellular cords, sinusoids carry blood from the portal triads to the central vein. In this lobule model of the liver, the lobule is divided into three areas: the centrilobular region surrounding the central vein, the periportal region at the periphery of the lobule that incorporates the portal triads, and the midzonal region between the centrilobular and periportal regions. Pathology reports on liver histology frequently use these terms associated with the lobular model of the liver (Moeller 2004).

From a functional point of view, the hepatic lobule can be divided differently based on the flow of blood as it passes through the liver. Blood enters the liver lobule through branches of the hepatic artery (carrying oxygen) and the portal vein (carrying nutrients and other absorbed compounds, including toxicants, from the gastrointestinal tract) of the portal triads. The blood then filters within the sinusoids along the cords of hepatocytes until it empties into the central vein, giving up oxygen and picking up waste as it passes from the triad to the central vein. Using the acinar model of the liver, the acinus is centered on a line from portal triad to portal triad. The area immediately around this line is termed Zone 1 and is equivalent to the periportal region. Zone 2 is equivalent to the midzonal region and Zone 3 is equivalent to the centrilobular region. Zone 1 receives blood with the highest oxygen and nutrient content, and Zone 3 is relatively oxygen and nutrient depleted. For instance, blood in Zone 1 contains approximately 9–13% oxygen compared to 4–5% in Zone 3 (Bischoff et al. 2018).

Figure 14.1. Schematic illustration of the microanatomy of the liver. Each hexagon represents a hepatic lobule centered around a central vein with portal triads at the periphery. The portal triads are each composed of a portal vein, hepatic artery, and bile duct. The central lobule is divided into the three anatomic and functional zones: Zone 1 or periportal region, Zone 2 or midzonal region, and Zone 3 or centrilobular region.

From a toxicological perspective, the acinar model tends to be more relevant because it can help predict where in the liver toxicant‐induced damage may occur (Table 14.1). Toxicants that are directly injurious to cells (e.g., iron salts, white phosphorus) will cause damage to the first hepatocytes they encounter, thus injury from these types of toxicants appears primarily in Zone 1 (periportal). Zone 3 contains a higher level of cytochrome P450 metabolic enzymes, making this area most prone to injury from compounds that are bioactivated by these enzymes (e.g., acetaminophen). Some toxicants can produce hepatocellular injury so severe that zonal patterns are lost as the entire lobule undergoes massive necrosis, with necrosis extending from portal triads to central veins.

Table 14.1. Patterns of hepatotoxicity

Causes of nonzonal hepatic injury

NSAIDs

Cyclophosphamide

Phenobarbital

Phenytoin

Sulfonamides

Ketoconazole

Causes of Zone 1 (periportal) hepatic injury

Aflatoxin

Iron salts

Organic arsenic

White phosphorus

Causes of Zone 2 (midzonal) hepatic injury

Cisplatin

Hexachlorophene (cats)

Causes of Zone 3 (centrilobular) hepatic injury

Acetaminophen

Aflatoxin

Blue‐green algae (cyanobacteria)

Castor bean (Ricinus)

Chloroform

Cycad palms (Cycas, Zamia)

Diazepam (cats)

Hepatotoxic mushrooms (e.g., Amanita phalloides)

Naphthalene

NSAIDs (e.g., carprofen, ibuprofen)

Phenols

Xylitol

Causes of massive hepatic necrosis

Acetaminophen

Cisplatin

Cycad palms (Cycas, Zamia)

Diazepam (cats)

Iron

Mebendazole (dogs)

Microcystin‐LR (Microcystis aeruginosa)

NSAIDs, nonsteroidal anti‐inflammatory drugs.

Source: Bischoff et al. (2018), Cattley and Cullen (2018), and Plumlee (2004).

In contrast to blood flow through the hepatic acinus, bile flows from the canaliculi between hepatocytes into channels that empty into the bile ducts within the portal triad; these bile ducts in turn empty into the gall bladder, which stores and concentrates bile prior to emptying the bile into the duodenum (Bischoff et al. 2018). Bile is a complex mixture of bile acids, phospholipids, proteins, and other compounds that is important in the uptake of lipids from the small intestine, protection of the small intestine from oxidative injury, and the excretion of endogenous and xenobiotic compounds (Roth et al. 2019). Biliary excretion is an important route of elimination for certain xenobiotics (e.g., ivermectin and naproxen in dogs) that are poorly excreted through the urine. Compounds excreted through the bile may undergo enterohepatic recirculation whereby the compound that is excreted into the duodenum from the bile duct is then reabsorbed and reenters the portal and systemic circulations. Compounds that undergo enterohepatic recirculation tend to have half‐lives that are measured in days rather than hours. For example, naproxen in humans is eliminated primarily through the kidneys and has a half‐life of about 6 hours. In dogs, naproxen is eliminated primarily through the bile, undergoes enterohepatic recycling, and has a half‐life of 74 hours (Frey and Rieh 1981; Talcott and Gwaltney‐Brant 2013).

MECHANISMS OF TOXICOLOGIC INJURY

The mechanisms behind hepatic injury can be divided into two categories: intrinsic and idiosyncratic. Intrinsic liver injury is a dose‐dependent, predictable reaction to a toxicant and it is the most common type of liver injury in animals (Bischoff et al. 2018). There is frequently a predictable latent period between exposure to the toxicant and the development of clinical signs of liver insufficiency. Intrinsic liver injury is often caused by highly reactive by‐products of xenobiotic metabolism, especially free radicals and electrophiles. Idiosyncratic liver injury is an unpredictable response to a xenobiotic. Idiosyncratic reactions are rare and non‐dose‐dependent, and may be associated with extrahepatic lesions. Idiosyncratic reactions frequently occur following unremarkable initial exposure (sensitization) and manifest on re‐exposure to the xenobiotic. With idiosyncratic drug reactions, it is not uncommon for there to be a delay of a few weeks to several months between the time of initial exposure and development of liver injury. Extrahepatic changes associated with idiosyncratic drug reactions may include fever and dermal erythema or rash.

Free Radical‐Induced Injury

The generation of free radicals within hepatocytes can occur during xenobiotic biotransformation, normal metabolic processes involving oxidation/reduction reactions, inflammatory states (mediated by nitric oxide [NO]), and exposure to ionizing radiation (Bischoff et al. 2018). Free radicals have unpaired electrons, which make them highly susceptible to binding to other macromolecules, including lipoproteins of cell membranes, enzymatic proteins, and DNA. Binding of free radicals to cellular macromolecules generates even more free radical production, resulting in an escalating effect. Normally cells have scavenger molecules (e.g., glutathione) to react with and detoxify free radicals, but excessive free radical production can result in depletion of scavenger stores, resulting in increased binding of free radicals to vital cellular structures. Free radical damage can cause alterations of cell membrane permeability, inactivation of membrane‐associated proteins, and loss of polarity to mitochondrial membranes. Inactivation of enzymatic proteins can interfere with normal cellular metabolism, leading to cellular degeneration or necrosis. Free radical‐induced DNA damage can result in interference with transcription or translation, resulting in decreased protein synthesis.

Calcium Homeostasis Disruption

Within the cell, calcium is sequestered within organelles such as mitochondria and the endoplasmic reticulum, which maintain a relatively low level of calcium within the cytosol. Xenobiotics that interfere with the pumps that maintain calcium balance can result in increased release of calcium into the cytosol. The released calcium ions impede normal cytoskeletal function and activate a variety of cytosolic enzymes, including ATPases, phospholipases, and proteases. Subsequently, mitochondrial membrane permeability increases, which causes induction of necrosis and apoptosis (programmed cell death) (Bischoff et al. 2018).

Mitochondrial Injury

Mitochondria are the source of energy production within the cell, and toxicants that disrupt mitochondrial function can result in cell death. Toxicants induce mitochondrial injury by altering mitochondrial DNA, interfering with oxidative phosphorylation, damaging mitochondrial membranes, or inactivating mitochondrial enzymes.

Cytoskeletal Disruption

The cytoskeleton of the cell is vital to maintaining the normal shape and position of hepatocytes. Agents that damage cytoskeletal structure result in cellular deformation and detachment. The cyanobacterial toxin microcystin‐LR, produced by Microcystis aeruginosa, causes hepatocellular cytoskeletal injury and severe liver damage (Cattley and Cullen 2018).

Cholestasis

Toxicants that interfere with bile transport can result in cholestasis, leading to injury to biliary ducts and hepatocytes. Bile duct hyperplasia and biliary fibrosis may result. Cholestasis can also occur secondary to hepatocellular swelling due to degeneration or lipidosis. Clinically, cholestatic disorders can result in dermal photosensitization, whereby areas of skin exposed to the sun develop burns similar to sunburn. Epidermal and dermal burns from photosensitization are rapid in onset and occur following exposure to wavelengths of light that would cause no injury in normal animals. Animals with white areas on their haircoats and unpigmented skin are most susceptible to photosensitization. In veterinary medicine, photosensitization is more commonly seen in large animals grazing plants that cause bile stasis, but it has occasionally been reported in dogs with hepatic injury.

Idiosyncratic Reactions

Many idiosyncratic drug reactions are considered to be immune‐mediated, triggered by the formation of adducts of reactive drug metabolites with cellular macromolecules. These adducts are identified by the immune system as foreign, and an immune response is mounted, leading to death of individual hepatocytes (“piecemeal necrosis”). This mechanism has been postulated, but not proven, as the mechanism by which the nonsteroidal anti‐inflammatory drug carprofen causes idiosyncratic liver injury in dogs (McPhail et al. 1998). The exact mechanisms of other types of idiosyncratic liver injury await further study to be elucidated.

PATTERNS OF TOXICOLOGIC INJURY

Toxic hepatic injury can manifest as hepatocellular degeneration, hepatocellular necrosis, immune‐mediated injury, biliary disorders, and sinusoidal disorders.

Hepatocellular Degeneration

Hepatocellular degeneration is a common, nonspecific response of the liver to toxic insult. Hepatocellular degeneration represents a sublethal insult to the liver that can often resolve if the inciting cause is removed. Although some cellular processes may be altered, the degenerative hepatocyte still retains some degree of functional integrity. Degenerating hepatocytes are generally swollen and may accumulate various compounds, including metals, pigments, water, and lipids. It is important to realize that in most situations the accumulation of these compounds is a result of some form of hepatocellular dysfunction rather than the primary cause of hepatocellular degeneration.

Hepatic Lipidosis

Hepatic lipidosis (steatosis, fatty liver) is a form of hepatocellular degeneration characterized by accumulation of lipid within the hepatocyte cytosol. Lipidosis can be the result of transient disruptions in lipid metabolism or it can reflect a more serious metabolic condition. Severe lipid accumulation can result in sufficient hepatocellular swelling to cause cholestasis.

Hepatocellular Necrosis or Apoptosis

Both hepatocellular necrosis and apoptosis represent death of hepatocytes, with the difference being that apoptosis is a controlled, orderly “shutdown” of cellular processes leading to death of the cell. Necrosis occurs when cells are subject to insurmountable insults resulting in loss of cellular membrane integrity and disruption of cellular machinery. What follows is cellular swelling, leakage of cellular contents into the adjacent environment, disintegration of nuclear material, and an influx of inflammatory cells to remove cellular debris (Roth et al. 2019). Because the necrotizing insult is generally locally intense, whole groups of hepatocytes, as well as support structures, may be affected. In contrast, apoptosis results when enzymes termed caspases trigger the activation of various cytosolic and nuclear enzymes that compartmentalize cellular structures and proceed to shut down cellular activity. Apoptotic cells are shrunken, with condensed cytosol and fragmented nuclei that pinch off along with the cell membrane (which has remained intact) to form apoptotic bodies. Apoptotic bodies are then phagocytized by hepatic macrophages (Kuppfer cells) or are taken up into adjacent hepatocytes without inciting an inflammatory response. Apoptosis is the means by which normal tissues eliminate unneeded or senescent cells, and it generally affects single cells. Apoptosis can be triggered by a variety of external stimuli, including ionizing radiation, drugs (nonsteroidal anti‐inflammatory drugs, corticosteroids), and physiologic conditions such as stress.

HEALING AND REPAIR

The liver has a tremendous capacity for regeneration—so much so that human liver transplants can be done from liver lobes donated by living donors. Following successful transplant, both recipient and donor will eventually regenerate sufficient hepatic parenchyma to have normal liver function. As with most organs that have regenerative ability, the capacity to regenerate is dependent on the retention of the basic tissue scaffold. Conditions that result in loss of this scaffold can result in hepatic healing via fibrosis instead. Fibrosis occurs most commonly along the terminal plates at the edges of the hepatic lobule and surrounding the central vein. Fibrous tissue that bridges between the portal triad and central vein can result in loss of functional integrity of the acinus. Regenerative nodules of hepatocytes within bands of fibrous tissue are often disconnected from access to central veins and are minimally functional. Cirrhosis is the term in human medicine for the end‐stage form of liver injury, with irregular patches of fibrous tissue surrounding rounded nodules of hepatocytes.

Although the liver has a high regenerative capacity, massive acute loss of hepatocytes can result in death from liver failure if insufficient hepatocytes remain to allow the patient to survive long enough for regenerated hepatocytes to begin to function.

CHAPTER 14 STUDY QUESTIONS

Milo, a 2‐year‐old, 135‐lb, neutered male St. Bernard dog has been successfully treated for acute hepatic insufficiency. A liver biopsy had been taken and the pathology report indicated that there was substantial centrilobular necrosis. All of the following toxicants are potential causes for Milo's liver injury except

Iron

Blue‐green algae (cyanobacteria)

Acetaminophen

Hepatotoxic mushrooms

Xylitol

In what way does enterohepatic recirculation alter the kinetics of a xenobiotic?

Increases elimination

Increases absorption

Shortens the half‐life

Lengthens the half‐life

Enhances metabolism

Intrinsic liver injury is characterized by all of the following except

Dose‐dependent

Predictable latent period

Rare in animals

Often caused by free radicals and electrophiles

Predictable clinical course

Cyanobacteria (blue‐green algae) induce liver injury by which of the following mechanisms?

Free radical formation

Disruption of calcium homeostasis

Cytoskeletal damage

Immune‐mediated mechanisms

Cholestasis

ANSWERS

1. a. Iron causes primarily periportal or Zone 1 injury in the liver.

2. d. Enterohepatic recirculation increases the half‐life of a xenobiotic.

3. c. Intrinsic liver injury is the most common type of liver injury identified in animals.

4. c. Cyanobacteria disrupt the structural support of hepatocytes resulting in cytoskeletal failure.

REFERENCES

Bischoff, Karyn, Mukai, Motoko, and Ramaiah, Sashi K. 2018. Liver toxicity. In Veterinary Toxicology: Basic and Clinical Principles, 3rd ed., edited by Ramesh C Gupta, pp. 239–258. London: Elsevier.

Cattley, Russel C and Cullen, John M. 2018. Liver and gall bladder. In Fundamentals of Toxicologic Pathology, 3rd ed., edited by Matthew A Wallig, Wanda M Haschek, Colin G Rousseaux, Brad Bolon, and Beth W Mahler, pp. 125–152. London: Elsevier.

Frey, Hans‐Hasso and Rieh, B. 1981. Pharmacokinetics of naproxen in the dog. American Journal of Veterinary Research 42(9):1615–1617.

McPhail, Catriona M, Lappin, MR, Meyer, DJ, Smith, SG, Webster, CR, and Armstrong, PJ. 1998. Hepatocellular toxicosis associated with administration of carprofen in 21 dogs. Journal of the American Veterinary Medical Association 212(12):1895–1901.

Moeller, Robert B. 2004. Hepatobiliary system: toxic response of the hepatobiliary system. In Veterinary Clinical Toxicology, edited by Konnie H Plumlee, pp. 61–68. St. Louis: Mosby.

Plumlee, Konnie H. 2004. Hepatobiliary system: differential diagnosis. In Veterinary Clinical Toxicology, edited by Konnie H Plumlee, p. 61. St. Louis: Mosby.

Roth, Robert A, Jaeschke, Hartmut, and Luyendyk, James P. 2019. Toxic responses of the liver. In Casarett and Doull's Toxicology, the Basic Science of Poisons, 9th ed., edited by Curtis D Klaasen, pp. 719–766. New York: McGraw‐Hill Medical.

Talcott, Patricia A and Gwaltney‐Brant, Sharon M. 2013. Nonsteroidal antiinflammatories. In Small Animal Toxicology, 3rd ed., edited by Michael E Peterson and Patricia A Talcott, pp. 687–708. St. Louis: Saunders.

Watkins, Paul B and Seef, Leonard B. 2006. Drug‐induced liver injury: summary of a single topic clinical research conference. Hepatology 43:618–631.

15
Urinary System

Erin Freed

INTRODUCTION

This chapter focuses on the basic anatomy and physiology of the urinary system, the mechanisms and patterns of toxicological injury, including common toxic substances that affect the urinary system, and the healing and repair after toxicological damage.

ANATOMY AND PHYSIOLOGY

The urinary system of dogs and cats consists of the kidneys, ureters, bladder, and the urethra. The function of the urinary system is to filter blood, reabsorb important nutrients, and eliminate waste in the form of urine. The kidneys regulate the amount of water reabsorbed and excreted, maintain the pH of the blood, and control the concentration of electrolytes (Na, K, Ca, and Cl), proteins, and hormones in the blood. Additionally, the kidneys secrete hormones that regulate blood pressure, water balance, red blood cell production, and calcium homeostasis (Khan et al. 2018). The kidneys receive approximately 25% of the cardiac output and can be divided into three main parts: the outer cortex, which receives 90% of the renal blood flow; the medulla, which receives 6–10% of blood flow; and the renal papilla, which receives 1–2% of the total renal blood flow.

The functional unit of the kidney is the nephron, which is composed of a glomerulus, proximal convoluted tubule, loop of Henle, distal tubule, and collecting duct. The glomerulus is composed of an anastomosing tuft of fenestrated endothelial cells that form a filter for the blood, with the initial filtrate flowing into Bowman's space surrounding the glomerulus and progressing into the proximal tubule. The renal tubules reabsorb 60–80% of the filtered solute, including water, electrolytes, glucose, amino acids, small peptides, and organic acids. In the medulla, the loops of Henle play a significant role in the concentration of urine and maintenance of the blood's electrolyte balance. The filtrate then passes into collecting ducts, which control the excretion rates of electrolytes and urea as well as further maintain acid/base and water balances. The renal papilla empties the urine through the renal pelvis into the ureters. From the ureters the urine passes into the bladder, where it is stored until it is excreted through the urethra.

Renal function is mostly measured clinically by the serum renal markers blood urea nitrogen (BUN) and creatinine; due to the reserve capacity of the kidney, approximately 60–75% of nephrons must be damaged before these values become significantly elevated. Azotemia, the term for elevations of serum BUN and creatinine, can occur due to prerenal, renal, and postrenal causes. Prerenal azotemia is most commonly the result of dehydration and occurs without renal insufficiency. Renal azotemia is caused by kidney dysfunction, generally due to injury by infectious, metabolic, toxic, or neoplastic processes. Postrenal azotemia is usually associated with obstruction (urolithiasis) or rupture (uroabdomen) of urinary outflow tracts. Determination of whether azotemia is prerenal, renal, or postrenal is essential to aid in the diagnosis and therapeutic management of the patient. When azotemia is present along with the clinical signs associated with renal failure (vomiting, gastrointestinal bleeding, gastritis, depression, weight loss, oliguria/anuria/polyuria), the condition is termed uremia.

MECHANISMS OF TOXICOLOGICAL INJURY

Renal tubular injury is the most common form of nephrotoxic insult in animals (Khan et al. 2018). Tubular damage may result from direct injury to the epithelial cells by the toxicant or its metabolites, from mechanical obstruction of the tubules, from mineralization of the basement membrane, or from ischemia due to vasoconstriction of renal blood vessels. Toxicants such as lead, arsenic, aminoglycoside antibiotics, and many anticancer drugs cause direct injury to the tubular epithelium. Renal epithelium, particularly in the proximal tubules, contains high levels of metabolic enzymes that can detoxify some compounds present in the filtrate. However, other compounds (e.g., diquat, acetaminophen) can be bioactivated into toxic metabolites by these same enzymes and result in injury to the epithelial cells. Pigments such as hemoglobin (e.g., due to intravascular hemolysis from zinc toxicosis) or myoglobin (e.g., due to muscle damage from monensin toxicosis in dogs) are also directly injurious to the renal tubular epithelium.

Some toxicants will result in the precipitation of crystals into the urine as the tubular filtrate becomes more concentrated. Overdoses of drugs such as penicillins, cephalosporins, and acyclovir may result in transient crystalluria, and the crystals can cause mild epithelial damage, which is usually reversible. Tubular obstruction by calcium oxalate crystals is a major cause of renal injury in ethylene glycol intoxication; however, direct tubular epithelial injury due to acidosis also contributes to lesions seen in ethylene glycol toxicosis. Mineralization (deposition of calcium) of renal tubules can result from hypercalcemia associated with some toxicoses (e.g., cholecalciferol rodenticide toxicosis) and can also occur as a sequela of uremia. Mineralization along the tubular basement membrane, within epithelial cells and within renal blood vessels (impeding blood flow), results in degeneration and necrosis of tubular epithelial cells, cell sloughing, and decreased tubular regenerative ability.

Agents that cause vasoconstriction can impede glomerular filtration as well as cause ischemic damage to the renal tubules. The renal papilla is especially susceptible to ischemic injury because it normally receives only 1% of total renal blood flow, but any portion of the nephron may be affected. Nonsteroidal anti‐inflammatory drugs (NSAIDs; e.g., ibuprofen, aspirin, phenylbutazone) decrease prostaglandin levels within the kidney, decreasing prostaglandin mediated vasodilation and resulting in vessel constriction (Gwaltney‐Brant 2018). Other agents (e.g., the antifungal amphotericin B) induce vasoconstriction by direct interaction with renal arterioles (Sawaya et al. 1995).

Injury to renal tubules impairs water and solute reabsorption, resulting in dilute urine (isosthenuria) due to loss of concentrating ability, as well as spillage of amino acids, glucose, small peptides, and other solutes into the urine. Polyuria will occur unless the tubules become obstructed by swollen tubular epithelium, crystals, sloughed epithelial cells, pigments, or other debris; in these instances, oliguria or anuria can occur. When blockages occur, increased tubular pressure counteracts the capillary hydrostatic pressure in the glomerulus, resulting in further decrease in glomerular filtration. A nephron that has damaged tubules can leak filtrate into the systemic circulation, contributing to azotemia as BUN and creatinine are reintroduced into the bloodstream from the damaged tubules.

PATTERNS OF TOXICOLOGICAL INJURY

Nephrotoxic agents can cause renal insufficiency that may progress to acute kidney injury (AKI) or chronic kidney disease (CKD) depending on the toxicant involved, dose, and duration of exposure. AKI often results from exposure to a relatively high dose of a nephrotoxic agent, causing sudden loss of kidney function, whereas CKD tends to occur more insidiously and may be the result of repeated insults to the kidney (e.g., from repeated exposures to nephrotoxins over time) or may reflect the progression of acute disease. An individual may be more susceptible to toxic renal damage due to genetic factors, age, prior renal disease, general overall health, or concurrent medication administration. For example, dogs are a species with a unique sensitivity to tartaric acid, which is the suspected toxic component in grapes and raisins, leading to AKI after ingestion of the fruit (Wegenast et al. 2022). Patients with CKD oftentimes adapt to their renal disease and may maintain a relatively normal clinical appearance for quite some time despite high elevations of serum BUN and creatinine (compensated CKD). Generally, these patients display polyuric renal failure and can maintain themselves, provided they have access to adequate fresh water to compensate for the increased fluid losses. However, with progression of the renal disease or sudden change in hydration status, these patients may suddenly decompensate and present with clinical signs like an AKI patient.

Because of its high blood flow, high metabolic activity, and concentration of wastes, the kidney is especially susceptible to toxic injury. While the glomeruli and proximal tubules are exposed to large amounts of bloodborne toxicants, the more distal aspects of the nephron and lower urinary tract are exposed to higher concentrations of toxicants for a longer period of time as a result of accumulation of toxicants within tubular lumens.

Renal toxicants may cause glomerular damage, resulting in a decrease in glomerular filtration and resulting in azotemia, or increasing the “pore” size of the glomerular filter, resulting in the leakage of proteins into the urine. Renal toxicants affecting glomeruli are rare in animals, although some rattlesnake venoms have been associated with glomerular injury (Fitzgerald and Rumbeiha 2004).

Their relatively high metabolic activity, high content of metabolic enzymes, and closer proximity to glomerular filtrate make the proximal tubules more susceptible to a wider range of toxicants than the rest of the nephron (Gwaltney‐Brant 2018). In domestic animals, the proximal renal tubules are most affected by nephrotoxicants, although the distribution of tubular lesions can vary depending on the toxicant involved. For example, tubular injury from melamine:cyanuric acid crystals, the lesion seen in the kidneys of animals affected by melamine‐contaminated pet foods in the United States in 2007, tends to occur in the distal tubules and collecting ducts, whereas calcium oxalate crystals from ethylene glycol metabolism tend to affect primarily the proximal tubules (Puschner et al. 2007). In nephrons undergoing degeneration necrosis, affected tubular cells will swell, then shrink and slough. Cellular debris from damaged tubules manifests as granular casts in the urine sediment.

Damage to the renal papilla can disrupt the loops of Henle, resulting in loss of urine‐concentrating ability as well as electrolyte imbalances. Toxic damage to the distal areas of the urinary tract—renal pelvis, ureters, urethra, and bladder—is relatively uncommon. The rapid flushing of urine through the pelvis, ureters, and urethra may explain their relative resistance to toxicologic injury. The urinary bladder, because it stores urine, has occasionally been associated with syndromes arising from toxicants (e.g., cyclophosphamide‐induced cystitis).

HEALING AND REPAIR OF THE URINARY SYSTEM

Because much of the nephron is composed of epithelial cells there is potential for cellular regeneration following toxic injury, provided the tubular basement membrane has remained intact and adequate residual epithelial cells are present. Regeneration of the tubular epithelium is usually visible microscopically within 3 days of insult, but it can take up to 3 weeks for the tubules to return to normal structure (Khan et al. 2018) and up to several more weeks for return to full renal function. The glomerulus tends to be less forgiving, and glomeruli damaged by toxic insults may be permanently dysfunctional (Table 15.1).

Table 15.1. Nephrotoxicants

Lesion
Toxicant
Species

Nephrosis (renal tubular degeneration and necrosis)
Aminoglycoside antibiotics (gentamicin, amikacin)
Amphotericin B
Antineoplastics (cisplatin)
Diquat/paraquat
Ethylene glycol
Lilies (Lilium and Hemerocallis)
Melamine
Metals (lead, mercury, arsenic, cadmium)
Dogs, cats
Dogs, cats
Dogs, cats
Dogs, cats
Dogs, cats
Cats
Dogs, cats
Dogs, cats

Nonsteroidal anti‐inflammatory drugs (ibuprofen, phenylbutazone, carprofen, deracoxib)
Dogs, cats

Tartaric acid (grapes/raisins/Zante currants/sultanas [Vitis spp.], tamarinds, cream of tartar)
Dogs

Zinc phosphide
Dogs, cats

Mineralization
Cholecalciferol and analogues (vitamin D₃, cholecalciferol rodenticides, calcitriol, calcipotriene)
Dogs, cats

Glomerular injury
Rattlesnake venom
Dogs, cats

Bladder injury
Cyclophosphamide
Dogs, cats

CHAPTER 15 STUDY QUESTIONS

The most common form of renal injury in animals is

Glomerular injury

Renal tubular injury

Interstitial injury

Tubulointerstitial injury

Papillary necrosis

In renal tubular injury, the most common manifestation is _____________, except when massive necrosis of tubular epithelial cells results in occlusion of the lumens of renal tubules, in which case _________________ or ______________________ may occur.

Anuria, polyuria, oliguria

Oliguria, polyuria, anuria

Oliguria, anuria, polyuria

Polyuria, oliguria, anuria

Anuria, oliguria, polyuria

Cellular debris from damaged renal tubules can be seen in the urinary sediment in the form of

Hyaline casts

Oxalate crystals

Granular casts

Struvite crystals

Dhole bodies

The ability of renal tubular epithelium to regenerate depends on the presence of sufficient residual cells and on the integrity of the

Renal papilla

Interstitium

Glomerular mesangium

Tubular basement membrane

Vascular endothelium

ANSWERS

1. b. Tubular injury is the most common form of renal injury in animals.

2. d. Polyuric renal insufficiency is the most common manifestation of renal tubular injury.

3. c. Granular casts.

4. d. The integrity of the renal tubular basement membrane is considered an essential factor in whether tubular epithelium can regenerate following an injury.

REFERENCES

Fitzgerald, Scott D and Rumbeiha, Wilson K. 2004. Urinary system. In Clinical Veterinary Toxicology, edited by Konnie H Plumlee, pp. 91–96. St. Louis: Mosby.

Gwaltney‐Brant, Sharon M. 2018. Renal toxicity. In Veterinary Toxicology Basic and Clinical Principles, 3rd ed., edited by Ramesh C Gupta, pp. 259–271. London: Elsevier Inc.

Khan, Kanwar NM, Hard, Gordon C, Li, Xiantang, and Alden, Carl L. 2018. Urinary system. In Fundamentals of Toxicologic Pathology, 3rd ed., edited by Matthew A Wallig, Wanda M Haschek, Colin G Rousseaux, Brad Bolon, and Beth W Mahler, pp. 213–271. London: Elsevier.

Puschner, Birgit, Poppenga, Robert H, Lowenstine, Linda J, Filigenzi, Michael S, and Pesavento, Patricia A. 2007. Assessment of melamine and cyanuric acid toxicity in cats. Journal of Veterinary Diagnostic Investigation 19(6):616–624.

Sawaya, BP, Briggs, JP, and Schnemann, J. 1995. Amphotericin B nephrotoxicity: The adverse consequences of altered membrane properties. Journal of the American Society of Nephrology 6(2):154–164.

Wegenast, Colette A, Meadows, Irina D, Anderson, Rachele E, Southard, Teresa, Barrientos, Gonzalez, Cristy, R, and Wismer, Tina A. 2022. Acute kidney injury in dogs following ingestion of cream of tartar and tamarinds and the connection to tartaric acid as the proposed toxic principle in grapes and raisins. Journal of Veterinary Emergency and Critical Care 32(6):812–816.

16
Other Systems

Tina Wismer

INTRODUCTION

Other systems can also be affected by toxicants. Special senses such as seeing and hearing will not be discussed here.

ALIMENTARY TRACT

Many conditions, toxic and nontoxic, can cause gastrointestinal signs (nausea, hypersalivation, vomiting, abdominal discomfort, and diarrhea) (see Figure 16.1). This makes a diagnosis of alimentary tract toxicosis difficult. When presented with a patient displaying gastrointestinal signs, the list of potential differential diagnoses is quite long. Patients presenting with gastrointestinal signs should be worked up thoroughly to rule out other potential etiologies. Infectious, inflammatory, metabolic, nutritional, neoplastic, and mechanical (e.g., foreign body) diseases need to be considered in addition to toxic agents. Table 16.1 lists toxicants that have a primary effect on the gastrointestinal tract.

Many agents that damage the alimentary tract do so by causing erosion or ulceration to the tissues (Wallig 2018). Erosion is the loss of integrity of the superficial mucosal (epithelial) layer of the alimentary tract. Ulceration occurs when the lesions extend deeper into the tissues, penetrating into the blood vessels and tissues of the submucosa. Perforation is a full‐thickness defect in the wall of the gastrointestinal tract leading to leakage of ingesta into the pleural (esophageal perforation) or peritoneal cavity.

Oral Cavity

The most common toxicological injuries to the oral cavity are direct irritation or corrosion. Irritants (e.g., insoluble calcium oxalate crystals) cause discomfort and possibly mild erythema but do not compromise the integrity of the oral mucosa. Corrosive agents (acids, alkalis, cationic detergents) cause chemical burns to the tissues of the oral cavity that can result in severe pain, extensive tissue damage, and, potentially, sloughing of oral tissues (e.g., tongue). In severe cases, damage to pharyngeal and/or esophageal tissues may also occur.

Gastrointestinal Tract

Toxic injury to the gastrointestinal tract can occur through several mechanisms (Wallig 2018). Mild gastrointestinal irritation can occur from agents such as hydrocarbons, household detergents, and insoluble calcium oxalate‐containing plants. These agents will cause local irritation, leading to nausea (often manifested by hypersalivation), vomiting, and/or diarrhea, but they are not appreciably absorbed and are not expected to cause any systemic signs. (Note: volatile hydrocarbons such as gasoline have a high risk of aspiration if vomiting occurs, which can result in aspiration pneumonia; see Chapter 29). Intense vomiting caused by these agents may result in rupture of gastric blood vessels, leading to blood‐tinged vomitus. Corrosive injury resulting in erosion, ulceration, and/or perforation of the gastrointestinal tract can occur through ingestion of corrosive agents such as acids, alkalis (e.g., leaking alkaline batteries), or cationic detergents, resulting in gastrointestinal hemorrhage. Agents that alter blood supply to the gastrointestinal mucosa (e.g., nonsteroidal anti‐inflammatory drugs, arsenic) can cause injury due to hypoxia, resulting in necrosis, ulceration, and/or perforation. Toxicants that damage the rapidly dividing cells of the mucosal crypts (e.g., colchicine, 5‐fluorouracil) can result in villous atrophy and loss of absorptive capacity of the gastrointestinal tract; this type of injury is sometimes termed radiomimetic because the lesion resembles that seen following exposure to ionizing radiation. Some gastrointestinal toxicants alter the absorption of water or nutrients without causing significant physical derangement of gastrointestinal tissues. For example, cadmium can alter the absorption of calcium from the gastrointestinal tract (Wallig 2018), while compounds having a laxative effect (e.g., high viscosity hydrocarbons) can result in decreased nutrient absorption due to rapid gastrointestinal transit time as well as increased water loss due to diarrhea. Other toxicants can reduce (e.g., opioids) or increase (e.g., organophosphorous insecticides) motility by altering the neuromuscular activity of the gastrointestinal tract.

Figure 16.1. Dog is alert but hypersalivating. There are many differentials to be ruled out.

Photograph courtesy of Pamela Rohlfing.

HEMATOPOIETIC

Many toxicants can alter the number, structure, or function of hematic cells (red blood cells, white blood cells, platelets) (Ramaiah et al. 2018). Some agents (e.g., estrogen, 5‐fluorouracil) can result in suppression of bone marrow with decreased red and/or white blood cell production. Other agents (e.g., lead) can cause anemia by inhibition of enzymes that allow normal red blood cell maturation. Certain oxidative compounds (e.g., acetaminophen metabolites, garlic) can denature hemoglobin to form methemoglobin within red blood cells. Other oxidants (e.g., zinc, naphthalene) cause nonimmune‐mediated hemolytic anemia. Platelet function can be altered by toxicants such as aspirin, and platelet numbers can be reduced through the action of toxicants such as estrogen. Alteration of coagulation factors can result in uncontrolled hemorrhage, such as that seen with anticoagulant rodenticides. Anticoagulant rodenticides inhibit vitamin K epoxide reductase, preventing the recycling of vitamin K and the formation of vitamin K‐dependent clotting factors. When existing clotting factor stores are depleted, hemorrhage occurs. Some toxicants inhibit the ability of the blood to carry oxygen or to deliver oxygen to tissues (e.g., carbon monoxide, cyanide). Table 16.2 lists some common hematopoietic toxicants.

The sensitivity of the feline red blood cell to oxidative injury is well known, and it is no surprise that cats are more sensitive to oxidant‐induced hemoglobin damage. A large part of this sensitivity is due to the fact that cats have eight sulfhydryl groups on each hemoglobin molecule, compared to four in dogs and two in humans (Bischoff 2018). These sulfhydryl groups are highly reactive areas of the molecule and interact with oxidants such as the acetaminophen metabolite para‐aminophenol, which denatures the hemoglobin molecule to form methemoglobin (McConkey et al. 2009). Additionally, compared to other species, cat red blood cells are relatively deficient in methemoglobin reductase, resulting in a diminished ability to convert methemoglobin back to hemoglobin (Bischoff 2018).

INTEGUMENTARY

The skin is the largest organ in the body and acts as a barrier against exogenous injury and excessive water loss (Diegel et al. 2018). The skin has an outer epidermis composed of an outer stratum corneum that consists of keratinized epithelium and an inner basal layer of proliferating epithelial cells that replenish the stratum corneum as they mature into keratinocytes. The thickness of the epidermis varies significantly between species and is relatively thin in dogs and cats compared to many other species. The dermis is the tissue immediately under the epidermis and is composed of fibrous connective tissue, blood vessels, and adnexal structures such as hair follicles and sebaceous glands. Beneath the dermis is the subcutaneous adipose tissue.

Toxicants that are lipophilic can more readily penetrate the outer layers of the epidermis to reach the more metabolically active cells in the lower epidermis (Diegel et al. 2018). This is why many topical products feel “greasy.” These cells have the ability to metabolically deactivate many potential toxicants, preventing them from reaching the dermis. Compounds reaching the dermis may be removed through the blood or lymphatics. In this way, the skin serves as an effective barrier against a large number of potential toxicants. Some highly lipophilic organic solvents (e.g., dimethyl sulfoxide) have the ability to penetrate these layers and can be used as “carriers” to aid other molecules in passing through the integument.

Table 16.1. Toxicants affecting the gastrointestinal tract

Mechanism (Clinical Effects) | Toxicant | Comment
Irritation (hypersalivation, nausea, vomiting, diarrhea, abdominal discomfort) | Bleach | Household bleaches are irritants; industrial/commercial strength may be corrosive
Boric acid | Ant baits, borax powder
Cycad palms | Primary concern is liver injury
Detergents | Household cleaners, shampoos, and soaps
Fertilizers | Other ingredients (e.g., insecticides, herbicides) may pose other risks
Hydrocarbons/petroleum products | Risk of aspiration of volatile hydrocarbons
Ice melts | See corrosive injury
Insoluble calcium oxalate‐containing plants | Aglaonema, Alocasia, Colocasia, Anthurium, Arisaema, Arum, Caladium, Calla, Dieffenbachia, Epipremnum, Monstera, Philodendron, Scindapsius, Spathiphyllum, Symplocarpus, Syngonium, Xanthosoma, Zantedeschia and others
Ornamental bulb plants | Amaryllus, Crocus, Hyacinthus, Iris, Narcissus, Tulipa, and others
Zinc | US pennies minted after 1983 (also cause hemolysis), zinc oxide ointments
Corrosive injury (similar to irritants but more severe; can see oral, pharyngeal, or esophageal burns; gastric ulceration, hematemesis, melena, or hematochezia) | Acids | Car/boat batteries, drain openers, oven cleaners, etching compounds, gun barrel cleaners, pool sanitizers, rust removers
Alkalis | Anhydrous lime, cement, drain openers, fabric softeners, industrial strength bleaches, liquid dishwasher detergents, low phosphate laundry detergents, pool chemicals
Batteries | Car/boat batteries contain acid; alkaline and disk batteries contain alkali
Calcium chloride ice melts | Corrosive to gastrointestinal tract and skin
Cationic detergents | Disinfectants, sanitizers, pool algicides
Essential oils | Concentrated forms can be corrosive
Phenols | Concentrations <5% are corrosive; lower concentrations are found in household cleaners, sore‐throat lozenges, gargles, ointments, mouthwashes
Altered mucosal blood flow (leads to gastrointestinal hemorrhage) | Arsenic | Damages endothelium of gastrointestinal mucosa, causing submucosal hemorrhage
Cadmium | Inhibition of prostaglandin formation, resulting in decreased blood flow
Nonsteroidal anti‐inflammatory drugs | Inhibition of prostaglandin formation, resulting in decreased blood flow
Epithelial cell necrosis (hemorrhagic gastroenteritis, ± mucosal shreds) | 5‐Fluorouracil | Topical treatments for skin cancers, dermatosis
Abrus precatoris (precatory pea, rosary pea) | Damage to seed coat (e.g., chewing) allows toxin release
Colchicine | Pharmaceutical, autumn crocus (Colchicum), glory lily (Gloriosa)
Corrosives | See Corrosive injury above
Iron salts | Vitamins, fertilizers, hand warmers
Methotrexate | Rheumatoid arthritis medications, anticancer therapy
Quercus spp. (oak) | Tannins are toxic principle precipitate proteins
Ricinus communis (castor bean) | Damage to seed coat (e.g., chewing) allows toxin release
Impeded nutrient or water absorption (weight loss, dehydration) | Cadmium | Inhibits calcium absorption, alters fat and protein metabolism
| Ethanol | Reduces absorption of B vitamins and carbohydrates
Laxatives | Increases gastrointestinal transit time, resulting in decreased time for nutrient absorption; osmotic laxatives can decrease free body water stores
Altered motility |  |
Hypomotility (constipation, obstipation, ileus) | Opioids | Decreases gastric emptying and gut contractility through local and central effects
Hypermotility (watery diarrhea, ± blood) | Organophosphorus or carbamate insecticides | Overstimulation of cholinergic receptors enhances gastrointestinal smooth muscle contraction

There are three basic mechanisms of toxic skin injury: (1) direct injury to the skin, (2) immune‐mediated injury, and (3) phototoxic (photosensitization) injury (Diegel et al. 2018). Direct injury from a topically applied agent results in irritation that can range from mild dermatitis to severe corrosive injury depending on the toxicant and degree of exposure. Immune‐mediated skin injury results from stimulation of the immune system by exposure to a compound that is ingested, inhaled, or injected; only rarely is this reaction seen due to topical exposure. As with any other reaction involving the immune system, immune‐mediated skin injury requires prior sensitization before an immune reaction will occur. Phototoxic injury is a direct immediate interaction between light and a photosensitizing compound within the dermis. The photosensitizing compound may be a toxicant or its metabolite, and it interacts with certain wavelengths of light to produce free radicals in the skin, resulting in damage to cellular structures. The net effect resembles a severe sunburn. Phototoxicity is less commonly seen in dogs and cats than humans or grazing animals due to their protective hair coats and lack of exposure to the types of compounds (plant toxins, some pharmaceuticals) that cause photosensitization. Table 16.3 lists toxicants that affect the skin.

Table 16.2. Toxicants affecting the hematopoietic system

Mechanism | Toxicant | Comments
Hemolytic anemia | Allium spp. | Onions, garlic, etc.; powdered, concentrated forms more toxic
Crotalid snake venom | Direct RBC membrane damage
Naphthalene | Mothballs, urinal disks, toilet bowl blocks
Propylene glycol | Heinz body anemia in cats
Zinc | US pennies minted after 1983; other zinc‐containing hardware; zinc oxide ointments
Methemoglobinemia | Acetaminophen | Primarily cats; dogs with high doses
Benzocaine/lidocaine | Primarily cats
Chlorates | Matches, fireworks, gunpowder
Phenols | Primarily cats
Decreased formation of RBC, WBC, and/or platelets | 5‐fluorouracil | Bone marrow suppression; WBC ± RBC
Estrogen | Suppresses bone marrow formation of RBC and platelets
Methotrexate | Bone marrow suppression
Phenylbutazone | Bone marrow suppression
Sulfonamides | Bone marrow suppression; hemolytic anemia
Lead | Interferes with RBC maturation
Trichothecene mycotoxins | Bone marrow suppression
Coagulopathy | Anticoagulant rodenticides; warfarin | Prevents vitamin K recycling resulting in clotting factor deficiency
Aspirin | Inhibits platelet function
Crotalid snake venom | Contains platelet aggregation inhibitors and inhibitors of fibrin formation
Asphyxiants | Carbon dioxide | Displacement of oxygen
Carbon monoxide | Interference with oxygen delivery to tissues
Cyanide | Uncoupling of cellular respiratory chain
Hydrogen sulfide | Paralysis of respiratory center in the central nervous system
Methane | Displacement of oxygen

RBC, red blood cell; WBC, white blood cell.

MUSCULOSKELETAL SYSTEM

The musculoskeletal system is composed of bones, joints, and skeletal muscle (Plumlee 2004). Bones and joints are relatively spared from the effects of acute toxic insults and most toxic changes are due to chronic exposure to toxicants. Toxicants affecting bone or cartilage can alter their formation or remodeling. Skeletal muscle is similar to cardiac muscle in structure and function, and many toxicants that affect the myocardium will also affect skeletal muscle cells. Skeletal muscle toxicants can alter neuromuscular action, interfere with myofiber biochemical processes, or cause direct myofiber degeneration or necrosis (Berridge et al. 2018). Table 16.4 contains a listing of musculoskeletal toxicants.

ACKNOWLEDGEMENTS

The author would like to thank Sharon Gwaltney‐Brant for her contributions to the first edition of this chapter.

Table 16.3. Toxicants affecting the skin

Mechanism | Toxicant | Comments
Direct injury (irritation, erosion or ulceration of skin) | Acids | Car/boat batteries, drain openers, oven cleaners, etching compounds, gun barrel cleaners, pool sanitizers, rust removers
Alkalis | Anhydrous lime, cement, drain openers, fabric softeners, industrial strength bleaches, liquid dishwasher detergents, low phosphate laundry detergents, pool chemicals
Cationic detergents | Disinfectants, sanitizers, pool algicides
Essential oils | Concentrated D‐limonene, tea tree oil, eugenol
Hydrocarbons (e.g., motor oil, mineral spirits) | Volatile hydrocarbons (e.g., kerosene, mineral spirits) very damaging to canine and feline skin
Immune‐mediated | Essential oils | D‐limonene
Medications | Idiosyncratic; penicillins, cephalosporins, levamisole, thrimethoprim‐sulfa, others

Table 16.4. Toxicants affecting the musculoskeletal system

Mechanism | Toxicant | Comments
Alteration of cartilage formation | Fluoroquinalones (e.g., enrofloxacin) | Growing animals
Muscle weakness, paralysis | Ionophores (e.g., monensin) | Dogs
Macadamia nuts | Dogs
Muscle tremors, fasciculations | Tremorgenic mycotoxins | Dogs most commonly affected
| Pyrethroids | Concentrated pyrethroids, especially in cats

CHAPTER 16 STUDY QUESTIONS

The Dieffenbachia plant can cause drooling and gagging by what mechanism?

Ingestion of zinc metal causes which of the following?

Methemoglobinemia

Bone marrow suppression

Hemolysis

Neutropenia

Coagulopathy

Which of the following consists of keratinized epithelium?

Epidermis

Statum corneum

Dermis

Macadamia nuts cause muscle weakness in what species?

ANSWERS

1. Insoluble calcium oxalate crystals

2. c.

3. b.

4. Dogs

REFERENCES

Berridge, Brian R, Bolon, Brad, and Herman, Eugene. 2018. Skeletal muscle system. In Fundamentals of Toxicologic Pathology, 3rd ed., edited by Matthew A Wallig, Wanda M Haschek, Colin G Rousseaux, Brad Bolon, and Beth W Mahler, pp. 196–212. London: Elsevier.

Bischoff, Karen. 2018. Toxicity of over‐the‐counter drugs. In Veterinary Toxicology: Basic and Clinical Principles, 3rd ed., edited by Ramesh C Gupta, pp. 357–384. London: Elsevier.

Diegel, Kelly L, Danilenko, Demitry M, and Wojcinski, Zbigniew W. 2018. The integumentary system. In Fundamentals of Toxicologic Pathology, 3rd ed., edited by Matthew A Wallig, Wanda M Haschek, Colin G Rousseaux, Brad Bolon, and Beth W Mahler, pp. 791–822. London: Elsevier.

McConkey, Sandra E, Grant, Dennis M, and Cribb, Alastair E. 2009. The role of para‐aminophenol in acetaminophen‐induced methemoglobinemia in dogs and cats. Journal of Veterinary Pharmacology and Therapeutics 32(6):585–595.

Plumlee, Konnie H. 2004. Musculoskeletal system. In Clinical Veterinary Toxicology, edited by Konnie H Plumlee, p. 69. St. Louis: Mosby.

Ramaiah, Lila, Bounous, Denise I, and Elmore, Susan A. 2018. Hematopoietic system. In Fundamentals of Toxicologic Pathology, 3rd ed., edited by Matthew A Wallig, Wanda M Haschek, Colin G Rousseaux, Brad Bolon, and Beth W Mahler, pp. 315–350. London: Elsevier.

Wallig, Matthew A. 2018. Digestive system. In Fundamentals of Toxicologic Pathology, 3rd ed., edited by Matthew A Wallig, Wanda M Haschek, Colin G Rousseaux, Brad Bolon, and Beth W Mahler, pp. 395–441. London: Elsevier.

Section 3
Specific Toxicants

17
Rodenticides

Eric Dunayer

INTRODUCTION

Rodenticides are pesticides that are intended to kill rodents and other small mammals. Frequently, however, dogs, cats, pet rodents, and other “nontarget” animals ingest the agent either unintentionally or due to malicious poisoning. At the American Society for the Prevention of Cruelty to Animals (ASPCA) Animal Poison Control Center (APCC), rodenticides were the eighth most common ingestion for pets (ASPCA 2023).

There are several different rodenticides currently available. They come in various forms including pellets, blocks (see Figure 17.1), dust, and place packs (paper packages left out for the rodents to chew open). Some rodenticides are mixed with seeds or grain to attract the rodents. Many rodenticides are dyed green or blue, but other colors such as red, tan, and white are also common. Rodenticides cannot be identified by their color or form; they can be identified only by locating their active ingredient or the US Environmental Protection Agency (EPA) registration number (EPA Reg. no.) on the packaging. Properly identifying the agent is necessary for determining the appropriate treatment for the ingestion. However, even if the agent cannot be identified, treatment should not be delayed while trying to obtain the information.

ANTICOAGULANT RODENTICIDES

Sources and Formulations

Anticoagulant rodenticides (ARs) were originally derived from studying the effects of moldy sweet clover on cattle. Mold infecting sweet clover (Melilotus officinalis and M. alba) converted the harmless chemical coumarin into the toxic metabolite dicoumarol. Chronic ingestion of the infected hay led to bleeding and death in cattle (Knight and Walter 2001). Warfarin, the first commercially available AR, was developed in the 1940s as a derivative of dicoumarol; it was named for the Wisconsin Alumni Research Foundation (WARF), the organization that uncovered the link between dicoumarol and coagulopathy (Merola 2002; Murphy 2018). Warfarin is also used therapeutically as an anticoagulant in human and veterinary medicine.

While warfarin was the original AR, others were soon synthesized. Warfarin requires many days of ingestion to cause signs. Also, rodents developed resistance to warfarin's effects. To overcome these drawbacks, second‐generation ARs were developed. These are capable of being lethal with a single feeding (Murphy 2018). The various compounds are listed in Table 17.1.

ARs are sold in various forms (as discussed in the introduction) and under dozens of trade names. Warfarin baits generally contain 0.025% of active ingredient or 7 mg of warfarin per ounce of bait. Second‐generation ARs come as a 0.005% bait (1.4 mg of active ingredient per ounce of bait) with the exception of difethialone, which is 0.0025% (0.7 mg of difethialone per ounce of bait).

Due to the unintended poisoning of children, pets, and wildlife by rodenticides, the EPA in 2008 announced a regulation to ban the over‐the‐counter sale of second‐generation ARs directly to consumers. The use of certain ARs is restricted to licensed pest control operators and the rodenticide must be in a tamperproof bait station. Other ARs are still available for direct purchase by consumers, but they can only be sold in a bait station; loose pellet baits are banned (US EPA 2008).

Figure 17.1. Blocks of rodenticide.

Photograph courtesy of Tim Williams.

Table 17.1. Anticoagulant rodenticides

First‐generation | Second‐generation
Warfarin | Brodifacoum
Chlorophacinone | Bromadiolone
Diphacinone | Difenacoum
Pindone | Difethialone

Kinetics

Most ARs are well absorbed after ingestion. Once absorbed, a large percentage is bound to plasma proteins. Ingestion of other highly protein‐bound drugs (such as nonsteroidal anti‐inflammatory drugs, thyroid supplements, and corticosteroids) can increase the toxicity of the anticoagulant by displacing it from the protein. The half‐lives of the agents vary but, in general, first‐generation agents have a much shorter half‐lives (14 hours) than second‐generation products (up to 6 days) (Merola 2002).

Mechanism of Action

ARs interfere with the ability of the liver to recycle vitamin K, which is necessary for the production of the active forms of clotting factors II, VII, IX, and X. Without continuous production of new factors, the animal depletes those that are present in the blood. When the factors are depleted (generally 3–7 days or more after ingestion), spontaneous hemorrhage begins (Merola 2002).

Toxicity

The toxicity of these products varies greatly by compound and by form (Murphy and Talcott 2013). Often, when the chemical is incorporated into bait, its toxicity is greatly increased. Warfarin requires a much higher single dose to cause toxicosis compared to repeated daily ingestions. Because of the wide variation in toxic doses in the literature, it is recommended using 0.02 mg/kg as a dosage of concern for all second‐generation agents.

Clinical Effects

Signs

The initial signs of AR toxicosis are generally vague and include anorexia, weakness, and lethargy. Once bleeding begins, signs depend on where the hemorrhage has occurred. For instance, hemorrhage into the chest can lead to signs of dyspnea. Heavier dogs, due to pressure on their joints, might bleed into joint spaces and subsequently develop lameness. Hemorrhage under the skin can cause swelling of limbs. Bleeding into the brain and spinal cord can cause a sudden onset of paralysis and seizures. Most commonly, hemorrhage occurs into body “spaces” such as pleural or peritoneal cavities. Some dogs die suddenly without any obvious signs. Bleeding generally will not start until 3–7 days after the exposure due to the requirement that existing vitamin‐K‐dependent clotting factors be consumed. Younger animals, which have less of a reserve of coagulation factors, potentially start to develop coagulopathy sooner. Also, animals with preexisting liver disease are also more susceptible to intoxication (Merola 2002).

Laboratory

Depending on the length of time bleeding has occurred, the animal might be anemic, with a decreased hematocrit. Platelet counts are often slightly decreased as platelets are consumed to try to stop the bleeding. Increases in the coagulation parameters prothrombin time (PT) and partial thromboplastin time (PTT) are the most consistent findings. Factor VII (critical for the extrinsic coagulation pathway) has the shortest half‐life in dogs (6.2 hours) and as it is depleted, the PT (which assesses both the extrinsic and common coagulation pathways) will become abnormal first, generally by 48–72 hours (Murphy 2018).

Differential Diagnoses

Differential diagnoses include naturally occurring bleeding defects such as hemophilia, von Willebrand disease, and other inherited or acquired clotting disorders. Because the liver produces the clotting factors, liver failure can lead to spontaneous bleeding. Finally, bleeding due to trauma should be ruled out.

Diagnostics

Antemortem

A diagnosis of AR toxicosis is based on history and the results of coagulation testing. In some cases, particularly where there is no history of exposure, analysis of whole blood or serum for the presence of a specific AR can confirm exposure (Murphy 2018).

Postmortem

Typically, no microscopic lesions are noted. The animal will have widespread hemorrhage into body cavities, joints, skin, central nervous system (CNS), or other tissues. AR can be detected, most typically in liver tissue, to confirm exposure (Murphy 2018).

Management of Exposures

In animals with recent exposures (<4 hours), emesis should be performed. This can be followed with a single dose of activated charcoal, although due to the possibility of hypernatremia developing, this step can be skipped in lieu of monitoring coagulation parameters or starting vitamin K treatment. Multiple doses of activated charcoal have not been shown to be any more beneficial. Next, one of two courses should be followed (Merola 2002). Vitamin K₁ can be started at a dose of 3–5 mg/kg divided twice a day. The length of treatment depends on the agent ingested. For warfarin, a minimum of 14 days is recommended, for bromadiolone the recommended treatment period is 21 days, and for all other first and second‐generation agents at least 30 days of treatment should be done. Injections of vitamin K₁ should not be used if possible as this increases the risk of allergic or anaphylactic reactions. Oral vitamin K₁ should be given with a small, fatty meal, such as canned dog or cat food because this enhances absorption. For rodents and small puppies or kittens, the injectable vitamin K₁ solution can be given orally if appropriately sized tablets are not available. Approximately 48–72 hours after stopping the vitamin K₁, a PT should be run to see if additional treatment is necessary (Merola 2002). Alternatively, instead of starting vitamin K₁ immediately, the patient's PT can be monitored. A PT level should be obtained at 48–72 hours after exposure. If the PT becomes prolonged, vitamin K₁ therapy, as indicated above, should be instituted (Merola 2002).

A study done at the University of Pennsylvania showed that over 90% of dogs decontaminated with emesis and/or activated charcoal after anticoagulant ingestion did not need treatment with vitamin K₁ when their PT was monitored; none of the animals developed signs during the period that the PT was being run (Pachtinger et al. 2008), therefore waiting to monitor PTs rather than immediately starting vitamin K₁ is an acceptable treatment plan. Cost and turnaround time for testing results may determine the course of action.

In patients who are actively bleeding, emesis should not be performed as exposure likely occurred several days before presentation. The animal should be stabilized for shock with fluids. If the anemia is severe, a blood transfusion should be performed (Merola 2002). Vitamin K₁ therapy should be started as soon as possible. However, since vitamin K₁ takes 6–12 hours before new clotting factors can be produced, the patient should receive a fresh‐frozen plasma, frozen plasma, and/or whole‐blood transfusions to supply clotting factors until the body manufactures a sufficient quantity on its own (Murphy and Talcott 2013). Strict cage rest should be enforced. For animals that are dyspneic due to bleeding into the pleural cavity, the chest can be carefully tapped to allow lung expansion (Merola 2002). Blood from a thoracocentesis can be autotransfused back to the patient, especially if anemia is present, but it has no clotting factors.

Prognosis

For asymptomatic animals, vitamin K₁ therapy is effective and should prevent signs from developing. If bleeding has begun, the prognosis is more guarded, depending on the extent and location of the hemorrhage. However, most symptomatic animals can recover with appropriate therapeutic intervention.

BROMETHALIN

Sources and Formulations

Bromethalin was developed to kill AR‐resistant rodents. Despite its name being similar to some of the ARs (bromadiolone, brodifacoum), it is not an anticoagulant; it is neurotoxic. It generally comes as a 0.01% concentration (2.84 mg bromethalin per ounce of bait) (Dunayer 2003). For mole control, it is also sold in the form of a “worm” bait. In these products, the bromethalin concentration is 0.025%.

Kinetics

Bromethalin is rapidly absorbed after ingestion and plasma levels peak in about 4 hours. In the liver, bromethalin is converted to a toxic metabolite desmethylbromethalin. Bromethalin is excreted in the bile and undergoes enterohepatic recirculation. The half‐life of bromethalin is about 6 days in rats (Dunayer 2003; Gupta 2018).

Mechanism of Action

Bromethalin and its metabolite desmethylbromethalin uncouple oxidative phosphorylation. This leads to decreased production of energy in cells so levels of adenosine triphosphate (ATP) fall. Without ATP, Na‐K ATPase pumps in the cell membrane are unable to pump sodium out of the cell. Because sodium builds up inside the cell, water is pulled in and the cell swells. Nerves cells are the most sensitive tissue and so signs of neurotoxicity are seen. In the CNS, myelin sheaths that surround nerve cells swell and vacuoles form within the nerve cell. As the cells and the myelin sheaths swell with fluid, internal pressure increases; there is also an increase in cerebrospinal fluid pressure. Together, these changes cause nerve dysfunction (Dunayer 2003; Gupta 2018).

Toxicity

For most species, the toxicity of bromethalin is very similar (see Table 17.2). However, cats are much more sensitive to the effects of bromethalin than dogs. Guinea pigs are relatively insensitive to bromethalin as they are unable to produce the toxic metabolite desmethylbromethalin (Dunayer 2003). If guinea pigs are fed desmethylbromethalin, the toxic dose is similar to bromethalin (Van Lier and Cherry 1988). Based on cases reported to the APCC, dogs have died at dosages of 0.95 mg/kg and cats have developed signs at 0.24 mg/kg (Dunayer 2003). Because of their immature blood–brain barriers, puppies under 6 months of age are more sensitive to bromethalin than older dogs.

Table 17.2. Toxicity of bromethalin in various species

Source: Van Lier and Cherry (1988).

Species | Oral LD₅₀ (mg/kg)
Cat | 1.8
Rat | 2.0
Dog | 4.7
Mouse | 5.3
Rabbit | 13.0
Guinea pig | <1000

LD₅₀, lethal dose 50 (amount of toxin needed to kill 50% of the animals).

Clinical Effects

Signs

In dogs, the onset of signs depends on the dose ingested. At lower doses, the onset is slow, taking up to 24–86 hours to be seen. Initial signs include hindlimb weakness, which can progress to paresis and paralysis. CNS depression also develops. Once signs develop, they may last for days to weeks before they resolve (Dorman et al. 1990a). In dogs ingesting doses at or above the LD50 (>2.38 mg/kg), the onset of signs is more rapid, from 4 to 36 hours. In these dogs, hyperexcitability develops followed by tremors, seizures, and death (Dorman et al. 1990a).

In cats, the most common sign is ataxia. Other signs include focal motor seizures, recumbency, abdominal distension, decreased conscious proprioception, and a decerebrate posture. Onset of signs occurs from 3 to 7 days after exposure. As noted with dogs, higher ingested doses generally lead to earlier onset of signs (Dorman et al. 1990b).

Laboratory

There are no significant laboratory changes expected with bromethalin toxicosis. (Dorman et al. 1990a).

Differential Diagnoses

For the paralytic form of bromethalin toxicosis, toxic differentials include botulism, ivermectin toxicosis, and ionophore toxicosis. In seizing patients, differentials include metaldehyde (snail bait), strychnine, zinc phosphide, and sodium fluoroacetate (Compound 1080) intoxications.

Diagnostics

Antemortem

Antemortem diagnosis relies on a history of exposure and occurrence of compatible clinical signs. Although blood can be tested for the presence of bromethalin, this is not a standard test and results are typically not available prior to the need to institute treatment.

Postmortem

Bromethalin can be detected in various organs, including the brain and liver. Histopathology of the CNS shows spongy degeneration of the white matter with an accumulation of fluid within the myelin sheaths (Dunayer 2003).

Management of Exposures

There is no antidote for bromethalin, so the management of exposure is focused on decontamination. Decontamination recommendations vary depending on the species, dosage, and time since ingestion. Age may also play a factor (immature blood–brain barrier) in dogs (Tourdot 2017). Tables 17.3–17.5 summarize recommendations for decontamination (Dunayer 2003; Tourdot 2017). Since bromethalin is not an anticoagulant, vitamin K₁ is not indicated as a treatment.

Once signs begin, treatment is supportive and symptomatic. Recumbent animals should be well padded to prevent pressure sores. Seizures should be controlled as needed. Mannitol, furosemide, and corticosteroids have been suggested to treat the cerebral edema. Although these might slow progression of signs, they do not prevent their occurrence. In addition, when the treatment is stopped, the animal may deteriorate rapidly (Dunayer 2003).

Table 17.3. Decontamination recommendations for bromethalin ingestion: recommendations for dogs older than 6 months

Source: Adapted from ASPCA.

Time Since Exposure | Dosage Ingested (mg/kg) | Action
Any | <0.3 | No treatment needed
<4 hours | 0.3–0.49 | Emesis or one dose of activated charcoal
>4 hours | 0.3–0.49 | One dose of activated charcoal
<4 hours | 0.5–0.75 | Emesis and three doses of activated charcoal over 24 hours
>4 hours | 0.5–0.75 | Three doses of activated charcoal over 24 hours
<4 hours | >0.75 | Emesis and three doses of activated charcoal a day for 48 hours
>4 hours | >0.75 | Three doses of activated charcoal a day for 48 hours

Table 17.4. Decontamination recommendations for bromethalin ingestion: recommendations for puppies less than 6 months of age or nursing bitches

Source: Adapted from ASPCA.

Time Since Exposure | Dosage Ingested (mg/kg) | Action
Any | <0.1 | No treatment needed
<4 hours | 0.1–0.49 | Emesis or one dose of activated charcoal
>4 hours | 0.1–0.49 | One dose of activated charcoal
<4 hours | 0.5–0.75 | Emesis and three doses of activated charcoal over 24 hours
>4 hours | 0.5–0.75 | Three doses of activated charcoal over 24 hours
<4 hours | >0.75 | Emesis and three doses of activated charcoal a day for 48 hours
>4 hours | >0.75 | Three doses of activated charcoal a day for 48 hours

Table 17.5. Decontamination recommendations for bromethalin ingestion: recommendations for cats

Source: Adapted from Dunayer (2003).

Time Since Exposure | Dosage Ingested (mg/kg) | Action
<4 hours | 0.05–0.1 | Emesis or one dose of activated charcoal
>4 hours | 0.05–0.1 | One dose of activated charcoal
<4 hours | 0.1–0.3 | Emesis and three doses of activated charcoal over 24 hours
>4 hours | 0.1–0.3 | Three doses of activated charcoal over 24 hours
<4 hours | >0.3 | Emesis and three doses of activated charcoal a day for 48 hours
>4 hours | >0.3 | Three doses of activated charcoal a day for 48 hours

Prognosis

Prompt decontamination can often prevent signs from occurring. In mild cases, recovery is possible but full recovery can take weeks to months. Animals who are paralyzed or having seizures have a guarded prognosis, although even these animals can recover with intensive care.

CHOLECALCIFEROL

Sources and Formulations

Cholecalciferol is a form of vitamin D₃. It is generally found in a 0.075% bait (21.3 mg cholecalciferol per ounce of bait). As with other rodenticides, it is available in different forms and from different manufacturers (Morrow 2001). Vitamin D toxicosis can also occur due to chronic overdosing with vitamin D supplements or as a result of improperly formulated dog or cat foods. Although over‐the‐counter daily multivitamins contain vitamin D, it is generally present in such low concentrations (<1000 IU per capsule) that vitamin D toxicosis from acute overdoses of these products is rare. However, single ingredient vitamin D products can contain 5000–50,000 IU per capsule may result in toxicosis if sufficient numbers are ingested. Additionally, certain medications that contain vitamin D analogs, such as calcipotriene, a topical cream for treating psoriasis, can cause toxicosis similar to cholecalciferol (Rumbeiha 2013). As previously mentioned, the 2008 EPA rules that banned over‐the‐counter sale of AR have significantly changed the percentage of cases seen for AR, bromethalin, and cholecalciferol rodenticides (see Table 17.6).

Table 17.6. Change in the percentage of cases of various rodenticides reported to the APCC for dogs

Source: Adapted from ASPCA.

Rodenticide | 2010 (%) | 2020 (%)
Anticoagulant rodenticides | 75.7 | 37.1
Bromethalin | 19.3 | 51.7
Cholecalciferol | 0.8 | 9.4

Kinetics

Cholecalciferol is rapidly absorbed after ingestion. It is mainly excreted by the liver and undergoes enterohepatic recirculation (Morrow 2001). Vitamin D₃ is highly fat‐soluble so it can be stored in body fat. After absorption, cholecalciferol is transported to the liver on vitamin D‐binding proteins. In the liver, cholecalciferol is metabolized to 25‐hydroxycholecalciferol, also known as calcifediol. Calcifediol circulates in the blood and, in the kidneys, is further metabolized to 1,25‐dihdroxycholcalcerifol or cacitriol, which is the most active form of vitamin D (Morrow 2001; Rumbeiha 2013).

Mechanism of Action

Calcitriol increases blood calcium and phosphorus levels via various mechanisms: increased gastrointestinal absorption of calcium, increased calcium reabsorption by the kidneys, and increased bone resorption and release of phosphorus and calcium into the blood (Morrow 2001; Rumbeiha 2013). The overall effect is to increase blood phosphorus and calcium levels. Soft tissue mineralization may occur and is not reversible. Mineralization of the kidneys can lead to acute renal failure, although any tissue can be affected (Morrow 2001).

Toxicity

In dogs, dosages of 10 mg/kg have been fatal (Gupta 2018). Based on experience at the APCC, dosages of 0.5 mg/kg can cause signs (Morrow 2001), therefore the APCC recommends that decontamination and monitoring for signs be performed on dogs ingesting more than 0.1 mg/kg. (Note: For vitamin D₃, 1 IU = 0.025 mcg or 0.000025 mg.)

Clinical Effects

Signs

Onset of signs is usually within 12–36 hours of ingestion. Initial signs include vomiting and diarrhea (possibly bloody). The animal will then show depression, polyuria, and polydipsia. Acute renal failure can occur in as little as 24 hours (Morrow 2001).

Laboratory

After ingestion, serum phosphorus usually increases first, generally around 12 hours. The serum calcium increases by about 24 hours. Increases in blood urea nitrogen (BUN) and creatinine consistent with renal failure can begin shortly after the phosphorus and calcium product exceeds 60 (Morrow 2001).

Differential Diagnoses

Any condition that increases serum calcium levels should be considered as a differential. This includes primary hyperparathyroidism in which the parathyroid gland produces excessive levels of parathormone (PTH), usually due to a tumor of the gland. In addition, certain tumors, such as lymphoma and anal gland carcinomas, can secrete a protein that acts like PTH. In these syndromes, unlike cholecalciferol toxicity, phosphorus levels are usually normal (Rumbeiha 2013).

Diagnostics

Antemortem

In addition to measuring serum calcium, phosphorus, and assessing renal function, vitamin D₃ and calcitriol levels can be measured in blood. In cholecalciferol toxicosis, these are markedly elevated. In addition, PTH levels should be determined since they will be reduced (Rumbeiha 2013).

Postmortem

Lesions on postmortem examination include mineralization of soft tissues, especially the kidneys. However, this can occur with any condition that causes hypercalcemia. The bile and kidneys can be tested for calcifediol levels to confirm toxicity (Rumbeiha 2013).

Management of Exposures

If ingestion is within 6–8 hours, emesis can be performed. A single dose of activated charcoal can be administered, then cholestyramine can be started. Cholestyramine blocks bile‐acid resorption, which prevents vitamin D from being reabsorbed from the intestine. Cholestyramine comes as powder and is dosed at 300 mg/kg q8h for 4 days; the powder can be mixed with canned dog food for administration. (Note: Some cholestyramine products are sweetened with xylitol and should be avoided in dogs.) Baseline levels of calcium, phosphorus, BUN, and creatinine should be obtained, and calcium monitored daily for at least 4 days (Morrow 2001).

In patients with elevated calcium and phosphorus concentrations, intensive therapy is indicated to prevent renal failure and other signs. The animal should receive 0.9% saline intravenously at a diuretic rate; sodium competes for reabsorption with calcium in the kidney and increases calcium loss. Furosemide should be administered as it increases calcium excretion by the kidneys. Corticosteroids such as prednisone will decrease bone resorption and decrease intestinal absorption while increasing renal excretion of calcium. In addition, a low calcium/phosphorus diet should be fed and phosphate binders, such as aluminum or magnesium hydroxide, can be given (Morrow 2001; Rumbeiha 2013).

If these measures are not successful in reducing calcium levels, other treatments should be initiated. The preferred treatment is pamidronate, a bisphosphonate used to lower serum calcium in people with hypercalcemia due to malignancy. Pamidronate is given in normal saline by slow intravenous infusion over 2–4 hours. Its effects can last up to a week. It can be repeated as needed. Other bisphosphonates, such as zoledronate, are also effective (Schenk et al. 2018). Treatment should be continued until the calcium normalizes. At that point, treatments can be slowly reduced while the calcium values are watched closely for signs of recurrence over the course of several weeks (Morrow 2001).

Prognosis

The prognosis is good with prompt decontamination and if no signs develop. The prognosis is guarded once signs develop because mineralization is poorly reversible. Chronic renal failure can be a permanent sequela. Sudden deaths have occurred weeks later, probably due to cardiac arrhythmias from calcified heart muscle or the rupture of a major artery like the aorta (Morrow 2001).

STRYCHNINE

Sources and Formulations

Strychnine is an alkaloid obtained from the seeds and bark of the strychnine tree (Strychnos nux‐vomica and S. ignatti). These trees grow in Southeast Asia and Australia (Gupta 2018). Strychnine is one of the oldest rodenticides; it was first used in the 16th century (Talcott 2013). Strychnine is sold in various formulations, usually mixed with grain. It is often dyed red or green. Formulations contain 0.5–3% strychnine. It is intended for killing rodents as well as porcupines, rabbits, and pigeons (Talcott 2004). Strychnine is labeled for use underground in animal burrows (Talcott 2004).

Kinetics

Strychnine is rapidly absorbed from the small intestine (Gupta 2018). It is metabolized in the liver, but up to 20% of the dose may be excreted in the urine unchanged (Talcott 2004). It rapidly distributes to many different tissues and has a half‐life of about 6 hours (Gupta 2018).

Mechanism of Action

Strychnine competitively blocks the effects of the amino acid glycine, an inhibitory neurotransmitter in the spinal cord. Normally, glycine prevents repetitive nerve activity that stimulates muscle contractions. Without this inhibition, the nerve continues to fire rapidly and leads to muscle spasms. Eventually, the animal develops muscle rigidity (tetanic spasms) (Gupta 2018; Talcott 2004). Because extensor muscles are stronger than flexor muscles in the limbs and neck, extensor rigidity develops.

Toxicity

Strychnine is considered extremely toxic. In dogs, the minimum lethal dosage is about 0.75 mg/kg (Gupta 2018); this is about 0.15 g/kg of a 0.5% bait or about half a teaspoon in a 35‐lb (16‐kg) dog. In cats, the LD₅₀ is about 2 mg/kg (Talcott 2004).

Clinical Effects

Signs

Signs can occur from 10 minutes to 2 hours after ingestion depending on when the stomach empties since strychnine is better absorbed in the intestines (Talcott 2004). Vomiting is uncommon (Gupta 2018). Initially, the animal may be anxious, tachypneic, and salivating heavily. Signs then progress to ataxia followed by collapse with violent muscular seizures. The legs will be extended and rigid, and the neck may be arched. Stimulation by noise or lights typically causes signs to worsen. The animal can be hyperthermic due to extreme muscle activity. Death is likely due to anoxia and respiratory arrest from paralysis of the diaphragm and the inability to expand the chest (Gupta 2018; Talcott 2004).

Laboratory

There are no specific changes associated with strychnine toxicosis (Talcott 2004).

Differential Diagnoses

Many toxicants and conditions can cause severe tremors similar to strychnine. These include metaldehyde, bromethalin, tremorgenic mycotoxins, zinc phosphide, tetanus, organochlorine insecticides, anticholinesterase insecticides, and Brunfelsia spp. (Talcott 2013).

Diagnostics

Antemortem

Strychnine can be detected in urine and stomach contents from gastric lavage (Gupta 2018; Talcott 2004). However, some animals die so quickly that strychnine cannot be detected in their urine. In addition, the results of the tests are not likely to be available before the patient has either died or recovered.

Postmortem

There are no specific lesions associated with strychnine toxicosis. Strychnine can be detected in stomach contents, urine, bile, liver, and kidney to confirm exposure (Talcott 2004).

Management of Exposures

Emesis can be induced before the animal is symptomatic; however, due to rapid onset of signs in most cases, this may not be practical. Activated charcoal may be useful but care should be taken to avoid aspiration (Talcott 2004). In general, treatment is aimed at controlling tremors and seizures. Barbiturates, methocarbamol, propofol, and gas anesthesia may be used to control signs. In severe cases, the patient may need to be kept under anesthesia for 24–48 hours. Anecdotally, intravenous lipid therapy may help reduce treatment time. Intravenous fluids to support hydration should be administered. Sensory stimulation should be kept to a minimum to prevent worsening of the signs. Treatment should be continued until signs have resolved, which may take 24–72 hours (Gupta 2018; Talcott 2004).

Prognosis

Prognosis is guarded once signs have begun.

ZINC PHOSPHIDE

Sources and Formulations

Zinc phosphide is an inorganic rodenticide that has been available for over 70 years (Albretson 2004). It is sold as a 2% bait (566 mg zinc phosphide per ounce of bait). Zinc phosphide can be found in several different forms such as in pellets, in place packs, and mixed with grains. In addition to mice and rats, it is also used to kill voles, moles, rabbits, and other rodents (Gupta 2018).

Kinetics

After ingestion, zinc phosphide reacts with acids in the stomach to produce phosphine gas, which can be absorbed from the stomach or may be inhaled as it escapes the stomach (Albretson 2004). Intact zinc phosphide may be absorbed as well from the gastrointestinal tract.

Mechanism of Action

The exact mechanism of zinc phosphate and phosphine gas intoxication is not known. It is thought that phosphine gas blocks the enzyme cytochrome oxidase, which decreases energy production by cells. Without energy, cells are unable to maintain normal function and cell death occurs (Albretson 2004; Gupta 2018). Phosphine gas is also thought to be directly irritating, especially to the lungs (Albretson 2004). In addition to its immediate effects, zinc phosphide can cause delayed liver and kidney failure. It is not known whether this is due to phosphine gas or the absorption of intact zinc phosphide.

Toxicity

The LD₅₀ of zinc phosphide is about 40 mg/kg in dogs and cats. The LD₅₀ in rats is 12 mg/kg. Because zinc phosphide is a strong emetic, dogs and cats are less sensitive to zinc phosphide than rodents because they can vomit and partially decontaminate themselves after ingestion (Albretson 2004).

Clinical Effects

Signs

The onset of signs varies from 15 minutes to 4 hours. Rapidity of onset appears to be influenced by whether or not the animal has food in its stomach. The presence of food increases the production of hydrochloric acid, which in turn increases the production of phosphine gas (Albretson 2004). Vomiting, often bloody, is common. The animal's breath or its vomitus can have a garlicky or rotten fish smell from the phosphine gas (Knight 2013). Severe gastrointestinal pain can develop. CNS signs include anxiety, initial depression progressing to increased activity, tremors, and seizures. Increased respiratory sounds and rate are common (Knight 2013).

Laboratory

There are no specific clinical laboratory changes noted (Albretson 2004).

Differential Diagnoses

The differential diagnoses are similar to those for strychnine. These include metaldehyde, bromethalin, tremorgenic mycotoxins, zinc phosphide, tetanus, organochlorine insecticides, anticholinesterase insecticides, and Brunfelsia spp.

Diagnostics

Antemortem

Diagnosis is based on history and the presence of the characteristic smell of phosphine gas. Stomach contents samples can be tested for the presence of phosphine.

Postmortem

Diagnosis can be made by the detection of phosphine in stomach contents.

Management of Exposures

If exposure was recent, the patient should be given oral liquid antacids to neutralize stomach acid and reduce the production of phosphine gas. Emesis can be performed early but a centrally active emetic such as apomorphine or ropinirole should be used rather than hydrogen peroxide, which could increase the production of phosphine gas (Albretson 2004). Emetics are not indicated in animals that have already vomited. In patients who are seizuring, gastric lavage can be considered. Activated charcoal has been recommended, but there is no proof of efficacy (Knight 2013). In vomiting animals, activated charcoal may increase the risk of aspiration and may delay healing of gastric erosions.

There are no antidotes for zinc phosphide toxicosis. Treatment should be directed to providing support and controlling signs such as fluids for shock, seizure control, and correcting acid‐base imbalances. Liver protectants such as n‐acetylcysteine, B vitamins, S‐adenosyl methionine, and dextrose may be useful, but proof of efficacy is lacking (Albretson 2004; Knight 2013).

When presented with a poisoned animal, there is a real risk to attending medical staff. Phosphine gas coming from the patient's stomach or vomitus can affect human personnel in the room. The odor of phosphine gas can be detected by the human nose at about 2 ppm However, levels of 1 ppm or less, depending on the length of exposure, can be toxic (Knight 2013). If possible, induction of emesis should be performed outdoors or in a well‐ventilated room. Vomitus or gastric lavage material should be cleaned up rapidly and placed in an airtight bag. If the smell of phosphine gas is detected, personnel should be evacuated, and the room aired out thoroughly.

Prognosis

In asymptomatic animals, the prognosis is good. If signs do develop, the prognosis is guarded, especially for the first 48 hours. Even those animals that survive the initial period may develop acute renal and hepatic failure over the next 2 weeks.

REFERENCES

Albretson, Jay C. 2004. Zinc phosphide. In Clinical Veterinary Toxicology, edited by Konnie H Plumlee, pp. 456–458. St. Louis: Mosby.

ASPCA. 2023. Official Top 10 Pet Toxins of 2022. https://www.aspca.org/news/official‐top‐10‐pet‐toxins‐2022 Accessed 12/15/23.

Dorman, David C, Parker, Alan J, and Buck, William B. 1990a. Bromethalin toxicosis in the dog: Part I: Clinical effects. Journal of the American Animal Hospital Association 26:589–594.

Dorman, David C, Parker, Alan J, Dye, Janice A, and Buck, William B. 1990b. Bromethalin neurotoxicosis in the cat. Progress in Veterinary Neurology 1(2):189–196.

Dunayer, Eric. 2003. Bromethalin: the other rodenticide. Veterinary Medicine 98(9):732–736.

Gupta, Ramesh C. 2018. Non‐anticoagulant rodenticides. In Veterinary Toxicology: Basic and Clinical Principles, 3rd ed., edited by Ramesh C Gupta, pp. 613–628. London: Elsevier.

Knight, Anthony P and Walter, Richard G (eds). 2001, pp. 192–194. Jackson, Wyoming: Teton New Media.

Knight, Michael W. 2013. Zinc phosphide. In Small Animal Toxicology, 3rd ed., edited by Michael E Peterson and Patricia A Talcott, pp. 853–864. St. Louis: Saunders.

Merola, Valentina. 2002. Anticoagulant rodenticides: deadly to pests, dangerous to pets. Veterinary Medicine 101(6):339–342.

Morrow, Carla. 2001. Cholecalciferol poisoning. Veterinary Medicine 96(12):905–911.

Murphy, Michael. 2018. Anticoagulant rodenticides. In Veterinary Toxicology: Basic and Clinical Principles, 3rd ed., edited by Ramesh C Gupta, pp. 583–611. London: Elsevier.

Murphy, Michael J and Talcott, Patricia A. 2013. Anticoagulant rodenticides. In Small Animal Toxicology, 3rd ed., edited by Michael E Peterson and Patricia A Talcott, pp. 435–445. St. Louis: Saunders.

Pachtinger, Garret E, Otto, Cynthia M, and Syring, Rebecca S. 2008. Incidence of prolonged prothrombin time in dogs following gastrointestinal decontamination for acute anticoagulant rodenticide ingestion. Journal of Veterinary Emergency and Critical Care 18(3):285–291.

Rumbeiha, Wilson K. 2013. Cholecalciferol. In Small Animal Toxicology, 3rd ed., edited by Michael E Peterson and Patricia A Talcott, pp. 489–498. St. Louis: Saunders.

Schenk, Ashley, Lux, Cassie, Lane, Jeanne, and Martin, Olya. 2018. Evaluation of zoledronate as treatment for hypercalcemia in four dogs. Journal of the American Animal Hospital Association 54(6):e54604.

Talcott, Patricia A. 2004. Strychnine. In Clinical Veterinary Toxicology, edited by Konnie H Plumlee, pp. 454–456. St. Louis: Mosby.

Talcott, Patricia A. 2013. Strychnine. In Small Animal Toxicology, 3rd ed., edited by Michael E Peterson and Patricia A Talcott, pp. 827–832. St. Louis: Saunders.

Tourdot, R. 2017. The Decontamination Dilemma: Bromethalin Ingestion. Today's Veterinary Practice Jan/Feb:97–100.

US EPA. 2008. Final Risk Mitigation Decision for Ten Rodenticides. https://www.epa.gov/rodenticides/restrictions‐rodenticide‐products Accessed 12/15/23.

Van Lier, Robert B and Cherry, Linda D. 1988. The toxicity and mechanism of action of bromethalin: a new single‐feeding rodenticide. Fundamental and Applied Toxicology 11:664–672.

18
Insecticides

Brandee Bean

INTRODUCTION

Insecticides are used directly on animals, in the house and in the yard. This means there are many opportunities for pets to be exposed. There are different classes of insecticides and their risks will vary.

AMITRAZ

Sources and Formulations

Amitraz is a formamidine acaricide with activity against ticks, mites, and lice. It is used in veterinary medicine for the control and eradication of demodex mites and has been used for the prevention of tick infestations. For small animals amitraz is commercially available under the trade name Mitaban® dip (19.9% for dilution), and as a miticide for beehives. Most other mammal applications have been replaced by other insecticides.

Kinetics

Amitraz is rapidly absorbed following oral administration of technical material. Clinical signs can be seen by 1 hour of ingestion and peak plasma concentrations occur by 5 hours. The elimination half‐life is approximately 23.4 hours (Hugnet et al. 1996). Absorption and duration of effects following ingestion of amitraz‐impregnated collars tend to be prolonged due to slow release of the active ingredient from the collar. Although dermal absorption is low, intoxication has been reported following topical application in dogs, especially if they have inflamed or broken skin (Paradis 1999).

Mechanism of Action

The alpha‐2 adrenergic agonist characteristics of amitraz account for its sedative and hyperglycemic effects. The effects on blood glucose are thought to be due to alpha‐2–mediated inhibition of insulin release (Hugnet et al. 1996).

Toxicity

Amitraz is classified by the US Environmental Protection Agency (EPA) as slightly toxic to mammals if ingested orally. The oral LD₅₀ (the dose where 50% of the animals die) for amitraz in rats is 523–800 mg/kg and for mice is greater than 1600 mg/kg. The dermal LD₅₀ for rats and rabbits is greater than 1600 mg/kg and greater than 200 mg/kg, respectively (Extoxnet 1995). Cats tend to be more sensitive than dogs to the effects of amitraz.

Clinical Effects

Signs

Signs of amitraz toxicosis can begin within 1–4 hours but can be delayed as long as 12 hours. Intoxicated dogs and cats exhibit vomiting, depression, somnolence, ataxia, disorientation, ileus, bradycardia, hypertension or hypotension, coma, hypothermia, and seizures. Some of the neurological signs might be attributed to the xylene carrier found in dip formulations.

Laboratory

Biochemical changes include hyperglycemia and elevated hepatic enzymes.

Differential Diagnosis

Toxicants causing central nervous system (CNS) depression should be considered. These include ethanol, methanol, isopropanol, ivermectins, marijuana, ethylene glycol, barbiturates, benzodiazepines, opioids, and antidepressants. Other differentials include CNS trauma and primary CNS disease.

Diagnostics

Antemortem

Amitraz can be detected in stomach contents, urine, feces, and skin, although laboratories performing the analysis are limited.

Postmortem

No specific gross or histopathological lesions are expected on necropsy. Tissue analysis for the presence of the compound can confirm exposure.

Management of Exposures

For dermal exposures, the animal should be stabilized according to clinical signs and then bathed in a liquid dish detergent to remove any product remaining on the skin. Care should be taken to prevent the development of hypothermia after bathing. Mild signs following label use often do not require treatment and resolve in 24–72 hours. For more severe signs, yohimbine and atipamizole are alpha‐2 adrenergic antagonists that effectively reverse bradycardia, CNS depression, hyperglycemia, and ileus (Andrade and Sakate 2003). Atipamezole is thought to have fewer cardiorespiratory effects than yohimbine (Andrade and Sakate 2003). Atropine should not be used in the treatment of amitraz‐induced bradycardia because it can potentiate hypertension and ileus (Hsu et al. 1986). Seizures can be treated with diazepam or a barbiturate. Animals should be closely monitored for severe CNS depression following the use of these drugs. In all cases exhibiting clinical signs, symptomatic and supportive care, including intravenous (IV) fluids and thermoregulation, is indicated.

Oral exposures are usually the result of ingestion of either spot‐on or concentrated dip formulations containing volatile hydrocarbons, or from ingestion of an amitraz‐containing collar. The induction of emesis should be avoided if symptomatic. Activated charcoal binds amitraz; however, administration may also aggravate an already upset stomach and cause vomiting and possible aspiration. If the animal is symptomatic, yohimbine or atipamezole may be given to reverse clinical signs. Once normal, emesis may be induced.

Prognosis

Animals receiving prompt, aggressive treatment have a good prognosis. Animals exhibiting severe signs such as coma or seizures have a guarded to poor prognosis.

ISOXAZOLINES

Sources and Formulations

Isoxazolines are novel ectoparasiticides, mostly used in small animals for prevention and treatment of flea and tick infestations with off‐label use as a miticide. Afoxolaner was the first isoxazoline approved by the US Food and Drug Administration for use in dogs in 2013, followed by fluralaner, sarolaner, lotilaner, and esafoxolaner. Isoxazolines are available in both oral and topical formulations (Zhou et al. 2022).

Kinetics

Oral isoxazolines are generally more bioavailable when given with food. Both oral and topical forms are highly protein bound and lipophilic. Peak levels vary, with sarolaner peaking at 3 hours, afoxolaner at 2–6 hours, and fluralaner at 2 hours to 3 days (Boehringer Ingelheim Animal Health USA Inc. 2020; Merck Animal Health, Intervet Inc. 2024; Zoetis Inc. 2020).

Mechanism of Action

Isoxazolines work though inhibition of the arthropod nervous system. They antagonize the gamma‐aminobutyrid acid (GABA) and glutamate‐receptor. This blocks sodium transfer across these receptors and in insects and acarines extended periods of excitation results in uncontrolled activity and death. The difference in sensitivity between mammals and arthropods GABA receptors explains the difference in toxicity (Zhou et al. 2022).

Toxicity

The LD₅₀ and median lethal dose of these drugs is unknown. In safety studies, both topical and oral isoxazolines were given up to five times the therapeutic dose, with only transient effects seen. Isoxazolines appear safe in multidrug resistance 1 (MDR1)‐deficient dogs (Walther et al. 2014).

Clinical Effects

Signs

Gastrointestinal upset with vomiting, diarrhea, anorexia, and dermal effects, such as dry, flakey, and pruritic skin, and transient CNS signs with increased likelihood for animals with history of seizures are the most common (Boehringer Ingelheim Animal Health USA Inc. 2020; Merck Animal Health, Intervet Inc. 2024; Zoetis Inc. 2020). All isooxazoline class medications have been associated with neurological effects, including tremors, incoordination, and seizures. There appears to be no dose–response relationship. Topical formulations given orally result in hypersalivation and oral parathesis.

Laboratory

Biochemical changes of mildly increased blood urea nitrogen in dogs and cats have been seen with lotilaner.

Differential Diagnosis

Differentials include idiopathic epilepsy, tremorgenic mycotoxins, and concentrated pyrethrins.

Diagnostics

There are no typical laboratory or postmortem changes expected.

Management of Exposure

Decontamination of topical exposures can be managed with a mild, grease cutting, liquid dish soap. Pets with oral exposure to topical products may be treated with antinausea medications and dilution of the oral cavity. With oral chewable exposures occurring less than 30–60 minutes earlier, emesis can be considered when the pet is neurologically appropriate. Usually, further decontamination is not necessary. Neurologic symptoms can be treated with muscle relaxants and anticonvulsants (Gaens et al. 2019).

Prognosis

Prognosis is generally favorable with symptomatic and supportive care. Long‐term clinical effects are not expected. Neurologic signs are usually short lived, and seizures are typically singular.

ORGANOPHOSPHORUS AND CARBAMATE INSECTICIDES

Sources and Formulations

This group of compounds is characterized by their ability to inhibit the enzyme acetylcholinesterase. There are several organophosphorus (OP) and carbamate insecticides developed for use on animals and crops, as well as around buildings or in structures such as ships and airplanes. The development of newer and safer insecticides has limited the use of this class of compounds to some extent, but many of these products are still available and in use. Residential use of organophosphates was stopped in 2001. Older formulations can turn up from storage in old outbuildings such as sheds and barns. Most OP and carbamate insecticides are applied topically to the animal or plant, but some are designed to be absorbed and act systemically. OP and carbamate insecticides can be found in various formulations, including dusts, wettable powders, and emulsifiable concentrates. They have been historically used in dips, sprays, flea collars, shampoos, flea foggers, and ant and roach baits (Wismer and Means 2018).

OP insecticides are aliphatic carbon, cyclic, or heterocyclic phosphate esters. They can be identified by the presence of the terms phosphate, phosphorothioate, phosphoramidate, phosphonate, phosphoryl, or phosphorothiolate somewhere in their long chemical name. Carbamates are derivatives of carbamic acid and generally have the terms carbamate or carbamoyl somewhere in their long chemical name. Tables 18.1 and 18.2 provide common and chemical names of some representative OP and carbamates, and their acute oral LD₅₀.

Kinetics

Ultimately, absorption is dependent on lipid solubility and carrier formulation, but in general, the cholinesterase inhibitors tend to be well absorbed from any exposure route. They are rapidly distributed to tissues throughout the body. The cholinesterase inhibitors are metabolized primarily in the liver. In most cases the metabolic process detoxifies the compound, but some OP insecticides may be activated or have an increase in activity following metabolism. Phosphorothioates and phosphorodithioates (sulfur‐containing compounds) undergo oxidative desulfuration reactions to form the oxon derivatives, which have increased potency. General oxidation and hydrolysis reactions, in particular the cleavage of the ester linkage, markedly reduce toxicity (Taylor 2023). Most OP and carbamate insecticides are excreted as degradation products in the urine.

Mechanism of Action

OP and carbamate insecticides inhibit the enzyme acetylcholinesterase (AChE). AChE functions to break down the neurotransmitter acetylcholine (ACh) into acetate and choline, which are then recycled to form more acetylcholine. Acetylcholine is the neurotransmitter found between preganglionic and postganglionic neurons of the autonomic nervous system; at the junction of postganglionic parasympathetic neurons in smooth muscle, cardiac muscle, or exocrine glands; at neuromuscular junctions of the somatic nervous system; and at cholinergic synapses in the CNS. AChE is also found on the surface of red blood cells, although its function there is uncertain. Inhibition of AChE results in excess ACh at the postsynaptic receptor, and thus exaggerated stimulation. Normally, depolarization and transmission of the action potential occurs with temporary binding of acetylcholine and ends on degradation. When AChE is phosphorylated (due to binding of OP) or carbamylated (due to binding of carbamates) ACh binds to the postsynaptic membrane but is not broken down. Continued stimulation and depolarization of the postsynaptic membranes may progress to paralysis because repolarization cannot occur (Wismer and Means 2018).

Table 18.1. Common organophosphorus compounds

Compound | Chemical Name | Acute Oral LD₅₀ (mg/kg; rat)
Chlorpyrifos | O,O‐diethyl O‐(3,5,6‐trichloro‐2‐pyridyl) phosphorothioate | 135
Diazinon | O,O‐diethyl O‐(2‐isopropyl‐4‐methyl‐6‐pyrimidyl) phosphorothioate | 300
Dichlorvos | 2,2‐dichloro‐vinyl dimethyl phosphate | 25
Disulfoton (aka Disyston) | O,O‐diethyl S‐2‐[(ethylthio) ethyl] phosphorodithioate | 2
Phosmet | O,O‐dimethyl S‐phthalimidomethyl phosphorodithioate | 147
Terbufos | S[(tert‐butylthiomethyl] O,O‐diethylphosphorodithioate | 1.6
Trichlorfon | Dimethyl (2,2,2‐trichloro‐1‐hydroxyethyl) phosphonate | 630

Table 18.2. Common carbamate compounds

Compound | Chemical Name | Acute Oral LD₅₀ (mg/kg; rat)
Aldicarb | 2‐methyl‐2‐(methylthio)propionaldehyde‐O‐(methylcarbomoyl)oxime | 0.9
Carbaryl | 1‐naphthyl methylcarbamate | 307
Carbofuran | 2,3‐dihydro‐2,2‐dimethyl‐7‐benzofuranyl methylcarbamate | 8
Methomyl | S‐methyl N‐(methylcarbamoyloxy) thioacetimidate | 17
Propoxur | O‐isopropoxyphenyl methylcarbamate | 95

The OP and carbamates occupy the anionic and esteratic sites of AChE. The binding of OP to AChE is considered “irreversible” since the phosphorus atom of the OP attached to the esteratic site of AChE is a strong bond with a half‐life of hours or days. The binding of the carbonyl structure of carbamates to the esteratic site is considered a “reversible” bond because of its relatively shorter half‐life of 30–40 minutes. The phenomenon of “aging” can occur with some OP compounds but not with carbamates. Aging occurs when the phosphorus atom attached to the esteratic site is demethylated or deethylated, resulting in a stable, unbreakable bond (Fukuto 1990; Sultatos 1994). The rate at which aging occurs varies with the OP. Once aging has occurred, the enzyme will no longer be active and the body must synthesize new enzyme over days to weeks. Re‐exposure to a cholinesterase‐inhibiting compound during this time will cause further depression of already compromised AChE activity with potentially devastating results.

Toxicity

The acute oral toxicity of this class of compounds varies widely, from highly toxic (<1 mg/kg) to practically nontoxic (>5 mg/kg) depending on the formulation, route, and species. Cats and fish tend to be very sensitive to cholinesterase inhibitors. The minimum oral lethal dose of chlorpyrifos in cats is 10–40 mg/kg (Fikes 1992). Information on toxicities of specific insecticides can be found on material safety data sheets, other product data literature, and reputable websites. In most cases, acute toxicosis is the most likely problem encountered. Tables 18.1 and 18.2 provide acute oral LD₅₀ for some commonly encountered OP and carbamate insecticides.

Clinical Effects

Signs

Clinical signs can be related to either muscarinic or nicotinic effects, and the predominance of a particular sign as well as the rate of its progression can vary with the OP and species involved. Muscarinic signs are the classic cholinergic or SLUDDE signs (salivation, lacrimation, urination, diarrhea, dyspnea, and emesis). In addition, animals can exhibit miosis and/or bradycardia. Alternatively, due to sympathetic override, mydriasis or tachycardia can be seen. Dyspnea is the result of excess bronchial secretions. Nicotinic signs are related to effects at the neuromuscular junction and can manifest as muscle fasciculations or tremors, generalized tetany, and paralysis. CNS signs, though less common, can include depression or hyperstimulation, and seizures (Wismer and Means 2018).

Laboratory

No diagnostic changes are noted on routine complete blood count (CBC) or chemistry evaluations. Although performing CBC and chemistry profiles will not rule in or out a diagnosis of OP or carbamate toxicosis, they are recommended to determine the overall health of the poisoned patient.

Differential Diagnosis

Differential diagnoses include agents causing neuromuscular effects as well as those producing muscarinic‐type signs, including tremorgenic mycotoxins, amitraz, pyrethrins/pyrethroids, pancreatitis, and garbage intoxication.

Diagnostics

Confirmation of OP or carbamate poisoning is based on a history of exposure and appropriate clinical signs, detection of the compound in tissues, and suppression of cholinesterase activity. Samples for cholinesterase determination should be chilled, not frozen.

Antemortem

A test dose of atropine can be used to help differentiate an OP/carbamate toxicosis from another cause of signs. Administration of a preanesthetic dose of atropine (0.02 mg/kg intravenous) will not produce signs of atropinization in these cases (Wismer and Means 2018). A much higher dose is required (see below in treatment).

Appropriate samples for chemical detection are ingesta, bait, urine, and hair (if dermal exposure is suspected). Whole blood should be collected in the clinical patient for determination of cholinesterase activity. Whole blood should be refrigerated, not frozen. Depression of cholinesterase activity of 50–80% of normal is typical and is consistent with exposure and intoxication.

Postmortem

Liver, ingesta, hair, urine, and any suspect bait should be collected on necropsy for chemical identification. In addition, collect retina (collect entire globe of eye) and brain (entire brain or hemisphere) for cholinesterase determination. Retina and brain should be chilled, not frozen.

Management of Exposures

The clinical course of many OP and carbamate intoxications progresses rapidly and requires immediate and intensive therapy. The goals of treatment are to correct and support respiratory and cardiovascular function, control nervous stimulation, and eliminate further exposure through decontamination.

The goal of decontamination is to prevent further absorption. Care should be taken to protect personnel from exposure. Animals exposed should be bathed in a liquid dish detergent. Care should be taken to maintain normal body temperature. Insecticide collars should be removed. Clipping may be necessary for animals with long or matted hair. Because clinical signs can develop rapidly with some agents, and the carriers for some products may be hydrocarbon‐based, induction of vomiting should be done with caution following oral exposures (see Chapter 7). Gastric lavage might be preferable in some cases. Activated charcoal is effective in binding OP and carbamate insecticides (Wismer and Means 2018).

Respiratory compromise is the most common cause of death from this class of compounds due to bronchoconstriction, increased bronchial secretions, and bradycardia. Oxygen therapy should be instituted. Atropine (0.2 mg/kg intravenous or subcutaneous) is indicated for life‐threatening muscarinic signs (Wismer and Means 2018). Give to effect, but do so cautiously because atropine toxicosis can occur with overzealous administration. Atropine is not effective against nicotinic signs.

Pralidoxime chloride (2‐PAM; protopam chloride), a cholinesterase reactivator, at 10–15 mg/kg intramuscular or subcutaneous twice daily is indicated for the treatment of neuromuscular (nicotinic) signs (Fikes 1992). Pralidoxime binds to the OPAChE complex, liberating the enzyme. It is not effective for treatment of muscarinic signs or if aging has occurred. However, because the aging process varies with the OP, administration of 2‐PAM is worthwhile. If no improvement is seen after three consecutive doses, 2‐PAM should be discontinued because at high doses (150 mg/kg) it can also inhibit AChE. Diazepam or another anticonvulsant medication is indicated for seizures. In all cases of exposure, animals should be monitored and provided with appropriate supportive therapy if necessary.

Prognosis

The prognosis is dependent on the OP or carbamate involved, the dose and time of exposure, formulation, and species. The more potent AChE agents can produce clinical signs and death within minutes to hours. For these cases, the prognosis is guarded even with prompt and aggressive intervention.

PYRETHRINS AND PYRETHROIDS

Sources and Formulations

Because of concern for the toxicity and environmental persistence of the organochlorine and OP insecticides, there was a shift toward greater use of pyrethrins and pyrethroids in the 1970s. Recent estimates state that pyrethrins and pyrethroids currently make up more than 25% of the world insecticide market (Vais et al. 2001). This class of insecticides is effective against several insect pests and products are marketed as sprays, dusts, dips, shampoos, spot‐ons, gels, foggers, ear tags, pour‐ons, back rubbers, and face rubbers.

Pyrethrum is a mixture of six active insecticidal compounds termed pyrethrins: pyrethrin I and II, cinerin I and II, jasmolin I and II. Pyrethrum occurs naturally in the flowers of Chrysanthemum species. Chemically, pyrethrins are esters of alcohols and acids. Synthetic modification of the basic pyrethrin structure has resulted in a series of “pyrethroids,” which tend to have greater insecticidal potency and are more environmentally stable than the pyrethrins. Potency is enhanced with the addition of a cyano group, leading to the classification of the type I (lacking a cyano group) and type II (containing a cyano group) pyrethroids.

Kinetics

The pyrethrins and pyrethroids tend to have poor dermal absorption (>2% in humans) (Woollen et al. 1992). However, the grooming behavior of animals results in oral exposure even when products are applied dermally. Carriers and solvents can also influence absorption. Pyrethrins and pyrethroids are incompletely absorbed following oral exposure, with approximately 40–60% of an oral dose absorbed (Anadon et al. 2009). Once absorbed they are rapidly distributed and because of their lipophilicity will accumulate in nervous tissue (Anadon et al. 2009). Pyrethrins and pyrethroids are hydrolyzed in the gastrointestinal tract and metabolized by a variety of tissue types throughout the body. Metabolites and parent compounds are eliminated via bile and urine.

Mechanism of Action

The primary mode of action of the pyrethrins and pyrethroids is through disruption of normal sodium channel function, resulting in a prolongation of sodium channel opening, a less polarized membrane, and ultimate repetitive firing of action potentials. Differences in type I and type II mechanisms have been identified, with type II pyrethroids more likely to cause depolarization, but this has little significance in either the occurrence of clinical signs or the treatment of the poisoned patient. Pyrethrins also act on GABA receptors at high doses, but this mechanism also appears to be of little clinical significance (Anadon et al. 2009).

Toxicity

Toxicity varies widely and is dependent on the individual pyrethrin or pyrethroid, species of animal, formulation, and route of exposure. In general, the pyrethroids are considered less acutely toxic than OP and carbamate insecticides. Adverse effects are often the result of extra‐label use but can also occur from individual hypersensitivity reactions and genetic‐based idiosyncratic reactions (Hansen and Khan 2013). Fish are highly sensitive to this class of compounds. Care should be taken to avoid contamination of water bodies when using these compounds outdoors. Indoor aquaria should be protected when using foggers or sprays in the home. The air pump intake should be turned off and the tank and intake covered during application. The home must be well ventilated before returning to use (Volmer 2004). Cats are exquisitely sensitive to concentrated permethrin products, likely because of their reduced ability to metabolize permethrin.

Clinical Effects

Signs

Because the pyrethrins and pyrethroids are applied via the dermal route, most signs are attributed to skin sensitivity. Cats sprayed with a pyrethrin‐based spray might exhibit paw shaking, ear twitching, flicking of the tail, and twitching of the skin on their backs. Some cats hide or are reluctant to move or walk, holding a leg out to the side. Signs generally begin within minutes to hours post application and resolve with minimal treatment by 24–48 hours (Volmer 2004). Hypersalivation can occur from grooming soon after application. This might be due to the unpleasant taste or to a tingling sensation on the tongue and mouth. Dermal reactions might also be due to a tingling sensation (paresthesia) produced by the product.

Cats mistreated with concentrated permethrin spot‐on products (36–65% permethrin) intended for dogs can develop life‐threatening tremors and seizures. Cats can also develop toxicosis following grooming of freshly treated dogs before the product has dried. Signs develop within 12–18 hours and include initial apprehension and agitation, hypersalivation, and vocalization, progressing to tremors and seizures by 18–24 hours. Death can occur in untreated cats (Volmer 2004).

Dogs can also develop signs associated with dermal hypersensitivity. They act uncomfortable, lick or chew at their skin, roll on the floor, or rub their backs. Occasionally an episode of vomiting or diarrhea occurs and is not considered a true toxic effect but a nonspecific stress effect.

Laboratory

No specific clinical pathological alterations are associated with exposure to the pyrethrins and pyrethroids. However, for animals with severe signs, a CBC and chemistry is recommended to assess the overall health of the poisoned patient.

Differential Diagnosis

The differential diagnosis list should include any toxic agents or other conditions that cause nervous stimulation. Toxic agents include strychnine, metaldehyde, methylxanthines, illicit drugs (cocaine, amphetamines), and OP or carbamate insecticides.

Diagnostics

Diagnosis is based on history of exposure and appropriate clinical signs.

Antemortem

Analysis for pyrethrins and pyrethroids is limited to a few laboratories. Preferred samples include whole blood, serum, and urine. Unfortunately, concentrations are not well correlated to clinical signs. Hair samples can be analyzed for permethrin to verify exposure in cats suspected of receiving an inappropriate application. A spot‐on application should be considered if a greasy or oily area is noted on the animal's fur.

Postmortem

Hair, brain, and liver can be used for chemical analysis. Because analyses for pyrethrins and pyrethroids are not widely available, consultation with a diagnostic laboratory is recommended prior to submission. No pathognomonic lesions are expected on gross necropsy or histopathology.

Management of Exposures

Treatment is aimed at controlling excess neurological stimulation and preventing further exposure. For mild effects such as hypersalivation, ear twitching, and paw shaking that are often associated with use of a pyrethrin spray, no treatment is usually required. Offering a tasty treat such as milk or water from the tuna tin can alleviate hypersalivation. If mild signs persist the animal can be bathed in a liquid dish detergent and kept warm. Rinsing alone will not remove most topical products. Clinical signs usually resolve rapidly following bathing. Animals with moderate to severe discomfort may require treatment with an antihistamine. In addition, vitamin E oil applied to the application site might help to alleviate the irritation.

Cats treated with a permethrin product intended for dogs should be considered a medical emergency. If the exposure was recent and the animal is not exhibiting clinical signs, the cat should be thoroughly bathed in a liquid dish detergent, dried well, and kept warm. The animal should be monitored for the next 12–18 hours for the development of clinical signs. If the cat is already exhibiting tremors or seizures, hospitalization is required. Methocarbamol, a centrally acting skeletal muscle relaxant, is effective in controlling the tremors and seizures. One‐third to one‐half of the dose is administered as a slow bolus. As the cat begins to relax the administration is paused and the remainder is given to effect. Methocarbamol can be repeated as needed. Complete termination of the tremors might not occur and is not necessary (Volmer 2004). Diazepam alone is ineffective in controlling severe signs. Barbiturates, lipid emulsion, gas anesthetics, and propofol have also been used with varying results to control the signs (Di Pietro et al. 2022).

Once stabilized the cat should be bathed in liquid dish detergent to remove any residual permethrin, dried well, and kept warm. Activated charcoal is not indicated unless the permethrin product was administered orally to the cat. General supportive care should be instituted including intravenous fluids, blood glucose monitoring and correction, and thermoregulation. For most cats receiving appropriate treatment, recovery is achieved by 24–72 hours, and permanent sequelae are not expected. Fine muscle tremors may linger for several days. However, this should not preclude releasing the patient to the owners if the animal is able to eat, drink, and use the litter box. Atropine is not indicated.

Prognosis

Most animals experiencing pyrethrin or pyrethroid toxicosis are expected to have an excellent prognosis. Cats exposed to concentrated permethrin products have a good prognosis if timely and intensive treatment is initiated. Cats exhibiting severe or prolonged signs, or for which timely treatment is denied, have a guarded prognosis.

NEONICOTINOIDS

Sources and Formulations

Neonicotinoids have been synthesized for use against insect pests on crops and companion animals. Worldwide annual sales of neonicotinoids account for 11–15% of the total insecticide market (Tomizawa and Casida 2005). Of the seven neonicotinoids in use today, only three are of primary significance to companion animals: imidacloprid, nitenpyram, and dinotefuran. Imidacloprid and dinotefuran are used in topical formulations, and nitenpyram is the active ingredient in an oral product. Imidacloprid and nitenpyram are chloronicotinyl compounds developed based on the structure of nicotine. Dinotefuran is a furanicotinyl compound developed using acetylcholine as the lead compound. The chloronicotinyl compounds are considered first‐generation neonicotinoids, and the furanicotinyl compounds are third generation. The second‐generation neonicotinoids are thianicotinyl compounds and are used primarily for crop protection (Wakita et al. 2005).

Kinetics

The neonicotinoids tend to be rapidly absorbed following oral exposure. There are several pathways for metabolism depending on the specific neonicotinoid and species. Elimination is primarily via urine with some fecal excretion. The neonicotinoids tend to have short half‐lives in the body and thus pose little risk for bioaccumulation.

Mechanism of Action

Neonicotinoids are considered neurotoxins that bind to the nicotinic acetylcholine receptor (nAChR). They have a much higher binding affinity to the nAChR of insects than mammals (Tomizawa and Casida 2005). Dinotefuran is thought to bind to a unique location on the receptor compared to imidacloprid and nitenpyram (Wakita et al. 2005). In normal nerve tissue, the neurotransmitter acetylcholine is rapidly broken down by AChE to end the synaptic transmission and return the membrane to its normal resting state. The neonicotinoids bind at or near the site where nicotine binds, producing unregulated stimulation and ultimately death of the insect.

Toxicity

Because of their low affinity for mammalian nicotinic receptors and rapid metabolism, the neonicotinoids in general have a wide margin of safety. Table 18.3 lists some toxicity values of the three common neonicotinoids.

Clinical Effects

Signs

Because of their wide margin of safety, toxic effects from imidacloprid, nitenpyram, and dinotefuran are rare and are likely due to other components of the formulation. Oral exposure can result in self‐limiting vomiting. Dermal exposures can result in erythema, pruritus, and alopecia.

Table 18.3. Toxicological profiles of neonicotinoid insecticides

| Rat | Bird
Compound | Acute oral LD₅₀ (mg/kg) | NOAEL (mg/kg/day) | Acute oral LD₅₀ (mg/kg)
Imidacloprid | 450 | 5.7 | 31
Nitenpyram | 1628 | – | >2250
Dinotefuran | 2400 | 127 | >2000

NOAEL, no observed adverse effect level.

Source: Adapted from Tomizawa and Casida (2005).

Laboratory

No clinical laboratory changes are expected from the neonicotinoids.

Diagnostics

Antemortem

There are no routine diagnostic tests for the neonicotinoids in tissues. Consultation with a diagnostic laboratory is recommended prior to submission.

Postmortem

No lesions are expected on gross necropsy or histopathology.

Management of Exposure

For most clinical cases the signs are transient and require no treatment. Bathing and administration of an antihistamine may be required for some cases of dermal discomfort. Oral exposure can be treated by diluting with milk or water. If vomiting occurs, food and water should be removed for a brief period (1–2 hours) to allow the gastrointestinal tract to settle down.

Prognosis

Because of their exceptional safety profiles, rapid metabolism, and availability only in limited quantities for companion animals, exposures carry an excellent prognosis.

ACKNOWLEDGMENTS

The author would like to thank Petra Volmer for her contributions to the first edition of this chapter.

REFERENCES

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Boehringer Ingelheim Animal Health USA Inc. 2020. NexGard® product insert. https://nexgardforpets.com/sites/default/files/2023‐05/2022_NexGard_PI.pdf Accessed 3/1/24.

Di Pietro, Simona, Falcone, Annastella, Arfuso, Francesca, Pennisi, Melissa, Piccione, Guiseppe, and Giudice, Elisabetta. 2022. Treatment of permethrin toxicosis in cats by intravenous lipid emulsion. Toxics 10(4):165.

EXTOXNET. 1995. Pesticide information profile for amitraz, Oregon State University, http://extoxnet.orst.edu/pips/amitraz.htm Accessed 23 January 2024.

Fikes, James D. 1992. Feline chlorpyrifos toxicosis. In Current Veterinary Therapy XI: Small Animal Practice, edited by Robert W Kirk and John D Bonagura, p. 188. Philadelphia: W.B. Saunders.

Fukuto, T Roy. 1990. Mechanism of action of organophosphorus and carbamate insecticides. Environmental Health Perspectives 87:245–254.

Gaens, Daniela, Rummel, Christoph, Schmidt, Martin, Hamann, Melanie, and Geyer, Joachim. 2019. Suspected neurological toxicity after oral application of fluralaner (Bravecto®) in a Kooikerhondje dog. BMC Veterinary Research 15:283.

Hansen, Steven R and Khan, Safdar A. 2013. Pyrethrins and pyrethroids. In Small Animal Toxicology, 3rd ed., edited by Michael E Peterson and Patricia A Talcott, pp. 769–776. St. Louis: Saunders.

Hsu, Wen‐Hung, Lu, Zhi‐Xiang, and Hembrough, Frederick B. 1986. Effect of amitraz on heart rate and aortic blood pressure in conscious dogs: influence of atropine, prazosin, tolazoline, and yohimbine. Toxicology and Applied Pharmacology 84(2):418–422.

Hugnet, Christophe, Buronrosse, Florence, Pineau, Xavier, Cadore, Jean‐Luc, Lorque, Guy, and Berny, Philippe J. 1996. Toxicity and kinetics of amitraz in dogs. American Journal of Veterinary Research 57(10):1506–1510.

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Taylor, Palmer. 2023. Anticholinesterase inhibitors and antagonists. In Goodman & Gilman's the Pharmacological Basis of Therapeutics, 14th ed., edited by Laurence L Brunton and Bjorn C Knollmann, pp. 221–234. New York: McGraw‐Hill.

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Vais, Horia, Williamson, Martin S, Devonshire, Alan L, and Usherwood, Peter N. 2001. The molecular interactions of pyrethroid insecticides with insect and mammalian sodium channels. Pest Management Science 57(10):877–888.

Volmer, Petra A. 2004. Pyrethrins and pyrethroids. In Clinical Veterinary Toxicology, edited by Konnie H Plumlee, pp. 188–190. St. Louis: Mosby.

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Wismer, Tina and Means, Charlotte. 2018. Toxicology of newer insecticides in small animals. Veterinary Clinics of North America: Small Animal Practice 48(6):1013–1026.

Woollen, BH, Marsh, JR, Laird, WJ, and Lesser, JE. 1992. The metabolism of cypermethrin in man: differences in urinary metabolite profiles following oral and dermal administration. Xenobiotica 22(8):983–991.

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19
Other Pesticides

Kristi D. Long

INTRODUCTION

Pesticides are defined as any substance, or mixture of substances, intended for preventing, destroying, repelling, or mitigating any pest. The term “cide” comes from the Latin word “to kill.” There are many types of pesticides, ranging from chemical substances, biological agents (such as viruses or bacterium), antimicrobials, and disinfectants to devices used against any pest with the intention of preventing, destroying, or deterring a pest from causing harm or detriment to humans or human concerns. Pests include insects, plant pathogens, weeds, mollusks, invasive and noninvasive species of birds, mammals, fish, parasites, and microbes that destroy property, spread disease, or are a vector for disease or cause a nuisance. Pesticides can be categorized based on the type of pest they are intended to control (i.e., insecticides, rodenticides, herbicides, fungicides, molluscicides, etc.). There are literally hundreds of different chemicals used as pesticides with diverse chemical structures, formulations, and toxicities. Although there are obvious benefits to the use of pesticides, there are also potential risks, such as potential toxicity to humans and their pet companions as well as wildlife.

Insecticides and rodenticides are commonly involved in animal intoxications and are discussed in separate chapters. This chapter is intended to discuss several other diverse pesticides that have been associated with pet intoxication; it is not intended to be comprehensive in its scope. Interested readers are referred to an excellent website under the auspices of the National Pesticide Information Center that has a wealth of information on various pesticides. This website has numerous pesticide fact sheets and toxicity information, and a section specifically addressing pesticide use on or around animals. It is important to keep in mind that there is limited species‐specific toxicity data for many pesticides and that for the majority of pesticides discussed below treatment of poisoned animals involves appropriate and timely decontamination along with symptomatic and supportive care; specific antidotes are typically not available.

MISCELLANEOUS INSECTICIDES AND REPELLANTS

Boric Acid and Borates

Sources and Formulations

Boric acid and its sodium borate salts are pesticides that are found in nature and many products. Borax is one of the most commonly used products today. It is used to control a wide variety of pests, such as insects, spiders, mites, algae, molds, fungi, and weeds. Products containing boric acid come in liquids, granules, pellets, tablets, wettable powders, dust, and baits, which makes them easily accessible to our pets and other animals.

Kinetics and Toxicity

Absorption of boric acid from the gastrointestinal (GI) tract is rapid (Welch 2004). Following absorption, it is found at the highest concentrations in the brain, liver, and kidneys. It is eliminated unchanged by the kidneys with a half‐life of 5–21 hours. The acute oral LD₅₀ (the amount it takes to kill 50% of the animals) reported for rats ranges from 2 g/kg to approximately 5 g/kg. Thus, it is considered slightly toxic. However, chronic exposure to lower doses is a potential problem.

Mechanism of Action

The mechanism of action of boric acid is unknown, but it is considered to be cytotoxic.

Clinical Effects

The GI tract, vascular system, brain, and kidneys are the primary target organs. In acute, single‐dose, oral exposures, signs include hypersalivation, vomiting, depression, anorexia, diarrhea, and abdominal pain. Depending on the dose ingested, weakness, ataxia, tremors, focal or generalized seizures, oliguria or anuria, renal tubular nephrosis, and liver damage may occur, although the latter is uncommon (Welch 2004). Seizures can be followed by metabolic acidosis, depression, coma, and death. Chronic, toxic exposures cause anorexia, weight loss, vomiting, loose stools, rashes, alopecia, anemia, and death.

Diagnostics

Antemortem

A history of exposure, the occurrence of compatible clinical signs, and possibly the detection of elevated levels of boron in blood, plasma, or urine support a diagnosis. A bench chemistry test is available for detecting boric acid in urine. Due to turn around time, these tests are not used clinically.

Postmortem

Significant lesions can be found in target organs such as the GI tract, kidneys, brain, liver, and skin. No lesions are unique to boric acid, but a constellation of lesions might support a diagnosis. Measurement of boron in kidneys and liver might also be helpful to confirm exposure.

Management of Exposures

Standard decontamination procedures should be followed with suspected exposures. Exposed hair and skin should be washed with a mild liquid dishwashing detergent and warm water followed by thorough rinsing. General GI management, such as taking away food and water for an allotted time frame, will allow for the management of mild gastric symptoms. Typically, emetics or cathartics may not be indicated if an animal has already vomited or exhibited diarrhea. Activated charcoal is generally not administered due to poor adsorption of boric acid. Symptomatic and supportive care should be given as needed. This may include the administration of intravenous balanced electrolyte solutions with or without glucose, GI protectants, and antiemetics as needed. Maintaining urine flow is important to prevent or correct kidney damage. Although dialysis (hemo‐ or peritoneal dialysis) might be indicated if renal failure occurs, it does not appear to increase borate clearance. Benzodiazepines can be given to control seizures.

Prognosis

Most exposures result in rather mild GI signs; in such cases the prognosis is good. With large acute ingestions or chronic exposures, the prognosis is more guarded.

Diethyltoluamide

Sources and Formulations

Diethyltoluamide (DEET) is a widely used liquid insect repellant suitable for application to the skin, clothing/gear, or as an area spray. It is colorless and has a faint odor. Products contain a range of concentrations from 5 to 100% (Dorman 2004).

Kinetics and Toxicity

DEET is absorbed dermally, orally, and ocularly. When DEET and alcohol are applied to the skin, more DEET is absorbed. DEET is broken down by the liver and eliminated primarily via the kidneys. Its half‐life is 28 minutes to 20 hours depending on species and exposure route. The level of concern is unknown as is the minimum lethal dose (MLD). LD₅₀ amounts vary depending on route and species. DEET does cross the placenta and has been found in cord blood, with no reported teratogenic (Dorman 1990).

Mechanism of Action

The mechanism of the toxic action of DEET is unknown. It is thought to interfere with the electrophysiological response of olfactory sensory neurons to attractive odors in target species.

Signs

Clinical signs of oral exposure include hypersalivation, nausea, retching, anorexia, and depression. Ataxia, disorientation, tremors, and seizures can be seen with larger exposures. Dermal exposures can lead to excitation, lethargy, erythema, and potentially tremors if large exposure occurred. Ocular exposures can result in pain, redness, lacrimation, uveitis, and potentially corneal ulceration (Dorman 2004).

Diagnostics

Antemortem

An antemortem diagnosis relies on a history of exposure (perhaps noticing a residue on skin or hair). Testing for DEET is not widely available, although contacting a veterinary diagnostic laboratory might be helpful; detection of residues on hair or in biological specimens only confirms exposure and not necessarily intoxication.

Postmortem

There are no characteristic postmortem findings. Preferred samples taken at necropsy are skin, kidney, liver, stomach, and brain. These specimens should be frozen and preserved in 10% formalin.

Management of Exposures

Treatment should start with stabilization of the pet where signs are present. Decontamination of dermal exposure should be a bath with liquid dishwashing detergent. A second bath should be given 2–4 hours later with exposures to >80% DEET agents that are lotions or liposphere in nature (Dorman 2004). Oral decontamination is recommended in the form of dilution. Inducing emesis is not recommended. For ocular decontamination, rinse eyes with tepid water or 0.9% NaCl for 15 minutes. Pets may require breaks during ocular flushing. Inhalation exposure requires fresh air within appropriate temperature ranges. Other symptomatic and supportive care is provided as needed.

Prognosis

Animals with DEET exposures have an excellent prognosis with appropriate treatment.

Macrocyclic Lactone Parasiticides

Sources and Formulations

Macrocyclic lactone parasiticides (also known as macrolides) are compounds used to treat or prevent a variety of parasitic diseases in domestic animals and humans. They are often referred to as endectocides due to their ability to kill both internal (endo) and external (ecto) parasites (Lanusse et al. 2018). Macrolides include abamectin, doramectin, eprinomectin, ivermectin, milbemycin oxime, moxidectin, and selamectin. These products are used for prevention of heartworms in dogs and cats, treatment of feline ear mites, prevention of internal nematode infestation, and management of a variety of other parasitic diseases such as scabies and infestations of lice (Mealey 2013). Several macrolides are used in food animals and horses for the prevention and treatment of internal and external parasites. Abamectin b₁ is a macrocyclic lactone that is present in some household insecticides, in ant and roach bait stations, and in agricultural insecticides. Products containing macrolides include tablets, chewable tablets, spot‐on products, gels, pour‐on liquids, injectable solutions, otic solutions, premixes, and granules.

Kinetics and Toxicity

In general, macrolides are well absorbed orally and some (e.g., selamectin) are also well absorbed dermally (Mealey 2013). Many of these compounds are lipophilic, with moxidectin being the most lipophilic of the group (Lanusse et al. 2018). The macrolides have relatively long half‐lives due to their wide tissue distribution, lipophilicity (fat storage), extensive biliary and intestinal secretion, and enterohepatic recycling (Lanusse et al. 2018).

The macrolides have a wide margin of safety in mammals due to the fact that they do not cross the blood–brain barrier under normal circumstances (Lanusse et al. 2018). Animals with blood–brain barrier defects are at increased risk for toxicosis from doses of macrolides that would not affect animals with intact blood–brain barriers. A genetic polymorphism in some breeds of dogs causes a defect in the P‐glycoprotein of a multidrug‐resistant pump (coded for by the MDR1 or ABCB1 gene) in the blood–brain barrier. As a consequence of this defect, the blood–brain barriers of affected dogs do not exclude certain xenobiotics (including the macrolides) from the brain. Additionally, the same P‐glycoprotein acts within the intestine to limit absorption of macrolides, so dogs with the MDR1 defect may absorb more drug after ingestion and attain higher blood concentrations of macrolides (Lanusse et al. 2018). Higher blood and central nervous system (CNS) concentrations of macrolide put MDR1‐defective dogs at risk for toxicosis at dosages of macrolides that are well tolerated by dogs without this genetic polymorphism. About 5% of cats, no breed predilections noted, also have MDR1 mutations and are more sensitive to macrolides (Mealey and Burke 2015).

The doses of macrolides commonly used for heartworm prevention are well below the levels expected to cause clinical signs in MDR1‐defective dogs, and no problems are expected with the monthly heartworm treatments even in affected dogs. Table 19.1 lists the dog breeds that to date have had the MDR1 defect confirmed through genetic testing. Because this defect is an autosomal recessive trait, only a fraction of dogs within these breeds would be expected to be affected. Table 19.1 reflects breeds most commonly affected by the MDR1 gene according to Washington State University.

The minimum toxic dose of ivermectin in MDR1‐defective dogs is 100 mcg/kg, which is approximately 16 times higher than the monthly heartworm preventive dose; moxidectin toxicosis has been reported in a collie at 90 mcg/kg (30 times the monthly heartworm preventive dose), milbemycin toxicosis has been reported in MDR1‐defective collies at 5 mg/kg (10 times the monthly heartworm preventive dose), and selamectin caused ataxia when administered orally to MDR1‐defective collies at 2.5 times the therapeutic dose. In contrast, dogs without the MDR1 defect can generally tolerate ivermectin dosages up to 600 mcg/kg and milbemycin dosages up to 1.6 mg/kg for treatment of ectoparasites (Mealey 2013). Based on results in laboratory dogs, the minimum toxic dosage of ivermectin had been reported to be 2.5 mg/kg. A recent review of ivermectin toxicosis in dogs revealed that some individuals are intolerant of dosages as low as 0.2 mg/kg in spite of them belonging to breeds not associated with the MDR1 defect (Merola et al. 2009), so the potential for individual sensitivity to macrolides needs to be considered whenever treatment with higher doses is contemplated.

Table 19.1. Breeds known to carry the MDR1 P‐glycoprotein genetic polymorphism

Source: Adapted from Washington State University (2021).

Breed | Approximate frequency
Collie | 70%
Australian shepherd (standard and mini) | 50%
Long‐haired whippet | 50%
McNab | 30%
Silken windhound | 30%
Chinook | 25%
English shepherd | 15%
German shepherd | 10%
Herding breed cross | 10%
Old English sheepdog | 5%
Mixed breed | 5%
Border collie | <5%

Mechanism of Action

The macrolides cause the death of parasites by paralyzing nematodes and arthropods through actions on chloride channels of the pharyngeal pump and somatic musculature of the parasites. As a result, the parasite loses the ability to obtain nutrients and its muscular movements are inhibited. Macrolides also may stimulate some parasite gamma‐aminobutyric acid (GABA) receptors.

Mammals are largely protected from the actions of macrolides on the nervous system, as the target receptors exist only within the CNS in mammals, and the macrolides are excluded from the CNS by the P‐glycoprotein pump of the blood–brain barrier (Gramer et al. 2011). Animals with defects in the blood–brain barrier due to inflammation, anatomic anomaly, or trauma can be at increased risk of macrolide toxicosis. Additionally, the MDR1 pump can be overwhelmed in cases of macrolide overdose, allowing excessive amounts of macrolide into the CNS and resulting in toxicosis. Once in the CNS, the macrolides alter chloride channels and GABA activity, resulting in CNS depression.

Clinical Effects

Clinical signs associated with macrolide toxicosis include mydriasis, ataxia, CNS depression, disorientation, hyperesthesia, vocalization, hypersalivation, vomiting, clinical blindness, coma, tremors, and seizures (Mealey 2013; Roder 2004). Hypothermia may develop secondarily in recumbent animals. Signs generally occur soon after an overdose, but in animals being treated with daily doses signs may not develop until several days of treatment have passed. Additionally, dogs being treated with injectable macrolides may have a delay in onset and a delay in peak effect as the macrolide is slowly absorbed from the subcutaneous injection site.

Diagnostics

Macrolides can be detected in various body tissues, adipose tissue, liver, and serum to confirm exposure to the drug, but the utility of such analysis in aiding in diagnosis of emergent cases is minimal. The concentration of the drug in the brain is of clinical importance (Mealey 2013). Diagnosis is based on the history of exposure and consistent clinical signs. There are no expected consistent postmortem lesions in animals succumbing to macrolide toxicosis. A DNA test is available to detect dogs with MDR1 polymorphisms. The test uses cheek swabs and can be helpful in identifying dogs that are at increased risk for macrolide toxicosis.

Management of Exposures

The goals of managing exposures to macrolides are patient stabilization, decontamination, and supportive care for recumbent animals. In recent ingestions with no serious clinical signs, induction of emesis should be considered. Because of the rapid absorption of macrolides from liquids and gels, if more than 30–60 minutes have elapsed from ingestion, it may be more beneficial to administer activated charcoal. Repeated doses of activated charcoal should be administered to all animals showing more than mild signs to try to reduce the half‐lives of the macrolides. Physostigmine is an anticholinesterase agent that has been administered to temporarily reverse neurologic clinical signs in dogs with ivermectin toxicosis. The use of physostigmine may be of some benefit, but it is not recommended due to the association of a variety of adverse effects (Mealey 2013). Animals that become comatose will need intensive nursing care to prevent hypothermia, decubital ulcers, and aspiration. Ventilatory support may also be needed. Recently, intravenous lipid emulsion infusions have been used to successfully manage severe macrolide toxicosis (Crandell and Weinberg 2009), although anecdotally not all animals appear to respond to this treatment modality.

Prognosis

The prognosis depends on the dosage ingested, the MDR1 status of a dog, and the availability of good nursing care to manage comatose animals. Comatose animals surviving more than 24 hours have a reasonable chance of recovery if adequate nursing care is provided.

FUNGICIDES

Fungicides constitute a chemically diverse group of pesticides used to kill or prevent the growth of fungi and their spores. Largely fungicides are used to control diseases of plants, prevent the rotting of wood, and to control growth of molds and mildew. They work in a variety of ways, mostly by damaging the fungal cell membrane or interfering with energy production within the fungal cells. Risk of intoxication from fungicides that are used to prevent or treat plant fungal infections is relatively low in mammalian species. Common lawn and garden fungicides include captan, chlorothalonil, sulfur, and propiconazole.

Toxicity

Fungicides vary in terms of their acute toxicity. Many are almost nontoxic, with rodent LD₅₀ greater than 0.5 g/kg body weight (Osweiler 1996), for example propiconazole has a rat oral LD₅₀ of 1517 mg/kg (Yeary 2000).

Clinical Effects

Clinical signs are most often nonspecific and include anorexia, depression, weakness, and diarrhea (Osweiler 1996). Many fungicides are irritating to the skin, eyes, and mucous membranes. There are no characteristic laboratory findings.

Diagnostics

A diagnosis of intoxication primarily relies on a history of exposure. Testing for specific fungicides in biological samples is typically not available.

Management of Exposures

Treatment involves standard decontamination procedures. For known exposures to fungicides that have low toxicity, GI decontamination is probably not necessary due to the unlikely occurrence of clinical signs. There are no antidotes, so in the unlikely event of intoxication, symptomatic and supportive care is indicated.

HERBICIDES

Herbicides are chemicals designed to manipulate, kill, or control undesirable vegetation. Herbicides constitute a diverse group of chemicals that are widely used around farms and homes. They come in a variety of formulations that are designed to prevent plants from growing (preemergent herbicides) or kill plants that are already growing (postemergent herbicides). Preemergent herbicides are typically incorporated into soil to prevent germination, and postemergent herbicides are applied directly to the growing plant. Although a large number of herbicides are available for purchase, several have similar chemical properties. Herbicides with a common mechanism of action are grouped into “families.” The seven major modes of action are as follows: growth regulation, amino acid synthesis inhibition, lipid synthesis inhibition, seedling growth inhibition, photosynthesis inhibition, cell membrane disruption, and pigment inhibition. The following are some of the most common or most dangerous herbicides available.

Chlorophenoxy Herbicides

Sources and Formulations

Chlorphenoxy herbicides are plant growth regulators. These compounds are used alone or mixed into commercial fertilizers to control broadleaf weeds by disrupting plant hormone balance. There are numerous commercial products that contain chlorophenoxy herbicides. 2,4‐dichlorophenoxyacetic acid (2,4‐D) is one of the most commonly used herbicides around the home. 2,4‐D is available in several chemical forms including salts, esters, and an acid form; toxicity is dependent on the chemical form and concentration. Products containing 2,4‐D can be in liquid, dust, or granular formulations.

Kinetics and Toxicity

Following ingestion, 2,4‐D is rapidly absorbed; the degree of dermal absorption varies with the formulation of 2,4‐D and species (Talcott 2013). Absorbed 2,4‐D is widely distributed throughout the body, but it does not accumulate in fat. Elimination is via the renal anion transport system of the kidney; this system is not as efficient in dogs as other species, making dogs more susceptible to exposures to 2,4‐D. In dogs, oral dosages of 2,4‐D exceeding 175 mg/kg resulted in toxicosis, characterized primarily by myotonia and muscle tremors. Although dosages this high are possible if dogs were exposed to very concentrated solutions, at the concentrations used in residential areas (<1%) exposure of dogs to toxic levels of 2,4‐D is extremely unlikely (Talcott 2013).

Clinical Effects

Signs

Chlorophenoxy herbicides are moderately irritating to skin and mucous membranes. Ingestion of diluted or ready‐to‐use products just causes mild GI signs (vomiting, salivation). Inhalation of sprays can result in coughing. Concentrate exposure in dogs can cause muscle weakness, tremors, and moderate increases in body temperature. This is due to the fact that dogs do not excrete organic acids well. Laboratory changes include low arterial pH and bicarbonate, elevated serum creatine phosphokinase concentrations due to muscle damage, elevated blood urea nitrogen and creatinine, and electrolyte disturbances (hyperkalemia and hypocalcemia). Mild leukocytosis and liver enzyme elevations have also been noted (Talcott 2013).

Diagnostics

A diagnosis relies on a history of recent exposure. Depending on the nature of the exposure, a peculiar odor might be noted on the hair or breath of an exposed animal. Although antemortem or postmortem analysis of biological specimens is possible, such testing is not widely available.

Management of Exposures

Initial management should include consideration of standard skin and GI decontamination procedures. Significant vomiting prior to presentation would make induction of emesis contraindicated. Other treatment is largely symptomatic and supportive. Fluids and antiemetics should be used as needed to control vomiting and maintain hydration. Dogs presenting with myotonia may benefit from the use of muscle relaxants such as methocarbamol. Alkalinizing the urine with sodium bicarbonate dramatically accelerates excretion of 2,4‐D.

Prognosis

The prognosis is typically good.

Glyphosate

Sources and Formulation

Glyphosate is a herbicide that acts on a specific enzyme to prevent the production of specific amino acids needed for normal plant growth and development. It inhibits the 5‐enolpyruvyl‐shikimate‐3 phosphate synthase (EPSP synthase) enzyme, which mammals do not have. Glyphosate is commonly used in both agricultural fields and lawns.

Kinetics and Toxicity

Glyphosate is practically nontoxic by ingestion and dermal exposure (Burgat et al. 1998). Glyphosate is poorly absorbed from the GI tract and is largely excreted unchanged in the urine by mammals. The surfactants (soaps) that are added to help the herbicide penetrate the plant are very irritating to the mucous membranes and skin, and are responsible for most clinical signs. Some formulations may cause more irritation than others.

Clinical Effects

Vomiting and gagging are common after ingestion of the wet product (Burgat et al. 1998). Oral ulcers can be seen with ingestion of concentrated products.

Diagnostics

None.

Management of Exposure

Oral ingestions should be diluted with water or a small amount of milk. Ingestions of concentrated glyphosate products may need mucosal protectants like sucralfate.

Prognosis

Good in most ingestions.

Paraquat

Sources and Formulation

Paraquat is a cell membrane disruptor. It is a highly toxic compound. Paraquat may only be used by certified applicators. Unfortunately, it has been used to maliciously poison pets (Bischoff et al. 1998; Cope et al. 2004).

Kinetics and Toxicity

Paraquat is absorbed orally and concentrates in the lungs, where it is transformed to highly reactive free radical molecules. The lung heals by fibrosis, leading to dyspnea and death. Because of the time involved in the toxification of paraquat in the body, there is a delay after exposure of several hours up to 3 days prior to the onset of signs. Paraquat is normally applied at rates which are low enough that animals exposed to treated fields are not at risk of acute toxicosis. Problems arise if animals are exposed to the concentrates (Oehme and Pickrell 2004).

Clinical Effects

If large amounts of paraquat are ingested, initial clinical signs may include vomiting, oral ulcers, and diarrhea. These signs progress to respiratory distress.

Diagnostics

The suspected source material, urine, lung, or muscle may be tested for paraquat. There is a rapid urine screening test, but because of rapid excretion, it is only of value for the first 2 days or so after exposure (cross reacts with diquat). Gross and histologic changes are important in the diagnosis of paraquat toxicosis. Necropsy findings include dark, congested, and hemorrhagic lungs with fibrosis.

Management of Exposure

Rapid decontamination of the ingested paraquat is the most important aspect of treatment. Vomiting should be induced as soon as possible after ingestion and activated charcoal or bentonite clay should be administered. Monitor for respiratory difficulty for 5–7 days. Oxygen is contraindicated due to the possibility of aggravating oxidative injury to the lung.

Prognosis

Outcome appears to be related to dose and early decontamination.

Diquat Dibromide

Sources and Formulation

Diquat dibromide is commonly found in combination with other herbicides. It is used in both agricultural and lawn environments. Diquat interferes with cell respiration, the process by which plants produce energy (Oehme and Pickrell 2004).

Kinetics and Toxicity

Systemic absorption of diquat dibromide from oral and dermal exposure is low. While related to paraquat, diquat does not cause pulmonary injury. The surfactants (soaps) that are added to help the herbicide penetrate the plant are very irritating to the mucous membranes and skin, and are responsible for most clinical signs (Oehme and Pickrell 2004).

Clinical Effects

Ingestion of sufficient doses may cause vomiting and gagging. Oral ulcers can be seen with ingestion of concentrates.

Diagnostics

None available.

Management of Exposure

Oral ingestions should be diluted with water or a small amount of milk. Ingestions of concentrated diquat products may need mucosal protectants such as sucralfate.

Prognosis

Good prognosis in most cases.

Disodium Methanearsenate and Monosodium Methanearsenate

Sources and Formulation

Disodium methanearsenate (DSMA) and monosodium methanearsenate (MSMA) are arsenic‐containing herbicides. They are nonselective contact herbicides that defoliate or desiccate a wide variety of plant species.

Kinetics and Toxicity

Arsenic is readily absorbed into the bloodstream when ingested. It is excreted quickly. See Chapter 22 for more information on arsenic.

Clinical Effects

The signs of poisoning with arsenicals include vomiting and watery (bloody) diarrhea. Death is due to dehydration, electrolyte imbalances, low blood pressure, and seizures.

Diagnostics

Blood and urine levels of arsenic decrease rapidly following acute exposure, so evaluation for arsenic must be done within a few days.

Management of Exposure

Emesis for acute exposures. In the symptomatic animal monitor hematocrit, electrolytes, and kidney function. These animals should receive aggressive intravenous fluid therapy, GI protectants, and supportive care. Chelation is recommended only in those showing progressive signs. British anti‐Lewisite (BAL), succimer, or d‐penicillamine can be used (see Chapter 22).

Prognosis

Guarded to poor.

MOLLUSCIDES

Molluscicides are baits to target mollusk species. Snails and slugs are common pest for gardeners and farmers alike (Figures 19.1 and 19.2). Metaldehyde and ferric phosphate, ferric sodium ethylenediaminetetraacetate (ferric EDTA), and ferric sulfate are common molluscicides used today. Formulations and concentrations vary on brand and use. Ferric molluscides tend to be a safer option to their competitor metaldehyde.

Figure 19.1. Mollusk found under piece of timber.

Source: Kristi Long.

Figure 19.2. Common ground snail of the southeast region of the United States.

Source: Kristi Long.

Metaldehyde

Sources and Formulations

Metaldehyde is found in a number of snail and slug baits that are commonly used in and around gardens and horticultural crops (Brutlag and Puschner 2013). Baits are available in liquid, gels, paste, meal, powder, pellet, and granular formulations. The concentration of metaldehyde in these products differs by country and brand. Some regulatory agencies require that certain formulations be designed so that they are unattractive to nontarget species such as dogs (Talcott 2004).

Kinetics and Toxicity

In the stomach, metaldehyde undergoes acid hydrolysis to acetaldehyde, which is rapidly absorbed (Richardson et al. 2003). Metaldehyde is also absorbed from the stomach intact. Metaldehyde is rapidly metabolized in the liver by cytochrome P450. Acetaldehyde is also rapidly metabolized to carbon dioxide. Less than 1% of absorbed metaldehyde is eliminated in the urine as the parent compound. The half‐life of metaldehyde is unknown for dogs and cats but is approximately 27 hours in people. There are findings in various studies that metaldehyde is the actual toxicant contrary to acetaldehyde (Brutlag and Puschner 2013). Samples of plasma or urine had no traces of acetaldehyde in the sample, whereas metaldehyde was found for up to 3 years in samples of humans (Brutlag and Puschner 2013).

Mechanism of Action

The mechanism of toxic action is unknown but likely involves alterations of neurotransmitters such as GABA, serotonin or 5‐hydroxytryptamine, norepinephrine, and monoamine oxidase in the brain (Brutlag and Puschner 2013; Richardson et al. 2003).

Clinical Effects

SIGNS

A common presentation of intoxicated animals is termed “shake and bake”. This refers to the tremors and hyperthermia that can be seen. Signs can commence as soon as 30 minutes post exposure. The most common clinical signs in dogs include tachycardia, nystagmus, hyperpnea, ataxia, seizures, acidosis, cyanosis, diarrhea, dehydration, and hyperthermia (Richardson et al. 2003). Uncontrolled hyperthermia can lead to disseminated intravascular coagulation and multiple organ failure. Temporary blindness and liver damage have been reported in dogs (Brutlag and Puschner 2013). Heightened sensitivity to noise, light, and touch is also commonly noted. Signs are similar in other intoxicated species.

LABORATORY

There are no characteristic laboratory changes. Metaldehyde bait present in the contents of the stomach smells of formaldehyde (Brutlag and Puschner 2013). Hemoconcentration, alterations of renal and liver function (possibly secondary to uncontrolled hyperthermia), and mild metabolic acidosis have been reported. Veterinary diagnostic laboratories offer chemical analysis for metaldehyde. Samples should be kept frozen for analysis. Samples available for analysis are stomach contents (most reliable), serum, urine, and liver (Brutlag and Puschner 2013).

Diagnosis

ANTEMORTEM

A thorough history of exposure and occurrence of compatible clinical signs is the most reliable form of diagnosis. Laboratory detection of metaldehyde in stomach contents, serum/plasma, and urine can confirm exposure; such tests are commonly available in areas where metaldehyde‐containing products are frequently used.

POSTMORTEM

Analysis of GI contents or urine can confirm exposure. Hemorrhage may be present in the GI mucosa. Reports of hepatic, renal, and pulmonary congestion have been noted on necropsy of dogs (Brutlag and Puschner 2013).

Management of Exposures

Treatment is directed toward decontamination, controlling muscle tremors and seizures, correcting hyperthermia, and providing adequate cardiovascular and respiratory support (Brutlag and Puschner 2013). Standard decontamination protocols are recommended. In asymptomatic animals, emetics can be used. In symptomatic animals, they are not recommended due to the risk of aspiration. Alternatively, gastric lavage might be considered, particularly if the animal is anesthetized to control muscle tremors or seizures. Activated charcoal with or without a cathartic is indicated.

A variety of drugs are used to control muscle tremors or seizures, including benzodiazepines, barbiturates, gas anesthetics, propofol, and methocarbamol. Methocarbamol is likely to be effective and should be tried first (Richardson et al. 2003). Hyperthermia usually resolves once muscle tremors are controlled. If not, evaporative cooling, cool water baths, or cool water enemas might be indicated. Another treatment is symptomatic and supportive care. Regular monitoring of blood gas concentrations, anion gap, and urine pH is recommended to identify metabolic acidosis if present. Metabolic acidosis also tends to resolve once muscle tremors are controlled. Animals that receive proper care and observation generally recover within 24 to 72 hours (Brutlag and Puschner 2013).

Prognosis

The overall prognosis is good with timely and appropriate decontamination and sufficient management of clinical signs.

Ferric Molluscicides

Sources and Formulations

Ferric molluscicides (Figure 19.3) are fairly new and tend to be safer to use around pets compared to metaldehyde. Iron and phosphate are found naturally in the environment when combined and formulated together, these granules can kill slugs and snails when ingested. Ferric phosphate, ferric EDTA, and ferric sulfate are formulations found in concentrations of 0.28–3.0%. Both iron phosphate and ferric EDTA are not harmful to humans. Both products are used to prevent the targeted pest from consuming a wide variety of vegetation, namely agricultural crops, gardens (ornamental and food), lawns, greenhouses, etc. Appropriate utilization makes the indicated molluscicides safe and effective.

Figure 19.3. Example of ferric‐based snail bait.

Source: Kristi Long.

Kinetics and Toxicity

Both iron phosphate and ferric EDTA toxicities are low in small exposures. Toxicities vary on the dose of iron ingested in an exposure (Haldane and Davis 2009).

Mechanism of Action

The mechanisms of action are not fully understood. In Mollusca iron phosphate is a stomach toxin that interferes with calcium metabolism, damaging digestive tissue. The snails/slugs eventually stop eating altogether with continuous exposures (Young and Armstrong 2001). As a result, they perish within 7 days. Ferric EDTA works in a similar manner as it tends to make iron more available, thus produces a faster kill. It is a contact bait: snails and slugs absorb the toxin by way of their mollusk's foot and are deceased in the course of 3 days. In mammals, iron salts can cause vomiting, stomach ulcers, and potentially liver failure.

Clinical Effects

Iron phosphate and ferric EDTA are relatively safe molluscicides, and mild GI signs can be seen with small exposures. Signs of exposure can be seen within 30 minutes to 24 hours after ingestion. Most common signs are abdominal pain, vomiting, nausea, diarrhea, and hemorrhagic gastroenteritis. Larger exposures that lead to iron toxicosis can be accompanied by cardiovascular compromise, renal failure, hepatic failure, seizures, coma, and death (Haldane and Davis 2009).

Diagnosis

ANTEMORTEM

A thorough history of exposure and occurrence of compatible clinical signs is the most reliable form of diagnosis. Laboratory samples of iron serum levels can be evaluated to determine the severity of iron toxicosis.

MANAGEMENT OF EXPOSURES

Management of small exposures to ferric molluscicides is treatment of mild clinical signs with the use of basic GI management gastroprotectants, intravenous fluid therapy, and metronidazole. In cases of iron toxicosis, an iron chelator such as deferoxamine mesylate may be used as a constant rate of infusion. Adverse side effects are possible, and care should be taken when administering chelation therapy.

PROGNOSIS

The general prognosis is great in cases where minimal to small exposures occurred. In exposures where iron toxicosis is present, with timely and appropriate decontamination and sufficient management of clinical signs, prognoses are fair to good.

LARGE PREDATOR CONTROL

Sodium Fluoroacetate (Compound 1080)

Sources

Sodium fluoroacetate is a naturally occurring compound found in several plant species in Africa, Australia, and South America. In the United States, it has been used for predator control (particularly coyotes) under strict guidelines. Its use is limited to inclusion in livestock protection collars (LPCs) primarily used on sheep and goats in several states registered with the EPA (an EPA‐approved certification and training program is required) (Parton 2004). LPCs used on sheep and goats contain 30 ml of 1% sodium fluoroacetate (300 mg of active ingredient).

Kinetics and Toxicity

Fluoroacetate is readily absorbed from the GI tract, lungs, and mucous membranes. The parent compound is considered to be non‐toxic, but it is metabolized to monofluoroacetic acid by hydrolysis. The monofluoroacetic acid reacts with coenzyme A (CoA) to form fluoroacetyl CoA. Parent compound and metabolites are eliminated primarily via the kidneys. Fluoroacetate is highly toxic. Oral lethal dosages have been determined for a number of animal species and range from 0.06 to 0.2 mg/kg for dogs and from to 10 to 30 mg/kg for birds (Parton 2004).

Mechanism of Action

Fluoroacetyl CoA combines with oxaloacetate in the tricarboxylic acid cycle and is converted to fluorocitrate. Fluorocitrate inhibits the enzyme aconitase and the oxidation of citric acid, resulting in blockage of the cycle. This results in cellular energy depletion, increases in citrate and lactate concentrations and a decrease in blood pH.

Clinical Effects

Signs

Signs appear rapidly in intoxicated animals (as soon as 30 minutes after exposure). Signs are primarily related to CNS stimulation: anxiety, frenzied behavior, hyperesthesia, and seizures. Vomiting, salivation, urination, defecation, tenesmus, and hyperthermia also can occur. Seizures are tonic–clonic in nature and seizure episodes are interspersed with periods of relative normalcy. Anoxia associated with continuous seizing leads to respiratory failure, coma, and death. Cardiac arrhythmias are reported in cats. Animals exposed to sublethal doses of fluoroacetate exhibit severe depression, anorexia, listlessness, teeth grinding, and weakness.

Laboratory

Consistent clinical pathologic changes include hyperglycemia, hypocalcemia (ionized), acidosis, and elevations of citrate. Cardiac arrhythmias in cats might be secondary to hypocalcemia.

Differentials

Diseases associated with seizures and CNS stimulation should be strongly considered as differentials. These include numerous intoxications: strychnine, chlorinated hydrocarbon insecticides, bromethalin, lead, metaldehyde, methylxanthines, prescription and illicit drugs (e.g., amphetamines, cocaine), cyanide, and tremorgenic mycotoxins.

Diagnosis

A diagnosis is based on a history of exposure to the compound, compatible clinical signs, and detection of the toxicant in source material or vomitus. Analysis of tissues is possible, but the parent compound is typically present at very low levels and few laboratories offer sufficiently sensitive tests. Postmortem findings are nonspecific although rapid onset of rigor mortis is reported (Parton 2004).

Management of Exposures

The rapidity of onset of clinical signs often precludes institution of decontamination procedures. Administration of activated charcoal is recommended, but this might require control of seizures first. Perhaps the most critical intervention is the intravenous administration of sodium bicarbonate (Parton 2004). Although sodium bicarbonate administration might worsen hypocalcemia and cause hyperkalemia, the benefits outweigh the risks. Frequent monitoring of electrolytes is warranted.

Prognosis

The prognosis is typically poor.

ACKNOWLEDGMENTS

The author would like to thank Robert Poppenga for his contributions to the first edition of this chapter.

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20
Plants

Charlotte Means

INTRODUCTION

This chapter covers common household and yard plants that might cause household pet intoxication. There are a few details to keep in mind when managing a plant exposure. First, the plant must be positively identified (Figure 20.1). Potential sources of identification include local plant nurseries, garden stores, university extension offices, or veterinary diagnostic laboratories. Plant identification apps (and many are free) are available on phones, as long as a photo can be taken. There are a number of social media sites that can aid in plant identification as well. If the whole plant cannot be transported to a nursery, university extension office, etc., a small branch with leaves, fruit, flowers, or nuts should be obtained. Ideally, the scientific name of the plant rather than the common name should be sought because common names can be shared among totally unrelated plants. Next, it is important to keep in mind that even nontoxic plants can cause signs of digestive upset such as vomiting, diarrhea, and mild nausea or drooling if they are ingested. Plants do not always cause similar clinical signs in all species. For example, Lilium spp. causes renal failure in cats but not in dogs. Also, the toxicity of plant material can vary tremendously depending on growing conditions. Finally, in cases where signs have already developed, decontamination by induction of emesis may be contraindicated. Do ask pet owners about the use of fertilizers, herbicides, and insecticides. Sometimes, substances applied to the plants may be causing noted clinical signs.

There are several plant‐related intoxications that are discussed in Chapter 27, including Allium spp. (onions, garlic), Persea americana (avocado), grapes and raisins, and macadamia nuts. Additional plant‐related intoxications are discussed in Chapter 21.

DIGESTIVE SYSTEM

Aloe spp.

Aloe vera (aloe) (Figure 20.2) is also known as A. barbadensis. Aloe contains anthraquinone glycosides, which are potent purgatives concentrated in the latex of the leaves. Chewing on A. vera leaves can result in severe diarrhea. Fluid and electrolyte imbalances may need to be managed if dehydration develops (Burrows and Tyrl 2013, p. 24–27).

Asparagus spp.

Also called asparagus fern, these plants contain steroidal saponins, with the highest concentration being present in the berries. These plants are considered a contact allergen and can cause irritation after dermal contact. After ingestion, signs such as salivation, vomiting, and diarrhea can occur. Symptomatic treatment for gastrointestinal (GI) signs may be needed (Burrows and Tyrl 2013, p. 794). Do not confuse asparagus fern with Asparagus officinalis, garden asparagus, which are edible.

Begonia spp.

In contrast to plants that contain only insoluble calcium oxalate, Begonia spp. (begonia) (Figure 20.3) contains both insoluble calcium oxalates and soluble oxalates (soluble salts of oxalic acid such as sodium, potassium, ammonium, and acid potassium oxalates). The oxalate crystals are especially concentrated in the tubers and stems. Insoluble calcium oxalate crystals may cause dermal and mucous membrane irritation. Signs that develop can include salivation and vomiting.

Figure 20.1. This is not the time to wonder what type of plant this is.

Photograph courtesy of Meghan Dewey.

Figure 20.2. Aloe (Aloe vera).

Soluble oxalate intoxication is poorly documented in pets or people due to the large quantity of plant material required to induce toxicosis; livestock poisonings are more commonly reported. In animals, nausea, rapid respiration, and stupor occur early followed by vomiting, bloody diarrhea, coma, and tetany due to hypocalcemia. Oliguria, oxaluria, albuminuria, or hematuria can occur due to formation of calcium oxalate crystals in the kidney. Treatment of suspected intoxications has included administration of parenteral calcium salts to correct hypocalcemia as well as intravenous fluid support. These plants are rarely associated with poisonings in companion animals (Mrvos et al. 2001).

Figure 20.3. Begonia (Begonia spp.).

Photograph courtesy of T.D. Brant.

Capsicum spp.

Capsicum spp. (Figures 20.4 and 20.5) includes chili peppers and other pepper plants that are usually grown in gardens for food or as ornamental plants. The toxin in pepper plants is capsaicin. The highest concentration is found in the fruits, especially in the membrane that suspends the seeds. The Scoville scale is the measurement of the pungency (spicy heat) and is reported in Scoville heat units (SHU). Bell peppers have a SHU of 0 while the hottest pepper (Carolina reaper) has 1,400,000–2,200,000 SHU. The heat of an individual pepper depends on soil, temperature, and humidity levels. Hot peppers are irritating, causing a burning sensation and possibly oral blisters when ingested. Large exposures can cause vomiting and diarrhea. In experiments using rats, very high doses have caused convulsions. Effects of capsaicin are transient and may be relieved by dilution with water or milk. Demulcents and pain control might also be indicated (Burrows and Tyrl 2013, p. 1136–1138). Pepper spray generally contains capsaisin.

Figure 20.4. Ornamental pepper (Capsicum spp.).

Photograph courtesy of T.D. Brant.

Figure 20.5. Anaheim pepper (Capsicum spp.) Photograph courtesy of Jenny Schuett.

Chrysanthemum spp.

Chrysanthemum plants (Figure 20.6) contain a toxin called arteglasin A, a sesquiterpene lactone. This plant also contains natural pyrethrins and other irritants (Hansen and Khan 2013). Plant ingestion is associated with hypersensitivity and allergic contact dermatitis. GI upset and drooling may be noted as well. Ataxia has been reported, generally with large ingestions.

Figure 20.6. Chrysanthemum (Chrysanthemum sp.).

Photograph courtesy of T.D. Brant.

Clematis spp.

Clematis is also known as virgin's bower and traveler's joy. These plants cause intense GI irritation, vomiting, and diarrhea. Protoanemonin, which is related to the blister beetle vesicant cantharidin, is the toxin. Protoanemonin is a subepidermal vesicant, so plants can cause profound dermal irritation on contact. When ingested, plants are bitter and irritating. Excessive salivation, vomiting, and diarrhea are expected signs. Dried plant material contains a polymerized form of protoanemonin, called anemonin, which is not considered to be toxic. Thus, dried plants are considered nontoxic. Treatment includes GI protectants, antiemetics, and other symptomatic and supportive care (Burrows and Tyrl 2013, p. 1045–1046).

Cyclamen spp.

Cyclamen species (cyclamen) are native to the Mediterranean and may be known as Persian violet or sow's bread. The toxin contained in Cyclamen is a triterpenoid saponin. The saponin is found mainly in the roots, with a small amount in leaves. Ingestion of this plant may lead to nausea, vomiting, and diarrhea. Rarely will dogs or cats eat enough to cause additional signs. If larger quantities are ingested, the saponin may be absorbed, causing convulsions, seizures, cardiac dysrhythmias, and paralysis. Supportive treatment is typically all that is needed to ensure recovery (Burrows and Tyrl 2013, p. 1013–1014). Native varieties (found in the Mediterranean and Africa) are much more toxic and can cause hemolysis in addition to arrhythmias and seizures.

Figure 20.7. Hosta (Hosta spp.).

Photograph courtesy of T.D. Brant.

Euphorbia pulcherrima

Euphorbia pulcherrima is commonly known as poinsettia. The toxicity of poinsettia has been greatly exaggerated. Poinsettia plants do contain an irritating milky sap. Pets that chew on the plants develop hypersalivation, vomiting, anorexia, and depression. Signs are usually self‐limiting and require minimal treatment. Further GI irritation may be reduced by limiting food and water intake for 1–2 hours (Burrows and Tyrl 2013, p. 462).

Gypsophilia paniculata

Gypsophilia paniculata is commonly known as baby's breath and is often used in floral arrangements. Gypsophilia exposures can cause dermal irritation due to contact allergen. Ingestion of the plant may lead to vomiting and diarrhea.

Hosta spp.

Members of the Hosta genus are also known as hosta lily or August lily (Figure 20.7). Some species contain saponins, which can cause vomiting, diarrhea, depression, and anorexia. They are likely to cause a problem only if consumed in quantity (Yang and He 2021).

Ilex spp.

Holly (Figure 20.8) grows as a small shrub outdoors or can be brought indoors for holiday decoration. A variety of biologically active compounds have been identified in Ilex spp., including tannins, caffeine, theobromine, triterpenes, and a hemolytic saponin, among others. With small ingestions vomiting and diarrhea can occur. Anorexia, head shaking, and lip smacking can also occur. Flushing the oral cavity with water will reduce mucosal irritation (Burrows and Tyrl 2013, p. 127–129).

Figure 20.8. American Holly (Ilex opaca). Insert: closer view of leaves and berries.

Photograph courtesy of T.D. Brant.

Insoluble Calcium Oxalate‐Containing Plants

A number of plants, including Dieffenbachia spp. (Figure 20.9), Zantedeschia spp. (cala lily), Epipremnum aureum (pothos), Philodendron spp., and Spathiphyllum spp. (peace lily) (Figure 20.10), contain insoluble calcium oxalate crystals (Burrows and Tyrl 2013, p. 131–144; Means 2004). Chewing on calcium‐oxalate containing plants causes mechanical irritation to mucous membranes of the GI tract. As the plant cells are crushed or broken open, needlelike crystals called raphides are released and the surrounding tissues are penetrated by the crystals. The reaction may be rapid, causing oral pain and swelling of the lips and tongue. The irritation may extend to the esophagus and stomach. However, since the plant cells must be broken open, effects beyond the oral cavity are unlikely with small ingestions. The animal may be inappetent for several days following exposure due to oral discomfort. Vomiting and diarrhea occur rarely. Treatment for insoluble calcium oxalate crystal ingestion is often not needed. Dairy products have been recommended to ease the oral discomfort (Means 2004). In rare severe cases, a soft diet, pain control, nonsteroidal anti‐inflammatory drugs, or sedation may be useful.

Ornamental Bulbs

Ornamental bulb plants include tulips (Tulipa spp.; Figure 20.11), daffodils (Narcissus spp.), hyacinth (Hyacinthus orientalis), spring‐blooming crocus (Crocus spp., not to be confused with autumn‐blooming crocus, Colchicum, see below), and iris (Iris spp.). All parts of the bulb, especially the roots, flesh, and seed capsules, contain pentacyclic terpenoids, which are irritating and cause gastroenteritis (Burrows and Tyrl 2013, p. 718–720, 773–776, 778–780). Clinical signs include salivation, abdominal pain, profuse diarrhea with or without blood, and oral lesions. Signs may last hours to days. Treatment includes correction of fluid and electrolyte imbalances, and possibly GI protectants. Ingestion of plants parts that are found above the ground (leaves, stems, flowers) rarely result in more than mild GI upset.

Figure 20.9. Dieffenbachia (Dieffenbachia spp.).

Figure 20.10. Peace lily (Spathiphyllum spp.).

Photograph courtesy of T.D. Brant.

Figure 20.11. Tulip (Tulipa spp.).

Ricinus communis

Ricinus communis (Figure 20.12) is also known as castor bean or castor oil plant. The principal toxins are ricinine (or ricin) and toxalbumin. The seeds, when well‐chewed and ingested in amounts as low as 0.01% of body weight, can cause severe intoxication (Albretsen et al. 2000). Intact seeds are expected to pass through the GI tract with no negative effects. Leaves or pericarps of fruits require about 2% of body weight (ricin) ingested to cause intoxication. Ricin is water‐soluble and is not found in castor oil (Mouser et al. 2007). Heat and aging reduce its toxicity. When ingested, ricin is poorly absorbed, and its main site of action is the digestive epithelium. Ricinine appears to have some action on neuroreceptors, since seizures and muscular weakness have been seen in some animals that have chewed and swallowed castor beans (Albretsen et al. 2000). The toxins cause edema and necrosis of mucosa of stomach and small intestine. However, castor bean intoxication is associated with multiple organ effects: heart, stomach, lungs, liver, kidneys, and pancreas maybe affected.

If the seeds are chewed and swallowed, the most common sign is severe diarrhea within about 6 hours (Albretsen et al. 2000). The diarrhea may be hemorrhagic. Other signs include hypotension, depression, weakness, trembling, sweating, vomiting, abdominal pain, anorexia, hyperthermia, ataxia, hypersalivation, recumbency, and tachycardia. Signs can be delayed as long as 24–48 hours after exposure. Death is attributed to hypovolemic shock.

Figure 20.12. Castor bean plant (Ricinus communis). Insert: castor beans.

Photograph courtesy of T.D. Brant.

Treatment involves early decontamination in animals not exhibiting clinical signs. Symptomatic animals need to be stabilized first. Diazepam may be used to control seizures. Intravenous fluid therapy, such as Ringer's lactate solution, is recommended to prevent or treat hypovolemia and to maintain hydration and electrolyte balance. GI protectants such as sucralfate, omeprazole, and kaolin‐pectin might be indicated to protect and promote healing of the GI tract. Antiemetics and pain management might also be needed. Frequent complete blood count, serum chemistry, and electrolytes monitoring is recommended to assess the extent of organ damage (Albretsen et al. 2000).

Schlumbergera spp.

These plants are commonly called Christmas, Thanksgiving, or Easter cactus. Ingestion may result in mild GI upset although they are considered to be nontoxic for cats and dogs. If mild GI signs occur, withholding food and water for 1 or 2 hours should be sufficient.

CARDIOVASCULAR SYSTEM

Cardiac Glycosides

Several plants contain cardiac glycosides. Cardiac glycosides inhibit cell membrane sodium‐potassium ATPase, resulting in decreased electrical conductivity. This can result in the occurrence of a variety of cardiac arrhythmias, both tachy‐ and bradyarrhythmias, along with abdominal pain and diarrhea. Death can be rapid or delayed for up to 2 days. In general, standard decontamination protocols should be followed when possible and appropriate. Treatment of cardiac arrhythmias varies depending on the specific arrhythmia noted. The electrolytes status of affected animals should be monitored, and fluids and electrolytes administered as needed. Treatment with digoxin immune Fab (Digibind®) might be helpful but should be administered as soon as possible after exposure for maximum efficacy. Further information on the effects of cardiac glycosides can be found in Chapters 12 and 23.

Adenium obesum

This plant is known as desert rose and mock azalea. About 30 cardiac glycosides have been isolated from this plant (Yamauchi and Abe 1990). It has been a source for an arrow poison in Africa. The plant is toxic enough to warrant caution if exposure occurs. If sufficient amounts of the plant are ingested, cardiac arrhythmias, heart block, and death may develop. Treatment would be similar to that for other cardiac glycoside intoxications.

Convallaria majalis

Lily‐of‐the‐valley is the common name for Convallaria majalis (Figure 20.13), which contains approximately 38 cardenolides and various saponins. All parts of the plant are toxic, with the greatest toxin concentration in the rhizomes (Burrows and Tyrl 2013, p. 762–764). The toxin can leach into the surrounding soil and watering can flush the toxin into the drainage reservoir. Animals have been affected by drinking water from the pot reservoir or vases. Signs are as one would expect from cardiac glycosides: vomiting, diarrhea, cardiac arrhythmias, and death. Treatment considerations are as outlined above.

Digitalis purpurea

Foxglove is the common name for Digitalis purpurea (Figure 20.14). The plant contains the cardenolides digoxin and digitoxin. All plant parts are toxic, especially the seeds. The dried plant is also toxic (Burrows and Tyrl 2013, p. 879–882). Even water from vases where the flowers are kept can be a risk if ingested. The earliest signs of intoxication include marked weakness, stupor, and diarrhea with or without blood. The heartbeat at first may be loud and strong, but then later become faint and barely perceptible, eventually regressing to ventricular fibrillation. Vomiting, increased salivation, and more frequent urination can occur. Treatment is as for other cardiac glycoside‐containing plants.

Nerium oleander

Nerium oleander (Figure 20.15) is a shrub that is used as a landscaping plant in warmer parts of the United States. Oleander is extremely toxic; ingestion of as little as 0.005% body weight can be fatal. Both fresh and dried plant are toxic (Burrows and Tyrl 2013, p. 98–103).

Figure 20.13. Lily‐of‐the‐valley flowers (Convallaria majalis).

Figure 20.14. Foxglove (Digitalis spp.).

Oleander contains the cardenolide oleandrin, which is concentrated in the leaves, flowers, and seeds. The plant also contains terpenoids. The terpenoids may be responsible for the GI irritation seen. Weakness, depression, anorexia, vomiting, abdominal pain, hypersalivation, and diarrhea are likely in cats and dogs. Patients might exhibit signs for many hours and then recover. However, patients can die suddenly from cardiac arrest with few preliminary signs. Patients should be monitored closely, with particular attention paid to heart rate and rhythm and electrolyte concentrations. Hyperkalemia and hypocalcemia may develop. Treatment considerations are as outlined above. Intravenous fluids and electrolytes are provided as needed.

Figure 20.15. Oleander (Nerium oleander).

Kalanchoe spp.

Kalanchoe (kalanchoe) (Figure 20.16) formerly known as Bryophyllum. Mother‐of‐millions is one common name. The significant toxin in Kalanchoe is lanceotoxin A, which is a bufadienolide cardiotoxin (Burrows and Tyrl 2013, p. 381–384). These cardiotoxins are similar to the cardiac glycosides found in foxglove, oleander, and lily‐of‐the‐valley. Ingestion of as little as 1% body weight can cause intoxication. The flowers are especially toxic. Natural poisonings are most commonly reported during the plants' flowering season. Known intoxications have occurred in dogs and rabbits.

Signs include vomiting, diarrhea, ataxia, trembling, and sudden death due to cardiac failure. Other signs that have been reported include tachycardia, hypertension, dilated pupils, nystagmus, delirium, weakness, tetany, mild seizures, depression, anorexia, hypersalivation, and mucoid to bloody diarrhea. The diarrhea may persist for several days without other signs. Cardiac effects typically require a larger ingestion, and signs include increased or decreased heart rate, labored respiration or grunting, arrhythmias, heart block, and severe weakness. Serum chemistry abnormalities include increased blood urea nitrogen (BUN), creatinine, and glucose concentrations.

Figure 20.16. Kalanchoe (Kalanchoe spp.).

Photograph courtesy of S.M. Gwaltney‐Brant.

Treatment of Kalanchoe exposures includes appropriate and timely decontamination and symptomatic and supportive care. Digibind has not been evaluated for treatment of Kalanchoe intoxications. Atropine or propranolol can be used to increase the heart rate and reverse heart block.

Grayanotoxins

Several plants contain cardiotoxins called grayanotoxins. These include Rhododendron (azalea [Figure 20.17], mountain rosebay, red laurel, and great laurel, among others), Kalmia spp. (mountain laurel), and Pieris japonica (Japanese pieris). These plants contain diterpenoid grayanotoxins, which are present in all parts of the plant, although their concentrations vary between plants. Grayanotoxins increase sodium channel permeability, which opens cells to sodium instead of calcium. The channels are slow to close and the cell remains depolarized (Manhart et al. 2013). Significant effects occur in the heart, skeletal muscles, and central nervous system. Increased reflexes, increased vagal tone, hypotension, and cardiac arrhythmias occur. Signs include profuse salivation, anorexia, repeated swallowing, persistent retching or vomiting (possibly projectile), severe abdominal pain, and bloating. Severe cases may exhibit weakness and inability or reluctance to stand. Less frequent cardiac effects include bradycardia and atrioventricular block. Acute effects last about 24 hours. Weakness and other neurologic effects can last 2–3 days. Treatment includes appropriate and timely decontamination and symptomatic and supportive care.

Figure 20.17. Azalea (Rhododendron sp.).

Melia azedarach

This plant is known by many common names, including chinaberry, Persian lilac, and Texas umbrella tree, among others. The plant is native to Asia but has become widespread as a landscape plant across the southern United States. Several meliatoxins are present in all parts of the plant, but especially in the fruit. Only the berries have been known to cause intoxication; toxicity of the berries varies by location and species of plant. The toxic dosage is approximately 0.2–0.3% body weight (Hare et al. 1997). Five to six fruits were lethal to a young dog within 48 hours (Barr 2013). Clinical signs are variable and include hyperthermia, hypothermia, tachycardia, bradycardia, dyspnea, stranguria, muscle rigidity, mydriasis, and miosis. Early signs include hypersalivation, vomiting, anorexia, and diarrhea. If large enough quantities of berries have been ingested, muscle weakness, ataxia, seizures, and paralysis develop. Excitement occurs early, with paralysis developing later. It is possible for sudden death to occur as the only clinical sign. For a recent exposure where signs have not yet developed, emesis helps to remove berries from the stomach followed by activated charcoal administration. Treatment is symptomatic and supportive because no antidote exists. In severe cases, sedatives and fluid‐electrolyte therapy should be used. Animals that recover usually do so within 24–48 hours.

Taxus spp.

Members of Taxus spp. (Figure 20.18), also called yews, are shrubs found throughout the United States. Bark, leaves, and seeds are toxic, but not the red flesh of the fruit. The principal toxins are taxines, which cause cardiac conduction disturbances due to interference to the ion channels of cardiac muscle. All domestic animals and birds are at risk for intoxication (Burrows and Tyrl 2013, p. 1177–1185).

The plant seems to be more toxic in winter. Ingestion of as little as 1 oz of leaves can be lethal to a dog (Barr 2013). Both fresh and dried leaves are dangerous. Signs exhibited by intoxicated dogs include vomiting, muscle tremors, seizures, panting, dilated pupils, and significant tachycardia. Stressing the patient can cause sudden collapse and death. Sudden death can occur even days after ingestion. Once signs develop it is usually too late for effective treatment due to the peracute nature of intoxication. However, early decontamination and administration of atropine to reverse bradycardia and heart block should be considered. Syrup of ipecac should not be used to induce emesis due to the potential for vagal nerve stimulation to exacerbate the cardiac effects of yew.

Figure 20.18. Japanese yew (Taxus spp.).

LIVER

Cycas spp. and Zamia spp.

Members of Cycas and Zamia are referred to as cycad palms, which include common names such as sago palm (Figure 20.19), false sago palm, cardboard palm (Figure 20.20), and fern palm. There are two types of toxins present in cycads: cycasin and macrozamin. The seeds, leaves, and pulp of the cones are primarily hepatotoxic, but the digestive and neuromuscular systems can also be affected. The fruits and seeds of some species remain toxic even after being cooked. The fruits seem to be especially enticing to dogs.

Signs that develop after cycad ingestion include persistent vomiting, hypersalivation, excessive water consumption, anorexia, diarrhea or constipation, icterus, thrombocytopenia, hyperbilirubinemia, increase of liver enzymes, elevations of BUN and creatinine, and coagulopathy (Albretsen et al. 1998). Hepatic necrosis and subsequent fibrosis can develop if the patient survives. Treatment primarily involves appropriate and timely decontamination and symptomatic and supportive care. The latter might include the use of hepatoprotectants such as N‐acetylcysteine, silymarin, or S‐adenosyl‐L‐methionine (SAMe), although the efficacy of such therapy is unknown (Clarke and Burney 2017).

Figure 20.19. Sago palm (Cycas revoluta).

Photograph courtesy of T.D. Brant.

Figure 20.20 Cardboard palm (Zamia spp.).

Photograph courtesy of Tina Wismer.

Indigofera spp.

This plant is found in the southeastern coastal plains. Although there are a number of species in this genus, only a few are considered toxic. They include Indigofera hendecaphylla in the United States and Ideoblothrus linnaei in Australia. Low levels of 3‐nitropropionic acid, non‐protein alpha‐amino acids, indospicine, canavanine, and arginine analogs cause hepatotoxic disease. Ingestion of the plant causes disease in large animals such as horses and camels after multiple days of ingestion. Dogs are most likely to develop liver failure by ingesting fresh or cooked meat from animals suffering from hepatotoxicity (relay toxicity) (Fitzgerald et al. 2011; Hegarty et al. 1988; Salmon et al. 2022).

Clinical signs include vomiting, diarrhea, anorexia, potential hypoglycemia, elevated liver enzymes, and potential coagulopathy. Treatment is standard therapy for liver disease, including liver protectants. Prognosis is guarded once clinical signs develop.

Lantana spp.

Members of Lantana (Figure 20.21) are also known as shrub verbena, yellow/red/wild sage, and bunchberry. The toxins are triterpenes. There are some varieties much less toxic than others because their triterpene structure is different. All parts of the plants, especially the unripe berries, are toxic, but not all species are highly toxic. Fully ripe fruits are not toxic (Burrows and Tyrl 2013, p. 1201–1205). All animal species are at risk, with ingestions of as little as 1% body weight causing intoxication. Dogs and cats rarely ingest enough to cause more than mild GI signs. Signs associated with more severe intoxications include weakness, ataxia, depression, cholestasis, hyperbilirubinemia, hepatic damage, lethargy, cyanosis, labored breathing, depressed tendon reflexes, photophobia, coma, and death.

Figure 20.21. Lantana (Lantana spp.).

Photograph courtesy of T.D. Brant.

Triterpenoids cause damage to the bile canaliculi with subsequent development of obstructive cholangitis. They also irritate the GI mucosa and cause diarrhea or constipation. Subacute or chronic exposures are associated with photosensitization. The second or third day after exposure, icterus and photosensitization may be noticed as well as diarrhea with or without blood. Deaths from Lantana toxicoses are mainly due to hepatic and renal failure. Treatment includes appropriate and timely decontamination, fluids, and glucose and electrolyte administration. Symptomatic and supportive might include the use of hepatoprotectants such as N‐acetylcysteine, silymarin, or SAMe, although the efficacy of such therapy is unknown. Once signs of liver damage are present, treatment of animals is usually not successful.

URINARY SYSTEM

Lilium spp.

Lilium species including Lilium pardalinum, L. candidum, L. speciosum, L. lancifolium (rubrum or Japanese showy lilies), Lilium longiflorum (Easter lily; Figure 20.22), Lilium tigrinum (tiger lily; Figure 20.23), and Hemerocallis (day lilies; Figure 20.24) are nephrotoxic to cats. Peace lily (Spathiphyllum; Figure 20.10) and calla lily (Zantedeschia) are not true lilies and are not associated with renal issues, although they do contain insoluble calcium oxalate crystals (see earlier discussion). All true lily plant parts are toxic to cats, and cats are the only species known to be sensitive to lily ingestion. Ingestion of any plant material or pollen can cause severe toxicosis. Clinical signs include early vomiting, anorexia, and depression; these signs can begin within 2 hours of exposure (Langston 2002). Vomiting may resolve, but anorexia and depression continue as BUN, creatinine, potassium, and phosphorus concentrations rise 24–72 hours after exposure. Epithelial casts and glucose may be detected in the urine within 18 hours. Renal failure is due to an unknown mechanism causing renal tubular necrosis. Fortunately, in cats surviving the acute crisis, affected renal tubular epithelial cells can regenerate since the basement membrane remains intact. Treatment involves early decontamination. Fluid diuresis using lactated Ringer's solution at twice maintenance rates (approximately 30 ml/kg/day) should be started as soon as possible and continued for at least 48 hours. Baseline BUN and creatinine should be obtained and rechecked daily. Creatinine levels are often disproportionately high when compared to BUN. As long as BUN and creatinine are high, fluid diuresis is continued. If treatment is delayed, there is an increased risk for renal failure and death. Postponing treatment with fluid diuresis for longer than 18 hours post exposure can result in renal failure and death. Cats who continue to eat have a better prognosis. Anuric cats have a grave prognosis, but renal function has been restored after peritoneal or hemodialysis dialysis in some cases (Langston 2002).

Figure 20.22. Easter lily (Lilium longiflorum).

Figure 20.23. Tiger lily (Lilium tigrinum) buds.

Photograph courtesy of Laura Stern.

Figure 20.24. Day lily (Hemerocallis spp.).

Photograph courtesy of S.M. Gwaltney‐Brant.

Soluble Oxalate‐Containing Plants

Rhubarb (R. rhabarbarum; Figure 20.25) contains anthraquinones and soluble oxalates in small quantities (about 0.28% dry weight of leaf material) (Barr 2013). Oxalis spp. (sorrel, wood sorrel, shamrock, soursob, Bermuda buttercup, and Irish shamrock) can contain up to 16% of dry matter as soluble oxalates.

Figure 20.25. Rhubarb (Rheum rhabarbarum).

Most of the signs associated with rhubarb leaf ingestion can be attributed to the cathartic action of anthraquinones. In theory, soluble oxalates can precipitate within the renal tubules, causing kidney damage. However, renal oxalosis is unlikely to occur in dogs and cats unless very large amounts of plant material are ingested. If a large enough quantity is ingested, the oxalates can cause hypocalcemia in addition to renal oxalate precipitation. Signs typically are limited to vomiting, although hypocalcemic tetany and signs related to renal failure are possible.

CENTRAL NERVOUS SYSTEM

Brunfelsia spp.

There are a number of species in the Brunfelsia genus (Figure 20.26) and a variety of common names. B. pauciflora is known by the common names of yesterday‐today‐tomorrow, morning‐noon‐and‐night, or yesterday‐and‐today. Brunfelsia americana is called lady‐of‐the‐night or Franciscan rain tree. These are primarily outdoor ornamental plants but are sometimes used indoors. Dogs seem to find the fruits appealing and as a result have a higher risk of exposure. There are multiple toxins in the plant that cause both neuroexitatory and neurodepressant signs. Typical signs include anxiety and excitement followed by coughing, gagging, sneezing, and nystagmus. Initial signs are followed within a few hours by tremors and tetanic or paddling seizures, which can be precipitated by external stimuli. Tremors and seizures can last hours to days, with full recovery taking up to a week or longer (Burrows and Tyrl 2013, p. 1134–1136). Treatment involves appropriate and timely decontamination, and symptomatic and supportive care. Control of central nervous system excitation is achieved with diazepam or pentobarbital.

Figure 20.26. Yesterday‐today‐tomorrow (Brunfelsia spp.).

Laburnum anagyroids

This plant is also known as golden rain tree, golden chain tree, scotch laburnum, and alpine golden chain. It contains quinolizidine alkaloids, some of which are teratogenic (Burrows and Tyrl 2013, p. 553–555). The greatest concentration of the alkaloids is found in the seeds, but the toxins are present throughout all parts of the plant. The leaves, seed pods, and seeds are toxic. Ingestion of plant material equaling 0.1–1% body weight is toxic. Horses appear to be the most sensitive species to intoxication, but poisonings have been reported in dogs as well.

The main toxins are rapidly absorbed and excreted, and clinical signs would be expected to develop rapidly after a toxic dose of the plant has been consumed. The most common signs seen in dogs are centrally mediated vomiting and abdominal pain, and occasionally weakness, depression, ataxia, and tachycardia. Sweating, delirium, excitation, tonic–clonic convulsions, and death are reported. The signs are usually short‐lived due to rapid excretion of the alkaloid cystisine. If a large quantity of seeds has been consumed, myocardial degeneration and death can occur. With small ingestions, treatment might not be needed. If signs do occur, symptomatic and supportive care is needed to control vomiting and abdominal pain. Cleft palate and arthrogryposis are possible teratogenic effects in pregnant animals exposed to the plant more chronically.

Solanum lycopersicum and Other Solanum spp.

The toxins found in tomatoes (S. lycopersicum; Figure 20.27) and Solanum spp. (many species and common names, but many are referred to as nightshades) are steroidal glycoalkaloids. These include α‐solanine and α‐chaconine. Although for most species all plant parts are considered potentially toxic, with the exception of ripe fruits, the immature fruits typically contain the highest toxin concentrations. However, even the ripe fruits are poisonous for some Solanum spp. Uncooked sprouted or green potatoes are also toxic (Burrows and Tyrl 2013, p. 1155–1165).

The glycoalkaloids are irritating to the GI tract and large ingestions can cause dilated pupils, tachycardia, central nervous system depression, and respiratory difficulty. In severe cases, dilated pupils, muscle tremors, and incoordination may develop. Treatment involves appropriate and timely decontamination, and symptomatic and supportive care. Solanine can cause mild cholinergic effects due to cholinesterase inhibition, and atropine can be used to reverse such effects in severe cases.

Nicotiana spp.

Nicotiana spp. include tobacco and tree tobacco. These plants contain the pyridine alkaloids nicotine and nornicotine. The alkaloids are rapidly absorbed across skin, mucous membranes, and GI tract. All parts of the plant are toxic. Nicotine directly affects the brain and muscles, initially causing stimulation followed by paralysis due to a depolarizing blockade (Burrows and Tyrl 2013, p. 1149–1153). The minimum lethal dose in dogs and cats is 20–100 mg. The cardiovascular, urinary, and reproductive systems can also be affected.

Figure 20.27. Tomato (Solanum lycopersicum).

Photograph courtesy of S.M. Gwaltney‐Brant.

Initial signs include excitement, bradycardia, and a slow respiration rate. Subsequent signs can include depression, hypersalivation, vomiting, diarrhea, rapid and labored breathing, ataxia, tremors, severe weakness, muscle twitching or trembling (beginning at the shoulders and then extending to the whole body), stiff‐legged gait, and protrusion of the third eyelid. Death is most typically from respiratory failure. Signs are typically short‐lived and last 5–6 hours; the prognosis is good if an animal survives the first 12 hours after onset of signs. Treatment involves appropriate and timely decontamination and symptomatic and supportive care. Antacids should not be given; they increase the absorption of nicotine. Patients should be closely monitored. Oxygen, positive pressure respiration, and sedatives might be needed.

Prunus, Pyrus and Malus spp.

There are a number of Prunus species (cherry, plum, peach, almond, nectarine, apricot), Pyrus spp. (pears), and Malus spp. (apples) that contain cyanogenic glycosides. High concentrations are found in the kernels of the seeds. As a result of damage to the plant or following ingestion, cyanogenic glycosides are broken down to hydrocyanic acid (cyanide). Although many Prunus spp. contain cyanogenic glycosides, most do not present a significant intoxication hazard for dogs and cats. The ingestion of intact seeds does not release cyanide, and many seed kernels would need to be crushed and ingested for toxicosis to occur. In intoxicated animals, signs include sudden onset of apprehension and distress, weakness, ataxia, labored breathing, collapse, and lateral recumbency. Paddling and tetanic seizures may occur. Due to rapid metabolism of cyanide following absorption, signs usually last only 5–15 minutes; animals either die or recover quickly. The rapidity of onset of clinical signs and possibly death make timely initiation of treatment problematic.

Antidote kits for cyanide poisoning are available and include a nitrite salt such as sodium nitrite and sodium thiosulfate (Burrows and Tyrl 2013, p. 1084–1085). Amyl nitrite, which is used in intoxicated humans, is not recommended for use in animals. Nitrite forms methemoglobin, which combines with cyanide to form cyanmethemoglobin. Thiosulfate acts as a sulfur donor for the conversion of cyanide to thiocyanate by the action of the enzyme rhodanese, which is then rapidly excreted in the urine. Hydroxocobalamin (vitamin B12a) has also been used as an effective antidote.

MULTISYSTEMIC EFFECTS

Colchicum autumnale

Colchicum autumnale is known as autumn crocus, meadow saffron, and naked lady, and should not be confused with spring‐blooming crocuses (Crocus spp., see earlier discussion). C. autumnale contains the toxin colchicine, which is present in all parts of the plant with the greatest concentrations in the flowers and seeds. Glory lily (Gloriosa superba) is also known to contain colchicine and other alkaloids similar to those in C. autumnale. Colchicine is quite toxic. Ingestion of as little as 08 mg/kg body weight of colchicine, 1.5–2.0 g of plant material, two or three seeds, or half a flower can be fatal (Burrows and Tyrl 2013, p. 760–762). Colchicine is an antimitotic and is used in human medicine to treat a number of diseases, including gout. Thus, animals can be intoxicated following the ingestion of both the plant and prescription medication. Intoxication results in multiple organ failure impairing cardiovascular, pulmonary, renal, metabolic, and neuromuscular function.

Initial signs of toxicosis are related to effects on the digestive tract and include vomiting, abdominal pain, and severe hemorrhagic diarrhea. Soon after, the patient becomes weak and disoriented, and develops seizures and cardiac abnormalities. Additional signs developing within 2–12 hours and include dysphagia, paralysis, and hypovolemic shock. If the animal survives for 4–5 days, bone marrow depression may occur. Death is attributed to respiratory failure. Treatment involves appropriate and timely decontamination, and symptomatic and supportive care. In people, colchicine poisoning has been treated successfully using colchicine‐specific Fab fragments.

Humulus lupulus

Humulus lupulus is also known as hops, beer hops, European hops, and lupulin (Figure 20.28). The plant is native to Europe and Asia, and contains a number of biologically active constituents, including essential oils, phenolic compounds, resins, and proteins. Spent hops from beer brewing are a significant concern in dogs because they will readily eat them. A cup of spent hops has been reported to cause malignant hyperthermia in greyhounds (the responsible compound is not known) (Duncan et al. 1997). Acute signs reported within 1 hour of consumption include hyperthermia, restlessness, panting, vomiting, abdominal pain, and seizures. Creatinine phosphokinase levels become markedly elevated and urine becomes dark brown, suggesting muscle necrosis. Treatment includes standard decontamination procedures. Fluids should be administered to maintain renal function. Sedatives such as benzodiazepines can be used to control excitement or seizures. Dantrolene can be used to treat the hyperthermia.

Figure 20.28. Hops (Humulus lupulus).

Photograph courtesy of Tina Wismer.

A list of other potentially toxic plants and the general signs typically attributed to them is provided in Appendix 2.

NONTOXIC PLANTS

Although it is important to know whether a particular plant is potentially toxic or not, it is equally important to know which plants, when ingested, are considered to be nontoxic. Appendix 3 provides a list of nontoxic plants. Keep in mind that mild GI upset and perhaps vomiting is not unusual even when nontoxic plants are ingested.

REFERENCES

Albretsen, Jay C, Gwaltney‐Brant, Sharon M, and Khan, Safdar A. 2000. Evaluation of castor bean toxicosis in dogs: 98 cases. Journal of the American Animal Hospital Association 36(3):229–233.

Albretsen, Jay C, Khan, Safdar A, and Richardson, Jill A. 1998. Cycad palm toxicosis in dogs: 60 cases (1987–1997). Jounal of the American Veterinary Medical Association 213(1):99–101.

Barr, A Catherine. 2013. Household and garden plants. In Small Animal Toxicology, 3rd ed., edited by Michael E Peterson and Patricia A Talcott, pp. 357–400. St. Louis: Saunders.

Burrows, George E and Tyrl, Ronald J. 2013. In Toxic Plants of North America, 2nd ed., edited by George E Burrows and Ronald J Tyrl pp. 24–27, 98–103, 127–129, 131–134, 381–384, 462, 553–555, 718–720, 760–764, 773–776, 778–780, 794, 879–882, 1013–1014, 1045–1046, 1084–1085, 1134–1138, 1149–1153, 1155–1165, 1177–1185, 1201–1205. Ames, Iowa: John Wiley & Sons, Inc.

Clarke, Carolyn and Burney, Derek. 2017. Cycad palm toxicosis in 14 dogs from Texas. Journal of the American Animal Hospital Association 53(3):159–166.

Duncan, Kathryn L, Hare, William R, and Buck, William B. 1997. Malignant hyperthermia‐like reaction secondary to ingestion of hops in five dogs. Journal of the American Veterinary Medical Association 210(1):51–54.

FitzGerald, Louise M, Fletcher, Mary T, Paul, Amanda EH, Mansfield, Caroline S, and O'Hara, Amanda J. 2011. Hepatotoxicosis in dogs consuming a diet of camel meat contaminated with indospicine. Australian Veterinary Journal 89(3):95–100.

Hansen, Steven R and Khan, Safdar A. 2013. Pyrethrins and pyrethroids. In Small Animal Toxicology, 3rd ed., edited by Michael E Peterson and Patricia A Talcott, pp. 769–775. St. Louis: Saunders.

Hare, William R, Schutzman, Howard, Lee, Barry R, and Knight, Michael W. 1997. Chinaberry poisoning in two dogs. Journal of the American Veterinary Medical Association 210(11):1638–1640.

Hegarty, Mervyn P, Kelly, W Roger, McEwan, Denise, Williams, OJ, and Cameron, Ranald. 1988. Hepatotoxicity to dogs of horse meat contaminated with indospicine. Australian Veterinary Journal 65(11):337–340.

Langston, Cathy E. 2002. Acute renal failure caused by lily ingestion in six cats. Journal of the American Veterinary Medical Association 220(1):49–52.

Manhart, Ingrid O, Declementi, Camille, and Guenther, Cristine L. 2013. Mountain laurel toxicosis in a dog. Journal of Veterinary Emergency and Critical Care 23(1):77–81.

Means, Charlotte. 2004. Insoluble calcium oxalates. In Clinical Veterinary Toxicology, edited by KH Plumlee, pp. 340–341. St. Louis: Mosby.

Mouser, Pamela, Filigenzi, Michael S, Puschner, Birgit, Johnson, Valerie, Miller, Margaret A, and Hooser, Stephen B. 2007. Fatal ricin toxicosis in a puppy confirmed by liquid chromatography/mass spectrometry when using ricinine as a marker. Journal of Veterinary Diagnostic Investigation 19(2):216–220.

Mrvos, Rita, Krenzelok, Edward P, and Jacobsen, TD. 2001. Toxidromes associated with the most common plant ingestions. Veterinary and Human Toxicology 43(6):366–369.

Salmon, Sally E, Hall, SL, Phillips, Dianne E, Dries, Leanna R, Sarandopoulos, Julia, Coghill, Andrew, and Hawes, Mark C. 2022. Hepatopathy in Victorian dogs consuming pet meat contaminated with indospicine. Australian Veterinary Journal 100(10):456–475.

Yamauchi, Tatsuo and Abe, Fumiko. 1990. Cardiac glycosides and pregnanes from Adenium obesum (studies on the constituents of Adenium. I). Chemical & Pharmaceutical Bulletin 38(3):669–672.

Yang, Li and He, Junwei. 2021. Traditional uses, phytochemistry, pharmacology and toxicological aspects of the genus Hosta (Liliaceae): a comprehensive review. Journal of Ethnopharmacology 30(265):113323.

INTERNET RESOURCES

ASPCA Poison Control Center: http://www.aspca.org/pet‐care/poison‐control

Canadian Poisonous Plants Information System: https://www.gbif.org

Cornell Department of Animal Science, Poisonous plants affecting dogs: http://www.ansci.cornell.edu/plants/dogs/index.html

Humane Society of the United States: https://www.humanesociety.org/resources/plants‐and‐food‐can‐be‐poisonous‐pets

Pet Poison Helpline, Plants that are toxic to cats: https://www.petpoisonhelpline.com/?s=plants

Poisonous plants of North Carolina: https://www.ces.ncsu.edu/search‐results/?q=toxic+plants

21
Dietary Supplements and Herbs

Charlotte Means

INTRODUCTION

The sales of herbal dietary supplements have been on the rise. In 2007 the market totaled approximately US$4.8 billion dollars, while in 2021, the global herbal supplements market reached US$32.1 billion (Cision PR Newswire 2022). Because of the popularity of herbal supplements, dogs and cats are exposed from accidental overdoses or by owner administration. Adverse effects can occur because of dosage, species differences in metabolism, or drug–herb interactions.

SYMPATHOMIMETICS

Sources and Formulations

Herbs that contain sympathomimetics include ma huang (Ephedra sinica), Indian common mallow (Sida cordifolia), and bitter orange (Citrus aurantium). Historically, these herbs were used to treat asthma, cough, and colds. Today, these herbs are most commonly sold as weight loss aids, decongestants, and also for illicit recreational use (such as herbal ecstasy) or to improve athletic performance (such as weightlifters). Supplements containing ma huang were among the first widely marketed and advertised herbal products. When used as a weight‐loss aid, frequently caffeine‐containing plants are included in the formulation, which can increase toxicity (Means 1999). The active components of E. sinica and S. cordifolia are alkaloids, including ephedrine and pseudoephedrine. Bitter orange contains synephrine (McQueen and Der Marderosian 2023; Means 1999). In 2004, the US Food and Drug Administration (FDA) banned all dietary supplements containing ephedrine alkaloids, such as ephedra, ma huang, S. cordifolia, and pinellia because they presented an unreasonable risk of illness or injury under the conditions of use recommended or stated in labeling. However, such products can still be purchased on the internet and because the rule does not include traditional Chinese herbal medicines, the potential for exposure to ephedra still exists.

C. aurantium, also known as the Seville orange, or bitter orange, is used to make orange marmalade. The unripe peel contains synephrine, neohesperidin, and five other adrenergic amines. Proponents for bitter orange use claim that bitter orange stimulates only beta‐3 receptors in the adipose tissue and liver. They claim that bitter orange will not increase blood pressure or heart rate and thus is safer and a substitute for ephedra. However, a study using healthy volunteers showed that bitter orange elevated systolic and diastolic blood pressure and heart rate following a single dose (Bui et al. 2006).

The potential for adulterated products must also be kept in mind when evaluating a patient. Multiple herbal medications, including weight‐loss supplements, have been found to be adulterated with various drugs, including sibutramine (a controlled intravenous drug found in the weight loss pharmaceutical Meridia®), caffeine and other stimulants (FDA 2023).

Mechanism of Action

Pharmacologically, ephedrine and pseudoephedrine are sympathomimetic alkaloids. The alkaloids stimulate alpha‐ and beta‐adrenergic receptors, causing the release of endogenous catecholamines at synapses in the brain and heart. This stimulation results in peripheral vasoconstriction and cardiac stimulation. This results in increased blood pressure, tachycardia, ataxia, restlessness, tremors, and seizures (Gurley et al. 1998).

Kinetics

Pseudoephedrine is excreted in urine as an unchanged drug (Means 1999). In humans, the elimination half‐life varies between 2 and 21 hours, depending on the urine pH.

Toxicity

Clinical signs have been seen in dogs at 5–6 mg/kg and deaths have occurred at 10–12 mg/kg. Dogs have a narrow margin of safety compared to other species (Means 1999). Toxicity can be increased if other sympathomimetic substances (such as phenylpropanolomine) are taken at the same time. Underlying disease can also increase an animal's susceptibility to toxicosis. Some of these conditions include heart disease, diabetes, and seizure disorders (Brinker 2010).

Clinical Signs

Effects are generally limited to the cardiovascular and central nervous systems. Initial signs usually begin with restlessness, pacing, and agitation. Vocalization may occur. Dogs may exhibit hallucinogenic behavior. On clinical examination, mydriasis, tachycardia, hypertension, muscle tremors, and seizures may be present. Death is usually due to cardiovascular collapse. Hypertension can cause pulmonary edema, although it is rare. Once an animal becomes symptomatic, clinical signs may last for 36–48 hours (Means 1999).

Management of Exposures

For a recent ingestion (15 minutes or less) in an asymptomatic animal, emesis may be induced followed by administration of activated charcoal with a cathartic. Agitation, nervousness, and tremors are best controlled by acepromazine maleate, chlorpromazine, or if seizures develop, a barbiturate such as phenobarbital is recommended (Ooms et al. 2001). For acepromazine and chlorpromazine, start at the low end of the dosage range and increase as needed. Dissociative effects of benzodiazepines are frequently exaggerated in dogs with pseudoephedrine toxicosis; dogs may actually become more agitated after the administration of diazepam. Serotonin syndrome may be present, and cyproheptadine is a serotonin antagonist that may aid in management of serotonergic signs (disorientation, vocalization, hyperthermia). Propranolol or another beta‐blocker can be used to control tachycardia. Supportive care includes administration of intravenous fluids and monitoring the patient. Baseline blood tests, including serum potassium and glucose concentrations, should be obtained and any abnormalities corrected.

METHYLXANTHINES

Sources

Guarana (Paullinia cupana) is a plant containing high levels of caffeine. Guarana may contain 3–5% caffeine by dry weight compared to coffee beans (1–2% caffeine) and tea (1–4% caffeine). Common names include Brazilian cocoa and Zoom. Theobromine and theophylline have also been found in the plant. Historically, guarana was used to provide energy during fasting, as an aphrodisiac, and to prevent malaria and dysentery. Guarana is frequently found in herbal weight‐loss aids (with or without ma huang) and in products promising increased energy (McQueen and Der Marderosian 2023). Because guarana contains methylxanthines, it produces a clinical syndrome similar to chocolate (see Chapter 27), coffee, or over‐the‐counter stimulant products, which contain caffeine.

Mechanism of Action

Caffeine is a methylated xanthine. It increases cyclic adenosine monophosphate, releases catecholamines, and increases muscular contractility. The net effect is a positive inotropic and chronotropic effect on the heart, cerebral vasoconstriction, renal vasorelaxation, and smooth muscle relaxation in the gastrointestinal tract (Means 2004).

Kinetics

Caffeine is well absorbed orally. The plasma half‐life in the dog is 4.5 hours. Caffeine is metabolized in the liver and undergoes enterohepatic recirculation. Caffeine is excreted through the urine (Kisseberth and Trammel 1990; Means 2004). Caffeine has caused birth defects in animals (Brinker 2010).

Toxicity

The LD₅₀ (the dose at which half the animals die or lethal dose 50) of caffeine in dogs is reported to be 140 mg/kg. However, serious toxicity and death have been reported at doses much lower than the LD₅₀. For combinations of ma huang and guarana, the minimum dose at which clinical signs were reported in dogs is 1.3 mg/kg ma huang and 4.4 mg/kg guarana. The minimum dose at which death was reported was 5.8 mg/kg ma huang and 19.1 mg/kg guarana. These doses were obtained from cases reported to the American Society for the Prevention of Cruelty to Animals (ASPCA) Animal Poison Control Center (Ooms et al. 2001). There are multiple drugs that can interact with caffeine. Besides pseudoephedrine and ma huang, monoamine oxidase inhibitors, aspirin, and cimetidine are commonly used medications that should not be combined with caffeine. The sedative effects of benzodiazepines may be decreased by caffeine (Brinker 2010). As with ma huang, there are several medical conditions, which may enhance toxicity. These conditions include heart and kidney disease and ulcers.

Clinical Effects

Clinical signs include vomiting, restlessness and hyperactivity, polydipsia, and polyuria. Tachycardia and other cardiac arrhythmias such as premature ventricular contractions are possible. Clinical signs progress to muscle tremors and seizures, and finally death (Means 2004; Ooms et al. 2001).

Management of Exposure

Treatment consists of early decontamination. Induce emesis in an asymptomatic animal or perform gastric lavage. Because enterohepatic recirculation occurs in caffeine toxicosis, repeated doses of activated charcoal are beneficial. Cardiac function should be monitored. Tachycardia can be treated with a beta‐blocker such as metoprolol or propranolol. The dose is the same as in ma huang toxicosis. Premature ventricular contractions can be treated with lidocaine. Lidocaine is dosed as an initial bolus slowly intravenously, followed by an intravenous drip. Muscle tremors and seizures are treated with diazepam or a barbiturate can be used (dose as per ma huang). Intravenous fluids may enhance excretion. A urinary catheter should be placed because methylxanthines can be absorbed through the bladder wall (Means 2004; Ooms et al. 2001).

HYPOGLYCEMICS

Alpha Lipoic Acid

Sources

Alpha lipoic acid (ALA), also known as thioctic acid, is considered a “vitaminlike” antioxidant. It is found in yeast, liver, kidney, heart, skeletal muscle, spinach, broccoli, and potatoes. ALA increases intracellular glutathione and regenerates ascorbic acid, vitamin E, coenzyme Q10, and nicotinamide adenine dinucleotide phosphate hydrogen/nicotinamide adenine dinucleotide hydrogen (NADPH/NADH). It is thought to protect against single‐strand DNA breaks and glycation (thought to contribute to many of the complications in diabetes) (Nicols 1997). Alpha lipoic acid is synergistic with insulin, causing reduced blood sugar and increased liver glycogenesis. It is used in alternative veterinary practices to treat diabetic polyneuropathy, cataracts, and glaucoma. In toxicology, it has been used to treat amanita mushroom poisoning. However, the doses used in human medicine for mushroom toxicity can cause toxicity in dogs.

Toxicity

ALA is taken orally, usually in 100‐ or 300‐mg capsules. The reported LD₅₀ in dogs is 400–500 mg/kg. However, suspicious deaths have been reported at doses below 100 mg/kg and confirmed deaths at 330 mg/kg (Hill et al. 2004). Cats are about 10 times more sensitive than dogs (Hill et al. 2004). The minimum toxic dose in cats is 13 mg/kg, and at 30 mg/kg neurologic signs and hepatotoxicity develop.

The therapeutic dose for cats is 1–5 mg/kg, with a maximum dose of 25 mg/day. For dogs, the therapeutic dose is up to 200 mg/day. Decontamination is recommended for all cats if the calculated dose is >5 mg/kg and dogs if the dose is >30 mg/kg.

Clinical Effects

Clinical signs include hypersalivation, vomiting, ataxia, tremors and seizures, and death. Serum chemistry abnormalities include profound hypoglycemia and increased liver enzymes. Acute renal failure has occurred in some patients. The onset of clinical signs is within 30 minutes up to several hours postingestion.

Management of Exposure

Treatment is symptomatic and supportive. Treat hypoglycemia, if present, with dextrose, support liver function, correct dehydration and control vomiting, and control tremors and seizures. Monitor blood glucose as well as renal and liver enzymes. See the section on xylitol in Chapter 27 for specific treatment.

Cinnamon

Sources and Formulations

Cinnamon (Cinnamomum cassia and Cinnamomum zeylanicum) is currently touted as an adjunct therapy in the treatment of type II diabetes (Chase and McQueen 2007; Baker et al. 2008). Cinnamon can be purchased in capsular form at natural food stores or wherever vitamins and supplements are sold. Most of the clinical trials reported at this time have had a small number of patients, or used rats, and some studies had conflicting results. Cinnamon is NOT the same as cinnamon oil (see essential oils section).

Mechanism of Action

The mechanism of action is generally described as an insulin‐like effect. Cinnamon contains an active constituent classed as a methylhydroxychalcone polymer that may be linked to the effect. This substance, when combined with insulin, has synergistic effects. People are advised to monitor blood glucose carefully when taking cinnamon, especially when concurrent diabetic medications are used.

If a dog ingests large quantities of cinnamon, the potential for hypoglycemia exists. Cinnamon is also reported to cause hypotension in dogs. It does have an emetic effect in large quantities, so many dogs will self‐decontaminate after ingestion. Some concerns with long‐term usage do exist. Some sources of cinnamon may have significant pesticide contamination, and there have been reports of hepatic injury with long‐term use. Cinnamon also contains coumarin and can have drug interactions.

Management of Exposures

In asymptomatic animals, emesis should be induced following large ingestions. Home care will be appropriate in many cases. Owners can monitor and feed small frequent meals and transport to a veterinary clinic if clinical signs develop.

MISCELLANEOUS HERBS

Griffonia Simplicifolia

Sources and Formulations

Seeds from this plant are used as a source of 5‐hydroxytryptophan (5‐HTP). This extract is generally used to treat depression, headaches, obesity, and insomnia in humans. 5‐HTP is reported to increase serotonin in the central nervous system. Label information may list 5‐HTP, 5‐hydroxytryptophan, or griffonia seed extract as an ingredient. Drug interactions with monoamine oxidase (MAO) inhibitors, antidepressants, and herbs such as St. John's Wort can occur (Gwaltney‐Brant et al. 2000).

Kinetics and Toxicity

5‐HTP is rapidly and well absorbed from the gastrointestinal tract, and readily crossed the blood–brain barrier. Once target cells are reached, 5‐HTP is converted to serotonin (5‐hydroxytryptamine). Serotonin is important in the regulation of sleep, cognition, behavior, temperature regulation, and other functions.

In dogs, the minimum toxic dose reported is 23.6 mg/kg and the minimum lethal dose reported in dogs is 128 mg/kg (Gwaltney‐Brant et al. 2000). Signs have been reported from 10 minutes up to 4 hours post ingestion. Signs can last up to 36 hours (Gwaltney‐Brant et al. 2000).

Clinical Effects

Clinical signs resemble serotonin syndrome in humans. Signs include seizures and tremors, depression, ataxia, disorientation, vocalization, and hyperesthesia. Gastrointestinal effects including vomiting, diarrhea, and drooling are common. Severe hyperthermia and blindness have been reported (Gwaltney‐Brant et al. 2000).

Management of Exposures

Treatment includes early decontamination. Seizures, tremors, and other neurologic signs usually respond well to diazepam or barbiturates. Fluid therapy should be initiated. Hyperthermia can be managed with cool water baths and fans. Baseline blood and chemistry panels should be obtained. Cyproheptadine is a serotonin antagonist and can be used orally or rectally until signs resolve (Gwaltney‐Brant et al. 2000). See Chapter 23 for more information on managing serotonin syndrome.

Echinacea purpurea

Sources and Formulations

This herb is one of the most popular supplements in use today. The common names of Echinacea include purple coneflower, comb flower, scurvy root, and others. Echinacea is indigenous to the United States and cultivated elsewhere. The plant is a perennial herb with narrow leaves and can grow up to 3 ft. Historically, echinacea was used by Native Americans and adopted by settlers. Uses ranged from “blood purifiers” to treating dizziness and rattlesnake bites. Extracts were widely used as anti‐infectives until antibiotics were discovered (McQueen and Der Marderosian 2023).

Echinacea contains essential oils, as well as glycoproteins, alkamides, and flavonoids. All parts of the plant are used in various herbal preparations. Echinacea is taken as a tincture and in capsular form, and is applied topically to wounds. Echinacea is typically used as an immune stimulant and as supportive therapy for the common cold or coughs, urinary tract infections, and stomatitis. Echinacea is recommended for chronic skin ulcers or poorly healing wounds. Because echinacea is suspected of being an immunostimulant, it should not be taken for more than 8 consecutive weeks (Brinker 2010; McQueen and Der Marderosian 2023).

Toxicity

Echinacea has a wide margin of safety. Arabinogalactan, a purified compound found in E. purpurea, has been dosed at 4 g/kg intraperitoneally and intravenously with no toxic effects. People have reported a variety of adverse effects, including hypotension, dizziness, fever, chills, nausea and vomiting, dyspnea, and dermatological effects. At least some of the effects are probably due to hypersensitivity and allergic reactions (Brinker 2010; McQueen and Der Marderosian 2023).

Signs

In cases where Echinacea was the only active ingredient ingested, the most common clinical signs were vomiting and drooling. Both hyperactivity and lethargy were reported (ASPCA Animal Poison Control Center, unpublished data).

Management of Exposures

A small ingestion of echinacea generally does not require medical intervention. Any gastrointestinal upset is generally self‐limiting and the pet owner will be able to treat with supportive care (nothing per os [NPO, withhold food and water], kaolin/pectin). It is imperative to determine whether the animal ingested other herbal products or medications. Large recent ingestions can be treated with gastric decontamination. If an animal develops severe vomiting, symptomatic treatment with intravenous fluids and other supportive care should be initiated.

Chamomile

Sources

Chamomile refers to both German chamomile (Matricaria recutita) and Roman chamomile (Chamaemelum nobile). Common names for German chamomile include wild chamomile and pin heads. Common names for Roman chamomile include garden chamomile, sweet chamomile, ground apple, and whig plant. The plant is indigenous to Europe and northwest Asia, and naturalized in America. German chamomile is an annual and Roman chamomile is a slow‐growing perennial. The plant is erect and grows to about 20–40 cm. Flowers are white with yellow centers (Eisenberg 1997; Klepser and Klepser 1999). Chamomile has been used medicinally since the Roman Empire. It was used as an antispasmodic and sedative. In folk medicine, chamomile is used for rheumatism and intestinal parasitism. Chamomile has also been used as a hair tint and cigarette flavoring (Brinker 2010; McQueen and Der Marderosian 2023). In veterinary medicine, the most common uses are as a natural dewormer, a sedative, and a treatment for aggression.

Chamomile contains essential oils, flavanoids, and hydroxycoumarins. Both fresh and dried flower heads are used. Some preparations will use the entire plant. Chamomile is most frequently taken as a tea. Ointments, gels, and bath salts are also available. Chamomile is used as a sedative and gastrointestinal antispasmodic. It may also be taken to treat colds, bronchitis, and fevers. In one study using rats, the development of gastrointestinal ulcers caused by indomethacin (a nonsteroidal anti‐inflammatory) was prevented by chamomile (McQueen and Der Marderosian 2023). Topically, chamomile is used to treat wounds and burns. Chamomile is contraindicated in pregnancy (especially early pregnancy) (Brinker 2010; Gardner and McGuffin 2013).

Toxicity

Bisabolol, which accounts for 50% of the essential oils found in chamomile, has an acute LD₅₀ of 15 mL/kg in rats and mice. In a 4‐week subacute toxicity study, 1–2 mL/kg given orally to rats produced no significant effects (McQueen and Der Marderosian 2023).

Clinical Effects

Most cases in dogs and cats cause mild stomach upset. With chronic use in cats, coagulopathies can occur. Epistaxis and hematoma development is probably due to the hydroxycoumarin content in the plant (Gwaltney‐Brant 2009).

Management of Exposures

Management of recent ingestions includes gastric decontamination. In cases of large ingestions, activated charcoal can be given. Treatment for gastric irritation is symptomatic and supportive (NPO, gastrointestinal protectants, fluid therapy if severe vomiting or dehydration occurs). If anaphylaxis occurs, standard therapy with epinephrine, steroids, and antihistamines should be initiated. For cats, or dogs with bleeding disorders such as von Willebrand's disease, a packed cell volume and activated clotting time or coagulation profile may be required. If necessary, a blood transfusion could be administered.

St. John's Wort (Hypericum perforatum)

Sources and Formulations

St. John's wort is also known as goatweed, rosin rose, and Klamath weed. It is a perennial native in Europe, Canada, and the United States. This plant can be found throughout much of the United States, but northwestern states have had the greatest livestock economic losses due to Hypericum. There are several Hypericum species, some with overlapping ranges, but the most important is H. perforatum. The plant grows aggressively in roadside areas and ditches, meadows, and woods. The height is usually 2 ft. Yellow flowers bloom from June through September. The plant must be harvested between July and August and dried immediately to retain pharmacological properties.

St. John's Wort has been used since the Middle Ages. Traditionally, this herb is used as an antidepressant and to treat diarrhea and gastritis. It was also used to treat insomnia and cancer. Topically, the herb is mixed with olive oil to create “red oil” and used for inflammation (McQueen and Der Marderosian 2023). In veterinary medicine, this plant is well known for causing photosensitization in livestock and horses. St. John's wort has been responsible for devastating economic losses to livestock producers.

Mechanism of Action

The major active constituents are anthraquinone derivatives, hypericin, and pseudohypericin, as well as flavanoids. The concentration varies considerably depending on harvest time, drying process, and storage. St. John's wort is used primarily as an antidepressant and sedative. Studies have shown that St. John's wort inhibits serotonin uptake, accounting for the antidepressant effects. It is taken as an infusion or as dried herb. The most common preparation is a standardized 300‐mg capsule. St. John's wort can interact with several medications. It decreases the activity of protease inhibitors, antagonizes reserpine, and increases stupor when consumed with alcohol. MAO inhibitors such as seligiline (Anipryl®) are potentiated when taken concomitantly. Serotonin syndrome is possible if St. John's wort is taken with selective serotonin reuptake inhibitors (SSRIs) due to synergistic activity. Common SSRIs include fluoxetine (Prozac®) and sertraline (Zoloft®). Serotonin syndrome has also been noted when St. John's wort is taken with dextrometorphan and meperidine. Sympathomimetics combined with St. John's wort may lead to a hypertensive crisis (Shannon 1999).

Clinical Effects

Adverse gastrointestinal effects occur commonly in dogs and cats. Photosensitization has occurred, generally after large doses or long‐term usage.

Management of Exposures

Recent ingestions are best treated by decontamination. Gastrointestinal disorders are generally easily managed with symptomatic and supportive care. In large ingestions, or unknown quantities, especially if early decontamination is not possible, baseline liver enzymes should be obtained. If evidence of serotonin syndrome develops (tremors, seizures, hyperthermia, vomiting, and diarrhea), standard therapy as discussed in the section Griffonia simplicifolia is initiated. If evidence of photosensitization occurs, keep the animal out of sunlight and provide supportive care for hepatic damage.

Valerian Root (Valeriana officianalis)

Sources and Formulations

Valerian root is one of the most popular herbs on the market. Common names include all‐heal, heliotrope, Vandal root, and Capon's tale. It is an herbaceous perennial found widely over the United States. The dried rhizome contains a volatile oil with an odor many find offensive. The fresh drug does not have an odor. The plant grows to about 50–100 cm high and is erect without a branching stem. Flowers are bright pink to white. The fruit is yellow with a tuft of white hair. There are over 200 species of valerian, with various degrees of pharmacologic activity. Valeriana officianalis is considered the standard genus and species used in herbal medicine (McQueen and Der Marderosian 2023).

The primary active ingredients are volatile oils, alkaloids, and, most importantly, valepotriates. The root is the only part of the plant that is used. Valerian is classed as generally recognized as safe (GRAS) for food use. The volatile oils are used as flavoring in some food products. Valerian is used primarily as a sedative and as a sleeping aid. It has also been used in epilepsy, headaches, colic, and numerous other minor ailments. Valerian is frequently taken as a tea or as an extract. Valerian increases the length of sedation induced by pentobarbital and length of anesthesia produced by thiopental. Valerian has helped ease the effects of withdrawal from benzodiazepines due to similar receptor sites, but it increases the effects of sedatives if taken concomitantly (McQueen and Der Marderosian 2023).

Toxicity

Most reports of adverse effects of valerian in human literature occur after chronic use. These effects include headache, cardiac arrhythmias, and agitation. In one case report, 200 mg in a human caused fatigue, tremors, abdominal pain, and mydriasis (Shannon 1999). Animal studies included injections of 50 mg/kg intravenous in cats, which caused a drop in heart rate and blood pressure. Another study found no pharmacological effect in cats at 250 mg/kg orally. Mice given up to 4600 mg/kg orally produced mild clinical effects. Signs of toxicity included ataxia, hypothermia, and muscle relaxation (McQueen and Der Marderosian 2023).

Clinical Effects

Most ingestions produced no clinical effects, although lethargy and sedation have been reported.

Management of Exposures

Generally, significant treatment would be unnecessary. The sedative effects are generally short‐lived and can be managed by an owner at home. Large ingestions in an asymptomatic animal could be treated by decontamination.

ESSENTIAL OILS

Sources and Formulations

Essential oils are produced by a large number of plants (Woolf 1999). The oils are a mixture of terpenes and other chemicals. Essential oils are used from food flavorings to perfumes to medications. The most commonly used essential oils in veterinary medicine include Melaleuca or tea tree oil (Melaleuca alternifolia), pennyroyal oil (Mentha pulegium), D‐limonene and linalool (Citrus spp.), citronella (Cymbopgum nardus), thuja (Thuja occidentalis), and wormwood or absinthe (Artemisia absinthium).

In veterinary medicine, essential oils are most commonly used to treat flea infestations, hot spots or other dermatological conditions, or as dewormers. Oils may be found in shampoos, dips, liniments, teas, tinctures, syrups, or other formulations (Bischoff and Gaule 1998; Villar et al. 1994; Woolf 1999). Dose determines the toxicity.

Kinetics

Essential oils are rapidly absorbed both orally and dermally. They are metabolized by the liver to glucuronide and glycine conjugates. Repeated exposure can cause inductions of the hepatic enzyme cytochrome P‐450 and uridine 5′‐diphospho‐glycuronosyltransferase‐glycuronyl transferase systems. Thus, preexisting liver disease can increase the risk of toxicity.

Toxicity

The dose determines the poison and concentrated products can be toxic. Cats appear to be more sensitive to essential oils than dogs (Bischoff and Gaule 1998; Villar et al. 1994; Woolf 1999). The acute LD₅₀ varies significantly between various essential oils. Formulations mixed with an organic solvent, such as alcohol, can allow increased absorption and toxicity. Generally, a greater volume of fresh product is required to produce the same effects as a concentrated essence. The route of exposure also plays a role in toxicity. The basic mechanism of action is unknown (Villar et al. 1994).

Clinical Effects

The most common clinical signs after dermal exposures include ataxia, muscle weakness, depression, and behavioral abnormalities. Severe hypothermia and collapse have occurred in cats. Transient paresis can occur in small breed dogs when 100% melaleuca oil is applied down the spine as a topical flea treatment (Kaluzienski 2000, Khan et al. 2014; Villar et al. 1994). Cats have developed scrotal dermatitis after exposure to D‐limonene or linalool (Hooser 1990). Liver failure has been associated with essential oils, especially pennyroyal and melaleuca (Bischoff and Gaule 1998; Kaluzienski 2000; Sudekum et al. 1992; Villar et al. 1994).

Oral ingestions cause vomiting and diarrhea. Central nervous system depression may occur, and seizures are possible with large doses. Aspiration pneumonia can occur when essential oils are inhaled. Death can occur with sufficient doses. Signs usually develop from almost immediately up to 8 hours postexposure (Bischoff and Gaule 1998; McQueen and Der Marderosian 2023; Villar et al. 1994).

Management of Exposures

Recent dermal exposures should be treated by bathing using a liquid hand dishwashing detergent. Emesis should not be induced due to the potential for aspiration pneumonia. The efficacy of activated charcoal is not known. If activated charcoal is given, vomiting should be controlled first. Intravenous fluids help correct hypotension and aid in renal elimination. Body temperature should be monitored and regulated as needed, and electrolytes, cardiac, and respiratory function should be monitored. Seizures and tremors usually respond to diazepam. Aspiration pneumonia may require oxygen and broad‐spectrum antibiotics. Monitor liver enzymes if animals have more than mild clinical signs. Hepatic damage usually responds to good supportive care, although N‐acetylcysteine has been used experimentally in humans diagnosed with pennyroyal toxicosis (Buechel et al. 1983). Signs usually resolve over a few hours up to a few days. Most animals do have a good prognosis with appropriate treatment. Many mild cases require only mild home treatment and observation (Bischoff and Gaule 1998; Buechel et al. 1983; Villar et al. 1994).

Oral Joint Supplements

Sources and Formulations

These products are nutraceuticals used to treat joint disease, especially osteoarthritis. The supplements frequently contain glucosamine, chondroitin sulfate, eggshell membrane, dimethylsulfone/methylsulfonylmethane, avocado powder, and perna (green lipped mussel) and other nutritional supplements. In cats, they may be used to treat interstitial cystitis or lower urinary tract disease or urethral obstruction. The FDA does not regulate these products, and therefore, no standards of purity, potency, safety, or efficacy exist. Some products have been linked to hepatic damage, but at this time conclusive statements cannot be made. Products are available from veterinarians, pet stores, feed stores, and online.

Mechanism of Action

Glucosamine (2‐amino‐2‐deoxy beta‐D‐glucopyranose) is an endogenous aminomonosaccharide synthesized from glucose and utilized for biosynthesis of glycoproteins and glycosaminoglycans. The sulfate salt of glucosamine forms half of the disaccharide subunit of keratan sulfate, which is decreased in osteoarthritis, and of hyaluronic acid, which is found in both articular cartilage and synovial fluid (Adebowale et al. 2002). Supplementation is thought to stimulate the manufacturing of substances essential for proper joint function and repair.

Chondroitin sulfate possesses several pharmacologic effects. It appears to inhibit destructive enzymes in joint fluid and cartilage. Thrombi formation in microvasculature may be reduced. In joint cartilage, it stimulates the production of glycosaminoglycans and proteoglycans (Adebowale et al. 2002).

Hepatotoxicity etiology in dogs is not known.

Kinetics

Pharmacokinetics are difficult to evaluate due to differences in ingredients, purity, and studies. Dogs absorb glucosamine sulfate up to 12% better than glucosamine hydrochloride. Chondroitin sulfate bioavailability ranges from 4.8% to 5% after a single dose and 200–278% after multiple dosing (Adebowale et al. 2002; Meulyzer et al. 2008; Setnikar and Rovati 2001).

Toxicity

The no observable effect level (NOEL) for glucosamine orally in dogs is 2149 mg/kg. In general, joint supplements are considered to have a wide margin of safety. (Nobles and Khan 2015). Therapeutic doses vary among brands. There are three medical conditions seen with joint supplement ingestions. The first is gastrointestinal upset, typically limited to vomiting and diarrhea. The second is hepatotoxicity (dogs only), the mechanism is unknown. The third is a fluid shift resulting in hypernatremia. Fluid shifts can occur with soft chews as the osmotic agents in the chew will pull free water into the gastrointestinal tract.

Clinical Effects

The most commonly reported clinical signs are vomiting, diarrhea, lethargy, and polydipsia. If hepatotoxicity develops, elevated liver enzymes (alanine aminotransferase, ALT) occur and coagulopathies can develop. Hypernatremia is seen with fluid shifts. Fluid shifts also cause dehydration, ataxia, tremors, potentially seizures, and tachycardia. Death (or euthanasia) is rare.

Signs usually develop as early as 15 minutes up to 48 hours post exposure. Gastrointestinal signs usually develop first and will be present within 4 hours for vomiting and 12 hours for diarrhea and anorexia. Hepatic effects are usually seen within 48 hours, although in some cases enzymes may be rising within 5 hours post exposure. In most cases, clinical signs resolve in 12 hours to 6 days.

Management

Induce emesis if asymptomatic and if there are concerns for fluid shifting. Activated charcoal is not recommended as it can make hypernatremia worse. Baseline chemistry, complete blood count (CBC) or packed cell volume/total solids (PCV/TS) and electrolytes should be obtained. Monitor liver values for 48 hours. Asymptomatic patients can be treated as outpatients.

Symptomatic and high‐risk patients should be monitored in hospital. The CBC or the PCV/TS and electrolytes are used to evaluate for fluid shifts. Maintain hydration with a balanced crystalloid fluid. If the animal is vomiting, manage with an antiemetic. Start liver protectants like S‐adenosylmethionine (SAMe) or SAMe and silymarin. Acetylcysteine can be added as a liver protectant in addition to SAMe if vomiting. If coagulopathies develop or if the ALT is greater than 750, start vitamin K1 at 2.5 mg/kg, divided dose every 12 hours until clotting times are normal and administer fresh frozen plasma. Consider a whole blood‐transfusion if coagulopathy and anemia are present.

If hypernatremia develops and it is less than 24 hours since ingestion, you can treat it as acute hypernatremia. Acute hypernatremia occurs before idiogenic osmoles are formed in the brain and sodium can be dropped quickly (no concern with cerebral edema, as seem with chronic hypernatremia). Monitor electrolytes as needed. Use low sodium intravenous fluids (D5W, 0.45% NaCl) and consider warm water enemas (10 ml/kg every 1 hour) as the colon has a good absorptive surface for free water. If central nervous system signs are present, use a benzodiazepine to treat tremors and seizures. Levetiracetam can also be used for seizure management. Methocarbamol can be used for tremors.

Prognosis is generally good when only gastrointestinal signs and polydipsia are present. A guarded prognosis may need to be discussed when hypernatremia and fluid shift, as well as liver damage, are present.

HERBS AND PETS

One of the most important considerations in treating herbal ingestions is product quality assurance. Although most herbal companies are reputable, there are numerous reports of adulterated products (addition of substances not noted on the label). This has been particularly true of Chinese herbal products, which frequently contain pharmaceuticals. Plant identification errors occur, and entire batches of product have been mixed using the wrong herb. In some cases, labels are written in a foreign language, ingredients are proprietary, or contain directions only for administration, making interpretation difficult. In cases where a known ingestion produces unexpected clinical signs, the potential for adulteration or other errors should be considered. When a product is not standardized, a consumer cannot be sure what dosage of active constituents it contains or how bioavailable the product may be. Standardization also provides assurance that the actual herb is in the product (Winslow and Kroll 1998).

Clients who use herbal products should be advised to treat them as medications and keep them away from pets. Specifically ask clients if they take or use any natural or herbal products. Many people do not consider these substances to be drugs or assume “if natural, it is harmless.” Clients should be encouraged to learn about the herbal and nutraceutical products they are taking or giving their pets. Clients need to be encouraged to discuss proper use of herbal products in pets with their veterinarian. Clients can be encouraged to discuss alternative therapies by discussing a pet's diagnosis and suggested treatments thoroughly. Discuss the client's expectations and opinions of both alternative and conventional medicine. Issues of safety and efficacy must be explained to clients. They should be encouraged to report potential adverse reactions or to discuss different routes of therapy if a pet's medical condition is not improving. Clients who want to use alternative medical treatments should be encouraged to obtain a good medical workup to obtain a correct diagnosis and be referred to a veterinarian trained in alternative medicine. In choosing an alternative medicine practitioner, the same criteria would be used as for any other specialist: education, training, and professionalism (Libster 1999).

REFERENCES

Adebowale, Abi, Du, Jianpin, Liang, Shonming, Leslie, James L, and Eddington, Natalie D. 2002. The bioavailability and pharmacokinetics of glucosamine hydrochloride and low molecular weight chondroitin sulfate after single and multiple doses to beagle dogs. Biopharmaceutics and Drug Disposition 23(6):217–225.

Baker, William L, Guiterrez‐Williams, Gabriela, White, C Michael, Kluger, Jeffrey, and Coleman, Craig I. 2008. Effect of cinnamon on glucose control and lipid parameters. Diabetes Care 31(1):41–43.

Bischoff, Karyn and Gaule, Fessesswork. 1998. Australian tea tree (Melaleuca alternifolia) oil poisoning in three purebred cats. Journal of Veterinary Diagnostic Investigation 10:208–210.

Brinker, Francis. 2010. Herbal Contraindications and Drug Interactions Plus Herbal Adjuncts with Medicines, 4th ed. Sandy, Oregon: Eclectic Medical Publications.

Buechel, David W, Haverlah, VC, and Gardner, Madelin E. 1983. Pennyroyal oil ingestion: report of a case. Journal of the American Osteopathic Association 82(10):793–794.

Bui, Linda T, Nguyen, DiemThuy T, and Ambrose, Peter J. 2006. Blood pressure and heart rate effects following a single dose of bitter orange. Annals of Pharmacotherapy 40(1):53–57.

Chase, Celtina K and McQueen, Cydney E. 2007. Cinnamon in diabetes mellitus. American Journal of Health‐System Pharmacy 64(10):1033–1035.

Cision PR Newswire. 2022. Global Herbal Supplements Market Report (2022–2027) – Industry Trends, Share, Size, Growth, Opportunity and Forecasts. https://www.prnewswire.com/news‐releases/global‐herbal‐supplements‐market‐report‐2022‐to‐2027‐‐‐industry‐trends‐share‐size‐growth‐opportunity‐and‐forecasts‐301582904.html Accessed 12/13/23.

Eisenberg, David M. 1997. Advising patients who seek alternative medical therapies. Annals of Internal Medicine 27(1):61–69.

FDA. 2023 Tainted Weight Loss Products. US Food & Drug Administration. https://www.fda.gov/drugs/medication‐health‐fraud/tainted‐weight‐loss‐products Accessed 12/13/23.

Gardner, Zoe and McGuffin, Michael (eds). 2013. Achillea millefolium. In American Herbal Products Association Botanical Safety Handbook, 2nd ed. Boca Raton, FL: CRC Press.

Gurley, Bill J, Gardner, Stephanie F, White, Laura M, and Wang, Pei‐Ling. 1998. Ephedrine pharmacokinetics after the ingestion of nutritional supplements containing Ephedra sinica (ma huang). Therapeutic Drug Monitoring 20(4):439–445.

Gwaltney‐Brant, Sharon M. 2009. Selected herbal toxicities. https://www.dvm360.com/view/selected‐herbal‐toxicities‐proceedings Accessed 12/14/23.

Gwaltney‐Brant, Sharon M, Albretson, Jay C, and Khan, Safdar A. 2000. 5‐hydroxytryptophan toxicosis in dogs: 21 cases (1989–1999). Journal of the American Veterinary Medical Association 216(12):1937–1940.

Hill, Ana S, Werner, Jonathon A, Rogers, Quinton R, O'Neill, Sharron L, and Christopher, Mary M. 2004. Lipoic acid is 10 times more toxic in cats than reported in humans, dogs, or rats. Journal of Animal Physiology and Animal Nutrition 88(3–4):150–156.

Hooser, Stephen B. 1990. D‐limonene, linalool, and crude citrus oil extracts. Veterinary Clinics of North America: Small Animal Practice 20(2):383–385.

Kaluzienski, Mark. 2000. Partial paralysis and altered behavior in dogs treated with melaleuca oil. Journal of Toxicology. Clinical Toxicology 38(5):518–519.

Khan, Safdar A, McLean, Mary Kay, and Slater, Margaret R. 2014. Concentrated tea tree oil toxicosis in dogs and cats: 443 cases (2002‐2012). Journal of the American Veterinary Medical Association 244(1):95–99.

Kisseberth, William C and Trammel, Harold L. 1990. Illicit and abused drugs. Veterinary Clinics of North America: Small Animal Practice 20(2):405–417.

Klepser, Teresa B and Klepser, Michael E. 1999. Unsafe and potentially safe herbal therapies. American Journal of Health‐System Pharmacy 56(2):125–138.

Libster, Martha. 1999. Guidelines for selecting a medical herbalist for consultation and referral: consulting a medical herbalist. Journal of Alternative and Complementary Medicine 5(5):457–462.

McQueen, Cydney E and Der Marderosian, Ara. 2023. Philadelphia: Wolters Klewer.

Means, Charlotte. 1999. Ma huang: all natural but not always innocuous. Veterinary Medicine 94(6):511–512.

Means, Charlotte. 2004. Chocolate Toxicosis in a border terrier. NAVC Clinician's Brief:11–12.

Meulyzer, Michael, Vachon, Pascal, Beaudry, Francis, Vinardell, Tatiana, Richard, Helene, Beauchamp, Guy, and Laverty, Sheila. 2008. Comparison of pharmacokinetics of glucosamine and synovial fluid levels following administration of glucosamine sulphate or glucosamine hydrochloride. Osteoarthritis and Cartilage 16(9):973–979.

Nichols, Trent W. 1997. Alpha‐lipoic acid: biological effects and clinical implications. Alternative Medicine Review 2(3):177–183.

Nobles, Irma J and Khan, Safdar. 2015. Multiorgan dysfunction syndrome secondary to joint supplement overdosage in a dog. Canadian Veterinary Journal 56(4):361–364.

Ooms, Tara G, Khan, Safdar A, and Means, Charlotte. 2001. Suspected caffeine and ephedrine toxicosis resulting from ingestion of an herbal supplement containing guarana and ma huang in dogs: 47 cases (1997–1999). Journal of the American Veterinary Medical Association 218(2):225–229.

Setnikar, Ivo and Rovati, Lucio C. 2001. Absorption, distribution, metabolism and excretion of glucosamine sulfate. A review. Arzneimittel‐Forschung 51(9):699–725.

Shannon, Michael. 1999. Alternative medicines toxicology: a review of selected agents. Journal of Toxicology. Clinical Toxicology 37(6):709–713.

Sudekum, Margaret, Poppenga, Robert H, Raju, N, and Braselton, W Emmett Jr. 1992. Pennyroyal oil toxicosis in a dog. Journal of the American Veterinary Medical Association 200(6):817–818.

Villar, David, Knight, Michael J, Hansen, Steven R, and Buck, William B. 1994. Toxicity of melaleuca oil and related essential oils applied topically on dogs and cats. Veterinary and Human Toxicology 36(2):139–142.

Winslow, Lisa C and Kroll, David J. 1998. Herbs as medicines. Archives of Internal Medicine 158(20):2192–2199.

Woolf, Alan. 1999. Essential oil poisoning. Journal of Toxicology. Clinical Toxicology 37(6):721–727.

22
Metals and Minerals

Frank Davis

INTRODUCTION

Metals and minerals are intrinsic to nature and are ubiquitous in the environment of animals. Some of these compounds play an essential role in biological processes (iron, copper, zinc, selenium) while others do not. While the form or valence can be changed, metals themselves cannot be destroyed. The activities of humans have resulted in the large‐scale redistribution of these compounds in the environment. Perhaps the best example of this relates to lead, which originates as mead ore that is processed for numerous uses. The prior use of lead as an antiknock compound in gasoline and pigment in paints contributed to widespread environmental contamination before such uses were banned. Despite curtailment of lead use, it still poses significant risk for intoxication. Lead in paint continues to cause adverse health effects in people and pets.

The toxicities of metals and minerals can be more difficult to define than for other toxicants. One reason is that the form (salt, valence state, elemental, inorganic, organic) plays a critical role in how readily it is systemically absorbed, resulting in intoxication. For example, elemental mercury when ingested is essential unavailable for systemic absorption. In contrast, organic forms of mercury such as methyl mercury are highly bioavailable. The interactions of these compounds also play an important role in the determination of toxicity. For example, high dietary calcium can reduce absorption of fluoride. Other factors that can influence toxicity include animal age, gender, and the capacity for biotransformation. The distribution of metals and minerals for storage in certain tissues of the body can mitigate damage. Lead accumulates in bone, where it is not available to affect target tissues such as the central nervous system (CNS). Also, metals can be sequestered in the body by cystine‐rich proteins called metallothioneins. Metallothioneins are highly inducible by metals and are essential for metal homeostasis and detoxification of metals (Ufelle and Barchowsky 2019). The interaction of metals with sulfhydryl‐containing groups like cystine is the basis for efficacy of metal chelators, such as succimer or dimercaprol, which contain numerous sulfhydry l groups.

Although the periodic table is full of potentially toxic metals, the following discussion is limited to those few metals that most commonly intoxicate or pose an intoxication risk for companion animals. Metals that are more frequently involved in livestock or wildlife intoxications will not be discussed. However, keep in mind that most metals, under appropriate circumstances, can poison animals and people.

ARSENIC

Sources and Formulations

Historically, various forms of arsenic have been used as herbicides, insecticides, wood preservatives, growth promotants, and therapeutic agents. Arsenic is found in various valiances and forms. These are trivalent and pentavalent inorganic and organic arsenic forms. The trivalent inorganic arsenic trioxide was formerly used as an insecticide and herbicide, and as a source for other arsenicals (Ensley 2004). Pentavalent (arsenic; H₃AsO₄) and trivalent (arsenite; H₃AsO₃) forms of arsenic include sodium, potassium and calcium salts. Paris green (copper acetoasenite) and lead arsenate have been used as insecticides, and trivalent inorganic arsenic forms such as monosodium methanarsentate and disodium methanearsonate (DSMA) are used as herbicides. Pentavalent organic arsenicals such as sodium arsenilate and 3‐nitro, 4‐hydroxyphenylarsonic acid are used as feed additives for some livestock species.

Although arsenic is still utilized in some products, it is not as ubiquitous as it once was due to restrictions on its use and the availability of newer, more targeted pesticides. For example, its use as a wood preservative in the form of chromated copper arsenic (CCA) has been replaced by other chemicals for residential use. Melarsomine is an organic arsenical used as a heartworm adulticide. The most common arsenic exposure of dogs and cats is to ant and roach baits, which are typically inorganic forms of arsenic (DeClementi 2013).

Kinetics

As for most metals, the bioavailability of arsenic is variable and depends on its form (organic vs. inorganic, solution vs. powder). The arsenic in solutions of organic arsenicals is almost completely absorbed from the gastrointestinal (GI) tract (DeClementi 2013). Alternatively, arsenic compounds of low solubility such as arsenic trioxide are absorbed less efficiently. Once absorbed, arsenic is widely distributed in the body and reaches its highest concentrations in the liver, spleen, kidneys, lungs, and GI tract. Persistent residues are found in keratinized tissue such as skin, hair, and nails. Clearance of arsenic from the blood is multiphasic, with the first phase having a 1‐ to 2‐hour half‐life. Around 40–70% of an absorbed dose is eliminated via the urine within the first 48 hours (DeClementi 2013). To a large extent, inorganic arsenic is metabolized in the liver by the addition of methyl groups prior to elimination.

Toxicity

The toxicity of arsenic is quite variable and depends on its form, purity, solubility, particle size, valence, species exposed, and the condition of the exposed individual (DeClementi 2013). For example, trivalent arsenicals are four to 10 times more toxic than pentavalent arsenicals. The cat is considered to be one of the more sensitive species. A lethal oral dose of sodium arsenite is reported to be less than 5 mg/kg body weight. More generally, the range of the lethal oral dose for sodium arsenite is 1–25 mg/kg body weight. Weak and debilitated animals are more susceptible to intoxication (DeClementi 2013).

Mechanism of Action

The mechanism of toxic action is dependent on the form of arsenic. Trivalent arsenic in organic arsenicals (i.e. arsenites) inhibit cellular respirations. They bind to sulfhydryl compounds, especially lipoic acid and alpha‐keto oxidase. Lipoic acid, a tissue respiratory enzyme cofactor, plays an essential role in the tricarboxylic acid cycle (TCA). Tissues with high oxidative energy requirements (e.g., activity dividing cells such as those of the intestinal epithelium, kidney, liver, skin, and lungs) are most severely affected. Trivalent arsenic affects capillary integrity by an unknown mechanism. The GI tract is most affected; capillary dilatation is followed by transudation of plasma into the GI tract, resulting in submucosal congestion and edema.

In contrast, pentavalent inorganic arsenicals (arsenates) appear to substitute for phosphate in oxidative phosphorylation. Uncoupling of oxidative phosphorylation produces a cellular energy deficit. Elevated body temperature is not characteristic of pentavalent arsenical poisoning as it is in poisonings by other oxidative uncouplers (e.g., mitrophenols).

The organic arsenicals also vary in terms of their mechanism of toxic action. Trivalent organic arsenicals appear to have a mechanism of toxic action similar to the inorganic arsenicals. However, pentavalent organic arsenicals (e.g., used as livestock feed additives) act on nerves by an unknown mechanism. They produce demyelination and eventual axonal degeneration, leading some researchers to believe that the pentavalent organic arsenicals interfere with the B vitamins essential for mechanism of nervous tissue.

Clinical Effects

Typically, arsenic intoxication in small animals is an acute illness. Signs can occur within minutes of exposure, with death occurring in several hours. Intoxication from chronic arsenic exposure is not well described in companion animals. However, there is one case report describing dermatitis in a German shorthaired pointer chronically exposed to arsenic (Evinger and Blakemore 1984). The source of exposure was from a container of 44% sodium arsenic that had been leaking into the dog's house.

Signs

Signs associated with acute arsenic intoxication generally develop in the following progression: intense abdominal pain, salivation, vomiting, staggering gait, diarrhea (often bloody; “rice water”), rapid and weak pulse, hypothermia, collapse, and death due to either hypovolemic or hemorrhagic shock.

Laboratory

There are no specific abnormalities noted from complete blood count (CBC) or serum chemistry tests. Because arsenic can damage multiple organs, changes associated with liver or kidney dysfunction can be present if the animal survives for several days. Protein, red blood cells, and casts can be noted in the urine.

Differential Diagnoses

Other disease etiologies to consider include intoxication from other metals or metal salts (e.g. lead, copper or zinc salts), ingestion of acid or alkaline caustics, ingestion of irritating plants (e.g. those containing insoluble calcium oxalates, castor bean), and infectious agents such as parvovirus.

Diagnostics

Antemortem

An antemortem diagnosis relies on a history of ingestion of arsenic, the occurrence of consistent clinical signs, and the detection of toxic concentrations of arsenic in vomitus or stomach contents, whole blood, or urine. Suspect sources of exposure can also be tested to confirm the presence of arsenic. The rapid elimination of the metal from the body makes the collection of appropriate samples as early as possible an important consideration. Most veterinary diagnostic laboratories can test for arsenic. It is important to point out that low‐level concentrations of arsenic in the blood or urine are not unusual and do not indicate arsenic intoxication. The interpretation of a given concentration of arsenic depends on an evaluation of the entire case and the timing of sample collection in relation to exposure.

Postmortem

Postmortem analysis of stomach contents, liver, kidney, or urine can confirm exposure. Again, the significance of detected concentration, especially relatively low concentration, needs to be interpreted in conjunction with other case variables. Postmortem lesions might be absent in cases of rapid death. Otherwise, severe GI lesions consisting of reddening of the gastric mucosa and proximal small intestine, watery GI contents, and blood and sloughed mucosa in the feces are commonly noted. Other organ lesions are not specific for arsenic.

Management of Exposures

The rapidity of onset of clinical signs such as vomiting often precludes initiating decontamination procedures. Activated charcoal is unlikely to absorb significant amounts of arsenic (Munday 2019). Symptomatic animals need to be stabilized first. This might entail treatment of circulatory shock and hypotension with intravenous fluids and maintenance of body temperature. Renal and liver failure and electrolyte abnormalities might need to be addressed. Glucose and glycogen stores should be maintained parentally with dextrose or parental alimentation solutions (Munday 2019).

Chelation therapy is rarely given due to the need to administer it within 2 hours. Historically, dimercaprol (British anti‐Lewisite, BAL) was the recommended chelator. It is a sulfhydryl‐ containing chelator that binds to arsenic and allows the arsenic chelator complex to be eliminated. However, available studies suggest that succimer is equal to or even superior to dimercaprol in increasing arsenic elimination (DeClementi 2013; Munday 2019).

Although the administration of B‐complex vitamins and amino acids has been recommended, the evidence for their efficacy is lacking. Parenteral antibiotic administration might be considered to prevent secondary bacterial infections of the GI tract. The use of GI protectants might also be indicated. Hemodialysis is not recommended in the absence of renal impairment (Munday 2019). Recovering animals should be fed a high‐quality diet in small portions, which can be increased as time and circumstances permit.

Prognosis

The prognosis in symptomatic animals is always guarded, particularly in the absence of early intervention and intensive monitoring and treatment.

FLUORIDE

Sources and Formulations

As a naturally occurring mineral salt, fluoride is made up of multiple compounds (e.g., sodium fluoride, sodium fluorosilicate, fluorosilicic acid) (Blakley 2022). Although most people associate fluoride with toothpaste, this mineral is available in multiple forms. Fluoride is added to drinking water in low levels to help promote strong teeth and prevent cavities. Fluoride can also be found in oral rinses, tablets, ointments, and drops to supplement low concentrations of fluoride in water.

Kinetics

In humans and laboratory animals, the absorption of ingested fluoride into the general circulation occurs primarily in the stomach and intestine and is dependent on the relative aqueous solubility of the form consumed. Soluble fluorides are almost completely absorbed from the GI tract; however, the extent of absorption may be reduced by complex formation with aluminum, phosphorus, magnesium, or calcium. Fluoride is rapidly distributed by the systemic circulation to the intracellular and extracellular water of tissues; however, approximately 99% of the total body burden of fluoride is retained in bones and teeth. In teeth and skeletal tissue, fluoride becomes incorporated into the crystal lattice. Fluoride crosses the placenta and is transferred from mother to fetus. Fluoride is eliminated from the body primarily in the urine (Blakley 2022).

Toxicity

Generally, acute fluoride poisoning (fluorosis), for example associated with massive ingestion of ascaricides (sodium fluoride), rodenticides (sodium fluorosilicate), or dental products for human oral use, will produce clinical signs of disease within 2 hours. The fatal dosage of sodium fluoride is ~5–10 mg/kg in most animal species. Signs of toxicosis may be evident after oral ingestion of fluoride compounds at a concentration of ~1 mg/kg. Serum calcium and magnesium concentrations decrease rapidly after the onset of clinical signs (Blakley 2022).

Mechanism of Action

The mechanism of fluoride toxicity can be broadly attributed to four mechanisms: inhibition of proteins, organelle disruption, altered pH, and electrolyte imbalance (Johnston and Strobel 2020). Oral ingestion of fluoride toothpaste produces hydrofluoric acid, which is locally corrosive. For dermal reactions, the mechanism is thought to be the formation of insoluble calcium fluoride salts that result in local tissue hypocalcemia in addition to the caustic burns from the acid component (Heard et al. 2001).

Clinical Effects

Signs

With small animals, most oral exposures are acute ingestion. With an acute exposure, signs may include moderate to severe gastroenteritis, anorexia, depression, dyspnea, stiffness, renal changes, and cardiovascular changes (ventricular tachycardia), which can lead to death.

Laboratory

Urine and blood fluoride levels can be measured but are not clinically relevant due to fast redistribution into bone. Baseline calcium levels should also be taken to monitor for developing hypocalcemia (Heard et al. 2001).

Differential Diagnosis

There are many causes of gastroenteritis.

Diagnostics

Antemortem

A detailed history is the best diagnostic test. Fluoride levels can be requested but are not timely.

Postmortem

Fluoride levels can be measured in tissue samples, water, and food.

Management of Exposure

With the most common sign being vomiting, stomach protectants, anti‐emetics, and intravenous fluids may be needed if hemorrhagic gastritis is noted. In more severe exposures, calcium gluconate can be administered IV and magnesium hydroxide or milk given orally, which helps to bind fluoride and minimize absorption (Blakley 2022).

Prognosis

With an acute exposure and immediate intervention, the prognosis is still favorable. As clinical signs develop, and given the severity, signs may worsen, leading to death.

IRON

Sources and Formulations

Iron is an element essential for life. Sources for iron exposure include multivitamins (especially prenatal vitamins), snail and slug bait, deoxidizers, handwarmers, and fertilizers (Hall 2013). In humans, the most commonly reported iron intoxication occurs in children ingesting iron supplements. There are a number of iron salts and formulations. The more common formulations and their respective percentage elemental iron concentrations are provided in Table 22.1. Some insoluble forms of iron such as elemental iron and ferric oxide (i.e., rust) are not hazardous when ingested due to low bioavailability.

Kinetics

The kinetics of iron absorption are complex. Iron body stores are regulated at the site of absorption from the GI tract because the body is not able to actively excrete iron. From the GI tract, iron must enter duodenal mucosal cells, possibly by a carrier‐mediated process. Next the iron is either lost as the mucosal cells slough into the GI lumen or is bound to ferritin for later transfer to transferrin, a serum iron‐binding transport protein. Serum transferrin concentrations greatly exceed the amounts necessary to bind iron under normal physiological processes (normal binding capacity is three to four times the serum iron concentration). However, during intoxications the binding capacity is exceeded, allowing free iron to cause cell damage.

Table 22.1. Percentages of elemental iron found in common iron formulations

Iron Formulation | % Elemental Iron
Ionic forms
Ferrous chloride | 28%
Ferrous fumarate | 33%
Ferrous gluconate | 12%
Ferrous lactate | 19%
Ferrous sulfate | 20%
Nonionic forms
Carbonyl iron | 98%
Iron polysaccharide | 46%

Toxicity

The toxicity of iron for dogs is believed to be similar to that for humans. Ingestion of less than 50 mg/kg body weight of elemental iron is not considered to cause more than mild gastric upset. Dosages of 50–80 mg/kg body weight cause vomiting and stomach ulcers, and dosages in excess of 80 mg/kg are associated with severe intoxication and liver involvement. It is important to determine the dose or dosage of elemental iron ingested by approximating how much of a product was ingested, knowing the form and amount of iron per unit of product weight, and then multiplying the total by the percentage of elemental iron based on the form (see Table 22.1). More recent labeling will have the amount of elemental iron listed and no conversions will be needed.

Mechanism of Action

Free iron can cause direct or indirect tissue and cell damage. Iron acts as a free radical and can also generate free radicals. Free radicals have one or more unpaired electrons, which can initiate lipid peroxidation resulting in cell membrane damage. Tissues that have first contact with free iron are primarily affected although all tissues are susceptible to damage if exposed. The primary targets are the GI, cardiovascular, and hepatic tissues. Iron also damages mitochondria, leading to loss of oxidative metabolism (Hall 2013). Iron might have a direct negative inotropic effect on the myocardium. (Perrone 2019).

Clinical Effects

Classically, the signs associated with iron intoxication follow more or less well‐defined stages.

Signs

Initial clinical signs are clue to GI upset (within 6 hours after ingestion). Bloody vomitus or stool can occur during this stage. The next stage (approximately 6–24 hours postexposure) mimics an apparent recovery as GI signs subside. The apparent recovery stage is followed by a worsening of signs that include vomiting, diarrhea, depression, GI hemorrhage, abdominal pain, circulatory shock, tremors, metabolic acidosis, coagulopathy, and in some cases, death. The last stage, 2–6 weeks after exposure, is characterized by GI obstruction secondary to fibrosing repair of prior GI damage.

Laboratory

Leukocytosis, hyperglycemia, metabolic acidosis, and normal‐to‐high aspartate aminotransferase (AST), alanine aminotransferase, alkaline phosphatase (ALP), and serum bilirubin concentrations can occur. Iron‐containing tablets or pills might be visualized by abdominal imaging.

Differential Diagnoses

A variety of diseases with a significant GI involvement need to be considered. Such diseases include garbage intoxication, toxic plant ingestion (e.g., castor bean), gastric torsion, caustic ingestions, snake bite, heat prostration, and infectious (bacterial or viral) enteritis.

Diagnostics

Antemortem

A diagnosis relies on a history of exposure and occurrence of compatible clinical signs. Serum iron in excess of 50 mcg/dl is consistent with exposure to excessive iron (Hall 2013). Analysis of vomitus or stomach contents might suggest a high iron exposure.

Postmortem

Postmortem tissue iron concentrations might help support a diagnosis of iron intoxication. Lesions in the liver tend to have a rather distinct periportal distribution because periportal regions of the liver are the first to be exposed to excessive free iron absorbed from the GI tract.

Management of Exposures

Early after exposure (within the first 2 hours), emesis can be induced in the asymptomatic patient or gastric lavage considered. Many patients present with significant prior vomiting; in such cases induction of emesis is not warranted. Activated charcoal does not bind iron and is not indicated.

Patient stabilization is a priority in symptomatic animals. Treating circulatory shock and metabolic acidosis is critical. Antiemetics, proton pump inhibitors, and sucralfate might be useful to provide some GI protection. Deferoxamine mesylate is an effective iron chelator. It combines with iron to form ferrioxamine, which is subsequently eliminated via the kidneys (Perrone 2019). Deferoxamine given intravenously too rapidly can cause cardiac arrythmias; it is a teratogen and should be used in pregnant animals only if the potential benefits outweigh the risks. It will change the urine color to “vin rose” (wine red) as iron is bound and excreted in the urine.

Prognosis

The prognosis is variable depending on the dosage ingested and availability of appropriate monitoring. In animals that recover from acute intoxication, owners should be instructed to watch for evidence of GI obstruction (strictures) several weeks after discharge. Prognosis is good with ingestion of hand warmers and deoxidizers.

LEAD

The true incidence of lead intoxication of household pets is unknown but is likely to be of decreasing prevalence due to curtailment of lead paint use and resulting decreases in exposure. At least historically, a higher prevalence of intoxication is reported during warmer months. There is also a higher prevalence in young animals, most likely due to their increased susceptibility as a result of greater bioavailability of lead and a more permeable blood–brain barrier (Wismer 2013). Additionally, the prevalence is higher in pets housed in older homes or buildings. Lead has not intentionally been added to most paint since 1978, although it has been estimated by the Centers for Disease Control that 74% of privately owned housing in the United States built before l980 still contains hazardous quantities of lead paint (Wismer 2013). Thus, animals kept in older homes have an increased risk of lead exposure from paint. Low socioeconomic status of a pet‐owning family is more likely to be associated with a high blood‐lead concentration in pets, although housing undergoing renovations in urban areas of “gentrification” is potentially hazardous. In one review of lead intoxication in cats, 84% of the cases involved exposure of the cats to old paint, most often as a result of home renovations (Knight and Kumar 2003).

Sources

Lead is used in an impressive array of products, including tank linings, piping, radiation shielding, paint pigments, inks, lead ammunition (shot and bullets), ballast and weights, solder, linoleum, wine bottle foil, lubricants, bearings, alloys, storage batteries, ceramics, plastics, electronic devices, leaded glass, stained‐glass framing, fishing gear, jewelry, and small toys (Wismer 2013). Animals can be intoxicated from lead‐contaminated soils, for example cats can ingest lead‐contaminated soil via grooming.

Kinetics

As for other metals, the bioavailability of lead following ingestion depends on its form. Elemental lead is less bioavailable than inorganic lead salts such as lead acetate or organic lead such as tetraethyl lead. Elemental lead is relatively insoluble in hard, basic water, but more soluble in acidic water, therefore elemental lead is more soluble, and therefore more bioavailable, in the acidic fluids of the stomach of mammals. Lead is actively transported across the GI tract using the same transport mechanism used for calcium absorption. This absorption mechanism explains the greater bioavailability of lead in immature, rapidly growing animals with an increased need for calcium. Irrespective of the form of lead, a significant amount of ingested lead is excreted in the feces without being absorbed (Wismer 2013).

Approximately 90% of absorbed lead is found in red blood cells, with small amounts bound to albumin or found in plasma as free lead. Within red blood cells, lead is associated with the cell membrane, hemoglobin, and possibly other cell components (Ufelle and Barchowsky 2019). Lead is widely distributed in soft tissues and bone serves as a long‐term storage site. The half‐life of lead is multiphasic due to redistribution within various compartments of the body (Gwaltney‐Brant 2004). For example, the half‐life of lead in whole blood is approximately 35 days, whereas in brain it is approximately 2 years. Lead can persist in bone for years. Enhanced bone remodeling can release lead into the blood and cause adverse effects. Elimination of absorbed lead can occur via sloughing of renal tubular epithelial cells via the bile or via pancreatic secretions (Gwaltney‐Brant 2004).

Toxicity

Few studies have determined the acute or chronic toxicity of lead for many species. The risk for lead intoxication is influenced not only by the amount and form of lead ingested, but species exposed, dietary factors, and size of ingested lead particles. The length of retention of lead particles in the GI tract varies among individuals within a given species and between species. Given the large number of variables that can affect the toxicity of lead, the availability of precise toxic or lethal doses is limited.

Mechanism of Action

Most cellular damage due to lead is caused by the ability of lead to substitute for a variety of polyvalent cations, especially calcium and zinc, in their binding sites (Garza et al. 2006). The role that metal ions play in biological systems are numerous and diverse. They serve as charge carriers, intermediates in catalyzed reactions, and structural elements in the maintenance of protein conformation. Metal transport, energy metabolism, apoptosis, ionic conduction, cell adhesion, inter‐ and intracellular signaling, and diverse enzymatic processes can all be affected. Lead produces oxidative damage to lipids and proteins as a result of release of iron, disruption of antioxidant mechanisms, and direct oxidative damage.

The neurotoxicity of lead is most likely due to such diverse mechanisms as lipid peroxidation, excitotoxicity (i.e., cell damage secondary to receptor overstimulation due to excitatory neurotransmitters such as glutamate), alterations in neurotransmitter synthesis, storage, and release, alterations in expression and functioning of receptors, interference with mitochondrial metabolism, interference with second messenger systems, and damage to astroglia and oligodendroglia.

The mechanism of lead‐induced altered GI mobility is not entirely clear, but it does not appear to be related to an effect of lead on peripheral nerves or calcium flux. Lead‐induced relaxation may be due to stimulation of adenylate cyclase activity resulting in an increase in intracellular cyclic adenosine monophosphate. Lead causes anemia by increasing erythrocyte fragility, delaying erythrocyte maturation and inhibiting heme synthesis. Heme synthesis is impaired as a result of aminolaevulinic acid synthetase, δ‐aminolevulinic acid dehydratase (ALAD), coproporphyrinogen decarboxylase, and ferrochelatase inhibition (Calello and Henritig 2019).

Clinical Effects

Signs

The primary organ systems affected are the GI, nervous, and hematopoietic systems. The most obvious and common signs reflect GI and CNS effects. Gastrointestinal signs often precede CNS signs and are predominant with chronic, low‐level exposure. CNS signs are more frequently observed following acute exposures and are more common in younger animals. Common signs include vomiting, diarrhea, anorexia, abdominal pain, regurgitation due to megaesophagus, lethargy, hysteria, seizures, and blindness. In intoxicated cats, central vestibular abnormalities such as vertical nystagmus and ataxia are reported (Wismer 2013). In a review of lead intoxication of cats, the most common clinical signs reported were anorexia, vomiting, and seizures (Knight and Kumar 2003.)

Laboratory

It is important to note that whole‐blood lead concentrations do not always correlate with the occurrence or severity of clinical signs. Diagnostic laboratory abnormalities are noted most frequently when the hematopoietic system is affected. The presence of five to 40 nucleated red blood cells (RBCs)/100 white blood cells without anemia strongly suggests lead exposure. However, the absence of nucleated RBCs does not rule out the diagnosis. RBC changes also include anisocytosis, polychromasia, poikilocytosis, target cells, hypochromasia, and basophilic stippling. The latter is often difficult to detect. A neutrophilic leukocytosis might be noted. In cats, elevated AST and ALP values are reported. Urinalysis can reflect mild nonspecific renal damage, glucosuria, and hemoglobinuria.

Diagnostics

Antemortem

Clinical signs associated with lead intoxication can be nonspecific, making a diagnosis more difficult. Radiographs might identify metallic objects in the GI tract. The absence of metal densities does not rule out metal exposure because metal objects may have been passed or exposure to lead was from a non‐radiodense form.

Diagnosis of lead exposure or intoxication is most directly made by measurement of whole‐blood lead. In contrast to the diagnosis of zinc intoxication, serum or plasma are not appropriate samples for lead analysis because lead associates with RBCs. Lead analyses are widely available through veterinary diagnostic laboratories. Fortunately, small sample sizes can be used; blood samples as small as 20 μl are often suitable. Whole‐blood lead concentrations consistent with lead exposure and/or intoxication are generally 0.20 ppm or greater (20 μg/dl or greater). There are no “normal” background blood lead concentrations in animals. Measurement of ALAD activity, blood zinc protoporphyrin, or free erythrocyte protoporphyrin concentrations are also good biomarkers of lead exposure, but these tests are not widely available (Gwaltney‐Brant 2004).

Postmortem

Postmortem diagnosis relies on an antemortem history of compatible clinical signs, detection of metallic particles or other forms of lead in the GI tract, and measurement of liver or kidney lead concentrations. Reported diagnostic liver or kidney concentrations are variable, but values of 4 ppm wet weight or greater in either tissue are likely to be significant. There can be significant differences in liver and kidney tissue concentrations in similar animals; as a consequence, it is often advisable to test both tissues.

Necropsy findings can include the observation of paint chips or lead objects in the GI tract. Intranuclear inclusion bodies in hepatocytes or renal tubular epithelial cells (intracellular storage form of lead) are considered highly suggestive. Cerebrocortical lesions can include spongiosis, vascular hypertrophy, gliosis, neuronal necrosis, and demyelination.

Differential Diagnoses

With the exception of CBC changes, clinical signs associated with lead intoxication are nonspecific and a number of differential diagnoses need to be considered. In dogs, the following diseases can mimic lead intoxication: canine distemper, infectious encephalitides, epilepsy, bromethalin, methylxanthine or tremorgenic mycotoxin toxicoses, nonsteroidal anti‐inflammatory drug toxicosis, heatstroke, intestinal parasitism, intussusception, foreign body, pancreatitis, and infectious canine hepatitis. In cats, degenerative or storage diseases, hepatic encephalopathy, infectious encephalitides, and organophosphorus/carbamate, bromethalin, or methylxanthine toxicosis need to be considered.

Management of Cases

Case management focuses on evacuation of the GI tract, stabilization of the patient, and reduction of lead body burden (Gwaltney‐Brant 2004). Typically, animals intoxicated by lead have not been exposed to a single dose of lead or developed signs immediately after a single exposure. Thus, gastric evacuation is not always indicated. The exception would be those cases in which a metallic object is detected in the stomach. In those cases, gastric lavage or endoscopy can be considered. Because a significant amount of lead might remain in the GI tract beyond the stomach, decontamination of the GI tract can be useful. This is accomplished using saccharide or saline cathartics such as sorbitol or sodium or magnesium sulfate. The advantage of using sodium or magnesium sulfate lies in the potential to form lead sulfate, which has relatively low bioavailability. However, use of sodium sulfate in combination with chelators such as calcium disodium ethylenediaminetetraacetic acid (CaNa₂EDTA) or succimer has not been shown to be more effective than a chelator alone. If animals present with neurologic symptoms such as seizures, control with a benzodiazepine can be tried. Seizure activity might suggest the presence of cerebral edema. This should be treated using mannitol and dexamethasone.

Chelation therapy may be indicated in symptomatic animals. The two chelators most commonly used are calcium disodium EDTA and succimer. D‐penicillamine and BAL have also been used to chelate lead in animals, but their use is associated with a number of possible adverse effects (Calello and Henritig 2019; Van Alstine et al. 1993). In human medicine, succimer has largely replaced the use of CaNa₂EDTA due to its efficacy, lack of adverse side effects, and ability to be given orally. If using EDTA, only the calcium salt should be used to avoid calcium chelation and resulting hypocalcemia (Wismer 2013). There are several significant disadvantages to the use of CaNa₂EDTA. It is potentially nephrotoxic, which can either induce renal dysfunction or exacerbate concurrent lead‐induced renal impairment. It has to be administered parenterally because oral administration of CaNa₂EDTA enhances the absorption of lead from the GI tract. Injections are painful and CaNa₂EDTA chelates important endogenous minerals such as zinc. Treatment periods of 5–10 days followed by a 3–5‐day “rest” period are recommended. Assessment of renal function every 2–3 days during chelation therapy is also recommended.

Succimer (dimercaptosuccinic acid, DMSA) is a newer chelating agent that has several advantages over CaNa₂EDTA. It can be given orally, which avoids the need for repeated intramuscular injections and potentially allows for in‐home treatment, it does not increase elimination of other essential minerals such as zinc, and it is not nephrotoxic. Succimer is more effective at removing lead from soft tissues compared to CaNa₂EDTA. Succimer decreases CNS lead concentrations more rapidly than CaNa₂EDTA (Gwaltney‐Brant 2004). As with CaNa₂EDTA use, the length of treatment should be based on clinical improvement and determination of blood lead concentrations. Whole‐blood lead should be determined following chelation to assess the need for additional chelation therapy. However, 3–5 days should be allowed for remaining lead to reequilibrate to obtain an accurate assessment of lead status. Succimer has been used successfully in dogs and cats (Knight et al. 2001; Ramsey et al. 1996).

Clinical improvement is likely to be more rapid (within 24 hours) following succimer use compared to CaNa₂EDTA. Neurologic signs may initially worsen in animals treated with CaNa₂EDTA. This is most likely due to CaNa₂EDTA‐induced mobilization of lead from bone in animals with chronic lead exposure, since acutely intoxicated animals would be expected to have lower bone lead concentrations. Combining CaNa₂EDTA and succimer does not appear to be more efficacious than CaNa₂EDTA or succimer alone. A comparison between CaNa₂EDTA and succimer is provided in Table 22.2.

Irrespective of what chelator is used, assessment of blood lead concentrations at the end of each rest period should dictate the length of time needed for chelation therapy. The goal is to chelate for the minimal amount of time necessary to resolve the intoxication (based on resolution of clinical signs and a decline in blood lead concentrations). There is evidence in mammals that the efficacy of chelation is improved when thiamine or antioxidants such as ascorbic acid are used in conjunction with chelators.

Table 22.2. Comparison of CaNa₂EDTA and succimer for the treatment of lead and zinc intoxications

| CaNa₂EDTA | Succimer
Tradenames | Calcium DisodiumVersenate (3M) 200 mg/mL | Chemet (Sanofi – Synthelabo) 100‐mg capsules
Routes of administration | Slow IV infusion, IM or SQ injection; dilution with saline or 5% dextrose needed if given IV | Oral
Advantages | Rapid absorption | Oral administration
| Can chelate lead and zinc | Not nephrotoxic
|  | Does not chelate essential minerals such as zinc, manganese, and copper
|  | More rapid clinical improvement in lead intoxication
|  | More effective at removing lead from soft tissues
Disadvantages | Need for repeated IM injections | Less effective chelation of zinc; efficacy uncertain in zinc intoxication
| Pain at injection site |
| Potential nephrotoxicity and therefore need to monitor renal function regularly | Regurgitation noted in cockatiels
| Chelation of essential minerals such as zinc, manganese, and copper with long‐term use |
| Potential to worsen CNS signs as a result of lead redistribution |

CNS, central nervous system; IM, intramuscular; IV, intravenous; SQ, subcutaneous.

Prognosis

The prognosis is favorable with treatment, although it is guarded in animals presenting with uncontrollable seizures. Signs should improve significantly within 24–48 hours of initiating chelation therapy.

MERCURY

Mercury is a cellular poison that disrupts multiple enzymes, proteins, and cellular membrane functions, affecting the respiratory tract, GI tract, and potentially the CNS. Mercury (Hg, CAS #7439‐97‐6, “quicksilver”) is a dense, silver‐white, odorless, heavy metal that is liquid at room temperature. The biggest risk is inhalation because when spilled or swept with a broom or vacuumed, it can break into very small droplets and in the air. When mercury volatizes at room temperature, it can accumulate indoors to levels that exceed safe airborne concentrations. Its vapor pressure increases with temperature; thus, airborne concentrations increase when it is heated. Even the small volumes found in devices available to the public represent relatively large amounts of elemental mercury. Elemental mercury vapor is heavier than air and can accumulate in poorly ventilated or low‐lying areas. This property can place animals at a greater risk because their breathing zone is closer to the ground (Caravati et al. 2008).

Sources and Formulations

Mercury is a naturally occurring element that is divided into three groups: elemental, organic, and inorganic. Elemental pet animal exposures occur through broken glass thermometers, barometers, and fluorescent light bults. Organic sources include topical agents (ammoniated mercury used to treat impetigo, psoriasis, and skin infections), seafood, and fish‐based pet food (methylmercury). Inorganic sources include button batteries (mercuric oxide).

Kinetics

The kinetics of the different forms of mercury vary considerably. Poorly absorbed from the GI tract, elemental mercury is absorbed mainly by inhaling volatilized vapor. It undergoes distribution to most tissues, with the highest concentrations found in the kidneys (Lieske et al. 2011). After elemental mercury is absorbed, it is oxidized in the tissues to inorganic forms. Blood concentrations decline initially with a rapid half‐life of approximately 1–3 days followed by a slower half‐life of approximately 1–3 weeks (Jonsson et al. 1999). The slow‐phase half‐life may be several weeks longer in persons with chronic occupational exposure (Lieske et al. 2011). After exposure to elemental mercury, excretion of mercury occurs predominantly through the kidney (Jonsson et al. 1999), and peak urine levels can lag behind peak blood levels by days to a few weeks; thereafter, for both acute and chronic exposures, urinary mercury levels decline with a half‐life of approximately 1–3 months (Jonsson et al. 1999; Lieske et al. 2011).

Less than 15% of inorganic mercury is absorbed from the human GI tract (Rahola et al. 1973); it is expected to be similar in other species. In contrast, inorganic mercury is well absorbed after inhalation or dermal exposure (Clarkson 1997). The half‐life of inorganic mercury in blood is similar to the slow‐phase half‐life of mercury after inhalation of elemental mercury. Excretion occurs by renal and fecal routes.

The fraction of methyl mercury absorbed from the GI tract is about 95% (Aberg et al. 1969; Clarkson 1997). Methyl mercury enters the brain and other tissues, and then undergoes slow dealkylation to inorganic mercury (Clarkson 1997). Dog pharmacokinetic studies indicate that methyl mercury declines in blood and the half‐life is approximately 49 days, with most elimination occurring through the feces (Lieske et al. 2011).

Mercury is not destroyed by metabolism but rather converted to different forms and oxidation states. The metabolism of mercury and mercury compounds appears to be similar for animals and humans, and involves an oxidation–reduction cycle. Inhaled mercury vapor is rapidly oxidized to the divalent form in red blood cells (Clarkson 1997). Oxidation of elemental mercury also occurs in the lungs of humans and animals, and some evidence suggests hepatic‐mediated oxidation. Animal studies have provided some data suggesting that the divalent inorganic mercury cation may be further reduced to elemental mercury (Clarkson 1997). Organic mercury compounds are also converted to divalent mercury by cleavage of the carbon–mercury bond with subsequent metabolism occurring via the oxidation–reduction cycle. Aryl mercury compounds (e.g., phenylmercury) undergo this conversion more readily than the short‐chain (methyl) mercury compounds.

Toxicity

Mercury generally poses a minimal risk when exposed orally or topically. Chronic or repeat exposures will increase the toxic levels, as well as the duration of clinical signs. When ingested, there is poor absorption in the GI tract. If mercury becomes aerosolized, injury to the lungs may occur, as well as other systemic effects. With larger amounts ingested, there is a greater likelihood of moderate toxicity. Repeat exposures can range from mild to moderate toxicity as well.

Mechanism of Action

When exposed topically, the most common sign is dermatitis. The severity of dermatitis may be influenced by the object/source. Signs like oral hemorrhage, pain, rubbing, or scratching at the exposure site may also be present.

Clinical Effects

Signs

Based on the type of exposure, clinical signs can vary. When inhaled, irritation to the lungs may occur, leading to dyspnea and respiratory function impairment. With larger ingestions, mercury can become systemically toxic, affecting red blood cells, kidneys, and the neurologic system. When ingested, with mercury's poor absorption capability, the most common signs seen are vomiting, diarrhea, inappetence, or anorexia. With acute exposures, the GI signs resolve quickly. When GI signs are prolonged, pursuing additional diagnostics will be warranted to determine if other organs are potentially affected, as well other causes of nonspecific GI signs. In severe cases, neurologic signs may be seen, including tremors, ataxia, CNS depression, and behavioral changes.

Laboratory

Mercury levels can be measured in blood, tissues, and urine. These diagnostics will be determined based on the type of animal, its concerns for public health, and whether the animal is deceased or alive. Blood chemistries and CBC should also be done, both a baseline and repeat laboratory work if more severe clinical signs are present.

Differential Diagnosis

A differential diagnosis may be difficult given the wide array of signs potentially seen. Other disease etiologies affecting target organs, including dermal etiologies, exposure to other heavy metals, obstruction, and/or exposure to some other toxicant, should all be considered. In the presence of neurologic signs, organophosphates, mycotoxins, and other possible neurologic etiologies should be considered.

Diagnostics

Antemortem

Blood chemistries, CBC, mercury levels, and radiographs can be performed.

Postmortem

Blood and tissues samples, including kidney (concentrations higher with chronic exposures) and brain.

Management of Exposure

GI signs being the most common, antiemetics, intravenous fluids, analgesics, and stomach protectants (i.e., sucralfate) should be administered. Emesis is contraindicated due to potential aerosolization and possible inhalation. Chelation therapy should be considered if the exposure has occurred recently. Dimercaprol can be used as a chelation agent. An important note: dimercaprol should not be used when treating a methylmercury because this could lead to redistribution of mercury back into the CNS (Bahri 2003).

Prognosis

In most cases, a favorable prognosis is likely. Once GI signs are controlled, and secondary dehydration assessed, the expectation is the animal will return to normal within a few days. In cases of chronic, repeat, or high concentration exposures, there is a greater likelihood of more serious signs developing, which can also be permanent. Death is a strong possibility if no treatment is done, treatment is started late, or signs are severe and the animal is unresponsive to treatment.

ZINC

Zinc intoxication is more commonly reported in dogs compared to cats. This is most likely due to canines' indiscriminate eating habits.

Sources and Formulations

Metallic zinc is commonly used to galvanize metals, such as iron and steel, to provide a protective coating to stop rust formation. Until 1982, United States pennies consisted mainly of copper (95%) and zinc (4%), but the copper‐clad pennies minted after 1982 contain 97% zinc and 2.5% copper (Barceloux 1999). Zinc is also used in a variety of medical formulations, pigments, wood preservatives, insecticides, and rubber. Zinc oxide ointments and creams can be licked from the skin following topical application or cause intoxication if the products are chewed and the contents swallowed (Talcott 2013).

Kinetics

The rate of absorption depends on the amount and form of ingested zinc. The acidity of the stomach provides an excellent environment for the quick release and dissolution of zinc from metallic objects (Talcott 2013). Once absorbed, zinc is distributed widely to tissues, including pancreas, liver, kidney, bone, muscle, brain, retina, and skin. In tissues, especially the pancreas, liver, kidney, intestinal mucosa, and brain, zinc is bound to metallothionein. Metallothionein is a low molecular weight, cysteine‐rich protein that has potent metal‐binding capabilities. Zinc has a high binding affinity for metallothionein, which may play an integral role in zinc metabolism. The major route of excretion of zinc is via the feces but there is some excretion via the pancreas.

Toxicity

Zinc is an essential metal, and animals and humans have the ability to regulate zinc effectively. Zinc is relatively nontoxic in animals as judged by their tolerance to dietary concentrations greater than 100 times the minimum recommended daily zinc requirement (Leonard and Gerber 1989). If dietary exposure is excessive and homeostatic metabolism fails, zinc toxicity can occur. In dogs, the ingestion of one penny is sufficient to cause intoxication. One report estimated that the toxic dose of zinc in the form of zinc oxide for dogs was 108 g of zinc (Breitschwerdt et al. 1986).

Mechanism of Action

Zinc is required for a large number of physiological processes, including bone formation, immunity, keratogenesis, reproduction, growth, vision, wound healing, brain development, normal functioning of the CNS, and many other physiological processes (Talcott 2013). Major pathophysiological mechanisms of zinc intoxication are attributed to direct and indirect toxic effects on the GI tract, liver, kidney, pancreas, red blood cells, and brain, although specific mechanisms for many of these effects have not elucidated. ln acute cases of zinc poisoning. Particularly when zinc salts are ingested, local corrosive effects occur in the GI tract followed by damage to the liver, kidney, and pancreas. The hemolytic anemia associated with zinc intoxication might be due to a direct damaging effect of zinc on RBC membranes. Zinc has been shown to cause acute pancreatic, hepatic, and renal failure, although underlying specific pathophysiological mechanisms have not been described (Talcott 2013).

Clinical Effects

Signs

In intoxicated dogs, the most common signs include anorexia, vomiting, diarrhea, lethargy, depression, pale mucous membranes, icterus, and orange‐tinged feces. Often metallic objects are noted on abdominal radiographs, although the absence of such findings does not rule out zinc intoxication. Arrhythmias and ST‐segment abnormalities have been reported (Talcott 2013).

Laboratory

In dogs, findings indicative of an oxidant‐induced hemolytic anemia predominant. These include Heinz body formation, target cells, spherocytosis, hemoglobinemia, hemoglobinuria, and bilirubinemia. Regenerative changes such as nucleated RBCs, basophilic stippling, and polychromasia might be noted.

Diagnostics

Antemortem

Antemortem diagnosis relies on a history of ingestion of zinc, the occurrence of compatible clinical signs (e.g., hemolytic anemia in conjunction with a metallic object in the GI tract), and measurement of zinc in serum samples. Serum zinc concentrations typically exceed 5 ppm and are often much higher (for dogs and cats a serum zinc reference range is 0.7–2.0 ppm). Because many rubbers can leach zinc, it is important to use appropriate serum tubes (i.e., royal blue top) for sample collection and submission or scrupulously avoid contact of the blood/serum samples with rubber (e.g., a plastic‐capped vial can be used to store and ship serum). Once exposure to zinc is stopped, follow‐up determinations of serum zinc concentrations might be useful.

Postmortem

A postmortem diagnosis relies on antemortem findings and measurement of zinc concentrations in appropriate tissue samples. Liver is the most commonly tested sample, although kidney and pancreatic tissue samples can also be used.

Differential Diagnoses

Differential diagnoses include immune‐mediated hemolytic anemia, Babesia, onion/garlic, naphthalene mothball, some mushrooms and acetaminophen intoxications, snake and brown recluse spider bites, caval syndrome, skunk spray, and numerous causes of GI signs.

Management of Exposures

The most important intervention is rapid removal of any identified zinc object by endoscopy or laparotomy. Severe hemolytic anemias might require blood transfusions. Fluid therapy and diuresis are important to both maintain hydration and minimize renal damage from hemoglobinuria. Although CaNa₂EDTA and D‐penicillamine can chelate zinc, their routine use is questionable, given the relatively rapid elimination of zinc. Once exposure to zinc is stopped, tissue and serum zinc concentrations drop rapidly. H2‐receptor blockers might help reduce stomach acidity and the rate of release of zinc from zinc objects, although rapid removal of the zinc object might make their use unnecessary. Frequent evaluation of packed cell volume and electrocardiograms is warranted. Periodic assessment of renal function might also be prudent.

Prognosis

The prognosis is good to guarded. In one retrospective study in dogs (N = 19), 17 dogs receiving treatment survived (one was euthanized without treatment and one was discharged but returned the next day in severe respiratory distress) (Gurnee and Drobatz 2007). Rapid removal of the source of zinc should result in progressive improvement over 2–3 days. The mean hospital stay in the retrospective study was 2 days. Multiple organ failure, disseminated intravascular coagulation, pancreatic disease, renal failure, and cardiopulmonary arrest are potential complications (Talcott 2013).

The author would like to thank Robert Poppenga for the previous edition of this chapter.

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23
Prescription Drugs

Jennifer Hopkins

INTRODUCTION

There are numerous prescription medications that can be found in homes with pets. This chapter discusses some of the most common and most problematic medications.

ALBUTEROL

Sources and Formulations

Albuterol (salbutamol) and albuterol sulfate are bronchodilators available as tablets (immediate‐ and extended‐release forms), oral syrups, liquids for nebulization, and aerosols for inhalation (Rosendale 2004a). Bronchodilators are used for the management of airway diseases such as asthma. Companion animals are most commonly exposed when they bite into pressurized inhalers or, less commonly, via accidental ingestion of tablet or liquid formulations.

Kinetics

Albuterol is rapidly absorbed via inhalation or ingestion. Albuterol crosses the blood–brain barrier and placenta; it is not known whether albuterol distributes into milk. Albuterol is metabolized to inactive metabolites in the liver and is excreted as metabolites and parent compound in the urine.

Mechanism of Action

The pharmacologic action of albuterol is due to stimulation of beta‐2‐adrenergic receptors on bronchial smooth muscle, causing bronchodilation (Mensching and Volmer 2007). In overdose situations, the beta‐2 selectivity is lost and beta‐1 receptors are also stimulated, resulting in increased rate and force of contraction of the heart. Peripheral vasodilation results in hypotension, potentiating tachycardia and increasing the likelihood of more severe cardiac arrhythmias such as premature ventricular contraction, atrioventricular block, etc. Stimulation of beta‐2 receptors on skeletal muscle results in muscle tremors. Hypokalemia can be a complication due to the beta‐2 receptor stimulation of the Na⁺/K⁺ pump that causes a transient decrease in serum potassium (Crouchley and Bates 2022).

Toxicity

Toxic doses for albuterol have not been established, but adverse clinical effects can be seen in some dogs at therapeutic dosages (0.05 mg/kg for dogs) (Rosendale 2004a). Animals biting into inhalers could have their entire contents expelled into the oral cavity and pharynx, resulting in exposures many times the therapeutic levels (Mensching and Volmer 2007).

Clinical Effects

Aerosolized products can have an almost immediate effect; tablets and liquids may have some delay in the onset of clinical signs.

Signs

Clinical signs of albuterol toxicosis include tachycardia or other arrhythmia, weakness, lethargy, tachypnea, aggression, agitation, hyperactivity, vomiting, and tremors (Mensching and Volmer 2007). Seizures, although uncommon, can occur. In some cases of animals presenting with severe hypotension, pulmonary edema has been noted (American Society for the Prevention of Cruelty to Animals Animal Poison Control Center [ASPCA APCC], unpublished data).

Laboratory

Hypokalemia and hypophosphatemia have been reported in dogs with albuterol toxicosis (Mensching and Volmer 2007).

Differential Diagnosis

Other central nervous system (CNS) and cardiovascular stimulants such as methylxanthines, amphetamines, cocaine, antidepressants, ethylene glycol, metaldehyde, pseudoephedrine, and phenylpropanolamine can cause signs resembling albuterol toxicosis.

Diagnostics

Plasma albuterol levels can be measured but require submission to a specialty laboratory, so they would not be helpful in making a prompt diagnosis.

Management of Exposures

The goals of management of albuterol toxicosis are control of clinical signs, control of heart rate, correction of electrolyte abnormalities, and supportive care until full recovery. Decontamination is inadvisable, and likely to be unrewarding, in cases involving aerosol or liquid formulations due to the rapidity of onset of clinical signs (Rosendale 2004a). Intravenous fluid therapy is key to providing cardiovascular support in patients with albuterol toxicosis. Diazepam or midazolam can be utilized first in mild cases to manage CNS stimulation because some tachycardia may be due to the agitated state of the patient. Propranolol is the beta‐blocker of choice in treating albuterol toxicosis and is considered a direct antagonist. It will control tachycardia that persists after CNS stimulation has been managed; additionally, since propranolol is a nonspecific beta‐blocker, it will assist in normalizing serum potassium and managing hypotension and the potential complication of pulmonary edema. Once the heart rate is within reasonable levels, the serum should be analyzed for hypokalemia and potassium supplementation administered as needed with caution used not to over supplement. Persistent hypotension after propranolol treatment should be corrected with vasopressors, not with aggressive fluid therapy, because of the risk of pulmonary edema.

Prognosis

Most animals receiving prompt and appropriate care will recover within 12 hours of exposure, but large overdoses may result in signs that last for 24–72 hours.

AMPHETAMINES

Sources and Formulations

Amphetamines are stimulant drugs available in prescription form as tablets, capsules, or patches. They can be immediate release products or delayed release. Some, such as Ritalin®, are a single amphetamine agent (methylphenidate); others, such as Adderall®, are a combination of several different amphetamine salts. Vyvanse® is a prodrug, lisdexamfetamine, that is metabolized to dextroamphetamine in the blood, which gives it extended‐release type activity.

Kinetics

Amphetamines are rapidly absorbed from the gastrointestinal tract and are able to enter the cerebrospinal fluid at up to 80% of plasma concentrations (Stern and Schell 2018). Amphetamines are primarily excreted in the urine unchanged, although there is some evidence that amphetamines undergo liver biotransformation in dogs.

Mechanism of Action

Amphetamines act to stimulate the CNS through the release of norepinephrine, dopamine, and serotonin in presynaptic terminals of neurons. The combination of increased catecholamine release and inhibition of reuptake causes both alpha and beta stimulation, resulting in vasoconstriction, hypertension, tachycardia, and CNS stimulatory signs (Stern and Schell 2018).

Toxicity

In general, mild signs can be seen as low as 0.1 mg/kg, with more significant signs expected over 0.6–0.8 mg/kg (Stern and Schell 2018).

Clinical Effects

Signs

Cardiovascular signs include hypertension, tachycardia, and tachyarrythmias; occasionally, bradycardia may be seen secondary to hypertension as a reflex response. CNS signs commonly include hyperactivity, agitation, mydriasis, and head bobbing; less commonly and at higher dosages, tremors and seizures can develop (Stern and Schell 2018). In cats, these stimulatory signs may be more difficult to discern – they may exhibit signs of staring, hiding, or behavioral changes, but will often still exhibit the cardiovascular signs despite the external CNS signs being more muted. Secondary concerns, especially due to uncontrolled CNS stimulation, include hyperthermia and development of disseminated intravascular coagulation (Stern and Schell 2018).

Differential Diagnosis

Other substances that can cause similar signs to amphetamine toxicosis include illicit drugs (methamphetamine, cocaine), methylxanthines (caffeine, chocolate), pseudoephedrine, ma huang, phenylpropanolamine (Proin®), nicotine, and serotonergic drugs (antidepressants/anxiolytics).

Diagnostics

Amphetamines can be detected in over‐the‐counter urine drug tests in cases of unknown exposure, although further investigation should be used with positive urine drug test results because there can be other agents that can cause false positives (e.g. trazodone, fluoxetine, pseudoephedrine, and buproprion, among others). Plasma samples can be obtained, especially for legal cases, and screened for amphetamine exposure (Stern and Schell 2018).

Management of Exposures

The goal of treatment is to prevent further absorption of the drug, control cardiovascular and CNS stimulation, and provide supportive care to prevent sequalae. In an asymptomatic animal, decontamination through emesis can be attempted for recent exposures. Activated charcoal can be administered to asymptomatic animals within several hours post exposure for extended‐release products. The preferred treatment for CNS stimulation in these cases is phenothiazines tranquilizers (acepromazine, chlorpromazine) due to their ability to inhibit the activity of dopamine in the CNS and their blockade of α‐adrenergic activity (Stern and Schell 2018). Dosages used for acepromazine for control of clinical signs associated with amphetamines are much higher than those recommended for sedation. If CNS signs are controlled but tachycardia remains, the addition of beta‐blockers should be considered to control arrythmias. For animals showing more classical serotonin syndrome signs of hyperactivity, hyperthermia, and tremors, cyproheptadine can be added to the treatment protocol. Intravenous fluid therapy should aim to correct electrolyte imbalances and provide management of blood pressure abnormalities to maintain renal perfusion and appropriate body temperature. Animals should be kept in a minimally stimulating environment. In the event of seizures, barbiturate anti‐epileptics or levetiracetam can be used for control; the use of benzodiazepines (midazolam and diazepam) is not recommended for treatment of amphetamine toxicosis due to the potential for increased paradoxical hyperactivity (Stern and Schell 2018).

Prognosis

Prognosis is good in animals with control of cardiovascular and CNS signs. Pets with underlying cardiac disease may be more susceptible to severe signs. Cause of death in these exposures is usually secondary to disseminated intravascular coagulopathy (DIC) or respiratory failure from untreated, prolonged signs (Stern and Schell 2018). In animals that fully recover, long‐term signs are not expected.

ANTIDEPRESSANTS/ANXIOLYTICS

Introduction

The use of psychotropic drugs to alter the behavior of humans and animals has dramatically increased in the last decade. The behaviors that these types of drugs are intended to alter include depression, anxiety, obsessive/compulsive behavior, and undesirable impulses such as smoking in humans. Increased usage of these drugs in human medicine means that accidental ingestion of these drugs is frequent in companion animals. Table 23.1 gives examples of the various classes of psychotropic drugs used in human and veterinary medicine.

Serotonin and Serotonin Syndrome

Serotonin is a neurotransmitter that appears to be extremely important in managing many CNS disorders and older drugs that targeted a variety of neurotransmitters (e.g., tricyclic antidepressants) have, in human medicine, largely given way to drugs that more selectively alter CNS serotonin levels, including selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs).

Enhancing serotonin levels in the CNS can result in dramatic and favorable alterations in behaviors of humans and animals. However, excessive levels of serotonin can result in a severe and potentially life‐threatening condition termed serotonin syndrome. Many CNS stimulants that primarily affect other neurotransmitters, such as norepinephrine and/or dopamine (e.g., amphetamines and cocaine), also have some degree of serotonergic action, so at least part of the clinical effects seen may be due to serotonin excess (Table 23.2). In humans, serotonin syndrome is most commonly seen when two different serotonergic drugs are administered simultaneously, or when insufficient time has elapsed between discontinuation of one class of serotonergic drug and institution of therapy with a different class of serotonergic drug. In dogs, serotonin syndrome has been associated with excessive ingestion of 5‐hydroxytryptophan as well as a variety of serotonergic drugs (Gwaltney‐Brant 2004a; Wismer 2000).

Table 23.1. Classes of antidepressants and anxiolytics

Tricyclic antidepressants

Amitriptyline (Elavil®)

Clomipramine (Clomicalm®)

Doxepin

Imipramine

Nortriptyline

Selective serotonin reuptake inhibitors

Citalopram (Celexa®)

Escitalopram (Lexapro®)

Fluoxetine (Prozac®)

Paroxetine (Paxil®)

Sertraline (Zoloft®)

Serotonin norepinephrine reuptake inhibitors

Desvenlafaxine (Pristiq®)

Duloxetine (Cymbalta®)
Venlafaxine (Effexor®)

Monoamine oxidase inhibitors

Phenylzine

Selegiline (Anipryl®)

Atypical antidepressants

Bupropion (Wellbutrin®)

Mirtazapine

Nefazodone

Trazodone

Vilazodone (Viibryd®)

Vortioxetine (Trintellix®)

Benzodiazepines

Alprazolam (Xanax®)

Diazepam (Valium®)

Lorazepam (Ativan®)

Clonazepam (Klonopin®)

Clinical Effects

Serotonin syndrome is characterized by a variety of effects, including altered mental status (agitation or depression, aggression, vocalization, seizures, etc.), altered neuromuscular activity (rigidity, myoclonus, tremors, hyperreflexia, ataxia, etc.), hyperthermia, autonomic derangements, and diarrhea. Death can be due to hyperthermia, respiratory compromise, or DIC.

Table 23.2. Mechanism of action of serotonergic drugs

Source: Chai and Boyer (2017) / with permission of Springer Nature.

Increase serotonin synthesis | Inhibit serotonin reuptake
L‐tryptophan | Tricyclic antidepressants
5‐hydroxytryptophan | Selective serotonin reuptake inhibitors
| Serotonin norepinephrine reuptake inhibitors
Increase serotonin release | Other serotonin reuptake inhibitors
Amphetamine | Amphetamine
Cocaine | Cocaine
Fenfluramine | Dextromethorphan
Reserpine | Meperidine (Demerol®)
Dextromethorphan | Nefazodone
| Tramadol
| Trazodone
Decrease serotonin metabolism |
Amphetamine (metabolites) |
Monoamine oxidase inhibitors |
Serotonin receptor agonist |
Buspirone (Buspar®) |
Lysergic acid diethylamide (LSD) |
Sumatriptan (Imitrex®) |

General Management of Serotonin Syndrome

Management of serotonin syndrome includes managing any severe CNS effects with diazepam or a phenothiazine; refractory seizures may require general anesthesia (Gwaltney‐Brant 2004a; Merola and Dunayer 2006; Wismer 2000). Once animals have been stabilized and severe signs managed (or in asymptomatic animals), decontamination can be attempted. If the animal has not already vomited, induction of emesis might be performed. Administration of activated charcoal is recommended in most cases and is especially important if extended‐ or sustained‐release products have been ingested. Due to its serotonin‐blocking effects, cyproheptadine is beneficial in managing agitation, hyperthermia, and vocalization and is considered a specific antagonist for serotonin syndrome. The drug may be administered orally, or crushed and administered in saline as a rectal enema in animals that cannot tolerate oral medications. Severe tachycardia may be managed with beta‐blockers such as propranolol. Fluid therapy is important to provide cardiovascular support and protect the kidney from hypotension‐related injury. Acid/base status should be monitored and managed as needed – most commonly, acidosis can be seen and managed with sodium bicarbonate therapy.

Differential Diagnosis

Other agents that may cause signs resembling serotonin syndrome (or have a serotonergic component themselves) include amphetamines, cocaine, methylxanthines, pseudoephedrine, albuterol, metaldehyde, ethylene glycol, strychnine, organophosphate or carbamate insecticides, and zinc phosphide.

Diagnosis

Most human hospitals can run quick screens for antidepressants and may be able to provide results immediately. Antidepressants can also be detected in blood and urine by a veterinary diagnostic laboratory. Tricyclic antidepressants are commonly detectable on over‐the‐counter urine drug tests. Some of the drugs listed above can cause false positives for amphetamines (buproprion, fluoxetine, trazodone).

Prognosis

The prognosis of serotonin syndrome is generally good if prompt veterinary medical care is obtained. In cases involving immediate‐release products, signs of serotonin syndrome usually resolve within 12–36 hours, while extended‐release (including controlled‐ and sustained‐release) products may have signs that persist up to 72 hours (Gwaltney‐Brant 2004a).

Tricyclic Antidepressants

Kinetics

Tricyclic antidepressants (TCAs) are rapidly absorbed from the gastrointestinal tract and widely distributed throughout the body. The half‐lives of these drugs vary considerably between individuals, and half‐lives can be extended during a toxicosis. Delayed gastric emptying and enterohepatic recirculation are features of TCA intoxication that can also prolong the clinical effects (Wismer 2000).

Mechanism of Action

Tricyclic antidepressants block the reuptake of norepinephrine and serotonin by the presynaptic neuron, resulting in increased levels of these drugs within the CNS. These drugs also have significant antihistiminic and cholinergic effects, as well as cardiac sodium channel blocking action, resulting in significant cardiovascular effects.

Toxicity

Many TCAs have narrow margins of safety, with signs of toxicosis possible at two to five times therapeutic doses. Amitriptyline at 15 mg/kg may be lethal to dogs. The oral lethal dosage of clomipramine is 100 mg/kg (Wismer 2000).

Clinical Effects

Signs of TCA intoxication may occur as soon as 30 minutes following exposure and include initial lethargy and ataxia that progresses to agitation, vocalization, hyperesthesia, hyperthermia, vomiting, tachycardia, hypotension, cardiac arrhythmia, dyspnea, pulmonary edema, seizures, coma, and death. Death due to cardiac arrhythmia may occur as early as 2 hours after ingestion in untreated animals (Wismer 2000).

Management

Management of TCA overdosage includes early decontamination of clinically stable animals. In addition to emesis and activated charcoal in asymptomatic animals, gastric lavage may be considered in cases with a large number of pills ingested, and a situation in which it can be safely performed with endotracheal intubation and sedation. Management of clinical signs would be as above for serotonin syndrome, but cardiac arrhythmias in TCA overdoses may be pronounced and require further treatment. Sodium bicarbonate should be considered in pets that are acidotic, hypotensive, or have arrythmias but should be instituted only if pH monitoring can be performed (Wismer 2000). Additionally, lipid therapy may be considered in more severe cases that are refractory to symptomatic care, especially those with cardiovascular symptoms such as hypotension (Harvey and Cave 2007).

Selective Serotonin Reuptake Inhibitors

Mechanism of Action

Selective serotonin reuptake inhibitors (SSRIs) are classed by function rather than structure; this class of drugs blocks the reuptake of serotonin by the presynaptic neuron, resulting in increased serotonin levels at the postsynaptic receptors.

Kinetics

Selective serotonin reuptake inhibitors are well absorbed orally and are highly protein‐bound. They tend to have rapid onsets of action, although delayed onset may occur when extended‐ or controlled‐release products are ingested (Gwaltney‐Brant 2004a).

Toxicity

At therapeutic levels, SSRIs have fewer histaminic, cardiovascular, and sedative side effects compared to TCAs or monoamine oxidase inhibitors (MAOIs); in overdose situations these effects, while present, tend to be less severe than the other two classes of antidepressants. At therapeutic and low overdose levels (<5 times therapeutic), these drugs tend to cause sedation; at higher doses, more severe signs, including CNS stimulation consistent with serotonin syndrome, may be seen.

Management

Because these agents tend to exert primarily a direct serotonin effect, the treatment outlined above for serotonin syndrome is the recommended management when overdosages occur. Sustained‐ or extended‐release products tend to have signs that may persist for up to 72 hours.

Serotonin Norepinephrine Reuptake Inhibitors

Serotonin norepinephrine reuptake inhibitors (SNRIs) act similarly to SSRIs to block serotonin reuptake but also block the reuptake of other amines, such as dopamine or norepinephrine. Venlafaxine capsules appear to be appealing to cats, who will readily ingest them (Merola and Dunayer 2006). Low dosages can cause lethargy and depression, while dosages over 4 mg/kg in dogs and 3.75 mg/kg in cats can cause more moderate to severe stimulatory signs (ASPCA APCC, unpublished data). The clinical effects of SNRI overdose include serotonin syndrome as well as potential cardiovascular stimulation, resulting in tachycardia or other cardiac arrhythmias. Management is the same as for SSRIs, but symptomatic treatment of cardiac arrhythmias may be needed.

Monoamine Oxidase Inhibitors

Monoamine oxidase is an enzyme that breaks down various amines, including epinephrine, dopamine, and serotonin. MAOIs therefore inhibit the breakdown of these amines, resulting in an increase in their concentrations both within the presynaptic neuron and at the synapse (Wismer 2000). Signs of MAOI overdose in companion animals include hypo/hypertension, tachycardia or other arrhythmias, depression, ataxia, agitation, hyperthermia, tremors, seizures, coma, and respiratory depression. The onset of signs may vary from 2 to 24 hours depending on dosage ingested and the form of the drug (immediate‐ vs. sustained‐release). Management is as for serotonin syndrome. It is recommended that animals ingesting large doses of MAOIs have liver enzyme values monitored through 6 weeks post exposure, as elevations in these values can sometimes occur with MAOI overdose (Wismer 2000).

Atypical (Novel) Antidepressants

The atypical, or novel, antidepressants comprise a class of drugs of varying structure and mechanism of action; essentially, they do not fit well into the previous categories and are lumped together as “atypical” (Wismer 2000). Signs expected from this class of antidepressant vary, but still tend to fall in line with signs seen with other antidepressants. Similarly, treatment of toxicoses will be the same as that of the other antidepressants outlined above.

Benzodiazepines

Mechanism of Action

This class of drugs are depressants that produce sedation to relieve anxiety. They are also used to reduce muscle spasms and seizures. They act through depression of the subcortical levels of the CNS and appear to exert their effects through increasing release and facilitating activity of gamma‐aminobutyric acid (GABA). There is also serotonin antagonist activity (Wismer 2000).

Toxicity and Clinical Effects

At therapeutic dosages, benzodiazepines do not exhibit significant side effects on the cardiovascular, respiratory, or autonomic nervous system. In overdoses, they can cause sedation, ataxia, hypotension, seizures, coma, and respiratory depression. There is a wide margin of safety for this drug class (Wismer 2000).

Management

The goal in treatment of benzodiazepine overdoses is to prevent significant CNS depression and cardiovascular (hypotension) and respiratory depression. Emesis can be performed quickly in an asymptomatic patient, but onset of signs is generally rapid. Activated charcoal for large ingestions can be considered in asymptomatic patients. Heart rate and blood pressure, respiratory status, and temperature should be monitored. Hypotension may be managed with intravenous fluid therapy. For pets with significant respiratory or CNS depression, flumazenil may be used. This is a specific reversal agent that binds to the benzodiazepine receptor to reverse sedative effects; it is considered in cases of respiratory depression and severe signs (Wismer 2000).

Differential Diagnosis

Other agents that may cause signs resembling CNS depression seen from benzodiazepines include alcohols, barbiturates, marijuana, ethylene glycol, muscle relaxants, and phenothiazine tranquilizers.

Diagnosis

Benzodiazepines are commonly detected on urine drug screens. False positives can occur (e.g., ibuprofen, sertraline). Serum testing for benzodiazepines is also available (Wismer 2000).

Prognosis

Prognosis is good for the majority of exposures. With smaller exposures, monitoring for significant signs may be all that is needed. For large exposures with symptomatic care, no long‐term effects are anticipated.

BACLOFEN

Sources and Formulations

Baclofen is a centrally acting skeletal muscle relaxant that is used to control spasticity and pain in humans with musculoskeletal disorders. In veterinary medicine, it has been used extra‐label for control of urethral resistance in treatment of urinary retention in dogs; however, due to the narrow margin of safety, use for this purpose is infrequent, and use is not recommended in cats (Khorzad et al. 2012).

Kinetics

Baclofen is well absorbed orally and can have a very rapid onset of action. Baclofen is lipid‐soluble and crosses the blood–brain barrier in overdose situations (but not at therapeutic levels) (Gwaltney‐Brant 2004b). Baclofen is excreted largely unchanged in the urine. The half‐life is dose‐dependent and increases significantly in overdose situations.

Mechanism of Action

At therapeutic levels, baclofen mimics GABA within the spinal cord, blocking excitatory responses to sensory input (Gwaltney‐Brant 2004b). In overdose situations, baclofen enters the CNS, where it inhibits substance P, a stimulatory compound within the brain stem. The mechanism of baclofen‐induced seizures is thought to be due to decreased GABA release from presynaptic neurons, causing excessive postsynaptic firing.

Toxicity

In dogs, clinical signs have occurred as low as 0.7 mg/kg, and deaths have occurred at 2.3 mg/kg, although the median ingested dose in those not surviving treatment was 14 mg/kg (Khorzad et al. 2012).

Clinical Effects

Clinical signs of baclofen toxicosis include vomiting, ataxia, vocalization, disorientation, depression, hypersalivation, weakness, recumbency, coma, hypothermia, hypotension or hypertension, bradycardia, hyperactivity, agitation, tremors, mydriasis, dyspnea, respiratory arrest, pulmonary edema, and death (Wismer 2004). Seizures and respiratory compromise secondary to paralysis of the diaphragm and intercostal muscles are the most life‐threatening signs. Often, animals will vacillate rapidly between depressive and stimulatory CNS signs.

Differential Diagnosis

Other compounds that can cause signs similar to baclofen include other CNS depressants (opioids, barbiturates, benzodiazepines, sleep aids such as zolpidem, etc.), ethylene glycol, isoxazole mushrooms, antidepressants, macrolide antiparasiticides (e.g., ivermectin, moxidectin, etc.), and marijuana. Agents that mimic the stimulatory signs include SSRIs and other serotonergic compounds, nicotine, amphetamines, and methylxanthines. Signs can also mimic other nontoxic differentials like tick paralysis or spinal trauma.

Diagnosis

Baclofen blood levels can be measured at a human hospital or veterinary diagnostic laboratory, although unless STAT results can be obtained, they may be of little value when dealing with the emergent patient.

Management

Treatment goals for baclofen exposures are decontamination, managing clinical signs, maintaining respiration, and supportive care. Decontamination (emesis and single dose of activated charcoal) can be considered in asymptomatic animals, but patients displaying even mild CNS effects may be at risk of aspiration so decontamination should be done with care. If the animal is already obtunded or comatose and requires intubation, gastric lavage may be considered for recent ingestions of a large number of pills. Patients developing respiratory compromise may need mechanical ventilation. Comatose animals should be monitored closely for respiratory insufficiency and hypothermia. Seizures generally respond to diazepam or midazolam, but the lowest dose necessary to control seizures should be used in order to prevent exacerbating the CNS depression that will follow seizure control. Intravenous fluid therapy is helpful in correcting hypotension and providing cardiovascular support and will also help enhance elimination of the drug (Khorzad et al. 2012). Vocalization and disorientation sometimes respond to cyproheptadine. Diphenhydramine may be helpful for control of more spastic, involuntary muscle movements. The use of lipid therapy should be considered for treatment of baclofen toxicosis and has shown promise in improvement of mentation in treated patients (Khorzad et al. 2012). Lipid therapy will also absorb some therapeutic compounds used for control of clinical signs into the same “lipid sink” as the baclofen, although levetiracetam will still be useful for seizure control in these cases.

Prognosis

Resolution of clinical signs can take up to several days in severe cases. Patients provided with prompt supportive care have a reasonable prognosis of recovery as long as adequate ventilatory support can be maintained. Patients experiencing seizures have a more guarded prognosis (Wismer 2004).

CARDIAC DRUGS

ACE Inhibitors

Sources and Formulations

Angiotensin‐converting enzyme (ACE) inhibitors include drugs such as enalapril, lisinopril, benazepril, and captopril. These drugs are used in human and veterinary medicine to manage heart failure or hypertension. These drugs are available as tablets and capsules alone or combined with other medication (e.g., diuretics).

Kinetics

ACE inhibitors are well absorbed orally. Food in the gastrointestinal tract can reduce the bioavailability of captopril by 30–40% (Kittleson 2005a). Some ACE inhibitors (e.g., enalapril and benazepril) are prodrugs that are converted to an active metabolite following absorption. In dogs, the half‐lives of benazepril and captopril are 3.5 and 2.8 hours, respectively. Enalapril has a slower onset of action (4–6 hours) but longer duration of action (12–14 hours) compared to benazepril and captopril (Kittleson 2005a). The half‐life of benazepril in cats is 16–23 hours. Half‐lives of all are increased in patients with renal failure.

Mechanism of Action

ACE inhibitors prevent the conversion of angiotensin I to angiotensin II by competing with angiotensin I for the ACE enzyme. The ACE enzyme has a higher affinity for ACE inhibitors than for angiotensin I and therefore binds ACE inhibitors preferentially. Decreased angiotensin II levels result in decreased aldosterone secretion and increased renin secretion, causing peripheral vasodilation.

Toxicity

Compared to other cardiac drugs, ACE inhibitors have a relatively wide margin of safety, with hypotension expected only at high doses. Generally, dosages equivalent to <20 mg/kg of lisinopril are not likely to cause any serious clinical problems in healthy adult dogs (ASPCA APCC, unpublished data).

Clinical Effects

The primary clinical effect of ACE inhibitor overdose is hypotension, which can result in nausea, vomiting, and weakness. A result of hypotension may be the development of refractory tachycardia.

Differential Diagnosis

Other causes of hypotension include primary cardiovascular disease, cardiac glycosides (drugs, plants, toads, fireflies), calcium channel blockers, nitroglycerine, alpha‐2 agonists (e.g., amitraz, xylazine), alpha‐adrenergic blockers (prazosin, doxazosin), imidazoline decongestants, beta‐blockers, local anesthetic agents, high doses of diuretics, minoxidil, pimobendan, and muscarinic mushrooms.

Diagnosis

Serum or plasma levels of ACE inhibitors are not readily available. Diagnosis of toxicosis is based on history and clinical signs.

Management

Large ingestions of ACE inhibitors should be managed with early decontamination (emesis followed by activated charcoal) and monitoring for hypotension. Patients developing hypotension should be treated with intravenous fluids to assist in maintaining blood pressure. In refractory cases, vasopressor therapy may need to be instituted.

Prognosis

The prognosis for patients ingesting overdoses of ACE inhibitors is excellent because serious consequences are rare.

Beta‐Blockers

Sources and Formulations

Beta‐adrenergic blockers (beta‐blockers) include propranolol, atenolol, metoprolol, carvediolol, esmolol, sotalol, and others. They are commonly used in human populations and while there are no veterinary‐approved beta‐blocking agents, they are also used extra‐label for cardiac treatment in animals.

Kinetics

Oral absorption of beta‐blockers is variable. Propranolol is well absorbed after oral administration but is only 2–27% bioavailable in dogs due to rapid first‐pass metabolism in the liver and has a half‐life of 0.77–2 hours in dogs. Atenolol is absorbed rapidly and is about 90% bioavailable in cats, with a half‐life of 3.2 hours in dogs and 3.7 hours in cats. Intravenous administration of esmolol and propranolol will result in rapid distribution; propranolol is highly lipid soluble and crosses the blood–brain barrier, whereas esmolol will not distribute into the CNS. Metoprolol is rapidly absorbed from the gastrointestinal tract in humans, has about 50% bioavailability after first‐pass metabolism, and will cross into the blood–brain barrier with a half life of 1.3 hours in cats and 1.7 hours in dogs. Metabolism and excretion also vary by agent; esmolol is metabolized in the blood by esterases into inactive metabolites, metoprolol is metabolized in the liver and excreted in the urine, atenolol undergoes minimal hepatic metabolism and is excreted largely unchanged in the urine and feces, and propranolol is metabolized in the liver and has less than 1% unchanged dose excreted in the urine (Kittleson 2005b).

Mechanism of Action

Beta‐blockers are competitive antagonists of either beta‐1, beta‐2, or both receptors. Propranolol blocks both beta‐1 and beta‐2 adrenergic receptors in the myocardium, bronchi, and vascular smooth muscle, resulting in decreased blood pressure and decreased sinus node rate. Atenolol and metoprolol are specific beta‐1 antagonists, although at high dosages specificity may be lost and beta‐2 blockage can occur (Kittleson 2005b).

Toxicity

The toxicity of beta‐blockers will vary depending on the medication ingested. For animals with pre‐existing cardiac disease, even therapeutic dosing may put them at risk for development of clinical signs (ASPCA APCC, unpublished data).

Clinical Effects

With overdoses of beta‐blockers, clinical signs include bradycardia, heart block, and hypotension. Propranolol can cause ventricular arrythmias (Kittleson 2005b).

Differential Diagnosis

Other causes of hypotension and/or bradycardia include those listed under ACE inhibitors.

Management

The goal of management is to provide decontamination if appropriate as well as to prevent or treat hypotension and cardiac effects. Emesis and activated charcoal can be considered for recent exposures to a large number of pills or extended‐release products. For hypotension, balanced crystalloid fluids can be started and rates titrated to affect. Vasopressor therapy can be added for refractory hypotension. For bradycardia, atropine can be considered. Pets should be monitored for rare occurrences of hypoglycemia and supplementation should be provided accordingly (Rotella et al. 2020). Rarely, hyperkalemia can be seen and should be managed with insulin therapy.

Prognosis

Prognosis with appropriate therapy is good in otherwise healthy animals.

Calcium Channel Blockers

Sources and Formulations

Calcium channel blockers include amlodipine, verapamil, diltiazem, nifedipine, and nimodipine. These drugs have been used to manage a variety of cardiovascular disorders in human and veterinary medicine.

Kinetics

Calcium channel blockers are rapidly absorbed from the gastrointestinal tract and undergo a significant first‐pass effect (Roder 2004b). These drugs are metabolized in the liver and metabolites are excreted through the urine. The half‐life of different drugs varies: the half‐life of diltiazem in cats is 1–2 hours and for verapamil in dogs is 1.8–2.5 hours, while the elimination half‐life of amlodipine is much longer, with a range of 7–30 hours in dogs and 53 hours in cats (Kittleson 2005c).

Mechanism of Action

Calcium channel blockers prevent the opening of voltage‐gated calcium channels within the heart, slowing the influx of calcium into the myocardiocyte and inhibiting calcium‐dependent processes in the myocardium (Atkins and Ames 2018; Roder 2004b). This results in coronary and peripheral vasodilation, decreased cardiac contractility, and decreased activity of cardiac pacemaker nodes. The net effect is slowing of heart rate and lowering of blood pressure. These effects are exaggerated in overdose situations.

Toxicity

Calcium channel blockers have a narrow margin of safety and signs may be seen even within therapeutic dose ranges. Exposures above a therapeutic dosage range should be treated (Holder 2000).

Clinical Effects

The clinical effects of calcium channel blockers include bradycardia and hypotension, resulting in weakness, recumbency, coma, vomiting, depression, and disorientation (Roder 2004b). Severe cardiac conduction disturbances (e.g., second‐ and third‐degree atrioventricular blockade) and pulmonary edema are possible. Hyperglycemia and metabolic acidosis may also occur (Holder 2000).

Differential Diagnosis

Other causes of hypotension and/or bradycardia include those listed under ACE inhibitors.

Management

Prompt decontamination of recent ingestions is recommended, including induction of emesis and administration of activated charcoal in asymptomatic patients. Patients should be monitored for a minimum of 6 hours following ingestion of immediate‐release products and 12 hours following ingestion of sustained‐, controlled‐ or extended‐release products; for amlodipine exposures, monitoring is recommended for 24 hours. Mild hypotension and bradycardia may be manageable with intravenous fluids alone, but more severe cardiovascular effects need more intensive treatment, including administration of intravenous calcium salts. Care must be taken with treatment of hypotension in these cases, as non‐cardiogenic pulmonary edema has been reported after amlodipine overdoses (Holder 2000) and presents a complication for fluid therapy resuscitation and management, therefore aggressive fluid therapy is not recommended. Treatment for refractory cases includes vasopressor agents (dopamine, dobutamine, norepinephrine, etc.), atropine or isoproterenol for bradycardia, and control of seizures with anti‐epileptics and hyperglycemia with insulin, if present (Holder 2000). Intravenous lipid solutions have been reported to be helpful in managing severe toxicosis from calcium channel blockers (Cave and Harvey 2009).

Prognosis

Prognosis will depend on dose ingested, time to presentation for veterinary care, severity of clinical signs, and response to therapy. Patients with poor response to appropriate therapy have a guarded to poor prognosis.

Cardiac Glycosides

Sources and Formulations

Cardiac glycoside drugs include digoxin and digitoxin. Cardiac glycoside compounds are also found in a variety of plants, including foxglove (Digitalis purpura), oleander (Nerium oleander), and lily of the valley (Convallaria spp.) (see Chapter 20), as well as the secretions of several species of Bufo toads. The use of these drugs in veterinary medicine is no longer as frequent in the management of heart failure.

Kinetics

Cardiac glycosides are well absorbed orally. Protein binding varies, with digitoxin being highly protein‐bound and digoxin having low protein binding (Roder 2004b). These drugs are metabolized in the liver.

Mechanism of Action

Cardiac glycosides interfere with normal functioning of Na+/K+‐ATPases, increasing intracellular sodium and extracellular potassium. The final result is an increase in force of contraction, an increase in cardiac output, and a decrease in heart rate.

Toxicity

Cardiac glycosides have a very narrow margin of safety, and adverse effects with chronic therapeutic use are not uncommon. Doses two to three times therapeutic doses can cause significant adverse cardiovascular effects (Roder 2004b).

Clinical Effects

Signs

Clinical signs of cardiac glycoside toxicosis include vomiting and diarrhea as well as cardiac effects (Roder 2004b). Cardiac effects can be seen without any initial gastrointestinal signs and can include just about any known arrhythmia. Clinical signs associated with the cardiovascular effects in acute intoxications include weakness, collapse, pale or gray mucous membrane color, hypotension, hypothermia, coma, and death. Pulmonary edema and renal failure may occur secondarily.

Laboratory

Serum potassium should be monitored because hyperkalemia is commonly seen with cardiac glycoside toxicosis.

Differential Diagnosis

Other causes of cardiac dysfunction include those listed under ACE inhibitors.

Diagnosis

Diagnosis is based on history of exposure and clinical signs. Most human hospitals can run serum digoxin levels on a STAT basis.

Management

Prompt decontamination of recent ingestions is recommended, including induction of emesis and administration of activated charcoal. Patients should be monitored a minimum of 8 hours following ingestion. There is a wide range of arrhythmias that can be seen with cardiac glycoside toxicosis so the cardinal rule of treatment is to “treat the patient, not the poison,” and manage the arrhythmias symptomatically (e.g., atropine for bradyarrhythmias and lidocaine for tachyarrythmias). For patients that are not responding to appropriate antiarrhythmic therapy, the use of digoxin immune Fab may be considered (see the section on antidotes in Chapter 8). Management of hyperkalemia may include the use of potassium‐free fluids and/or insulin therapy.

Prognosis

The prognosis will depend on the dose ingested, time to presentation for veterinary care, severity of clinical signs, and response to therapy. Patients with poor response to appropriate therapy have a guarded to poor prognosis.

Pimobendan

Sources and Formulations

Pimobendan (Vetmedin ®) is commonly prescribed in veterinary medicine for the treatment of congestive heart failure, usually in combination with ACE inhibitors or diuretics (Reinker et al. 2012). It is available as tablets or injectable and oral solutions.

Kinetics

Peak concentrations occur in 1–4 hours after administration. It undergoes oxidative demethylation into an active metabolite, which is then conjugated and excreted in the feces. Terminal half‐life of the parent compound is about 0.5 hours and of the active metabolite is 2 hours, with plasma concentrations below detection by 4 and 8 hours, respectively (Reinker et al. 2012).

Mechanism of Action

Pimobendan is a phosphodiesterase III inhibitor and calcium sensitizer that acts as an inodilator. It typically decreases heart rate while enhancing cardiac contractility through increased calcium sensitivity without increasing myocardial oxygen consumption and acts as a vasodilator (Reinker et al. 2012).

Toxicity

The margin of safety with pimobendan appears to be wide. Dose‐dependent effects are expected, however there is a range of individual responses to overdoses of pimobendan, with some animals remaining subclinical and some exhibiting more severe effects. Animals with pre‐existing cardiac disease may be more likely to have severe sequala from overdoses (Reinker et al. 2012).

Clinical Effects

The most common effects seen after overdose are hypotension and tachycardia. In some cases, a transient heart murmur or arrhythmias may develop. Additionally, hypertension may be seen (Reinker et al. 2012).

Differential Diagnosis

Exposure to other hypotensive agents, as discussed above, would cause similar clinical signs to pimobendan.

Management

Due to the rapid nature of action, early decontamination should be considered only for high dosages in recent ingestions in asymptomatic animals. Hypotension can be treated with intravenous balanced crystalloids and vasopressors may be considered for refractory cases. Electrocardiogram monitoring should be instituted in symptomatic patients. Fluid therapy rates should be closely monitored in pets with pre‐existing cardiac disease.

Prognosis

With treatment and monitoring, prognosis for healthy animals is excellent; in animals with underlying cardiac disease, prognosis is generally fair to good (Reinker et al. 2012).

5‐FLUOROURACIL

Sources and Formulations

5‐Fluorouracil is a pyrimidine analog in the class of antineoplastic dugs termed antimetabolites. 5‐Fluorouracil is used to treat a variety of cancers in human and veterinary medicine. Topical creams and solutions are used to treat dermal disorders such as solar keratosis in humans (Roder 2004a).

Kinetics

5‐Flurouracil is well‐absorbed both orally and following topical application.

Mechanism of Action

5‐Fluorouracil inhibits DNA synthesis, resulting in interference with cell division, so it is more toxic to rapidly dividing cells of the gastrointestinal tract and bone marrow (Albretsen 2001). Metabolites of 5‐fluorouracil are thought to contribute to the seizures that are frequently seen with 5‐fluorouracil toxicosis in dogs (Yamashita et al. 2004).

Toxicity

The minimum lethal dosage of 5‐fluorouracil in dogs is 20 mg/kg, although serious clinical effects can be seen at dosages well below this (Albretsen 2001). Any exposure should be considered potentially serious and merit evaluation of the patient by a veterinarian. As of September 2022, the US Food and Drug Administration has asked manufacturers to add a warning to labels for topical fluorouracil creams that states “May be fatal if your pet licks or ingests. Avoid allowing pets to contact this tube or your skin where fluorouracil has been applied. Store and dispose out of the reach of pets” (US Food and Drug Administration 2023).

Clinical Effects

Clinical signs in dogs exposed to 5‐fluorouracil include vomiting, lethargy, tremors, seizures, cardiac arrhythmias, and respiratory depression (Albretsen 2001). Severe vomiting can begin within minutes of exposure; seizures may occur quickly or can be delayed up to several hours. Patients surviving the acute crisis may develop evidence of bone marrow suppression and/or alimentary tract mucosal necrosis within days to weeks of exposure.

Differential Diagnosis

Other toxicants that can cause acute onset of signs similar to 5‐fluorouracil include CNS stimulant drugs (amphetamines, cocaine, antidepressants, etc.), organophosphorous or carbamate insecticides, strychnine, methylxanthines, ethylene glycol, nicotine, and zinc phosphide.

Diagnosis

Diagnosis is based on history of exposure and clinical signs. Serum levels of 5‐fluorouracil are not readily available.

Management

Management of 5‐fluorouracil toxicosis entails managing life‐threatening clinical signs, seizure control, gastrointestinal protection, supportive care, and monitoring for bone marrow suppression. Decontamination is indicated only in recent, asymptomatic exposures. Once clinical signs develop, decontamination is less rewarding and may add to the risk of aspiration. Seizures are often refractory to diazepam alone, but a dose of pentobarbital followed by a constant‐rate‐infusion of diazepam has been found to be helpful in managing seizures. Additionally, levitracetam should be considered as a primary anti‐epileptic in these cases. Antiemetics should be used to manage vomiting, and gastrointestinal protectants should be provided. Cardiac arrhythmias should be managed as they occur. General supportive care includes intravenous fluid administration, pain management (patients experiencing alimentary tract necrosis find them quite painful), thermoregulation, and antibiotics to prevent infection from the eroded gastrointestinal mucosa. Of importance to note is that metronidazole can reduce clearance of 5‐fluorouracil and increase its toxicity, so use for control of diarrhea should be avoided. Serum chemistry, complete blood count, acid/base, and electrolytes should all be monitored. Animals that survive beyond a few days should have serial complete blood counts twice weekly for 4 weeks to detect evidence of bone marrow suppression. Patients with bone marrow suppression may need to be treated with bone marrow stimulants (e.g., filgrastim for leukopenia).

Prognosis

The prognosis for patients with 5‐fluorouracil exposures is guarded, and mortality rates of >50% have been reported, despite intensive care (Albretsen 2001). Positive prognostic indicators include no seizures or seizures that respond well to therapy. Negative prognostic indicators include being a cat and poor response to anticonvulsant therapy.

ORAL DIABETIC MEDICATIONS

Sulfonylureas

Sources and Formulations

Sulfonylureas are oral hypoglycemic drugs used in the treatment of diabetes in human and veterinary medicine. Included in this class are glimepiride, glipizide, glyburide, chlorpropamide, and tolazamide (Rosendale 2004b).

Kinetics

Sulfonylureas are rapidly absorbed from the gastrointestinal tract and are highly protein‐bound. They are metabolized in the liver and excreted via the urine. Half‐life information in nonhumans is not available but glimepiride and glyburide appear to have duration of action of approximately 24 hours in cats, while glipizide has a hypoglycemic effect in cats lasting less than 60 minutes at therapeutic levels (Rosendale 2004b).

Mechanism of Action

Sulfonylureas are thought to act by triggering the endogenous release of insulin and may enhance the binding of insulin to receptors (Rosendale 2004b).

Toxicity

In normoglycemic animals, hypoglycemia can be seen at therapeutic doses (Rosendale 2004b).

Clinical Effects

Clinical signs of sulfonylurea toxicosis are primarily those of hypoglycemia. Liver dysfunction has been reported with therapeutic use of sulfonylureas in cats, but whether liver injury would occur following acute overdose is not known.

Signs

Vomiting, anorexia, lethargy, ataxia, weakness, behavioral changes, seizures, and coma can occur in patients experiencing hypoglycemia. Icterus, vomiting, and diarrhea were reported in cats experiencing adverse hepatic effects from glipizide (Rosendale 2004b).

Laboratory

Hypoglycemia is the primary laboratory abnormality expected with sulfonylurea overdose.

Differential Diagnosis

Other causes of hypoglycemia that should be considered include juvenile hypoglycemia, xylitol (dogs), alpha‐lipoic acid (dogs), primary liver disease, sepsis, iatrogenic insulin overdose, and insulinoma.

Diagnosis

Sulfonylurea serum levels can be determined by a veterinary diagnostic laboratory, but turnaround times can be long, making determination of serum levels of little use for diagnosing the acute patient.

Management

Management of sulfonylurea overdose should focus on managing serious clinical effects (coma, seizures), normalization of serum glucose, decontamination, and monitoring for return of hypoglycemia. Because of the potential for rapid onset of signs of hypoglycemia, emesis should only be induced in a hospital setting once serum glucose levels have been determined and, if necessary, corrected. Monitoring of serum glucose should be done for a minimum of 24 hours following exposure. Small, frequent meals may help in the management of mild intoxications. As needed, intravenous dextrose solutions should be administered to maintain normal blood glucose in patients experiencing more severe hypoglycemia. Seizing animals may also require diazepam or midazolam.

Prognosis

Most cases of sulfonylurea overdose will have a good prognosis provided prompt veterinary care has been obtained. Patients with protracted hypoglycemia prior to presentation have a more guarded prognosis.

Metformin

Sources and Formulations

Metformin is a biguanide antidiabetic agent with the trade name Glucophage®. Metformin is used to treat noninsulin‐dependent diabetes mellitus (type 2) in humans and is used extra‐label in cats for diabetes management and for horses for adjunctive treatment of equine metabolic syndrome (Rosendale 2004b).

Kinetics

Metformin is slowly absorbed in humans and variably absorbed in cats. Metformin is eliminated unchanged in the urine (Rosendale 2004b). The half‐life of metformin in cats is 12 hours.

Mechanism of Action

Metformin is thought to lower blood glucose by improving peripheral sensitivity to insulin and increasing insulin uptake by peripheral cells (Rosendale 2004b). Unlike sulfonylureas, metformin does not increase serum insulin levels.

Toxicity

No toxic doses exist for dogs or cats ingesting metformin; doses ranging from 58 to 170 mg/kg in dogs and cats did not result in hypoglycemia (Heller 2007). For dosages over 100 mg/kg, hypoglycemia and lactic acidosis are possible (ASPCA APCC, unpublished data); however, unlike sulfonylureas, ingestion of metformin is not expected to typically cause hypoglycemia in euglycemic animals (Rosendale 2004b). Animals with inadequate caloric intake or with recent excessive exercise could be at risk for hypoglycemia. Although gastrointestinal signs have been seen with metformin overdoses in animals, serious life‐threatening signs have not been reported.

Clinical Effects

Signs

Clinical signs of metformin are primarily related to gastrointestinal upset: nausea, vomiting, abdominal bloating, diarrhea, flatulence, and anorexia (Heller 2007).

Laboratory

Hypoglycemia is not anticipated with metformin exposures in most animals. Animals in a negative energy balance or those with recent excessive exercise without adequate food intake could develop hypoglycemia following metformin exposure (Rosendale 2004b). Lactic acidosis has been reported in humans taking metformin and in severe overdose situations, but this condition is rare in canine cases of high doses of metformin.

Differential Diagnosis

Differential diagnoses for signs of metformin exposure include other causes of gastrointestinal upset such as dietary indiscretion, infectious gastroenteritis, gastrointestinal foreign body, etc.

Diagnosis

Metformin serum levels can be measured, but because metformin is not expected to cause serious issues, measuring is not generally recommended.

Management

Management of metformin overdoses primarily involves managing gastrointestinal upset. Antiemetics can be utilized in vomiting patients. Decontamination is recommended in large exposures, including induction of emesis if within 1 hour of exposure followed by administration of activated charcoal. Animals appearing to be in a negative energy balance (e.g., emaciated, cachexic) should have blood glucose monitored; small frequent meals may help keep blood glucose within normal limits for these animals and for animals with dosages over 100 mg/kg. If hypoglycemia does develop, intravenous dextrose supplementation should be instituted. With large ingestions, monitoring for lactic acidosis may be prudent in symptomatic animals.

Prognosis

Most cases develop no more than gastrointestinal upset that is responsive to symptomatic care, so the prognosis in most cases is excellent.

ACKNOWLEDGMENTS

The author would like to thank Sharon Gwaltney‐Brant for her contributions to the first edition of this chapter.

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Roder, Joseph D. 2004a. Antineoplastics. In Veterinary Clinical Toxicology, edited by Konnie H Plumlee, pp. 299–302. St. Louis: Mosby.

Roder, Joseph D. 2004b. Cardiovascular drugs. In Veterinary Clinical Toxicology, edited by Konnie H Plumlee, pp. 307–309. St. Louis: Mosby.

Rosendale, MA. 2004a. Bronchodilators. In Veterinary Clinical Toxicology, edited by Konnie H Plumlee, pp. 305–306. St. Louis: Mosby.

Rosendale, MA. 2004b. Diabetes medications. In Veterinary Clinical Toxicology, edited by Konnie H Plumlee, pp. 311–319. St. Louis: Mosby.

Rotella, Joe‐Anthony, Greene, Shaun L, Koutsogiannis, Zeff et al. 2020. Treatment for beta‐blocker poisoning: a systematic review. Clinical Toxicology 58(10):949–983.

Stern, Laura and Schell, Mary. 2018. Management of attention‐deficit disorder and attention‐deficit/hyperactivity disorder drug intoxication in dogs and cats: an update. Veterinary Clinics of North America: Small Animal Practice 48(6):959–968.

US Food and Drug Administration. 2023. Fluorouracil and Pet Safety. https://www.fda.gov/consumers/consumer‐updates/fluorouracil‐and‐pet‐safety Accessed 12/20/23.

Wismer, Tina A. 2000. Antidepressant overdoses in dogs. Veterinary Medicine 95(7):520–525.

Wismer, Tina A. 2004. Baclofen overdose in dogs. Veterinary Medicine 99(5):406–410.

Yamashita, Kazumasa, Yada, Hideaki, and Yariyoshi, Toshihiko. 2004. Neurotoxic effects of alpha‐fluoro‐beta‐alanine (FBAL) and fluoroacetic acid (FA) on dogs. Journal of Toxicological Sciences 29(2):155–166.

24
Over‐the‐Counter Drugs

Jenny Schuett

INTRODUCTION

There are many medications found in most of our households. We use them for the treatment of aches and pains, for allergies and colds, and for prevention (vitamins). Pets can easily be exposed to a dropped pill or chew on entire bottles of medication.

ACETAMINOPHEN

Sources and Formulations

Acetaminophen (Tylenol®, non‐aspirin pain reliever, APAP) is a synthetic non‐opiate derivative of p‐aminophenol. Acetaminophen is available as an over‐the‐counter drug found in a variety of medications. When dealing with a potential exposure to acetaminophen, it is important to confirm the exact ingredients in a product, since many medications have nonsteroidal anti‐inflammatory drugs (NSAIDs, e.g., ibuprofen) rather than acetaminophen as their “non‐aspirin” component. Additionally, many of the other ingredients found in combination products (e.g., antihistamines, decongestants) may also contribute to the toxicosis, and their potential adverse effects need to be addressed (see Figure 24.1). Acetaminophen is used as an analgesic and antipyretic drug but has little anti‐inflammatory action. Most companion animals are exposed through accidental ingestion of medication, although many cats are poisoned when owners are unaware of the hazards of administering acetaminophen to cats.

Kinetics

Acetaminophen is rapidly and almost completely absorbed from the gastrointestinal (GI) tract (Sellon 2013). Peak plasma levels are seen at 10–60 minutes for regular release products and at 60–120 minutes for extended‐release forms. At therapeutic dosages, acetaminophen is metabolized in the liver by sulfation and glucuronidation to nontoxic metabolites that are eliminated in the urine. Because cats cannot effectively glucuronidate acetaminophen, they are particularly sensitive to its toxic effects. The serum half‐life in dogs and cats is dose‐dependent, increasing as the ingested dosage increases.

Mechanism of Action

Pharmacologic Action

The exact mechanism of pharmacologic action of acetaminophen is unknown but it is believed to act primarily in the central nervous system (CNS) to increase the pain threshold through cannabinoid receptors, and it may also inhibit chemical mediators that sensitize the pain receptors to mechanical or chemical stimulation (Ottani et al. 2006). The antipyretic activity of acetaminophen is achieved by blocking the effects of endogenous pyrogens by inhibiting prostaglandin synthesis through inhibition of cyclooxygenase 2 or 3 (Grosser et al. 2023).

Mechanism of Toxicity

Acetaminophen itself is of low toxicity. When normal hepatic sulfation and glucuronidation pathways are saturated (e.g., in overdose situations), cytochrome P450 enzymes convert acetaminophen to the oxidative metabolite, N‐acetyl‐para‐benzoquinoneimine (NAPQI). Intracellular glutathione acts as a scavenger to conjugate and neutralize NAPQI, but when glutathione stores are depleted, NAPQI binds to sulfhydryl groups on tissue macromolecules, leading to hepatocellular necrosis. At very high doses, the same mechanism occurs in renal tubules, resulting in nephrotoxicity.

Figure 24.1. Cold medication formulas that contain acetaminophen plus antihistamines, decongestants, cough suppressants, and expectorants.

Photograph courtesy of Tina Wismer.

Acetaminophen is also deacetylated to p‐aminophenol (PAP), which causes oxidative damage to red blood cells, resulting in methemoglobinemia (McConkey et al. 2009). Cats are more susceptible to acetaminophen‐induced methemoglobinemia because they are deficient in the enzyme that converts PAP back to acetaminophen, allowing buildup of high levels of PAP. Additionally, PAP causes methemoglobinemia by binding to sulfhydryl groups on hemoglobin. As cats have more sulfhydryl groups on their hemoglobin (eight –SH groups compared to four in dogs and two in humans) and are deficient in methemoglobin reductase, they are inherently more susceptible to oxidative injury to hemoglobin (Bischoff 2018).

Toxicity

Hepatotoxicity has been reported in dogs at 100 mg/kg, and 200 mg/kg can cause clinically evident methemoglobinemia (Talcott and Gwaltney‐Brant 2013). In dogs, dosages of >40 mg/kg have resulted in keratoconjunctivitis sicca 48 hours after ingestion (Mariani and Fulton 2001). In cats, methemoglobinemia has been reported at dosages as low as 10 mg/kg and hepatotoxicity is possible if dosages exceed 40 mg/kg.

Clinical Effects

In cats, methemoglobin values increase within 2–4 hours of ingestion, followed by Heinz body formation within 72 hours. Methemoglobinemia in dogs may occur within 4–12 hours or may be delayed up to 48 hours following exposure (Bischoff 2018). Liver injury may not become clinically apparent for 24–72 hours following exposure. In general, dogs typically develop liver injury while cats develop methemoglobinemia, although at acetaminophen doses over 200 mg/kg, dogs can develop both. Rare cases of cats developing liver injury without initial methemoglobinemia have been reported, but cats most often succumb to methemoglobinemia before liver injury develops.

Signs

Clinical signs seen in patients with methemoglobinemia can include depression, vomiting, weakness, hypersalivation, chocolate brown mucous membranes, hyperventilation, cyanosis, dyspnea, facial or paw edema, tachycardia, hypothermia, hemolysis, shock, and death. Clinical signs of methemoglobinemia may last 3–4 days. Clinical signs associated with liver injury include vomiting, anorexia, depression, abdominal pain, icterus, tachycardia, tachypnea, and death. Other less common clinical effects include renal insufficiency/damage, myocardial damage, hemolytic anemia, and coma. Hepatic injury may not resolve for several weeks. Clinical signs of keratoconjunctivitis sicca can include squinting, ocular discharge, and rubbing of the eyes within 48 hours.

Laboratory

Methemoglobinemia, Heinz bodies, hemolytic anemia, metabolic acidosis, hemoglobinemia, hemoglobinuria, and hyperbilirubinemia have been reported with acetaminophen toxicosis in both dogs and cats. Changes consistent with liver damage include elevated alanine transaminase (ALT; the most reliable indicator of liver injury), elevated aspartate transaminase, hyperbilirubinemia, bilirubinuria, decreased serum cholesterol and albumin, elevated prothrombin, and elevated partial thromboplastin times.

Differential Diagnoses

Other toxic causes of methemoglobinemia and Heinz body anemia include resorcinol in cats, benzocaine, chlorates, hydroxyurea, naphthalene, nitrites onions/garlic, other oxidant drugs (pyridium, phenazopyridine), propylene glycol (cats) toxicoses, skunk spray, and zinc (Plumlee 2004; Stockham and Scott 2013).

Other toxic causes of liver injury include (but are not limited to) blue‐green algae, diazepam (cat), iron, lead, phenazopyridine, melarsomine, mothballs, mushrooms, nonsteroidal anti‐inflammatories, mycotoxins, pennyroyal oil, phenol, phenobarbital, and xylitol (dogs).

Diagnostics

There are no in‐house tests for acetaminophen for animals, and diagnosis is often made based on history and clinical signs. Most human hospitals have the ability to measure acetaminophen levels in serum or plasma and may be helpful in determining whether an exposure has occurred if the turnaround time for obtaining the results is reasonably short. Veterinary diagnostic laboratories can also measure acetaminophen levels, but turnaround times can be long, making them less useful for the diagnosis of an acute exposure.

Management of Exposures

The goals of managing acetaminophen exposures include stabilization, decontamination (when feasible), prevention of liver damage, methemoglobinemia, and providing supportive care. Symptomatic patients need initial stabilization, including oxygen if dyspneic. To aid in replenishing glutathione stores, N‐acetylcysteine (Mucomyst®, NAC) is used. Adverse effects of the oral route of NAC administration include nausea and vomiting; NAC at concentrations over 5% can be corrosive to oral and esophageal tissue. An intravenous (IV) formulation of NAC (Acetadote®) is available. For hepatic injury, S‐adenosylmethionine (SAMe, Denamarin and Denosyl‐SD4®) has been recommended in the chronic management of hepatic injury and can be considered in cases of hepatotoxicosis from acetaminophen. Early studies and anecdotal reports show a positive effect for treatment of acetaminophen toxicosis. Over‐the‐counter formulations of SAMe have variable potency and prescription quality, enteric‐coated products are recommended (round the dose to nearest whole tablet and do not break tablet).

IV fluid therapy is used to correct dehydration and for maintenance needs, but not for diuresis. Oxygen supplementation and whole‐blood transfusions may be necessary to increase oxygen‐carrying capacity in patients with methemoglobinemia. Ascorbic acid provides a reserve system for the reduction of methemoglobin back to hemoglobin; however, ascorbic acid has questionable efficacy and when given orally may irritate the stomach. Cimetidine has been historically suggested as an adjunctive therapy to reduce the metabolism of acetaminophen, however, it is no longer recommended in humans and its use is coming into question in dogs (Bischoff 2018). Cimetidine is not recommended for cats because it may increase the accumulation of p‐aminophenol responsible for methemoglobinemia.

Decontamination of asymptomatic patients includes induction of emesis and administration of activated charcoal and cathartic. Emesis can be performed if the animal is asymptomatic, unless contraindicated. However, emesis is unlikely to be of benefit in cats, as they have peak plasma levels 30 minutes post exposure. A single dose of activated charcoal could be considered if it can be given to a cat within 30 minutes or a dog within 2 hours post exposure. In most cases where overdose is expected to cause severe signs and only oral NAC is available, the administration of a loading dose of NAC is recommended 30–40 minutes prior to the first dose of activated charcoal in order to achieve efficacious NAC concentrations as quickly as possible. A 2‐ to 3‐hour interval between subsequent activated charcoal and per os NAC is recommended because activated charcoal could absorb NAC as well as acetaminophen.

Liver function and methemoglobin concentrations should be monitored. Liver enzymes and bilirubin may rise within 24 hours after ingestion and peak within 48–72 hours. Serum albumin concentrations may decrease significantly after 36 hours and continue to decrease if liver failure occurs (providing a true index of liver function). Consider a Schirmer tear test in dogs, since keratoconjunctivitis sicca can develop within 48 hours after ingestion. Recommend baseline test and repeating in 48–72 hours.

Prognosis

The prognosis is good if the animal is treated promptly. Animals with severe signs of methemoglobinemia or with hepatic damage have a more guarded prognosis.

ANTIHISTAMINES

Sources and Formulations

Antihistamines are found in many over‐the‐counter allergy relief products, both as single drugs and in combination with decongestants and/or analgesics. They are also marketed to prevent motion sickness and as sleep aids. A wide variety of antihistamines are available. These include the first‐generation agents (FGAs) diphenhydramine, brompheniramine, dimenhydrinate, and chlorpheniramine, and the second‐generation agents (SGAs) fexofenadine, loratadine, and cetirizine. Other ingredients in antihistamine medications (e.g., pseudoephedrine) may pose higher risk for severe toxicosis, so it is important to verify all the active ingredients in a product when an exposure occurs.

Kinetics

Antihistamines are absorbed rapidly when ingested, reaching peak blood levels within 1–3 hours (Gwaltney‐Brant 2004). FGAs are small and lipophilic molecules that are able to cross the blood–brain barrier and cause CNS signs such as extensive drowsiness. Other central effects are the result of increased anticholinergic activity and include dry mouth and decreased tear release. SGAs are less lipophilic, less able to cross the blood–brain barrier, and thus less likely to cause CNS and anticholinergic side effects (Gonzalez and Estes 1998).

Mechanism of Action

Antihistamines are reversible, competitive inhibitors of the pharmacologic actions of histamine. Cetirizine, fexofenadine, and loratadine also decrease histamine release from basophils (Boothe 2011). The mechanism of the adverse effects of antihistamine is an exacerbation of normal pharmacologic action.

Toxicity

Antihistamines vary considerably in their toxicity, and many can cause mild adverse effects (e.g., lethargy) at therapeutic doses. Specific toxic doses have not been established for companion animals, although most will tolerate twice therapeutic doses with little more than sedation.

Clinical Effects

FGAs are more likely to cause sedation within 30 minutes of ingestion (Gwaltney‐Brant 2004). If no clinical signs are apparent at 3 hours following ingestion, development of significant signs is unlikely. At higher doses, especially in animals under 6 months, initial sedation may progress to agitation, tremors, tachycardia, hypotension, and seizures.

Differential Diagnoses

Many conditions can cause signs similar to antihistamine toxicosis. Differentials include systemic infectious/inflammatory disorders, ingestion of CNS depressants or stimulants, pseudoephedrine, ethylene glycol, alcohol, caffeine, and marijuana.

Diagnostics

No specific biochemical alterations are expected with antihistamine intoxication. Diagnosis is based on a history of exposure and development of consistent clinical signs. Antihistamine serum concentrations are not routinely measured, although most veterinary diagnostic laboratories would be able to perform the analysis.

Management of Exposures

If the ingested dose is above suggested therapeutic ranges and exposure was within 1 hour, induction of emesis should be considered for decontamination. Activated charcoal is indicated in large ingestions, within 2 hours of exposure. The patient should be monitored for at least 2–3 hours following decontamination, longer if signs develop. Additional care, if needed, is supportive and includes parenteral fluids for marked hypotension and diazepam for seizures or hyperactivity.

Prognosis

The prognosis for most exposures is good provided veterinary care is provided. Clinical signs can persist for up to 72 hours in severe cases. Animals exhibiting seizures or in a coma have more guarded prognoses.

ASPIRIN AND OTHER SALICYLATES

Sources and Formulations

Salicylates are found in many products. Aspirin (acetylsalicylic acid, ASA) is available alone or in combination with other drugs as tablets, capsules, powders, and effervescent tablets. Bismuth subsalicylate (Pepto‐Bismol®, Kaopectate®) is used to treat and prevent diarrhea. Pepto Bismol® (bismuth subsalicylate) contains 9 mg/ml of salicylate. Thus 2 tablespoons of bismuth subsalicylate is equivalent to 1 regular‐strength aspirin. Salicylate ointments are used for their anti‐inflammatory effects in arthritis and for their keratolytic properties in dermal conditions such as psoriasis. Topically applied salicylic acid can be absorbed through the skin and cause systemic problems. Salicylates are used in some teething ointments, sunscreens, and topical wart removal products.

Kinetics

Aspirin is rapidly absorbed from the stomach and proximal small intestines in monogastric animals (Gwaltney‐Brant 2001). Aspirin is metabolized in the liver and excreted through the urine. The elimination half‐life increases with the dosage. In dogs, the half‐life at therapeutic doses is 7.5 hours (when dosing every 12 hours) and 12 hours (when dosing every 8 hours) (Lees 2018). Cats are deficient in glucuronyl transferase and have prolonged half‐lives due to decreased aspirin metabolism. Feline dosages of 5–12 mg/kg have a half‐life of 22–27 hours; dosages of 25 mg/kg have a half‐life of approximately 44 hours. Elimination is also slower in neonates and geriatric animals.

Mechanism of Action

Aspirin reduces pain and inflammation by reducing prostaglandin and thromboxane synthesis through inhibition of cyclooxygenase. Decreased prostaglandin production results in a decrease secretion of the protective mucous layer in the stomach and small intestine, and causes vasoconstriction in gastric mucosa. At very high dosages, aspirin and other salicylates uncouple oxidative phosphorylation, leading to fever and seizures. Salicylates also impair platelet aggregation. Unlike other NSAIDs, salicylate toxicosis does not commonly produce renal injury; instead, the liver is the target organ (Gwaltney‐Brant 2001).

Clinical Effects

Clinical effects of salicylate overdoses include metabolic acidosis with respiratory alkalosis, GI irritation and ulceration, liver necrosis, and coagulopathy.

Signs

Signs may include vomiting (± blood), fever, hyperpnea, gastric irritation/ulceration, lethargy, weakness, pallor, diarrhea, pyrexia, increased bleeding times, dehydration, liver necrosis, icterus, coma, and seizures. GI signs (vomiting, diarrhea) were the most common signs in dogs and cats. Risk of GI ulceration, metabolic acidosis, CNS signs, liver, and kidney effects at higher doses. Renal insufficiency is uncommon with salicylate toxicoses but could develop secondary to rhabdomyolysis (from seizures) or hypotension. See Table 24.1 for associated doses.

Laboratory

Laboratory abnormalities expected with salicylate toxicosis include high anion gap metabolic acidosis, respiratory alkalosis, anemia, hypoproteinemia, elevated liver enzymes, and elevated white blood cell count.

Differential Diagnoses

Differential diagnoses include ethylene glycol, alcohol, or metaldehyde toxicoses, cycads, mushrooms, copper, inflammatory and infectious disorders, hemorrhagic gastroenteritis, viral enteritis, hypoadrenocorticism, GI foreign body, anticoagulant rodenticide toxicosis, acetaminophen, iron, and blue‐green algae toxicosis.

Diagnostics

Serum salicylate levels can be measured by veterinary diagnostic laboratories or human hospitals to determine if an exposure occurred, but turnaround times need to be considered when trying to confirm acute toxicosis.

Management of Exposures

The primary goals of treatment are to prevent or treat gastric ulceration, acidosis, hepatopathy, and coagulopathy. Decontamination of asymptomatic patients includes induction of emesis and administration of activated charcoal (repeat dose once in large exposures) and cathartic. Emesis management may be necessary. Hemodialysis can be effective in removing salicylates. Liver values, glucose, acid base status, and electrolytes should be monitored for 72 hours. GI protectant therapy should be initiated to help manage and/or prevent gastric ulcers and should include sucralfate and an acid reducer (H2 blocker or proton pump inhibitor). Misoprostol could be considered in patients at higher risk for GI bleeding (e.g., higher exposure levels, prior NSAID or corticosteroid use). In the asymptomatic patient, gastric protectants should be continued for a minimum of 14 days. Bismuth subsalicylate antacid formulations and corticosteroids are contraindicated. Assisted ventilation and supplemental oxygen may be required if the animal is comatose. Seizures should be treated with diazepam. IV fluids, whole blood, and electrolytes should be given as needed to control hypotension and hemorrhage, manage acute bleeding ulcers, maintain hydration, and correct electrolyte abnormalities. Acid base imbalances should be corrected. Hyperpyrexia should be treated conservatively because ice baths or cold‐water enemas could result in hypothermia. All cooling measures are stopped when rectal temperature reaches 102 °F to prevent rebound hypothermia (Gruenenfelder 2008).

Table 24.1. Therapeutic and toxic dosages for aspirin in dogs and cats

Source: Budde and McCluskey (2023) and Gwaltney‐Brant (2010).

Species
Therapeutic Dosage
Toxic Dosage (GI)
Toxic Dosage (liver)

Dogs
10–20 mg/kg q 12 h
<150 mg/kg; vomiting, diarrhea
150–300 mg/kg; vomiting, diarrhea, GI ulcerations
>300 mg/kg

Cats
10 mg/kg q 48 h
<20 mg/kg; vomiting diarrhea
>20 mg/kg; vomiting, diarrhea, GI ulcerations
No liver issues noted in acute aspirin dosing
Note: doses of 325 mg q 12 h were lethal

GI, gastrointestinal.

Prognosis

In most cases of salicylate toxicosis, the prognosis is good if the animal is treated promptly and appropriately. Delay in treatment can decrease survival potential with large dosages. The development of central lobular necrosis is considered to have a poor prognosis.

COMMON DECONGESTANTS

Sources and Formulations

Decongestants are found in cold and flu medications, allergy products, and eyedrops intended to decrease redness. The most common decongestants in over‐the‐counter oral medications are the sympathomimetics pseudoephedrine and phenylephrine (see Figure 24.2). These compounds are often found in combination with antihistamines or analgesics for cold and allergy relief. Because of the similarities with amphetamine, the reader is directed to the amphetamine discussion in Chapter 25 for further information on these compounds.

Kinetics

Pseudoephedrine and phenylephrine are rapidly absorbed from the GI tract, as well as across mucosal surfaces, within 1–2 hours (slower with extended‐release products). Pseudoephedrine is incompletely metabolized in the liver. Less than 1% of the dose is present as norpseudoephedrine in normal individuals and up to 6% of the dose in patients with chronically alkaline urine. Norpseudoephedrine is an active metabolite that produces CNS stimulation. Half‐life varies between 2 and 21 hours (depending on urinary pH). Elimination of pseudoephedrine is through the urine, with 55–75% excreted unchanged in the urine.

Figure 24.2. Pseudoephedrine.

Photograph courtesy of Tina Wismer.

Phenylephrine is metabolized by conjugation or deamination in the liver and GI tract. Monoamine oxidase rapidly metabolizes phenylephrine in the GI wall. Half‐life would be 2–3 hours in humans. Elimination of phenylephrine is through the kidneys in humans. It is not known if metabolites are excreted in the milk (Kanfer et al. 1993).

Mechanism of Action

Pseudoephedrine sulfate is a synthetic salt of naturally occurring ephedrine and is classified as indirect sympathomimetic amine. It acts on both alpha and, to a lesser degree, beta adrenergic receptors. In large doses, it can elevate both blood pressure and heart rate.

Phenylephrine is primarily a direct‐acting sympathomimetic amine at alpha‐1 receptors that does not depend on release of endogenous norepinephrine for its effects (Clode 2018; Hoffman and Nelson 2017). Stimulation of these receptors results in peripheral vasoconstriction and increased systolic and diastolic blood pressure. Substantial stimulation of cardiac beta receptors may occur with large doses. There is no stimulation of beta‐adrenergic receptors of the bronchi or peripheral blood vessels. It is believed that the direct alpha‐adrenergic effects of phenylephrine result from the inhibition of the production of cyclic adenosine‐3′,5′‐monophosphate (cAMP) by inhibition of the enzyme adenyl cyclase, whereas beta‐adrenergic effects result from stimulation of adenyl cyclase activity (Clode 2018).

Toxicity

Pseudoephedrine at 5–6 mg/kg in dogs can cause clinical signs of agitation, nervousness, hyperactivity, restlessness, panting, tachycardia, hypertension, and some other behavior changes. Pseudoephedrine at 10–12 mg/kg can be lethal in dogs (ASPCA 2023). The same effects will be expected in cats or other animal species.

Phenylephrine less than 1 mg/kg in dogs can cause mild GI upset and lethargy. Between 1 and 10 mg/kg in dogs can cause clinical signs of agitation, anxiety, hyperactivity, and tachycardia, and over 10 mg/kg signs are expected to be more severe. Dosages 1 mg/kg or lower in cats can cause some lethargy, agitation, and hyperactivity. Over 1 mg/kg in cats can cause tachycardia, hypertension, and vomiting (ASPCA 2023).

Clinical Effects

Clinical effects can be seen within 15–30 minutes and a peak effect within 30–60 minutes for prompt release. With extended‐release formulas, peak plasma concentration is within 3–6 hours. Clinical signs include agitation, nervousness, hyperactivity, restlessness, panting, tachycardia, hypertension, hyperthermia, head bobbing, and seizure‐like activity, followed by collapse and some other behavior changes (ASPCA 2023). Feline or other animals would be expected to show the same type of clinical signs as dogs, as well as staring into space. Duration of signs could last 24–72 hours post exposure.

Differential Diagnoses

Other causes of these signs include amphetamines, cocaine, methylxanthines, organochlorine‐type pesticides, lead, tremorgenic mycotoxins, ma huang, 5‐hydroxytryptophan, or any other CNS stimulant.

Management of Exposures

Emesis could be induced if exposure was within the last 60 minutes but is generally impractical due to the rapidity of onset of signs. Activated charcoal may be considered for extended‐release forms; unless contraindicated, give activated charcoal with a cathartic if exposure has taken place within the last 2–4 hours if the pet is asymptomatic.

Exposed asymptomatic animals should be monitored for the development of signs for a minimum of 6 hours following exposure. If signs occur, the animal may need monitoring for up to 24–72 hours, depending on severity of signs. Symptomatic animals should be administered IV fluids. CNS stimulation is commonly controlled with acepromazine or chlorpromazine. Diazepam is generally avoided for agitation and hyperactivity as it may worsen the stimulation and increase the risk for myocardial ischemia. Cyproheptadine as a serotonin antagonist may be considered. A muscle relaxant such as methocarbamol may be used for tremors. Propranolol or another appropriate beta‐blocker may be considered for controlling tachycardia. Hypertension is often controlled through acepromazine for CNS stimulation control; however, if that is insufficient, other vasodilators such as nitroprusside may be considered. Stronger sedatives such as barbiturates, propofol, or gas anesthesia may be considered if acepromazine is not effective. Alpha‐2‐adrenergic agonists such as medetomidine and dexmedetomidine should be avoided because they as well as pseudoephedrine cause peripheral vasoconstriction and have the potential to worsen hypertension.

Prognosis

Animals receiving appropriate treatment have a good prognosis for recovery. Animals with pre‐existing cardiac or hypertensive disorders (including renal disease and diabetes mellitus) would be at greater risk for signs (Lane and Stokes 2011).

Imidazoline Decongestants

Sources and Formulations

The most common active ingredients in ocular and nasal decongestants are imidazoline compounds such as naphazoline, oxymetazoline, or tetrahydrozoline. These compounds work as topical vasoconstrictives and are used to decrease ocular redness associated with conjunctivitis and to decrease nasal congestion due to colds, allergies, and sinusitis. Companion animals are most commonly exposed by chewing on bottles of medication and ingesting the contents.

Kinetics

Imidazoline decongestants are absorbed well from the GI tract as well as across mucosal surfaces. It is thought that the imidazolines are metabolized in the liver, although some fraction is excreted unchanged in the urine. In humans, the half‐life is 2–4 hours.

Mechanism of Action

In the CNS, imidazolines bind to alpha‐2‐adrenergic receptors, which inhibit norepinephrine release and decrease sympathetic effects. This results in hypotension, bradycardia, and sedation (Means 2004). Peripherally, stimulation of alpha‐2 receptors results in vasoconstriction and hypertension. With oral intoxications the central effects usually predominate.

Toxicity

Imidazoline decongestants have very low margins of safety, with even small exposures resulting in significant clinical signs.

Clinical Effects

Clinical effects can be seen within 30 minutes to 4 hours and reach peak plasma concentrations within about 1 hour. Clinical effects include vomiting, lethargy, weakness, bradycardia, hypotension, hypertension, possibly agitation, shaking, and panting (Means 2004). Clinic signs may persist for 8–24 hours.

Differential Diagnoses

Other causes of these signs include various sympathomimetic agents such as clonidine, tizanidine, dexmedetomidine, xylazine, prazosin, tamsulosin, opioids, antidepressants, calcium channel blocker exposures, and antihistamines.

Management of Exposures

Generally, decontamination is not practical due to the rapid absorption and onset of clinical signs. If a large exposure has taken place within the past few minutes, inducing emesis may be beneficial. Do not induce vomiting or give activated charcoal if animal is already showing clinic signs.

Animals should be monitored for at least 4 hours for clinic signs. Signs may take an additional 24 hours to resolve. The heart rate, rhythm, and blood pressure should be monitored and an electrocardiogram can be considered if indicated. If signs persist for several hours, assess serum electrolytes and correct them as needed. Give IV fluids as needed for supportive care. Diazepam can be given if significant nervous effects are present: anxiousness and shaking.

Specific antagonists that can be used are atipamezole (Antisedan®) or yohimbine. With atipamezole, 50 mcg/kg is recommended to be given at a quarter to a third of the dose intravenously and the rest intramuscularly to avoid furthering hypotension. If not improved within 30–60 minutes, a little more may be given intravenously. Yohimbine can be used at 0.1 mg/kg IV and may be repeated in 2–3 hours if needed based on clinical signs.

Prognosis

Animals receiving appropriate treatment have a good prognosis for recovery.

NONSTEROIDAL ANTI‐INFLAMMATORY MEDICATIONS

This section covers the nonsalicylate NSAIDs. Aspirin and other salicylates are discussed elsewhere in this chapter.

Sources and Formulations

NSAIDs are commonly used to treat pain and inflammation and to reduce fevers. Many are also available in combination with antihistamines and/or decongestants in cold, flu, and allergy products. It is important to verify the active ingredients in over‐the‐counter products because clients are sometimes confused as to which NSAID (e.g., ibuprofen vs. naproxen) the product contains, and there may be additional ingredients such as caffeine, antihistamines, or decongestants that might contribute to adverse effects (see Figure 24.3). There are several NSAIDs approved for use in veterinary medicine. Most exposures to NSAIDs in companion animals are due to accidental ingestion of human or veterinary formulations, although iatrogenic exposures through overzealous administration by pet owners are common.

Kinetics

In general, over‐the‐counter NSAIDs are well absorbed from the stomach and upper small intestine and are highly (>90%) protein‐bound (Grosser et al. 2023). They exhibit a higher degree of toxicity when other highly protein‐bound drugs are co‐ingested. Most NSAIDs undergo liver metabolism. Excretion is species and drug dependent. Many NSAIDs are excreted in the feces in dogs. Some also undergo enterohepatic recirculation, which can prolong the elimination half‐life. For example, naproxen, which is excreted via the bile in dogs, undergoes extensive enterohepatic recirculation and has a long half‐life (74 hours).

Figure 24.3. Ibuprofen 200 mg. Note the imprint code that identifies the pill by both active ingredient and mg strength.

Photograph courtesy of Tina Wismer.

Mechanism of Action

NSAIDs inhibit prostaglandin synthesis by blocking the conversion of arachidonic acid to various prostaglandins through the inhibition of the enzyme cyclooxygenase (COX). Although many modern NSAIDs are marketed as being specific for certain forms of COX (e.g., COX‐2), the fact that COX specificity is lost in overdose situations minimizes the importance of this distinction (Talcott and Gwaltney‐Brant 2013). The NSAIDs decrease secretion of the protective mucous layer in the stomach and small intestine, and cause vasoconstriction in gastric mucosa. Renal effects include inhibition of renal blood flow, glomerular filtration rate, tubular ion transport, renin release, and water homeostasis. Some NSAIDs also affect platelet aggregation and possibly hepatic function, although unlike salicylates, serious hepatotoxicosis does not appear to be a common problem with acute NSAID overdoses.

Toxicity

There is tremendous variation in the degree of toxicity among the many NSAIDs, as well as significant species and individual variation in sensitivity to the different NSAIDs (Table 24.2). Many over‐the‐counter NSAIDs (e.g., naproxen and ibuprofen) pose a risk for GI injury at commonly suggested doses, especially when given repeatedly. Larger overdoses can result in renal tubular injury. Ibuprofen can cause severe neurologic dysfunction when dosages exceed 350 mg/kg (Dunayer 2004).

Clinical Effects

The onset of GI upset is generally within the first 2–6 hours after ingestion, with GI hemorrhage and ulceration occurring 12 hours to 4 days post ingestion. In severe cases, GI perforation may occur, causing septic peritonitis and shock. The onset of renal failure usually occurs within the first 12 hours after massive exposure to an NSAID but may be delayed for 3–5 days.

Clinical signs include vomiting, hematemesis, depression, anorexia, hyperthermia, melena, abdominal pain, and hematochezia. Polydipsia, polyuria, dehydration, lethargy, hematuria, and oliguria have been reported in animals experiencing renal injury from NSAIDs. Central nervous signs include depression, ataxia, tremors, seizures, coma, and hypothermia.

Table 24.2. Therapeutic and toxic dosages for selected NSAIDs in dogs and cats

Source: Budde and McCluskey (2023), Dunayer (2004), and Gwaltney‐Brant (2010).

NSAID
Therapeutic Dosage
Toxic Dosage (GI Ulcers)
Toxic Dosage (Renal)

Ibuprofen (not recommended for dogs or cats)
Dogs: 5 mg/kg q 24 h
Cats: none
Dogs >50 mg/kg
Cats >5 mg/kg
Dogs >125 mg/kg (>350 mg/kg = CNS signs)
Cats >20 mg/kg

Naproxen (not recommended for dogs or cats)
Dogs: 2 mg/kg q 48 h
Cats: none
Dogs >5 mg/kg
Dog: > 10–20 mg/kg

Carprofen
Dogs: 2.2 mg/kg q 12 h; 4.4 mg/kg q 24 h
Dogs >20 mg/kg
Cat: > 4 mg/kg
Dogs >40 mg/kg
Cats >8 mg/kg

Deracoxib
Dogs: 1–2 mg/kg q 12 h
Dogs >15 mg/kg
Cats >4 mg/kg
Dogs >30 mg/kg
Cats >8 mg/kg

Meloxicam
Dogs: 0.1 mg/kg q 24 h
Cats: 0.3 mg/kg
Dogs >1 mg/kg
Cats: 0.06–0.3 mg/kg
Dogs >2 mg/kg
Cats >0.31 mg/kg

These dosages are for young‐adult, healthy animals; pediatric animals, geriatric animals, or animals with prior health issues may be more susceptible to the effects of NSAID overdose.

CNS, central nervous system; GI, gastrointestinal; NSAIDs, nonsteroidal anti‐inflammatory medications.

Laboratory

Complete blood cell counts may reflect GI hemorrhage and inflammation, with elevations in white blood cell and segmented neutrophil counts, and decreases in hematocrit noted. Patients with renal failure will have increases in blood urea nitrogen (BUN) and creatinine as well as isosthenuria. With larger overdoses of NSAIDs, transient elevations in liver enzymes (especially ALT) may be noted.

Differential Diagnoses

Other potential causes of GI upset and hemorrhage include hemorrhagic gastroenteritis, hypoadrenocorticism, GI foreign bodies, viral enteritis, and GI neoplasia. Other causes of renal failure include leptospirosis and ingestion of grapes/raisins (dogs), lilies(cats), ethylene glycol, and heavy metals.

Diagnostics

Antemortem

Serum measurements for many NSAIDs can be performed at veterinary diagnostic laboratories and many human hospitals, but turnaround time may be too long to assist in diagnosis of an acute case. Diagnosis is generally based on history of exposure and development of consistent clinical signs.

Postmortem

Lesions associated with ibuprofen overdose include perforations, erosions, ulcers, and hemorrhages in the upper (stomach and duodenum) and, on occasion, lower (colon) GI tract. Renal damage includes renal tubular necrosis and/or papillary necrosis.

Management of Exposures

Decontamination includes emesis if it can be performed within an hour of ingestion and activated charcoal if within 4 hours post ingestion. Activated charcoal should not be administered if there is evidence of GI bleeding because the charcoal may impede healing of ulcerated areas. GI protectants (H2 blocker or proton pump inhibitor, sucralfate, and misoprostol) should be maintained for 14 days or longer if evidence of GI bleeding occurs. For animals ingesting potentially nephrotoxic doses, IV fluid therapy at a diuretic rate for a minimum of 48 hours is recommended to maintain renal perfusion. Animals with evidence of renal insufficiency should be managed as for any type of acute renal injury. CNS signs should be treated symptomatically (i.e., diazepam for seizures, oxygen and thermoregulation for coma). Naloxone may be of benefit for treating ibuprofen‐induced coma.

Prognosis

The prognosis is dependent on the dose ingested, species of animal involved, and promptness of treatment. Those with mild GI and renal effects can be expected to make full recoveries; patients with GI perforation or severe renal insufficiency have more guarded prognoses.

PHENYLPROPANOLAMINE

Sources and Formulations

Phenylpropanolamine (PPA) is a sympathomimetic agent that has been withdrawn from the human market due to an association with increased stroke risk, but it is still used in veterinary medicine for controlling urinary incontinence in dogs. Chewable veterinary formulations are extremely palatable, especially to dogs, which may increase the risk of accidental overdose. PPA is also available in liquid and time‐release capsules.

Kinetics

PPA is quickly absorbed orally, although extended‐release products may have a delayed onset of action (Means 2004).

Mechanism of Action

Sympathomimetics like PPA stimulate alpha‐ and beta‐adrenergic receptors, resulting in the release of endogenous catecholamines in the brain and heart. This results in peripheral vasoconstriction, cardiac stimulation, and bronchodilation (Means 2004).

Toxicity

Signs can be seen at therapeutic and lower doses in some dogs, and serious signs appear at dosages above 20 mg/kg (Means 2004).

Clinical Effects

Signs normally start within 30–90 minutes and may continue up to 72 hours, depending on the dose ingested. Clinical signs of PPA toxicosis include tachycardia, hypertension, panting, agitation, hyperesthesia, piloerection, hyperthermia, tremors, seizures, and secondary depression. Bradycardia may result in response to hypertension; therefore, dogs may present either depressed, bradycardic, and hypertensive OR agitated, tachycardic, and hypertensive.

Differential Diagnoses

Differential diagnoses include intoxication from other CNS stimulants such as other sympathomimetics (e.g., pseudoephedrine, amphetamine), metaldehyde, cocaine, ethylene glycol, albuterol, strychnine, and 5‐hydroxytryptophan.

Diagnostics

Diagnosis is based on clinical signs and history. Serum levels can be measured at a veterinary diagnostic laboratory, but turnaround times may be too long to assist in prompt diagnosis of an acute case.

Management of Exposures

Because of the potential for rapid onset of signs, emesis should be induced at the veterinary hospital within 30 minutes of exposure. One dose of activated charcoal should be given if no contraindications exist. Heart rate and blood pressure should be closely monitored. Phenothiazines (acepromazine or chlorpromazine) may be used to control agitation and may also help to lower the blood pressure. Cyproheptadine has been found to be useful for alleviating some of the CNS signs. Nitroprusside or other vasodilating agents may be used to manage severe hypertension. Managing blood pressure often results in correction of the reflex bradycardia. Atropine is contraindicated in the management of bradycardia because it will worsen hypertension. Beta‐blockers should not be used on bradycardic animals because they will worsen the bradycardia. If marked hyperthermia is present, monitor for the development of disseminated intravascular coagulation. In tachycardic animals very low doses of metoprolol (preferred due to beta‐1 selectivity and short half‐life) or propranolol may be considered but should be used with caution and only after CNS signs (agitation, hyperactivity) have been controlled. Lidocaine can be given for frequent ventricular premature complexes and/or ventricular tachycardia. In dogs, an initial bolus of 2 mg/kg IV slowly can be given followed by a constant rate infusion (CRI) if needed at 25–80 mcg/kg/min. Frequently the CRI dosage may need to be near 50 mcg/kg/min. Lidocaine should be used very cautiously in cats, if at all, as they are more susceptible to adverse effects from lidocaine, such as methemoglobinemia. IV fluids are recommended to promote excretion, protect renal function, and aid in thermoregulation. Fluid rates should be adjusted accordingly in hypertensive animals to avoid fluid loading and high rates of fluids. Monitor glucose as some symptomatic animals will become hypoglycemic. Coagulation profile is recommended if disseminated intravascular coagulation is a concern.

Possible troponin 1 assays may be useful in monitoring cardiac damage. Consider checking 24 hours after exposure. If elevated, consider consultation with a cardiologist. Exercise restriction should also be encouraged with elevated troponin. Additional workup may include a holter monitor and/or echocardiogram. Ideally, patients should be monitored in the hospital until they are not exhibiting any clinical abnormalities and have not received any medications for CNS or cardiovascular signs for 6–8 hours.

Prognosis

The prognosis will depend on the dose ingested, severity of clinical signs, elapsed time between onset of signs and institution of therapy, and response to therapy. Animals experiencing seizures have a more guarded prognosis.

VITAMINS

Sources and Formulations

Vitamin supplements are widely available and include multivitamins as well as products containing single vitamins as ingredients. Many vitamin supplements also contain a variety of minerals (e.g., iron, selenium, etc.). Most products are designed to provide the minimum daily requirement (MRA) of vitamins, but some products have higher potencies and contain several times the MRA in each tablet or capsule. For instance, most vitamin supplements contain vitamin D₃ at 400 IU per serving, but high‐potency products containing 1000–50,000 IU have become available and these pose a higher risk of acute toxicosis.

Toxicity

Ingredients of concern in vitamin supplements include iron and vitamin D. Oral exposures to water‐soluble vitamins (B vitamins, vitamin C) are not likely to cause significant clinical effects because excess vitamins are eliminated through the urine. However, formulations with B vitamins can result in benign orange discoloration of the urine. High doses of niacin (vitamin B3) can cause a self‐limiting flushing of the skin of the face and ear pinnas in some dogs (though transiently uncomfortable, no serious harm will occur). Vitamin C can be irritating to the GI tract and result in mild, transient vomiting, or diarrhea.

Vitamin D is of concern if the ingested dosage exceeds 0.1 mg/kg (4000 IU/kg). (See the cholecalciferol section of Chapter 17 for information on risks and management of vitamin D exposures.) Iron dosages under 50 mg/kg can cause vomiting and diarrhea, dosages over 50 mg/kg can cause corrosive injury to the intestinal mucosa, and dosages 80 mg/kg and above can lead to liver injury (see the iron section of Chapter 22 for further information on iron toxicosis).

Management of Exposures

Vitamin B and vitamin C oral exposures commonly result in GI upset within 24 hours. Management of vomiting and diarrhea should be implemented as needed. Vitamin C oral exposures with large amounts ingested are sometimes recommended for in‐hospital monitoring, to keep the patient well hydrated. Vitamin C can give false‐negative urine glucose values and false‐negative stool occult blood results.

ACKNOWLEDGMENTS

The author would like to thank Mary M. Schell and Sharon Gwaltney‐Brant for their contributions to the first edition of this chapter.

REFERENCES

ASPCA (American Society for the Protection of Animals). 2023. Pseudoephedrine Toxicity in Pets. https://www.aspcapro.org/resource/pseudoephedrine‐toxicity‐pets Accessed 12/11/23.

Bischoff, Karen. 2018. Toxicity of over‐the‐counter drugs. In Veterinary Toxicology: Basic and Clinical Principles, 3rd ed., edited by Ramesh C Gupta, pp. 357–384. London: Elsevier.

Boothe, Dawn M. 2011. Drugs affecting the respiratory system. In Small Animal Clinical Pharmacology and Therapeutics, 2nd ed., edited by Dawn M Booth, pp. 745–782. St. Louis: Elsevier.

Budde, James A and McCluskey, Dawn M. 2023. Plumb's Veterinary Drug Handbook, 10th ed. Tulsa, OK: Educational Concepts LLC.

Clode, Alison. 2018. Ophthalmic pharmacology. In Veterinary Pharmacology and Therapeutics, 10th ed., edited by Jim E Riviere and Mark G Papich, pp. 1321–1331. Hoboken, NJ: John Wiley and Sons, Inc.

Dunayer, Eric K. 2004. Ibuprofen toxicosis in dogs, cats, ferrets. Veterinary Medicine 99(7):580–586.

Gonzalez, Mario A and Estes, Kerry S. 1998. Pharmacokinetic overview of oral second‐generation H1 antihistamines. International Journal of Clinical Pharmacology and Therapeutics 36(5):292–300.

Grosser, Tilo, Ricciotti, Emanuela, and FitzGerald, Garret A. 2023. Pharmacotherapy of inflammation, fever, pain, and gout. In Goodman & Gilman's the Pharmacological Basis of Therapeutics, 14th ed., edited by Laurence L Brunton and Bjorn C Knollmann, pp. 829–856. New York: McGraw‐Hill LLC.

Gruenenfelder, Fredrick. 2008. Seizures and sleep disorders. In Handbook of Small Animal Practice, 5th ed., edited by Rhea V Morgan, pp. 222–232. Philadelphia: Saunders.

Gwaltney‐Brant, Sharon M. 2001. Salicylate toxicosis in dogs and cats. Standards of Care: Emergency and Critical Care Medicine 4(7):1–5.

Gwaltney‐Brant, Sharon M. 2004. Antihistamines. In Clinical Veterinary Toxicology, edited by Konnie H Plumlee, pp. 309–311. St. Louis: Mosby.

Gwaltney‐Brant, Sharon M. 2010. Toxicology of Pain Medication. Proceedings from the CVC Baltimore, Baltimore, MD, April 11, 2010. https://www.dvm360.com/view/toxicity‐pain‐medications‐proceedings‐0 Accessed 12/11/23.

Hoffman, Robert J and Nelson, Lewis S. 2017. Sympathomimetic agents. In Critical Care Toxicology: Diagnosis and Management of the Critically Poisoned Patient, 2nd ed., edited by Jeffrey Brent, Keith Burkhart, Paul Dargan, Benjamin Hatten, Bruno Megarbane, Robert Palmer, and Julian White, pp. 851–865. New York: Springer.

Kanfer, Isadore, Dowse, Roslind, and Vuma, Vusumuzi. 1993. Pharmacokinetics of oral decongestants. Pharmacotherapy 13(6 Pt 2):116S–146S.

Lane, India F and Stokes, Jennifer E. 2011. Treatment of urinary disorders. In Small Animal Clinical Pharmacology and Therapeutics, 2nd ed., edited by Dawn M Booth, pp. 640–671. St. Louis: Elsevier.

Lees, Peter. 2018. Analgesic, antiinflammatory, antipyretic drugs. In Veterinary Pharmacology and Therapeutics, 10th ed., edited by Jim E Riviere and Mark G Papich, pp. 467–500. Hoboken, NJ: John Wiley and Sons, Inc.

Mariani, Christopher L and Fulton, Robert B Jr. 2001. Atypical reaction to acetaminophen intoxication in a dog. Journal of Veterinary Emergency and Critical Care 11(2):123–126.

McConkey, Sandra E, Grant, Denis M, and Cribb, Alastair E. 2009. The role of para‐aminophenol in acetaminophen‐induced methemoglobinemia in dogs and cats. Journal of Veterinary Pharmacology and Therapeutics 32(6):585–595.

Means, Charlotte. 2004. Decongestants. In Clinical Veterinary Toxicology, edited by Konnie H Plumlee, pp. 309–311. St. Louis: Mosby.

Ottani, Alesandra, Leone, Sheila, Sandrini, Maurizio, Ferrari, Anna, and Bertolini, Alfio. 2006. The analgesic activity of paracetamol is prevented by the blockade of cannabinoid CB1 receptors. European Journal of Pharmacology 531(1–3):280–281.

Plumlee, Konnie H. 2004. Hematic system. In Clinical Veterinary Toxicology, edited by Konnie H Plumlee, p. 59. St. Louis: Mosby.

Sellon, Rance K. 2013. Acetaminophen. In Small Animal Toxicology, 3rd ed., edited by Michael E Peterson and Patricia A Talcott, pp. 423–429. St. Louis: Saunders.

Stockham, Steven L and Scott, Michael A. 2013. Erythrocytes. In Fundamentals of Veterinary Clinical Pathology, 2nd ed., edited by Steven L Stockham and Michael A Scott, pp. 107–222. Ames, Iowa: Blackwell.

Talcott, Patricia A and Gwaltney‐Brant, Sharon M. 2013. Nonsteroidal antiinflammatories. In Small Animal Toxicology, 3rd ed., edited by Michael E Peterson and Patricia A Talcott, pp. 687–708. St. Louis: Saunders.

25
Illicit Drugs and Drugs of Abuse

Sharon Gwaltney‐Brant and Tina Wismer

INTRODUCTION

The legality of some of these substances will vary by location. Some owners are very forthcoming about what their pet got into, while others will take more questioning to get to the answer. As veterinary professionals we are most concerned about treating the patient appropriately.

ALCOHOL

Alcohol (ethanol) is the most commonly abused drug in the world, and accidental ingestion of ethanol by pets is not an uncommon event. A complete discussion of ethanol toxicosis can be found in Chapter 27.

AMPHETAMINES

Sources and Formulations

Amphetamines encompass a wide variety of drugs, both legal and illicit. The high level of dependency and abuse that these drugs can elicit has resulted in them being designated controlled substances by the US Drug Enforcement Agency. Amphetamines are prescribed legally for the treatment of obesity, narcolepsy, and attention deficit disorder in humans (Volmer 2013). Methamphetamine does have therapeutic uses but is most infamous as the street drug also known as “crystal,” “crank,” “meth,” and “glass.” Pseudoephedrine, an over‐the‐counter decongestant, is a precursor to illicitly manufactured methamphetamine, and the features of pseudoephedrine overdose will be similar to those seen with amphetamines (see Chapter 24). Companion animals are generally exposed to amphetamines through accidental ingestion of prescription or illicit medication.

Kinetics

Most amphetamines are quickly absorbed into the bloodstream, and clinical signs can occur very quickly, sometimes within minutes after ingestion (Volmer 2013). Amphetamines are lipophilic and cross the blood–brain barrier to enter the central nervous system (CNS). They are metabolized in the liver and both parent compound and its metabolites are excreted in the urine. Elimination by the urine is enhanced in acidic urine.

Mechanism of Action

Amphetamines produce their stimulatory activity through several neurotransmitters, including norepinephrine, dopamine, and serotonin in the CNS and through direct stimulation of alpha‐ and beta‐adrenergic receptors in the peripheral nervous system (Bischoff 2018). Amphetamines also inhibit monoamine oxidase and inhibit neuronal reuptake of catecholamines, both of which can result in accumulation of excess neurotransmitters such as serotonin and norepinephrine at the postsynaptic neuron.

Toxicity

Although the oral LD₅₀ (lethal dose 50, the amount it takes to kill 50% of the population) for amphetamine sulfate in dogs is listed as 20–27 mg/kg, serious and life‐threatening clinical signs can occur at much lower levels.

Clinical Effects

Signs

Signs associated with amphetamine intoxication include agitation, restlessness, hyperactivity, aggression, vocalization, hyperthermia, tachycardia, tachypnea, ataxia, tremors, and seizures.

Laboratory

No specific clinical pathology abnormalities are expected, although acidosis, electrolyte imbalances, and hypoglycemia may be seen in severe cases.

Differential Diagnoses

Other CNS stimulants such as cocaine, methylxanthines, other sympathomimetics (e.g., pseudoephedrine, phenylpropanolamine), metaldehyde, antidepressants, tremorgenic mycotoxins, organochlorine insecticides, organophosphorous and carbamate insecticides, 5‐fluorouracil, hypernatremia, ephedra (e.g., ma huang/guarana preparations), 5‐hydroxytryptophan, or lead should all be considered when presented with a patient with severe CNS and cardiovascular stimulation.

Diagnostics

Blood, saliva, and urine can be analyzed by most veterinary diagnostic laboratories for the presence of amphetamine, although the turnaround time may make the diagnostic laboratory of limited usefulness in diagnosing acute toxicosis. Over‐the‐counter drug test kits have the advantages of being inexpensive and readily available at most pharmacies and providing rapid results (Teitler 2009). These tests utilize urine and appear to be reasonably reliable for amphetamine exposures in dogs, although false positives can occur from exposure to certain antidepressants, beta‐adrenergic blockers (e.g., metoprolol), metformin, phenothiazines (e.g., acepromazine, some antihistamines), and over‐the‐counter nasal decongestants (i.e., ephedrine, pseudoephedrine). These kits are not validated in nonhumans, so further testing by a veterinary diagnostic laboratory may be needed in legal cases.

Management of Exposures

The goals of managing amphetamine exposures are to stabilize the patient, manage clinical signs, decontaminate (if feasible), and provide supportive care. Agitation, hyperactivity, and other stimulatory signs tend to respond well to phenothiazine tranquilizers such as acepromazine or chlorpromazine. Benzodiazepines should be avoided because paradoxical worsening of the neurologic effects has been reported (Volmer 2013). Seizures are best controlled with injectable anesthetics (pentobarbital or propofol). Hyperthermia should be managed by external cooling measures (ice packs, fans, etc.). For tachycardia that persists after sedation, a beta‐blocker such as propranolol should be used. Intravenous (IV) fluid therapy will aid in stabilizing the cardiovascular system as well as enhancing elimination of amphetamine via the urine. Although acidification of the urine can increase urinary excretion of amphetamine, severely symptomatic animals may already be acidotic, so urinary acidification is not recommended until it has been established that acidosis does not already exist.

In animals that have presented following recent exposure and are asymptomatic, induction of emesis and administration of activated charcoal is recommended. The patient should then be monitored in hospital for a minimum of 3–4 hours (prompt release products) or up to 12 hours following the ingestion of delayed‐release products (i.e., extended‐release, sustained‐release, controlled‐release products). It is important to realize that amphetamines can cause a very rapid onset of signs, so close monitoring during and after decontamination is recommended.

Prognosis

The prognosis for animals ingesting amphetamine depends on the dose ingested, the severity and duration of clinical signs at presentation, and the response to appropriate therapy. Complications from severe cases can include injury due to hyperthermia, hypoxia, trauma, uncontrolled seizure activity, or cerebral edema.

BARBITURATES

Sources and Formulations

Barbiturates are derivatives of barbituric acid that are used therapeutically as anticonvulsants and sedatives. Barbiturates are also the primary component of most euthanasia solutions. Most barbiturate poisonings in companion animals are the result of accidental ingestion of human or veterinary prescription products, although ingestion of illicit medications, iatrogenic overdoses, accidental injection of euthanasia solutions, and ingestion of meat from carcasses euthanized with barbiturate‐based solutions are other means of exposure (Bischoff 2018; Volmer 2013).

Kinetics

Barbiturates are well absorbed orally. Barbiturates are classified according to their duration of action as ultra‐short‐acting (less than 3 hours), short‐acting (3–6 hours), and long‐acting (6–12 hours), which is related to their lipid solubility (Volmer 2013). Highly lipid‐soluble barbiturates rapidly distribute throughout the body, including the CNS, and then are very rapidly redistributed into fat and total body water, which terminates their anesthetic effect. Barbiturates undergo hepatic metabolism, and metabolites as well as parent compound are eliminated in the urine. Chronic barbiturate use results in induction of their metabolic enzymes, which can result in accelerated metabolism of barbiturates and other compounds that are normally biotransformed by those enzymes.

Mechanism of Action

In the CNS, barbiturates stimulate gamma‐aminobutyric acid (GABA, an inhibitory neurotransmitter) receptors and inhibit glutamate (a stimulatory neurotransmitter) receptors, causing CNS depression. Some of the CNS depressive effects of barbiturates relate to their inhibition of the release of other neurotransmitters such as norepinephrine and acetylcholine. Very high doses of barbiturates depress respiration and cardiac contractility, leading to respiratory depression and hypotension.

Toxicity

Barbiturates have a narrow margin of safety and even small overdoses can result in significant CNS depression. The lowest reported oral lethal dosage of phenobarbital in cats is 125 mg/kg (Volmer 2013). The oral LD₅₀ (dosage at which 50% will die) for phenobarbital in dogs is 150 mg/kg.

Clinical Effects

Signs

The clinical effects of barbiturates relate to CNS depression, so the signs that can be seen include lethargy, ataxia, weakness, disorientation, recumbency, coma, respiratory depression, tachycardia or bradycardia, hypothermia, and death.

Laboratory

Although a minimum database should be established for patients in order to determine any preexisting conditions that may interfere with elimination of the drug (e.g., renal or hepatic insufficiency), no specific clinical pathologic abnormalities are expected in patients with barbiturate overdose. Severely comatose animals with compromised respiration may develop respiratory acidosis.

Differential Diagnoses

Other agents that can cause CNS and respiratory depression resembling barbiturate toxicosis include benzodiazepines, macrolide antiparasiticides (e.g., ivermectin, moxidectin), amitraz, ethanol and other alcohols, ethylene glycol, propylene glycol, other sedatives (opioids, phenothiazines, sleep aids such as zolpidem, etc.), and marijuana. Nontoxicologic rule‐outs include hypoglycemia, encephalopathy (infectious vs. metabolic), encephalitis, CNS trauma, and cerebral vascular accident.

Diagnostics

Blood, urine, stomach content, and feces can be analyzed by most veterinary diagnostic laboratories for the presence of barbiturates, although the turnaround time may make the diagnostic laboratory of limited usefulness in diagnosing an acute toxicosis. Over‐the‐counter drug test kits have the advantages of being inexpensive and readily available at most pharmacies and providing rapid results (Teitler 2009). These tests utilize urine and appear to be reasonably reliable for rapid identification of barbiturates exposures in dogs in a clinical setting, although false positives may occur from exposure to nonsteroidal anti‐inflammatory drugs (NSAIDS; ibuprofen, naproxen) or sleep aids such as doxylamine. These kits are not validated in nonhumans, so further testing by a veterinary diagnostic laboratory may be needed in legal cases.

Management of Exposures

The goals of managing a patient's exposure to barbiturates are to minimize absorption of the drug and provide symptomatic and supportive care to animals experiencing CNS depression. For exposures with no‐to‐minimal signs, emesis may be induced followed by administration of activated charcoal and monitoring in hospital for 4–6 hours. Animals that present with severe CNS depression should not have vomiting induced due to the risk of aspiration; in these patients, gastric lavage should be considered. Activated charcoal administration should be repeated every 12 hours until the animals are ambulatory because redistribution of barbiturate after activated charcoal has been eliminated from the gastrointestinal (GI) tract may result in recurrence of severe depression. Activated charcoal has been shown to act as a “sink” in enhancing movement of barbiturates from the circulation into the GI tract, and therefore it is of benefit even in cases where the barbiturate was administered parenterally (Volmer 2013).

Animals experiencing severe coma will need intensive supportive care. Endotracheal tube placement may be indicated in those animals with severe coma and subsequent respiratory depression; in some cases mechanical ventilation may be necessary. Oxygen and IV fluids should be administered, and standard nursing care for comatose animals (e.g., prevention of hypothermia and decubital ulcers) is important in those animals experiencing severe toxicosis. Depending on the lipid solubility of the barbiturate involved, IV lipid solutions may assist in removal of barbiturates from the circulation (see Chapter 8).

Prognosis

The prognosis of barbiturate intoxication depends on the amount ingested and the severity and duration of signs at presentation. Comatose animals provided with prompt and appropriate supportive care have a reasonable expectation of recovery, although it may take up to several days.

BENZODIAZEPINES

Sources and Formulations

Benzodiazepines are used in human and veterinary medicine as sedatives, anxiolytics, and anticonvulsants. There are a large number of different benzodiazepines that are distinguished by their onset and duration of action. Benzodiazepines can trigger dependency in human patients and are widely abused in certain populations, especially psychiatric and substance‐abuse patients (Longo and Johnson 2000). Additionally, flunitrazepam (Rohypnol®) has been used illicitly as a “date rape” drug.

Kinetics

Benzodiazepines are well absorbed from the GI tract and are widely distributed throughout the body. They are highly protein bound and highly lipophilic. Most are metabolized in the liver via glucuronide conjugation. Some benzodiazepines have pharmacologically active metabolites with half‐lives exceeding those of the parent compound (Volmer 2013).

Mechanism of Action

Benzodiazepines act on GABA receptors, triggering inhibitory impulses in the CNS and resulting in CNS depression.

Toxicity

Although benzodiazepines can produce intoxications that require veterinary care, they tend to have a wide margin of safety, and death is not common unless very large amounts have been ingested or there is coingestion of other CNS depressants. However, even low doses can cause sedation and ataxia. Dosages greater than or equal to a dosage equivalent to 20 mg/kg of diazepam can cause more severe clinical effects and will need veterinary intervention (American Society for the Prevention of Cruelty to Animals [ASPCA] Animal Poison Control Center [APCC], unpublished data).

Clinical Effects

Signs

Clinical effects of benzodiazepines can occur as rapidly as 10–15 minutes following exposure. The clinical signs associated with benzodiazepine toxicosis include sedation, ataxia, and disorientation. Severely affected animals may become comatose, hypothermic, and hypotensive. Seizures are possible, although uncommon, in comatose patients. Some animals exposed to benzodiazepines present with paradoxical agitation and hyperactivity; in the author's experience, this is most commonly seen with large, ingested doses or with juvenile animals (dogs and cats <6 months of age). Rarely, liver necrosis has been reported following IV use of diazepam in cats (Volmer 2013); whether this is an issue with acute intoxications due to diazepam ingestion is not known.

Laboratory

No significant clinical pathological abnormalities are expected with benzodiazepine overdose. With large exposures, a baseline minimum database is recommended.

Differential Diagnoses

Other CNS depressants that can cause signs similar to those of benzodiazepines include barbiturates, opioids, alcohols, ethylene glycol, marijuana, amitraz, xylitol, antidepressants, centrally acting skeletal muscle relaxants (e.g., baclofen), macrolide antiparasiticides (e.g., ivermectin), sleep aids such as zolpidem, and marijuana. Nontoxicologic rule outs include encephalopathy, encephalitis, head trauma, hypoglycemia, and cerebral vascular accident.

Diagnostics

Blood and urine can be analyzed by most veterinary diagnostic laboratories for the presence of benzodiazepines, although the turnaround time may make the diagnostic laboratory of limited usefulness in diagnosing an acute toxicosis. Over‐the‐counter drug test kits have the advantages of being inexpensive and readily available at most pharmacies and providing rapid results (Teitler 2009). These tests utilize urine and appear to be reasonably reliable for rapid identification of benzodiazepines exposures in dogs. However, false‐positive results may occur in patients previously treated with some NSAIDs (e.g., ibuprofen) or some antidepressants (e.g., sertraline). These kits are not validated in nonhumans, so further testing by a veterinary diagnostic laboratory may be needed in legal cases.

Management of Exposures

Because benzodiazepines have wide margins of safety, animals ingesting small doses (e.g., one tablet) generally can be managed at home provided they can be kept in a secure area away from obstacles (e.g., furniture or stairs) to avoid accidental trauma. Owners should be instructed to keep the animal in a quiet area to reduce the likelihood of paradoxical excitation. Mild ataxia can be dealt with at home, but if the animal becomes recumbent or develops paradoxical excitation, it should be brought to the veterinary hospital for monitoring and further care.

The goals of therapy in benzodiazepine exposures are to minimize absorption and provide symptomatic and supportive care. Because of the potential for rapid onset of signs, decontamination should be performed in the veterinary hospital under veterinary supervision. Ataxic and disoriented animals may be at risk of aspiration if vomiting is induced. For animals showing no or very mild signs, induction of emesis may be considered; otherwise, careful administration of activated charcoal is recommended. Most animals do very well with decontamination and careful monitoring. In the rare event that severe CNS depression develops, respiratory function should be closely monitored, and flumazenil, a benzodiazepine antagonist, may be used for those patients experiencing significant respiratory depression. Because flumazenil has a short duration of action, animals must be closely monitored for return of respiratory depression when the effects of flumazenil subside. Recumbent animals require careful nursing and supportive care, including IV fluid therapy, thermoregulation (hypothermia is common in comatose animals), and prevention of decubital ulcers. Animals experiencing paradoxical excitation should be given a very low dose of acepromazine (0.01–0.02 mg/kg) with the caveat that once the excitation has resolved, the CNS depression may be quite pronounced. Anecdotally, cyproheptadine has also been effective in managing the paradoxical excitation of benzodiazepines. The duration of signs will vary with the type of benzodiazepine, the dose ingested, and the effectiveness of decontamination measure instituted.

Prognosis

Most benzodiazepine overdoses have excellent outcomes, provided patients receive prompt and appropriate care.

COCAINE

Sources and Formulations

Cocaine is an alkaloid extracted from the leaves of the shrub Erythroxylon coca, which grows in Central and South America as well as Indonesia and the West Indies. Therapeutically, cocaine is used as a topical local anesthetic for oral and nasal mucous membranes. However, the most common exposures to cocaine in companion animals occur when they are exposed to illicitly obtained cocaine.

Kinetics

Cocaine is very rapidly absorbed across all mucosal surfaces, and clinical effects can be seen within minutes of exposure. Cocaine is metabolized in the serum and liver, and is excreted as parent compound and metabolites in the urine.

Mechanism of Action

Cocaine is a potent sympathomimetic that blocks the reuptake of norepinephrine and serotonin in the CNS, causing accumulation of these neurotransmitters in the synapse and resulting in prolonged stimulation of postsynaptic neurons. It also sensitizes the myocardial cells to endogenous catecholamines, resulting in tachycardia.

Toxicity

The LD₅₀ for cocaine in dogs is 3 mg/kg IV, and it is reported that dogs can tolerate oral doses two to four times that level (Bischoff 2018).

Clinical Effects

Signs

Signs of cocaine intoxication occur quickly following ingestion and include hyperactivity, hyperthermia, agitation, ataxia, mydriasis, vomiting, vocalization, tachycardia, tremors, and seizures. Severe seizures may result in myoglobinuria or disseminated intravascular coagulopathy secondary to hyperthermia.

Laboratory

Metabolic acidosis and electrolyte abnormalities may be seen with cocaine toxicosis. As with most intoxications, a minimum database should be established, including complete blood count, serum chemistries, and electrolyte status.

Differential Diagnoses

Other intoxications from CNS stimulants such as amphetamines, methylxanthines, other sympathomimetics (e.g., pseudoephedrine, phenylpropanolamine), metaldehyde, antidepressants, tremorgenic mycotoxins, organochlorine insecticides, organophosphorous and carbamate insecticides, 5‐fluorouracil, hypernatremia, ephedra (e.g., ma huang/guarana preparations), 5‐hydroxytryptophan, or lead should all be considered when presented with a patient with severe CNS and cardiovascular stimulation.

Diagnostics

Blood, stomach contents, and urine can be analyzed by most veterinary diagnostic laboratories for the presence of cocaine, although the turnaround time makes the diagnostic laboratory of limited usefulness in diagnosing an acute toxicosis. Over‐the‐counter drug test kits have the advantages of being inexpensive and readily available at most pharmacies and providing rapid results (Teitler 2009). These tests utilize urine and appear to be reasonably reliable for rapid identification of cocaine exposures in dogs. These kits are not validated in nonhumans, so further testing by a veterinary diagnostic laboratory may be needed in legal cases.

Management of Exposures

The goals of managing cocaine intoxications include stabilization of the symptomatic patient, decontamination (when feasible), and providing symptomatic and supportive care to minimize complications. Because of the potential for very rapid onset of severe signs with cocaine ingestion, emesis should only be induced in a veterinary setting and only in asymptomatic animals. Attempting emesis in even mildly symptomatic animals may trigger seizures. Sedation and gastric lavage should be considered, especially if animals have begun to show clinical signs of intoxication. Activated charcoal should follow emesis or lavage. Police dogs that have ingested bags of cocaine or dogs with surgically implanted bags (cocaine “mules”) should be anesthetized and the bags carefully extracted surgically or via endoscopy to avoid rupture and spillage of cocaine onto tissues (Bischoff 2018).

Diazepam should be used to manage existing seizures. Barbiturates should be used for seizures refractory to diazepam. Acepromazine or chlorpromazine may work better than diazepam at managing agitation in nonseizing animals. Cyproheptadine has been recommended by some to block the effects of excess serotonin caused by cocaine; this often helps with disorientation, hyperthermia, and vocalization (ASPCA APCC, unpublished data). Severe tachycardia may be treated with propranolol once the agitation and hyperactivity is under control. IV fluids will help with hyperthermia as well as provide cardiovascular support.

Prognosis

The prognosis will depend on the amount of cocaine ingested and the duration and severity of signs at presentation. Animals experiencing seizures have a more guarded prognosis.

ECSTASY

Sources and Formulations

Ecstasy (MDMA) is a type of amphetamine. It has hallucinogenic effects.

Kinetics

Clinical signs develop 30 minutes to 2 hours after ingestion.

Mechanism of Action

Ecstasy has a more potent effect on the release of serotonin when compared to other amphetamines.

Toxicity

Unknown, but small amounts appear to cause clinical signs.

Clinical Signs

Signs

See serotonin syndrome (Chapter 23).

Laboratory

No laboratory changes are expected.

Differential Diagnoses

See serotonin syndrome (Chapter 23).

Diagnostics

MDMA may cross react on urinary amphetamine screens.

Management of Exposures

See serotonin syndrome (Chapter 23).

Prognosis

Prognosis in most cases is good.

GHB

Sources and Formulations

Gamma‐hydroxybutyric acid (GHB, Liquid Ecstasy) is a naturally occurring CNS depressant. It was originally used as an anesthetic agent but was banned in the United States in the early 1990s. It is a schedule 1 controlled substance. GHB is now promoted illegally as a growth hormone stimulant, diet aid, anabolic, hypnotic, and euphoriant (Smith 2005). Despite the ban on the sale and manufacture of GHB, mail‐order kits and the internet have resulted in easy access to this agent. Health food products used as sleep aids may contain gamma‐butyrolactone (GBL) or 1,4‐butanediol (BD), which produce similar effects as GHB.

Kinetics

The onset of signs is rapid after oral ingestion (15–30 minutes). Peak blood levels of GHB occur 15–45 minutes after oral administration and elimination is rapid (complete elimination within 4–6 hours).

Mechanism of Action

The exact mechanism of GHB action in the CNS is unknown, but GHB is structurally related to GABA (precursor in GHB formation).

Toxicity

The toxic dose in dogs is unknown but appears to be small.

Clinical Signs

Signs

Clinical signs are dose‐related CNS depression, hypotonia, sedation, ataxia, disorientation, coma, bradycardia, tremors, respiratory depression, and vomiting (Smith 2005).

Laboratory

No laboratory changes are expected.

Differential Diagnoses

Toxic differentials include ethanol, barbiturates, benzodiazepines, opioids, and muscle relaxants.

Diagnostics

GHB is not detected on most routine urine and serum toxicology screens.

Management of Exposures

Emesis is contraindicated due to the rapid onset of CNS depression. GHB is rapidly absorbed, so activated charcoal is also not likely to be beneficial. There is no antidote. Treatment is symptomatic and supportive. Monitor pulse oximetry and/or arterial blood gases in patients with respiratory depression. Intubation and ventilation may be needed (Smith 2005).

Prognosis

Prognosis in most cases is good.

LSD

Sources and Formulations

Lysergic acid diethylamide (LSD, acid) is an indole derivative with strong hallucinogenic effects that acts as a nonselective serotonin agonist (Volmer 2013). LSD can come as a powder, tablet, capsule, sugar cube, or a drop of solution evaporated on filter or blotting paper (“blotter acid” or “postage stamps”). It can also be incorporated into a square of gelatin (“windowpane”). LSD is frequently adulterated. A natural source of LSD are the seeds of the morning glory family (Ipomoea sp.).

Kinetics

After ingestion, absorption is quite rapid and signs can be seen in 20–90 minutes. Signs may last for 0.7–12 hours depending on the dose (Volmer 2013).

Mechanism of Action

LSD is a serotonergic hallucinogen. In humans it binds to serotonin, dopamine, and alpha‐2 receptors. The exact mechanism is unknown in dogs.

Toxicity

There are no published oral doses, but 2 mcg/kg intraperitoneally in cats was enough to cause clinical signs (Jacobs et al. 1977).

Clinical Signs

Signs

Disorientation, mydriasis, tachycardia, hypertension, and tremors are the most commonly seen signs in dogs. Cats may vocalize, rub, tread, and groom (Jacobs et al. 1977). Larger amounts in cats have caused tachycardia, tachypnea, hyperglycemia, hypertonia, and hyperthermia (Passie et al. 2008).

Laboratory

No laboratory changes are expected.

Differential Diagnoses

Toxic differentials include all serotonergic medications.

Diagnostics

LSD is not detected on most routine toxicology screens.

Management of Exposures

Because of rapid absorption, the value of GI decontamination is limited. A quiet, dimly lit room should be provided, and benzodiazepines are the mainstay of therapy. Cyproheptadine and phenothiazines may also be used for their antiserotonin effects. Fluids and supportive care can be given as needed.

Prognosis

Deaths from LSD are usually due to misadventure during hallucinations.

MARIJUANA

Sources and Formulations

Marijuana is the flower (or bud), leaves, seeds, and stems of the Cannibis sativa plant, with the flowers containing the highest concentration of cannabinoids (see Figure 25.1). The major active ingredient of marijuana is the cannabinoid delta‐9‐tetrahydrocannabinol (THC). Marijuana may be legal for recreational or medical use at the state level in the United States, although it remains illegal on the federal level. It is used medicinally in humans to limit nausea in chemotherapy patients and to lower intraocular pressure in glaucoma patients (Janczyk et al. 2004). Marinol®, a tablet form of synthetic THC, is approved for the relief of nausea and vomiting in chemotherapy cancer patients and assists with loss of appetite in AIDS patients. Most companion animals are exposed when they ingest edibles or a “stash” of marijuana, although exposures to medicinal agents or, rarely, through inhalation of smoke from marijuana cigarettes intentionally blown into their faces are possible (Janczyk et al. 2004).

Figure 25.1. Marijuana buds or flower.

Kinetics

THC is rapidly absorbed after ingestion or inhalation, with onset of effects occurring within 6–12 minutes of inhalation and 30–60 minutes of ingestion (Donaldson 2002). THC is highly lipid‐soluble and highly protein‐bound, and undergoes a significant first‐pass effect when ingested. Because of high levels of storage of THC in body fat, the half‐life is relatively long (25–30 hours), with 80–90% being eliminated by 5 days after exposure.

Mechanism of Action

The cannabinoids in marijuana act on cannabinoid‐specific receptors within the CNS, which trigger most of the psychoactive effects of marijuana. Cannabinoids also interact with a variety of CNS neurotransmitters, stimulating the release of dopamine, enhancing GABA turnover, and enhancing the synthesis of norepinephrine, dopamine, and serotonin (Donaldson 2002).

Toxicity

The minimum toxic dosage of marijuana in dogs is reported to be 84.7 mg/kg of dry leaves, which is the equivalent of approximately half a teaspoon of dry leaves in a 30‐kg dog (Gwaltney‐Brant 2004). Although marijuana can produce significant clinical effects at low exposure levels, it does have a wide margin of safety, with the lethal dose being over 1000 times the behaviorally effective dose (Volmer 2013). Doses of 3–28 g/kg of marijuana did not result in deaths in dogs. Deaths from marijuana ingestion may be more likely the result of accidental misadventure (e.g., trauma) or leading to complications of preexisting serious health issues (e.g., prior cardiac dysfunction) than from a direct effect of the cannabinoids in marijuana. However, the breeding of more potent strains of marijuana in some areas along with the concentration of THC in “edibles” has at times resulted in more severe clinical signs, including deaths, in dogs exposed to these products. In addition, the combination of marijuana with other psychoactive substances (mushrooms) or methylxanthines (chocolate) or xylitol can result in more severe intoxications.

Clinical Effects

Signs

The most common clinical effects seen in marijuana toxicosis in dogs and cats are depression, ataxia, and bradycardia. Other common signs include agitation, disorientation, vocalization, vomiting, hyperesthesia, hypothermia, urinary incontinence, mydriasis, hypersalivation, and diarrhea; recumbency, urinary retention, coma, and seizures are reported less frequently (Bischoff 2018; Donaldson 2002; Gwaltney‐Brant 2004). More potent forms of THC from marijuana butter, “edibles,” and special marijuana strains may result in unexpected signs such as hyperthermia, hypertension, tachycardia, seizures, coma, and death. A single case of atopic dermatitis in a dog thought to be associated with marijuana has been reported (Evans 1989).

Laboratory

As with most intoxications, a baseline minimum database consisting of serum chemistry and complete blood count is recommended to identify any concurrent disease issues. Marijuana is not expected to cause any specific laboratory abnormalities.

Differential Diagnoses

Intoxication from other CNS depressants such as macrolide antiparasiticides (e.g., ivermectin), amitraz, benzodiazepines, barbiturates, opioids, alcohols, ethylene glycol, centrally acting skeletal muscle relaxants, sedatives, and isoxazole and hallucinogenic mushrooms should all be considered in the differential list if marijuana exposure is suspected but cannot be confirmed historically. Nontoxic differentials include head trauma, encephalopathy, encephalitis, and hypoglycemia.

Diagnostics

Stomach contents and urine can be analyzed by most veterinary diagnostic laboratories for the presence of cannabinoids, although the turnaround time makes the diagnostic laboratory of limited usefulness in diagnosing acute toxicosis. Over‐the‐counter drug test kits, which work so well on other drugs of abuse in dogs, appear to be less reliable in the detection of marijuana exposures (Teitler 2009). It is possible that the metabolite that many of these tests detect is not one that is excreted by dogs in sufficient quantities for the test to identify, or that veterinary patients tend to be presented very early in intoxication before sufficient metabolites have been produced. However, some veterinary emergency clinics have reported to the author that they have found some brands of test kits that do appear to work. So, when using the kits, it is important to remember that a negative test does not completely rule out marijuana exposure and confirmation from an analytical laboratory should be considered. False‐positive results may occur from prior exposure to NSAIDs (e.g., ibuprofen, naproxen). The over‐the‐counter kits are not validated in nonhumans, so further testing by a veterinary diagnostic laboratory may be needed in legal cases.

Management of Exposures

Fortunately, marijuana exposures are rarely life‐threatening, and providing good supportive care and decontamination is generally all that is needed for successful recovery. Emesis should be induced in animals with no clinical signs. Central nervous stimulation can be managed with diazepam. Body temperature should be monitored, and hypothermia corrected as needed. IV fluids will assist in cardiovascular support but will not enhance elimination of marijuana. For comatose or hypotensive animals, IV lipid therapy has been used (Robben and Dijkman 2017).

Prognosis

The prognosis in most uncomplicated cases of marijuana intoxication is excellent and most patients will make full recoveries within 2 to 5 days. Once the patient's disorientation has largely resolved and the patient is able to maintain normal body temperature and heart rate, it may be discharged from the hospital. Close supervision is recommended for 5 days after ingestion to avoid accidental injury from any residual ataxia.

NICOTINE

Sources and Formulations

Nicotine is an alkaloid derived from both cultivated (Nicotiana tabacum) and wild tobaccos (N. attenuata, Nicotiana trigonophylla). Animals can ingest nicotine by eating cigarettes, cigars, pipe tobacco, snuff, nicotine gum, patches, or vapes.

Kinetics

Nicotine is well absorbed orally (15–30 minutes after chewing gum, 30–90 minutes for ingestion of tobacco) from the small intestine. Gastric alkalinization enhances oral absorption of nicotine. The duration of signs is dose dependent and can vary from 1 to 2 hours following mild exposures up to 24 hours for severe exposures (Hackendahl and Sereda 2004).

Mechanism of Action

Nicotine mimics acetylcholine at sympathetic and parasympathetic ganglia, neuromuscular junctions of skeletal muscle, and some synapses in the CNS. Low doses cause depolarization and stimulation of receptors similar to acetylcholine. Higher doses cause stimulation followed by blockade at autonomic ganglia and myoneural junctions of skeletal muscle (Hackendahl and Sereda 2004).

Toxicity

The oral LD₅₀ in the dog is 9.2 mg/kg. See Table 25.1 for the nicotine content of various products.

Clinical Signs

Signs

Clinical signs include initial excitation, tachypnea, salivation, emesis, and diarrhea, followed by muscle weakness, tremors, and depression. Large doses can cause tachycardia, shallow, slow respirations, collapse, coma, cyanosis, cardiac arrest, and death.

Laboratory

No specific changes are expected.

Differential Diagnoses

Toxic differentials include strychnine, methylxanthines, tremorgenic mycotoxins, and organophosphate or carbamate insecticides (Hackendahl and Sereda 2004).

Diagnostics

Nicotine levels can be tested for in blood, vomitus, gastric contents, or urine, but are not clinically relevant due to turnaround time.

Management of Exposures

If asymptomatic, induce emesis and potentially give activated charcoal. Symptomatic care includes: IV fluids, oxygen and/or artificial ventilation, benzodiazepines or barbiturates for seizures, and atropine if parasympathetic effects are present. Antacids are contraindicated because they will enhance absorption.

Table 25.1. Nicotine content of commercially available products

Source: Modified from Hackendahl and Sereda (2004).

Product
Nicotine Content

Cigarette
9–30 mg/cigarette
3–8 mg/low‐yield cigarette

Cigar
15–40 mg/cigar

Chewing tobacco
6–8 mg/g

Snuff
4.6–32 mg/g (moist)
12–16 mg/g (dry)

Nicotine gum
2–4 mg/piece (may contain xylitol)

Nicotine patch
8.3–114 mg/patch

Nicotine nasal spray
100 mg/10 ml (0.5 mg/spray)

Nicotine inhaler (vape)
0–250 mg/ml

Black leaf 40 (insecticide)
400 mg/ml

Prognosis

Poor prognosis with large doses or if artificial ventilation is required.

OPIATES AND OPIOIDS

Sources and Formulations

There are many opiates and opioids used in human and veterinary medicine. Opiates are natural extracts derived from the opium poppy, Papaver somniferum. Opioids are semisynthetic or fully synthetic compounds that act on opiate receptors. Opiates include morphine and codeine, while semisynthetic opioids include oxymorphone, hydromorphone, hydrocodone, oxycodone, heroin, etorphine, and buprenorphine. Fully synthetic opioids include fentanyl, methadone, propoxyphene, and tramadol. For ease of this discussion, the term opioid will be used to include both opiates and opioids.

Opioids are used in veterinary and human medicine for their analgesic effects. Fentanyl suckers, lozenges, and transdermal patches are becoming more frequently used in both human and veterinary medicine. The lozenges or suckers contain fentanyl citrate in a sucrose and liquid glucose base and are attractive to animals. Companion animals are most commonly exposed when they ingest their own or their owner's medication, lozenges, or discarded fentanyl patches.

Kinetics

Most opioids are well absorbed from the GI tract. Although fentanyl in transdermal patches has poor absorption from the GI tract due to first‐pass effect, significant amounts of fentanyl can be absorbed transmucosally when animals chew the patches. Metabolism varies, but opioids generally undergo hepatic metabolism with some form of conjugation, hydrolysis, oxidation, glucuronidation, or dealkylation. The requirement for metabolism via glucuronidation may account for the relative sensitivity of cats to opioids.

Mechanism of Action

Opioids are generally classified by their ability to exert effects at the different opioid receptors (mu, kappa, delta, sigma), and by their agonist or antagonist effects on those receptors. Partial agonists act as agonists at one or more opioid receptors and as antagonists at others. Opioids act centrally to elevate the pain threshold and to alter the psychological response to pain. Most of the clinically used opioids exert effect at the mu receptor (mu‐1 subtype mediates analgesic effects, mu‐2 mediates respiratory depression). Opioids also can induce emesis through stimulation of the dopamine receptors in the chemoreceptor trigger zone (Volmer 2013). Opioids can, paradoxically, sometimes cause CNS excitation in overdose situations. The exact mechanism is not known but is postulated to involve stimulation of dopaminergic, adrenergic, cholinergic, and/or serotonergic receptors, possibly associated with inhibition of GABA receptors (KuKanich and Papich 2018; Tashakori and Afshari 2010).

Toxicity

The toxicity of individual opioid compounds varies considerably. The minimum lethal dosage of morphine in laboratory dogs is between 110 and 210 mg/kg (Bischoff 2018). Heroin given at 0.20 mg/kg to dogs (route not specified) caused sedation and respiratory depression. The minimum lethal dosage of heroin is 25 mg/kg subcutaneously in dogs and 20 mg/kg orally in cats. Oxymorphone, fentanyl, and etorphine have approximately 10, 80, and 10,000 times the potency of morphine, respectively.

Clinical Effects

Signs

In dogs, CNS signs include depression, ataxia, and seizures. Respiratory depression, vomiting, bradycardia, and hypotension may also be seen. Cats may show excitatory behavior and urinary retention. Some opioids, such as tramadol, can result in serotonin syndrome in overdose situations (see Chapter 23 for further information on serotonin syndrome).

Laboratory

As with most intoxications, a baseline minimum database consisting of serum chemistry and complete blood count is recommended to identify any concurrent disease issues.

Differential Diagnoses

Intoxication from other CNS depressants such as macrolide antiparasiticides (e.g., ivermectin), amitraz, benzodiazepines, barbiturates, alcohols, ethylene glycol, centrally acting skeletal muscle relaxants, sedatives, and isoxazole and hallucinogenic mushrooms should all be considered in the differential list if opioid exposure is suspected but cannot be confirmed historically. Nontoxic differentials would include head trauma, encephalopathy, encephalitis, and hypoglycemia.

Diagnostics

Blood, stomach contents, and urine can be analyzed by most veterinary diagnostic laboratories for the presence of opioids, although the turnaround time makes the diagnostic laboratory of limited usefulness in diagnosing acute toxicosis. Over‐the‐counter drug test kits have the advantages of being inexpensive and readily available at most pharmacies and providing rapid results (Teitler 2009). These tests utilize urine and appear to be reasonably reliable for rapid identification of opioid exposures in dogs, although false‐positive results may occur from prior exposure to dextromethorphan, doxylamine, quinolone antibiotics (e.g., enrofloxacin), some antipsychotic medications, and poppy seeds. These kits are not validated in nonhumans, so further testing by a veterinary diagnostic laboratory may be needed in legal cases.

Management of Exposures

The goals in the management of opioid overdoses include stabilizing and decontaminating the patient, providing ventilatory support, and providing supportive care until recovery. Treatment in an asymptomatic animal may include emesis if the ingestion is recent. Activated charcoal with cathartic should be administered and the patient monitored for up to 12 hours. If the animal becomes symptomatic, respiratory support may need to be given. If severe respiratory depression is seen, naloxone (a pure competitive antagonist with activity at the mu receptors) can be administered to reverse respiratory effects. As the duration of action of naloxone is much shorter than that of the opioids, repeat dosages may be necessary. Naloxone may not result in the animal regaining full consciousness. Partial agonists/antagonists (i.e., butorphanol) may be used to partially reverse the effects of pure agonists if no naloxone is available. Animals exhibiting signs of serotonin syndrome (agitation, vocalization, disorientation) may benefit from the use of cyproheptadine. Monitoring of temperature, cardiac function, and blood gases is important. Treatment times will vary with the half‐life of the opioid.

Prognosis

If respiratory and cardiovascular function can be maintained, the prognosis is good. For those cases that experience seizures, prognosis is more guarded.

PCP

Sources and Formulations

Phencyclidine (angel dust, PCP) is a potent analgesic and anesthetic. It is a sympathomimetic and hallucinogenic drug that is structurally similar to ketamine.

Kinetics

PCP is rapidly absorbed with the onset of action within 5 minutes. In a large overdose, effects may be seen for days following ingestion (Volmer 2013).

Mechanism of Action

PCP is thought to stimulate alpha‐adrenergic receptors, potentiating the effects of norepinephrine, epinephrine, and serotonin.

Toxicity

In one study in dogs, pronounced clinical symptoms were observed with a dose of 2.5–10 mg/kg PO and a dose of 25 mg/kg PO was lethal for all six poisoned dogs (Volmer 2013), but the first signs of intoxication were seen at doses as low as 1 mg/kg. In cats, marked clinical symptoms were seen at doses from 1.1 to 12 mg/kg IV (Volmer 2013).

Clinical Signs

Signs

Signs include nystagmus, ataxia, muscle rigidity, hyperesthesia, aggression, hypertension, coma, and seizures.

Laboratory

No laboratory changes are expected.

Differential Diagnoses

Toxic differentials include psilocybin, LSD, ketamine, cocaine, and amphetamines.

Diagnostics

Major laboratories can measure specific PCP levels and identify active metabolites as well.

Management of Exposures

Due to the quick onset of signs, decontamination is not a viable option. Monitor pulse oximetry, blood gases, body temperature, and electrolytes. Minimize all sensory stimuli. IV benzodiazepines should be given if the animal is agitated, seizuring, or hypertensive. Large doses may be required in severely agitated patients. If severe hypertension persists, treat with IV nitroprusside.

Prognosis

Prognosis is good to guarded.

PSILOCYBIN MUSHROOMS

See Chapter 28 for more information.

SALVIA

Sources and Formulations

Salvia divinorum (salvia) is a plant in the mint family that has been used historically for religious rituals and herbal healing. Salvia contains salvinorin A, which is hallucinogenic (Teksin et al. 2009). Salvia is not scheduled by the Drug Enforcement Agency but some states have restrictions.

Kinetics

Humans typically smoke salvia and hallucinations occur within seconds and may last for 30 minutes. There is some absorption through the oral mucosa, but hallucinogenic effects are not seen after oral ingestion in humans (Margalho et al. 2016).

Mechanism of Action

Salvia acts as an agonist at kappa opioid receptors and this is thought to be responsible for the hallucinogen effect in humans (Margalho et al. 2016; Teksin et al. 2009). The mechanism in dogs is unknown.

Toxicity

The toxic dose in dogs is unknown.

Clinical Signs

Signs

ASPCA APCC data shows dogs exposed to S. divinorum develop signs similar to THC (anxiety, ataxia, bradycardia, hyperthermia, nausea, panting, sedate, and urinary incontinence).

Laboratory

No laboratory abnormalities are expected.

Differential Diagnoses

Toxic differentials include THC, opioids, and alpha‐2 agonists.

Diagnostics

Salvia testing must occur through a diagnostic laboratory.

Management of Exposures

Treatment is the same as for THC (see the section on marijuana in this chapter).

Prognosis

Prognosis is good.

NEWER PSYCOACTIVE SUBSTANCES

Newer psychoactive substances (NPS) are a group of unrelated drugs that have been developed to mimic established drugs such as cocaine, MDMA, LSD, and marijuana. The creators of these compounds attempt to circumvent the legal system by creating unique chemicals that produce similar effects to their illicit counterparts but are chemically unrelated, so technically they fall outside of the existing laws (until they are subsequently specifically included in those laws). Some of the more common names for these substances include designer drugs, herbal ecstasy, party pills, bath salts, and legal highs. Several hundred of these compounds have been identified by law enforcement agencies around the world, and their usage in the Unted States has increased significantly over the past 10 years (Shafi et al. 2020).

Table 25.2. Examples of new psychoactive substances

Name | Street Names | Effects | Comments
Synthetic stimulants | Khat, Bath Salts, Monkey Dust, MDAI Gold, Pink Champagne | Agitation, disorientation, tachycardia, hyperthermia, hypertension, vomiting, seizures | Effects resemble amphetamines and other sympathomimetics
Synthetic cannabinoids | K2, Spice, Legal Weed, Black Mamba Scooby Snax, Skunk | Hyperesthesia, tremors, agitation, hypothermia/hyperthermia, ataxia, aggression, seizures | Effects resemble mix of marijuana and sympathomimetics
Synthetic hallucinogens | Foxy, Haze, Ecstasy, LSD | Disorientation, anxiety, vocalization, mydriasis, ataxia, vomiting, hyperthermia | Rarely life‐threatening; extreme behavior changes (especially aggression) common
Synthetic depressants | Legal benzodiazepines, research chemicals, Benzos, Pinky | Sedation, stupor, hypothermia, respiratory depression, coma, paradoxical stimulation | Effects resemble opioids or benzodiazepines

Although the proponents of NPS claim that these compounds are safer than the actual drugs they are mimicking, in reality these drugs tend to be more potent (and therefore more easily overdosed) and, because they are often manufactured in make‐shift laboratories, they frequently contain hazardous contaminants or adulterants that can cause significant health problems. NPS generally fall into four rough categories based on their clinical effects: synthetic stimulants, synthetic cannabinoids, synthetic depressants, and synthetic hallucinogens; Table 25.2 provides a brief summary of these four classes. It is important to note that there currently are no over‐the‐counter or cage‐side tests that will detect these drugs in a timely fashion, and for many, testing is only available through forensic laboratories. Management of these cases entails symptomatic and supportive care.

REFERENCES

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26
Zootoxins

Tamara Foss

INTRODUCTION

Zootoxins are toxins originated from animals. Toxins from poisonous animals are generally delivered through tissue contact with, or ingestion of, another animal. Venomous animals inject their toxin into another animal, effectively envenomating them. There are a multitude of animal species that are poisonous or venomous. Their geographic distribution and impacts vary greatly across the world. This chapter highlights zootoxins associated with animals primarily established in the United States that are clinically relevant to dogs and cats.

HYMENOPTERA: BEES, WASPS, AND HORNETS

Sources

The order Hymenoptera includes three medically important families of insects: bees of the family Apidae, wasps and hornets of the family Vespidae, and fire ants of the family Formicidae. Bees, wasps, and hornets are credited with being responsible for more human deaths than any other venomous animal (Cowell et al. 1991).

The family Apidae includes European honeybees, Africanized honeybees, bumblebees, and carpenter bees. All Apids feed on nectar and pollen, and can sting only once because they are eviscerated and die after their barbed stinger is left behind. European honeybees, although protective of their hives, are considered to be less aggressive than their Africanized honeybee relatives and Vespids. When honeybees, especially Africanized honeybees, sting, they release an alarm pheromone that alerts and attracts other bees (Diaz 2007). Africanized honeybees are more easily agitated, experience more prolonged agitation, and defend a greater distance of area around their hives than their European counterparts (Rodriguez‐Lainz et al. 1999). Although bigger than honeybees, bumblebees and carpenter bees do not receive as much discussion in the literature and are considered less aggressive than honeybees (Diaz 2007).

The family Vespidae includes yellow jackets, hornets, and wasps. Vespids are predatory carnivores; they feed on other insects and are attracted to sweet foods and meats. Vespid stingers are not barbed and are therefore not left behind in the victim, so a lone vespid has the ability to sting multiple times.

Solenopsis invicta, the red imported fire ant, a member of the Formicidae family, is the primary species of concern in regard to envenomation of animals (Gwaltney‐Brant et al. 2018). There are unique clinical signs that develop with fire ant envenomation, as discussed later.

Toxicity

The amount of venom delivered to a victim does not determine whether an anaphylactic reaction will result. A single sting can result in anaphylaxis. Cases involving multiple stings result in higher venom doses delivered to the victim and a greater toxic reaction (Fitzgerald 2013). The estimated lethal dose is approximately 20 stings/kg for most mammals (Fitzgerald and Flood 2006).

Toxicokinetics and Mechanism of Action

Only female bees and wasps are able to sting. The stinger is associated with venom glands within the modified ovipositor (Gwaltney‐Brant et al. 2018). Hymenoptera venoms contain proteins (which are largely responsible for allergic responses), peptides, and enzymes (which are also made up of proteins). The two major enzymes implicated in allergic responses in Apid envenomations are phospholipase and hyaluronidase (Gwaltney‐Brant et al. 2018). Phospholipase A2 is a major allergen and is regarded as the most lethal peptide in honeybee venom (Schmidt 1995). Melittin, which is unique to honeybee venom, is responsible for the local pain associated with a sting. Honeybee venom also contains the neurotoxin apamin (Fitzgerald and Flood 2006).

Vespid venoms contain serotonin, kinins, and acetylcholine, all of which are believed to play a role in production of the intense pain that follows envenomation (Fitzgerald and Flood 2006). Antigen 5 is the major allergenic component of vespid venom (Fitzgerald and Flood 2006). Mastoparans are peptide toxins found in wasp venom, which are similar to but less potent than mast cell degranulation peptide 401 found in Apid venom (Fitzgerald and Flood 2006).

Clinical Effects

Signs

A localized reaction including pain and swelling will generally occur in all victims of envenomation. Erythema can be seen, and embedded stingers can result in abscess formation. Local reactions can go unnoticed since the reaction often does not progress in severity and resolves without treatment within 24 hours (Fitzgerald and Flood 2006).

Allergic or hypersensitivity reactions can also occur and vary in their severity. They can be relatively moderate on the continuum of allergic reactions and present as more regional swelling of an area in which a sting was received (Rodriguez‐Lainz et al. 1999), or they can be as severe as an anaphylactic response and result in death. Anaphylaxis occurs fairly infrequently in animals, but if it is going to occur, signs typically develop within 10–15 minutes (Fitzgerald and Flood 2006; Rodriguez‐Lainz et al. 1999). Anaphylactic signs include urticaria, pruritus, angioedema, vomiting, diarrhea, lethargy, hematuria, laryngeal edema, dyspnea, hyperpnea, tachycardia, possibly hypotension in dogs and cats, ataxia, syncope, seizures, and death (Fitzgerald and Flood 2006; Gwaltney‐Brant et al. 2018; Reed and Landolt 2018; Rodriguez‐Lainz et al. 1999). Anaphylactic reactions in cats can involve salivation and collapse (Cowell and Cowell 1995).

Nonanaphylactoid systemic or toxic reactions typically are delayed for 6–24 hours, or even up to several weeks or months (Reed and Landolt 2018). Reactions seen include serum sickness, vasculitis, glomerulonephritis, neuropathy, disseminated intravascular coagulation, and arthritis (Fitzgerald and Flood 2006). Other possible conditions include acute lung injury/acute respiratory distress syndrome (Walker et al. 2005) and immune‐mediated hemolytic anemia (Noble and Armstrong 1999). Specific signs include ataxia, prostration, convulsions, CNS depression, shock, hyperthermia, bloody diarrhea, bloody vomiting, hematuria, leukocytosis, intravascular hemolysis, increased blood urea nitrogen (BUN), and elevated alanine transaminase (ALT) (Cowell et al. 1991; Fowler 1993; Gwaltney‐Brant et al. 2018). Cats can develop hepatic injury following hornet envenomation (Gwaltney‐Brant et al. 2018).

Laboratory

When systemic reactions or anaphylaxis occur, it is important to monitor laboratory values, including urinalysis and various blood chemistries such as ALT, total bilirubin, electrolyte levels, BUN, creatinine, arterial blood gases, and serum creatine kinase. Urine can be red or brown and might contain granular casts (Cowell and Cowell 1995). Blood hemograms reflect an inflammatory leukogram: leukocytosis with a left shift. Anemia may occur with marked spherocytosis (Cowell and Cowell 1995). Rhabdomyolysis and acute renal failure can occur. Electrocardiograph monitoring may be necessary.

Differential Diagnoses

In cases that develop anaphylaxis, it is prudent to rule out other potential toxicological causes such as spiders or other insects. Rule‐outs to keep in mind include infection, abscess, trauma, neoplasia, allergy, abscessed tooth, or foreign object (Fitzgerald 2013). Another possible differential diagnosis is heatstroke (Cowell et al. 1991). Differential diagnoses for animals presenting with respiratory distress should also include acute lung injury/acute respiratory distress syndrome, aspiration pneumonia, interstitial pneumonia, congestive heart failure, and pulmonary thromboembolism (Walker et al. 2005). A potential diagnosis for sudden unexplained death is insect sting, especially when death occurs outdoors (Diaz 2007).

Diagnostics

Antemortem

Evidence of stingers is diagnostic of Apid envenomation. Stingers will not be present with Vespid envenomation. Areas most commonly stung in animals include the head and neck, oral cavity, and limbs and paws (Oliveira et al. 2007).

Postmortem

Postmortem findings include facial edema, gastric hemorrhage, petechiation of the epicardium, and red‐black urine (Noble and Armstrong 1999). Facial cellulitis, lung and liver congestion, and pulmonary hemorrhage might also be noted (Noble and Armstrong 1999). Bees and wasps can be found in the gastrointestinal tract (Rodriguez‐Lainz et al. 1999).

Management of Exposures

Single sting envenomations can cause pain and swelling. In most cases, treatment will not be necessary (Fitzgerald and Flood 2006). If the incident is witnessed and a stinger is located, it can be removed by scraping it away from the injection site. The pet should be monitored for anaphylaxis for the first 10–15 minutes following an envenomation.

Anaphylaxis must be treated intensively. Epinephrine should be administered subcutaneously (Cowell and Cowell 1995). Cardiac monitoring and respiratory support are vital. Intubation and administration of oxygen may be needed. Fluid administration with a crystalloid solution is important to avoid vascular collapse (Fitzgerald and Flood 2006). Antihistamines are recommended in addition to oxygen for cases involving dyspnea and utilization of diazepam for convulsions (Fowler 1993). Corticosteroid administration did not increase survival (Fosset et al. 2023).

Cases involving more severe regional reactions and multiple stings should be hospitalized and closely monitored. If hypotension develops, an intravenous bolus of normal saline should be given (Fitzgerald and Flood 2006). Since hymenopterid venom can be nephrotoxic, it is important to provide continuous fluid administration to ensure normal urine output (Fitzgerald and Flood 2006). Additional treatment including continued fluid and electrolyte therapy and prevention of vascular stasis will be required if signs progress. Toxic reactions, most often associated with massive envenomations, also require closer monitoring of major systems including hematologic profiles, cardiac and respiratory function, and renal sufficiency for several days (Fitzgerald and Flood 2006). The more rapidly a patient can be stabilized and provided with supportive care, the better chance for a positive outcome. Even after resolution of signs, monitoring should continue for 24 hours in patients suffering anaphylactic or massive envenomation responses (Fitzgerald and Flood 2006).

Prognosis

Most animals that are victims of single‐sting Hymenoptera envenomation will not develop serious signs, so overall, prognosis is very good. Patients that develop anaphylaxis have a better chance of full recovery if they survive the first 60 minutes of the initial envenomation (Fitzgerald and Flood 2006). The chance of recovery increases for animals that experience anaphylaxis or develop severe reactions from multiple‐sting envenomation if treatment is sought immediately.

HYMENOPTERA: IMPORTED FIRE ANTS

Sources

Fire ants belong to the order Hymenoptera in the family Formicidae. Two species of imported fire ants, Solenopsis richteri (black imported fire ants) and S. invicta (the red imported fire ant), are the most problematic and dangerous formicids to humans, agriculture, companion animals, livestock, and wildlife. Due to its greater distribution as compared to S. richteri, S. invicta is the primary species of concern. Imported fire ants have bred with local native ants and in doing so have created hybrids that appear more cold tolerant and are estimated to be able to survive minimum temperatures of −17.8 °C (0 °F), which could result in at least 25% colonization of the continental United States (Fitzgerald 2013).

Toxicity

Animals that are young or advanced in age and that have reduced mobility are especially vulnerable due to not being able to move away from fire ants. Anaphylaxis can occur after fire ant envenomation and is not predictable based on dose or the number of stings received (Fitzgerald 2013). Fatalities associated with fire ant envenomation in humans are largely due to anaphylaxis (Fitzgerald 2013). However, there are no known reports of animal deaths from fire ant stings as a result of anaphylaxis (Reed and Landolt 2018). Since fire ant envenomations generally occur en masse due to their aggressive and swarming nature, multiple stings leading to systemic toxicity are possible. There is no established lethal number of stings for mammals.

Toxicokinetics and Mechanism of Action

Fire ants bite and sting. The stingers are not barbed, so they are capable of delivering multiple stings. Fire ants initially bite and then rotate about their fixed heads in a circular fashion as they repeatedly sting (Fitzgerald 2013). Formicid venom is unique compared to bee, wasp, and hornet venom. It comprises 95% water‐insoluble alkaloids (Fitzgerald 2013). The dermal necrosis that occurs with envenomation and local reactions are attributed to the alkaloid portion of the venom (Rakich et al. 1993; Reed and Landolt 2018). The alkaloid portion includes solenopsin A (trans‐2‐methyl‐6‐n‐undecylpiperidine), which is a piperidine alkaloid derivative (Conceicao et al. 2006). The alkaloids have cytotoxic, hemolytic, insecticidal, and bactericidal properties (Gwaltney‐Brant et al. 2018; Rakich et al. 1993). Unlike the high protein content in bee, wasp, and hornet venom, only approximately 1–5% of fire ant venom is proteinaceous (Cowell and Cowell 1995; Gwaltney‐Brant et al. 2018; Reed and Landolt 2018). The proteinaceous component of fire ant venom includes hyaluronidase and phospholipase, and is the cause of the allergic and anaphylactic responses that occur (Rakich et al. 1993; Reed and Landolt 2018).

Clinical Effects

Signs

Clinical signs range from mild dermatologic reactions to anaphylaxis and possibly death. It is unclear as to the annual incidence of bites involving pets or livestock. Generally, signs in dogs are associated with local sting reactions and may include erythema, pruritus, pain, swelling, and dermal necrosis. Fitzgerald (2013) categorized signs further by simple, local sting involving wheal and flare, erythema, warmth, pain and intense itching, and large, regional reaction as including erythema, warmth, pain, and itching. It is debatable as to whether pustules develop in dogs, but pustule formation is characteristic and diagnostic in humans (Conceicao et al. 2006; Fowler 1993; Gwaltney‐Brant et al. 2018; Rakich et al. 1993; Reed and Landolt 2018).

An anaphylactic reaction is associated with urticaria, cutaneous and laryngeal edema, bronchospasm, and vascular collapse and is mediated by immunoglobulin E (Fitzgerald 2013). Typically, anaphylaxis will develop a short time after an envenomation, whereas systemic toxicity from massive envenomations can result in death more than 24 hours after exposure (Fitzgerald 2013).

Laboratory

There are no laboratory tests that will confirm or determine fire ant exposure (Fitzgerald 2013).

Differential Diagnoses

Primary diagnoses to keep in mind are similar to those noted in the earlier discussion of bees, wasps, and hornets. Other differential diagnoses to consider include subcorneal pustular dermatosis, pustular psoriasis, and other skin diseases manifested by pustules (Conceicao et al. 2006).

Diagnostics

Antemortem

In humans, the unique circular pattern of stings and the resulting wheal and flare that develop are diagnostic. Typically, the wheals progress into papules that fill with fluid, which then develop into pustules within 24 hours (Gwaltney‐Brant et al. 2018). It is suggested that rather than developing pustules, dogs develop erythematous pruritic papules that commonly resolve within 24 hours (Gwaltney‐Brant et al. 2018).

Postmortem

No postmortem diagnostics are specifically described for fire ant envenomation.

Management of Exposures

Generally, fire ant exposures involving a small number of stings will not require treatment. Multiple sting envenomations involving neonatal or geriatric patients may require veterinary treatment. Severe systemic reactions or anaphylaxis, should they develop, are treated as noted in the previous bees, wasps, and hornets discussion. If live fire ants are observed when an animal is presented for treatment, they should be removed as soon as possible to limit further venom delivery. A soapy water bath or application of a low‐toxicity insecticide (e.g., pyrethrin) might be required (Drees 2014).

Fire ants target areas on animals with minimal hair growth and/or moist areas, including the muzzle, eyes, ears, ventral abdomen, and perineum (Drees 2014). Animals lick or bite at areas where fire ants congregate and sting; in so doing they may ingest a number of fire ants and potentially suffer stings in the oral cavity or gastrointestinal tract (Drees 2014). Gastrointestinal protectants and nutritional supplementation might be indicated (Drees 2014).

If the eyes are bitten, excessive lacrimation, blepharospasm, and mucopurulent exudates can be observed (Drees 2014). Focal necrotic ulcers can be present on the cornea and conjunctiva (Drees 2014). Topical ophthalmic antibiotic solutions should be administered. Corticosteroids should be avoided in cases involving corneal ulcers (Drees 2014).

Prognosis

Overall, the prognosis is very good. In most cases, a local reaction involving mild swelling and pain may be the extent of clinical signs. In many cases, owners will not be aware that their pet was stung.

TOADS

Sources

While there are many species of toad, there are only two of primary toxicological concern in the United States. Rhinella marina (formerly Bufo marinus, also known as the cane, giant, or marine toad) is generally found in southern Texas, coastal Louisiana, Florida, and Hawaii. R. marina gained access to the United States from Puerto Rico via Hawaii (Eubig 2001). Incilius alvarius (formerly Bufo alvarius, also known as the Colorado River toad or Sonoran Desert toad) is generally found in southern Arizona, southeastern California, and southwestern New Mexico (Eubig 2001). In the United States, the primary states where small animals exhibit signs of poisoning from toad exposures are Florida, Texas, Arizona, Colorado, and Hawaii (Peterson and Roberts 2013).

Toads have mucous and granular glands that aid in defense against predators. R. marina and I. alvarius have a pair of parotid glands, which begin caudal to the tympanum and continue over the shoulders (Eubig 2001; Fowler 1993). The parotid glands serve as the primary release site of a thick, creamy, poisonous secretion through pinhole orifices on the surface of the skin (Eubig 2001; Fowler 1993). I. alvarius, although considered less toxic than R. marina, is equipped with an additional pair of poison glands on the forelimbs and several pairs on the hindlimbs (Eubig 2001).

Toxicity

R. marina that reside in Florida are equipped with a more potent toxin than those residing in Hawaii; the mortality of dogs exposed to R. marina in Florida that subsequently receive no treatment is almost 100% compared to about only 5% for those exposed to R. marina in Hawaii (Palumbo 1983). The entire content of both parotid glands, which is approximately equivalent to 0.1 g of venom, is considered a potentially lethal oral dose for a dog (Reeves 2004). However, toxicity varies. The size of the animal exposed and the size of the toad delivering the venom, coupled with the length of time subjected to the venom, will largely impact the outcome of exposure (Peterson and Roberts 2013). Typically, a bite and release exposure is not as severe as one involving holding and chewing, or ingestion of a toad (Peterson and Roberts 2013). Clinical signs are expected in exposures involving a dose of 1 mg/kg (Peterson and Roberts 2013).

Toxicokinetics and Mechanism of Action

R. marina and I. alvarius secretions contain two primary components: bufogenins and bufotoxins (Eubig 2001; Fowler 1993; Peterson and Roberts 2013). Bufogenins are similar in activity to cardiac glycosides and, along with bufotoxins, are responsible for arrhythmias such as ventricular fibrillation that develop (Eubig 2001; Fowler 1993). The secretions also contain bufotenines (serotonin, 5‐hydroxytryptophan), catecholamines (dopamine, epinephrine, and norepinephrine), and indolealkylamines (similar to psilocybin) (Eubig 2001; Peterson and Roberts 2013). Bufotenines are associated with vomiting, diarrhea, depression, tremors, seizures, hyperthermia, and hypersensitivity to sensory stimuli (Eubig 2001). Tachycardia, hypertension, anxiety, and respiratory distress can develop as a result of the catecholamine activity in the secretions (Eubig 2001). Indolealkylamines and bufotenines have hallucinogenic effects (Peterson and Roberts 2013; Reeves 2004).

Clinical Effects

Signs

Initial signs after oral exposure include profuse salivation, deep‐red mucous membranes, pawing at the mouth, and vocalizing (Peterson and Roberts 2013). Vomiting and anxiety can also be noted (Roder 2004a). Commonly, signs include ataxia, seizures, stupor, coma, nystagmus, recumbency or collapse, and tachypnea (Eubig 2001; Roder 2004a). Signs can worsen quickly, and death can occur within 15 minutes (Eubig 2001; Roder 2004a). Various arrhythmias and hyperthermia or hypothermia can develop (Eubig 2001). Exposures to R. marina or I. alvarius are more likely to result in development of serious signs, especially for smaller, older pets or those with underlying health conditions (Eubig 2001).

Laboratory

Serum potassium may be elevated (Peterson and Roberts 2013). Elevated packed cell volume, hemoglobin, blood glucose, serum urea nitrogen, and serum calcium might be observed (Reeves 2004). Serum sodium and chloride concentrations drop minimally while serum inorganic phosphorus dramatically decreases.

Differential Diagnoses

Toxicology differentials include organophosphates, carbamates, pyrethroids, metaldehyde, chlorinated hydrocarbons, rhododendron (Rhododendron sp.), oleander (Nerium oleander), and foxglove (Digitalis purpurea) (Eubig 2001; Peterson and Roberts 2013).

Diagnostics

Antemortem

Since toad toxicosis is similar in presentation to a variety of other potential exposures ranging from insecticides to various medications, the only truly beneficial antemortem diagnostic information is a witnessed exposure to a toad with possible identification of R. marina or I. alvarius. (Fowler 1993).

Postmortem

No specific postmortem diagnostics are suggested. However, necropsy might reveal pulmonary edema and, if ingested, toad parts can be identified in stomach contents (Fowler 1993).

Management of Exposures

If a toad exposure is suspected or was witnessed, and the pet is showing no or only minor signs (such as excessive salivation and gagging), the mouth should be irrigated with large volumes of water (such as with a garden hose) to minimize any further secretion absorption via the mucous membranes. It is best to flush the mouth rostrally, to avoid ingestion of the water (Eubig 2001). If more severe signs are present, initial decontamination should take place under the care of a veterinarian, following stabilization and preferably intubation of the pet (Eubig 2001). In areas in which R. marina resides, especially Florida, it is important to seek veterinary care immediately.

Ingestion of an entire toad warrants inducing emesis under the direct supervision of a veterinarian (Eubig 2001). For those pets with more serious signs, it might be necessary to remove the toad endoscopically or surgically after stabilizing the patient (Eubig 2001). Activated charcoal has not specifically been assessed for its effectiveness in adsorbing toad toxins but it is nonetheless indicated in situations involving serious signs or observed ingestion of a toad (Eubig 2001).

Pets presented in areas in which R. marina or I. alvarius reside should be thoroughly examined, including auscultation of the heart. Continuous monitoring of an electrocardiogram is indicated if any cardiac abnormalities are detected or if severe neurologic signs or shock develop (Eubig 2001; Roder 2004a). Intravenous fluids should be given to provide additional cardiovascular support (Gwaltney‐Brant et al. 2018). Electrolytes, especially potassium, should be monitored and corrected as needed.

Patients experiencing severe toxicosis should receive intensive support. Diazepam or barbiturates may be administered to control seizures, tremors, and agitation (Eubig 2001). Atropine is contraindicated for treatment of hypersalivation due its potential to contribute to arrhythmias; however, it is indicated to treat severe bradycardia (Eubig 2001; Roder 2004a). Arrhythmias (such as tachycardia, ventricular and supraventricular arrhythmias) that do not respond to fluids may be treated using propranolol or esmolol (Eubig 2001; Gwaltney‐Brant et al. 2018). Body temperature should be continuously monitored in those patients with severe signs since it is common for secondary hypothermia to develop.

Digoxin‐specific antigen‐binding fragments (digoxin immune Fab) have been proven to be valuable in the treatment of humans exposed to toad glandular toxins (Eubig 2001). This treatment is especially beneficial for those patients experiencing severe arrhythmias, significant hyperkalemia, and marked neurologic signs (Eubig 2001; Gwaltney‐Brant et al. 2018). Fab is expensive and might not be readily available, so its use might not be a feasible option in many veterinary cases.

Prognosis

The prognosis is good when early decontamination and symptomatic treatment is effectively administered, especially in cases involving R. marina or I. alvarius exposure (Eubig 2001; Roder 2004a). However, death is more likely in cases involving advanced signs where treatment is delayed (Eubig 2001). Generally, exposure to toads other than R. marina or I. alvarius involves only mild signs that respond to oral decontamination and resolve without veterinary assistance (Eubig 2001).

ASIAN LADY BEETLE

Sources

Harmonia axyridis, commonly referred to as the Asian lady beetle (or ladybeetle), multicolored Asian lady beetle (MALB), lady bug/ladybug or lady bird/ladybird beetle, is a member of the order Coleoptera and family Coccinellidae. Native to Asia, it may have become established in the United States due to intentional release for its aphid and scale insect control benefits or by accidental importation on nursery products. It is now considered an invasive species that may be commonly encountered in the United States across areas east of the Mississippi River as well as coastal California, Oregon, and Washington.

The Asian lady beetle may congregate around building structures, including homes, in the spring and fall months. Situations involving congregative setting exposures are most concerning since large numbers of beetles can be more harmful when ingested. As a beetle, it has chewing mouth parts and can bite but does not contain venom; the bite is described as a feeling like a pinch (Stocks and Lindsey 2008). MALB contain hemolymph that is essentially their blood. MALB hemolymph is a foul smelling, yellow or yellow‐orange liquid that may exude from the insects when crushed or be released from their leg joints during reflex bleeding, which is apparently employed defensively to deter predators. It is believed that the hemolymph constituents are irritating and corrosive.

Toxicity

There is no established dosage of toxicity at this time. Exposure to large numbers of MALB is generally more concerning than casual encounters with one or two MALB. The hemolymph of the MALB is corrosive and is associated with a risk for corrosive lesions in the oral cavity and gastrointestinal tract.

Toxicokinetics and Mechanism of Action

MALB hemolymph contains alkaloids and odor‐producing methoxypyrazines (Stocks and Lindsey 2008). The hemolymph alkaloids, especially those believed to contain piperidine and/or piperidine derivatives, are associated with irritation (Stocks and Lindsey 2008). Additionally, MALB have been associated with inducing allergic and asthmatic responses in people.

Clinical Effects

Signs

Stocks and Lindsey (2008) noted a mixed‐breed dog presented with a foul odor emanating from the mouth where 16 MALB were embedded in the hard palate with chemical burn like injury to the oral and pharyngeal mucosa. It is unknown if any MALB were fully digested or the absolute number of MALB involved in the exposure, but the dog's recovery after removal of the MALB was unremarkable, with no additional signs reported. Hoenerhoff et al. (2002) reported a 10‐year‐old Australian shepherd dog died prior to initiation of treatment after it presented ventrally recumbent and in severe shock. Other reported signs include vomiting along with hemorrhagic gastrointestinal upset.

Laboratory

There are no specific clinical laboratory changes expected. It is prudent to run complete blood count (CBC) and chemistry profiles for insight on overall health.

Differential Diagnoses

Corrosive cleaning agents (acids, alkaloids, cationic detergents) and battery exposures should be ruled out.

Diagnostics

Antemortem

Antemortem diagnostic information may include witnessed insect ingestion/history of exposure, a foul smell associated with MALB hemolymph, and corrosive mucosal damage (Hoenerhoff et al. 2002; Stocks and Lindsey 2008).

Postmortem

Necropsy can reveal severe, acute, diffuse, and enteric mucosal hemorrhage and congestion along with hemorrhage, and thickening and ulceration of the jejunum and ascending colon. Additionally, the gastrointestinal contents reportedly exuded the offensive odor associated with MALB hemolymph (Hoenerhoff et al. 2002).

Management of Exposures

Management is largely symptomatic and supportive (antiemetics, gastroprotectants, pain medications). It is prudent to prevent small animal interaction with and ingestion of large quantities of MALB.

Prognosis

Incidental exposure to one or two MALB is not expected to be concerning. Situations involving ingestion of large numbers of intact beetles can be concerning but symptomatic and supportive care should result in full recovery.

ARACHNIDS – LATRODECTUS AND LOXOSCELES

Sources

There are more than 20,000 species of spider that live in the United States (Graudins 2007). Although most spiders are venomous, they are not all physically able to deliver the venom to humans or pets, or the venom may not be potent enough to be of medical concern (Fowler 1993; Graudins 2007; Mullen and Vetter 2018). Spiders belonging to the Latrodectus (widow spiders) and Loxosceles (recluse spiders) genera are of primary veterinary importance in the United States (Graudins 2007).

Latrodectus – Widow Spiders

In the United States, the Latrodectus genus is only lacking representation in Alaska. Only female black widow spiders have the characteristic, well‐rounded abdomen with the red hourglass. Females are much larger than males and are of greatest concern since males lack sufficiently sized jaws. Males have an oval‐shaped abdomen that is flatter than the females. The species generally prefers outdoor living. Latrodectus mactans (black widow) seems to be the most common species found indoors (Mullen and Vetter 2018). With its proclivity for unheated indoor areas such as barns, sheds, and garages, there is a greater potential for human and animal interaction (Mullen and Vetter 2018).

Toxicity

A single bite can deliver enough venom to cause death in domestic animals (Peterson and McNally 2013a). Latrodectus geometricus, with a median lethal dose (LD₅₀) of 0.43 mg/kg body weight, has the most potent venom of the five native Latrodectus species in the United States (Peterson and McNally 2013a). Comparatively, L. mactans has an LD₅₀ of 1.39 mg/kg of body weight (Peterson and McNally 2013a). Cats are very sensitive to black widow spider venom (Gwaltney‐Brant et al. 2018; Peterson and McNally 2013a). Dogs are considered more resistant but may develop severe clinical signs. The prevalence of Latrodectus envenomation of domestic animals is undetermined. It is believed that venom toxicity is increased in higher environmental temperatures (Peterson and McNally 2013a).

Toxicokinetics and Mechanism of Action

Both males and females are venomous but only the females are physically able to envenomate an animal or human (Peterson and McNally 2013a). The venom is supplied from two venom glands located behind the eyes. Venom is delivered via the paired fangs at the terminal ends of the chelicera (Fowler 1993). Not all bites are associated with venom transfer to the victim; black widows are capable of controlling the amount of venom they deliver (Peterson and McNally 2013a). Approximately 15% of the bites inflicted in humans are nonenvenomating (Peterson and McNally 2013a). The venom of black widow spiders is made up of five or six proteinaceous toxins, most notably alpha‐latrotoxin, a powerful mammalian neurotoxin (Peterson and McNally 2013a).

Clinical Effects

Signs

Latrodectism is the syndrome associated with black widow spider envenomation (Gwaltney‐Brant et al. 2018). The signs are generally CNS or muscular in origin due to the neurotoxic nature of the venom (Roder 2004b). The bite itself may not be felt and local reactions such as swelling and tissue changes are uncommon (Peterson and McNally 2013a). Clinical signs develop within 8 hours of envenomation and are generally serious (Peterson and McNally 2013a). Dogs may display progressive muscle pain and fasciculation (Peterson and McNally 2013a). A rigid abdomen without noted tenderness is a unique clinical sign associated with black widow spider bites (Peterson and McNally 2013a). The pain associated with the condition worsens with the severity of the envenomation. Restlessness and other signs associated with severe pain, such as contortions and writhing, may develop. Voluminous watery sputum, hypersalivation, and regional numbness may be noted (Peterson and McNally 2013a). Hypertension and tachycardia commonly develop, and seizures can occur (Peterson and McNally 2013a). Muscle cramping might be evident and can result in major respiratory difficulty (Peterson and McNally 2013a). When death occurs, it is due to respiratory or cardiovascular failure.

Cats might develop early and severe signs of paralysis (Peterson and McNally 2013a). Howling and other loud vocalizations are common and hypertension, hypersalivation, restlessness, diarrhea, and vomiting may occur (Peterson and McNally 2013a). Muscle tremors, cramping, ataxia, and difficulty standing due to muscle weakness may be noted and often occur prior to paralysis (Peterson and McNally 2013a). Respiratory collapse often precedes death.

Laboratory

Complete blood count and a serum chemistry panel are recommended. Creatine kinase can be elevated, especially when severe muscle spasms are noted. Leukocytosis, hyperglycemia, oliguria, albuminuria, and elevated specific gravity might be noted (Peterson and McNally 2013a).

Differential Diagnoses

Acute abdomen, intervertebral disk disease, and bromethalin toxicosis are the primary differential diagnoses to consider (Peterson and McNally 2013a). Additionally, in cats, rabies should be considered.

Diagnostics

There are no specific tests to confirm black widow spider bite.

Antemortem

A rigid abdomen without tenderness and accompanied by markedly severe pain in cases of severe envenomation is a unique clinical sign associated with black widow spider bites (Peterson and McNally 2013a). Cats might vomit the spider.

Postmortem

No postmortem diagnostics are characteristic for latrodectism.

Management of Exposures

Treatment is focused on alleviation of clinical signs. Diazepam and methocarbamol are recommended to alleviate muscular effects as well as seizures (Gwaltney‐Brant et al. 2018). Opioids are best utilized for pain management and acepromazine can help with hypertension in cats (Gwaltney‐Brant et al. 2018). Antivenin, although likely helpful, is difficult to obtain, even for human use, so is likely not practical for veterinary use.

Prognosis

The prognosis is difficult to determine because patients may not fully recover until weeks after envenomation (Peterson and McNally 2013a). Due to their sensitivity, death is common in envenomated cats (Peterson and McNally 2013a). The average survival time reported for 20 of 22 felines that died subsequent to envenomation was 115 hours (Gwaltney‐Brant et al. 2018). Cats that are presented early to the veterinarian have a good prognosis.

Loxosceles – Recluse Spiders

The Loxosceles genus includes an estimated 70 species (Mullen and Vetter 2018), 13 of which reside in the United States (Peterson and McNally 2013b). Loxosceles spiders are also known as recluse, violin, or fiddle‐back spiders. The most distinguishing feature of this genus is the violin shape located on the dorsal cephalothorax. They are more likely to be found indoors than black widow spiders. They are reclusive and prefer dark, warm, dry, undisturbed areas (Mullen and Vetter 2018). The most notorious and medically important is Loxosceles reclusa (Gwaltney‐Brant et al. 2018; Mullen and Vetter 2018). They are mostly found in the southern United States.

Toxicity

Male Loxosceles spiders have a smaller venom capacity than females (Peterson and McNally 2013b). Lethal envenomation can occur as the result of a single bite. An estimated 40 mcg of venom‐proteins is delivered per bite and less than 5 mcg of venom may potentially result in clinical lesions (Roder 2004b). The bigger and more mature a spider is, the larger the venom volume (Peterson and McNally 2013b).

Toxicokinetics and Mechanism of Action

Recluse venom contains a number of necrotizing enzymes, most notably sphingomyelinase D (Graudins 2007; Gwaltney‐Brant et al. 2018). Other enzymes include hyaluronidase, which acts as a spreading factor for venom, lipase, proteases, esterases, and alkaline phosphatases (Gwaltney‐Brant et al. 2018; Roder 2004b). Sphingomyelinase D binds to cell membranes and causes damage to small blood vessels and aggregation of platelets (Roder 2004b). Serum hemolytic complement is inactivated, which results in intravascular coagulation, small capillary occlusion, and tissue necrosis (Gwaltney‐Brant et al. 2018; Peterson and McNally 2013b). Activated partial thromboplastin time (PTT) is prolonged, and clotting factors VIII, IX, XI, and XII are exhausted (Gwaltney‐Brant et al. 2018; Peterson and McNally 2013b). In the presence of serum C‐reactive protein and calcium, sphingomyelinase causes hemolysis (Gwaltney‐Brant et al. 2018; Peterson and McNally 2013b). Free lipids in the blood, caused by the lipases, serve as inflammatory intermediaries and cause embolization (Peterson and McNally 2013b; Gwaltney‐Brant et al. 2018).

Clinical Effects

Signs

Loxoscelism is the syndrome associated with recluse spider envenomation (Mullen and Vetter 2018). There are two general manifestations of loxoscelism: tissue necrosis (most common) or systemic effects (which are rare but can be life‐threatening) (Peterson and McNally 2013b). Dogs are especially sensitive to recluse bites. The severity of a bite is dependent on the amount of venom injected, the size of the bite, and the immune status of the victim (Peterson and McNally 2013b).

The bite might not be felt, or a mild stinging sensation might be evident for up to 8 hours (Peterson and McNally 2013b). Blood vessels constrict, resulting in diminished supply of blood to the bite area, and pruritus and soreness may develop. Swelling of the bite area and a characteristic bull's‐eye lesion, with a dark necrotic center, develops (Peterson and McNally 2013b). Gravity can displace venom further and result in irregular expansion of the lesion (Peterson and McNally 2013b). A scab forms that sloughs in 2–5 weeks and results in a slow‐healing ulcer (Peterson and McNally 2013b). Generally, ulcers will not extend into muscle but if they extend into fatty tissue, they can become extensive and take months to heal while potentially leaving a deep scar (Peterson and McNally 2013b).

Loxoscelism with systemic signs is generally uncommon. Systemic signs, when they occur, typically develop 24–72 hours post envenomation and can be serious (Gwaltney‐Brant et al. 2018; Peterson and McNally 2013b). The most predominant systemic sign is hemolytic anemia with prominent hemoglobinuria (Peterson and McNally 2013b). Other potential but infrequent systemic signs include tachycardia, fever, muscle pain, vomiting, difficulty breathing, disseminated intravascular coagulation, and coma (Goddard 2013; Gwaltney‐Brant et al. 2018).

Laboratory

Assessment of a CBC and a serum chemistry panel with electrolytes is recommended. The CBC may indicate leukocytosis, anemia, and thrombocytopenia (Peterson and McNally 2013b). Urinalysis may reveal hemoglobinuria (Peterson and McNally 2013b). A Coombs‐negative hemolytic anemia may be noted (Roder 2004b; Peterson and McNally 2013b). A coagulation profile to monitor prothrombin time, partial thromboplastin time, platelet count, and fibrinogen is recommended (Peterson and McNally 2013b).

Differential Diagnoses

Differential diagnoses include pyoderma (such as Staphylococcus spp.) or mycobacterial infection, decubital ulcer, and third‐degree burn; all are potentially present with a necrotizing wound (Peterson and McNally 2013b). Causes of hemolytic anemia, such as immune mediated conditions, zinc poisoning, and onion poisoning, should be considered (Peterson and McNally 2013b). Other rule‐outs for the systemic manifestations are snakebite, insect sting, erlichiosis, jaundice, unexplained fever, and red blood cell parasitism (Peterson and McNally 2013b).

Diagnostics

There are no specific tests available in the United States to confirm recluse spider bite (Peterson and McNally 2013b).

Antemortem

There is a characteristic bull's‐eye lesion, with a dark necrotic center, that develops in association with brown recluse spider envenomation (Peterson and McNally 2013b).

Postmortem

No postmortem findings are characteristic for loxoscelism.

Management of Exposures

Treatment is primarily symptomatic and supportive because there is no specific antidote for loxoscelism. Necrotic wound care involves measuring and monitoring the size of the wound, honey or sugar bandages, and time. If pain is evident, nonsteroidal anti‐inflammatory medications or opioids may be given (Gwaltney‐Brant et al. 2018). Broad‐spectrum antibiotics may be given if the wound becomes infected (Gwaltney‐Brant et al. 2018; Peterson and McNally 2013b).

Prognosis

The prognosis for patients with advanced systemic signs is guarded (Peterson and McNally 2013b). Patients with dermonecrotic lesions generally recover but typically endure an extended healing process of weeks to months.

ARACHNIDS – SCORPIONS

Sources

Of the approximately 45 species of scorpions worldwide that are considered health risks, only Centruroides sculpturatus, or the Arizona bark scorpion, is of great concern to people and pets in the United States (Mullen and Sissom 2018; Thomas et al. 2007). While Centruroides sculpturatus is considered the most medically concerning scorpion in the United States, it is a threat primarily to young children (Mullen and Sissom 2018). ASPCA Animal Poison Control Center data from 2002 to 2021 included 150 cases involving scorpions (Smith and Swanson 2022). Canines represented the majority of species with scorpion encounters and most commonly included the states of Arizona, California, Nevada, Texas, and New Mexico (Smith and Swanson 2022). Felines were the second most reported species with scorpion encounters and included the states of Arizona, California, Florida, and Nevada (Smith and Swanson 2022).

Toxicity

With the less toxic scorpions, signs beyond those associated with a local reaction are uncommon. The risk of anaphylaxis does exist but does not often occur (Goddard 2013). With the more dangerous scorpions such as Centruroides sculpturatus, local effects are not typically noted. More severe, systemic signs associated with the neurotoxins in the venom are more prevalent. The venom composition varies among species as well as by the age and health of the scorpion and the time of year (Thomas et al. 2007). The size of a scorpion does not correlate with its toxicity; therefore, larger scorpion species are not automatically more toxic than smaller ones (Mullen and Sissom 2018; Thomas et al. 2007).

Toxicokinetics and Mechanism of Action

Scorpions generally sting once but are capable of stinging multiple times (Mullen and Sissom 2018). Proteins are common constituents of all scorpion venoms and include phospholipase A2 (Fowler 1993). Other enzymes like hyaluronidase and acetylcholinesterase are present in some species but not in others. Serotonin may also be present and is typically associated with the pain felt after envenomation (Mullen and Sissom 2018). The Hemiscorpius genus is equipped with a cytotoxic venom that can cause serious tissue injury on envenomation (Mullen and Sissom 2018).

All scorpions are equipped with chelicerae and pedipalps with pincers that are utilized to capture their prey (Fowler 1993; Thomas et al. 2007). Scorpions with slenderer pedipalps are generally more toxic than those with thicker pedipalps. The stinger is supplied with venom from the telson, both of which are located in the terminal end of the tail.

Clinical Effects

Signs

The occurrence of localized reactions is dependent on the scorpion species. If they occur, localized reactions include immediate pain at the injection site and edema that may or may not be associated with discoloration (Goddard 2013). Envenomation by C. sculpturatus is typically not associated with localized reactions but rather can cause more significant neuromuscular signs than other scorpion species in the United States (Smith and Swanson 2022). Smith and Swanson (2022) reported canines most commonly exhibited lameness, pain, vocalization, head shaking, licking feet, pawing face, foot edema, and facial edema while felines exhibited vomiting, licking feet, mydriasis, hypersalivation, foot edema, tachypnea, and hyperthermia.

Laboratory

Hyperkalemia and hyponatremia might be noted (Fowler 1993).

Differential Diagnoses

Rule‐outs for painful local reactions include other insect stings (Fowler 1993; Mullen and Sissom 2018). When neurologic signs are present, rule‐outs should include acute dystonic reaction, CNS stimulants, cholinergic agents, strychnine toxicosis, head trauma, CNS infections, botulism, and tetanus (Mullen and Sissom 2018).

Diagnostics

There are no specific antemortem or postmortem tests available in the United States to confirm scorpion envenomation.

Management of Exposures

Treatment of the majority of scorpion stings in the United States involves local wound management: analgesics, diphenhydramine, and steroids (Gwaltney‐Brant et al. 2018; Smith and Swanson 2022). Treatment of systemic signs is symptomatic and supportive. Special attention should be given to cardiovascular monitoring and management of hypertension and neurologic signs (Gwaltney‐Brant et al. 2018).

Prognosis

The prognosis is generally good for most pets envenomated by scorpions. Pet fatalities are not common, and signs typically improve within 24 hours of the envenomation (Fowler 1993).

SNAKES – ELAPIDS

Sources

Coral snakes belong to the family Elapidae. There are two genera of coral snake native to the United States: Micruroides (the Sonoran coral snake) and Micrurus. Coral snakes of the Micrurus genus, including the Eastern coral snake, Texas coral snake, and South Florida coral snake, are more clinically significant (Peterson 2013a).

All species of coral snakes in the United States have a similar color pattern that starts with a black snout and consists of small yellow (may be vibrant yellow or pale, almost white) bands, and larger red and black bands (Peterson 2013a). Sayings such as “red on yellow, kill a fellow” or “if caution (yellow) touches danger (red)” can prove to be helpful in the identification of poisonous coral snakes in the United States versus nonpoisonous snakes that have the same colors but in a different pattern (Peterson 2013a). The saying “red touches black, friend of Jack” can be helpful in identification of the similarly colored, nonpoisonous snakes in the United States.

Coral snakes have round (generally black) eyes, small, nontriangular heads, and small mouths (Peterson 2013a). They have short, fixed fangs that are not as efficient and streamlined for venom delivery as pit viper fangs. Coral snakes often employ a chewing action to deliver their venom (Peterson 2013a). Victims of coral snake bites may have to shake or pull the snake off, or it may still be attached on presentation.

Toxicity

The toxicity of a coral snake bite is dependent on the size of the coral snake involved, the volume of venom injected, and the size of the victim (Peterson 2013a). Larger snakes are capable of delivering larger volumes of venom. Up to 20 mg of venom may be delivered from a large coral snake; 4–5 mg of venom may be lethal to a human (Peterson 2013a). Coral snakes deliver nonenvenomating bites about 60% of the time (Peterson 2013a). Human fatality percentages from coral snake bites are believed to be about 10% (Peterson 2013a).

Toxicokinetics and Mechanism of Action

Coral snake venom is primarily neurotoxic. The venom consists of polypeptides and enzymes including hyaluronidase, proteinase, ribonuclease, desoxyribonuclease, phosphodiesterase, phospholipase A, and cholinesterase (Gwaltney‐Brant et al. 2018; Peterson 2013a). The neurotoxic peptides in coral snake venom have similar effects in humans and dogs as does curare in that they create a nondepolarizing, postsynaptic neuromuscular block (Peterson 2013a). Phospholipase A is believed to play a role in the hemolysis and hemoglobinuria that are often noted in dogs following coral snake envenomation (Peterson 2013a). Paralysis, CNS depression, and vasomotor effects are also common.

Clinical Effects

Signs

Clinical signs are not the same for all species. Signs associated with coral snake bites in dogs include acute depression, vomiting, hypersalivation, quadriplegia involving diminished spinal reflexes in all the limbs, and respiratory paralysis (Peterson 2013a). Anemia, intravascular hemolysis, hemoglobinuria, morphologic red blood cell effects, hypotension, and ventricular tachycardia with or without pulse deficits may also be noted (Peterson 2013a). Other signs noted in dogs include difficulty breathing, difficulty swallowing, and muscle fasciculations (Gwaltney‐Brant et al. 2018).

Signs associated with coral snake envenomation in cats include acute, ascending, flaccid quadriplegia, depression, reduced spinal reflexes, and inhibited recognition of painful stimuli (Gwaltney‐Brant et al. 2018; Peterson 2013a). Other signs include unequal pupil size, hypothermia, hypotension, respiratory depression, and lack of cutaneous trunci reflex (Peterson 2013a). Unlike with dogs, no clinical evidence of hemolysis or hemoglobinuria has been observed in cats (Peterson 2013a).

Laboratory

It is recommended that baseline data be obtained from a CBC, electrolytes, and serum chemistries (Peterson 2013a). Abnormalities that might be noted include hyperfibrinogenemia, moderate leukocytosis, and high increases in creatine kinase (Peterson 2013a). The only laboratory findings considered highly suggestive of coral snake envenomation are an early increase in creatine kinase and burring and spherocytosis of canine red blood cells (Peterson 2013a).

Differential Diagnoses

Rule‐outs for coral snake bite include tick‐associated paralysis, macadamia nut exposure in dogs, botulism, bromethalin toxicosis, ionophore toxicosis, acute polyneuritis, myasthenia gravis, polyradiculoneuritis, organophosphate toxicosis, and various drugs that might be associated with neurologic signs (Peterson 2013a).

Diagnostics

There are no specific antemortem or postmortem tests to confirm coral snake envenomation (Peterson 2013a).

Management of Exposures

Although development of signs can be delayed 10–18 hours after envenomation, it is important to seek medical treatment as soon as possible once signs develop. Antivenin is suggested but unavailable for animal use. In the absence of antivenin, treatment is generally symptomatic and supportive, and may require respiratory support (Peterson 2013a).

Hospitalization for at least 48 hours, with special attention given to monitoring oxygenation and preventing aspiration pneumonia, is of utmost importance (Peterson 2013a). Endotracheal intubation is recommended at the onset of respiratory difficulty to prevent aspiration. Maintenance intravenous fluid administration is recommended. Assisted mechanical ventilation may be necessary for up to 48 to 72 hours.

Prognosis

Overall, the prognosis is guarded. It is dependent on variables such as where the bite occurred, the severity of envenomation, and the time at which treatment is initiated (Peterson 2013a). Some pets have recovered without administration of antivenin. Smaller pets are at greater risk due to their smaller body weight and therefore higher dosage of venom.

SNAKES – PIT VIPERS

Sources

The family Viperidae includes three genera of snakes that are collectively referred to as pit vipers. These include rattlesnakes, water moccasins, cottonmouths, and copperheads. All three genera are indigenous to the United States and include Crotalus, Sistrurus, and Agkistrodon (Peterson 2013b). The only states in the United States that are not home to a venomous snake of some kind are Maine, Alaska, and Hawaii (Peterson 2013b).

All pit vipers are similar in appearance. They have heat‐sensing pits located between their vertical pupil and nostril, triangular‐shaped heads, retractable fangs, and a single row of subcaudal scales distal to the anal plate (Peterson 2004). Rattlesnakes in the United States have hollow, dried skin segments at the end of their tails that rattle when the snakes vibrate their tails, but they do not always rattle prior to striking (Peterson 2013b). Rattlesnakes are most responsible for deaths in humans and animals (Peterson 2013b). Pit vipers are believed to be involved in 99% of snakebites delivered to animals in North America (Peterson 2004; Peterson 2013b).

Toxicity

There is significant variation of venom toxicity both between and within various species of pit vipers (Peterson 2013b). Some rattlesnake venoms can be toxic at less than 2 mg/kg body weight, whereas copperhead venom toxicity requires a dose of greater than 10 mg/kg. The three main types of pit vipers arranged in order of greatest toxicity to least are rattlesnakes, water moccasins, and copperheads (Peterson 2013b) (see Figure 26.1). The Eastern diamond‐back rattlesnake is the most dangerous snake in the United States based on its size, strength, and long fang length, which all contribute to its high venom volume delivery (Meerdink 1983).

Figure 26.1. Northern blacktailed rattlesnake (Crotalus molossus molossus) (photograph courtesy Bryan Hughes).

Venom composition varies considerably among rattlesnakes. During the hottest summer months, when the daylight hours are at their maximum, snakes are more active and aggressive, and contain the highest venom yields compared to other times during the year (Peterson 2013b). A nonenvenomating bite is estimated to occur about 25% of the time and the amount of venom delivered can be controlled by pit vipers (Peterson 2013b). Bites initiated in response to pain are the deadliest because the maximum amount of venom available is delivered (Peterson 2013b). Toxicity is also dependent on the number of strikes and the depth of fang penetration per bite (Meerdink 1983). Older snakes might have more potent venom and larger snakes typically have a larger amount of venom to deliver (Gwaltney‐Brant et al. 2018).

Species vary in their sensitivity to pit viper venoms; cats are considered more resistant (Gwaltney‐Brant et al. 2018). The size and health status of the victim, the site of the bite, and the immediacy with which treatment is sought also impact the severity of the envenomation (Gwaltney‐Brant et al. 2018). Bites to the thoracic area result in more rapid venom uptake, bites to the tongue are equivalent to intravenous envenomation, and bites to the muzzle area are capable of inducing life‐threatening facial swelling and airway obstruction (Gwaltney‐Brant et al. 2018).

Toxicokinetics and Mechanism of Action

Pit viper venom is delivered from venom glands via muscular contractions that force the venom through the hollow fangs and into the victim (Gwaltney‐Brant et al. 2018). The venom is 90% water while the remaining portion consists of enzymatic and nonenzymatic proteins, peptides, cytotoxins, myotoxins, cardiotoxins, neurotoxins, coagulants and anticoagulants, lipids, nucleosides and nucleotides, organic acids, and cations (Gwaltney‐Brant et al. 2018; Peterson 2004, 2013b). Venom makeup varies among species but generally consists of at least 10 of the previously named components (Gwaltney‐Brant et al. 2018). Rattlesnake envenomation typically results in one of three presentations. Diamondback rattlesnake venom is representative of the classic syndrome of significant tissue destruction, coagulopathy, and hypotension (Gwaltney‐Brant et al. 2018). Mojave A rattlesnake venom contains neurotoxins and does not impact tissues or result in coagulopathy (Gwaltney‐Brant et al. 2018) (see Figure 26.2). The venom from nine species and 12 subspecies contains proteins that are similar to those found in Mojave toxin, which is a powerful neurotoxin (Peterson 2013b). Other snakes contain a combination of both classic and neurotoxic venom components (Gwaltney‐Brant et al. 2018).

Figure 26.2. Northern Mojave rattlesnake (Crotalus scutulatus scutulatus) (photograph courtesy Bryan Hughes).

Clinical Effects

Signs

Dogs most commonly receive bites to their front legs or head (Peterson 2004). In contrast, cats most commonly are presented with bites to their torso (Gwaltney‐Brant et al. 2018). Cats often present later for treatment due to their tendency to run and hide following injury (Gwaltney‐Brant et al. 2018). Signs will vary because they are dependent on dose of venom, bite location, age, health status and species of victim, and the physical activity of the victim following envenomation. Commonly, signs will include severe pain in the area of the bite, tachycardia, swelling, profuse bleeding in the bite area, and as tissue destruction occurs, blood will accumulate in the subcutaneous tissues, leading to hypovolemic and hemorrhagic shock (Buckley 2020; Peterson 2004). Local tissue response cannot be the sole predictor of severity of envenomation; severe systemic signs can develop with only mild tissue effects, and neurotoxic venom typically has little tissue effect (Peterson 2004). Serious signs can be delayed over a few hours after envenomation (Peterson 2004). More severe, systemic developments include hemolysis, rhabdomyolysis, thrombocytopenia, and coagulopathy (Gwaltney‐Brant et al. 2018). See coral snakes for the neurologic signs that can occur with Mojave toxin.

Laboratory

Baseline data including a CBC with differential and platelet count, serum chemistries, urinalysis, and coagulation profiles should be obtained. Red blood cell morphology should be examined; transient echinocytosis may be evident within 48 hours in dogs and is indicative of pit viper envenomation (Peterson 2013b). Urinalysis should include free protein, hemoglobin, and myoglobin evaluation. Coagulation profile tests should include activated clotting times (ACT), prothrombin time (PT), activated partial thromboplastin time (PTT), fibrinogen, and fibrin degradation products if available. Animals with severe envenomations might require electrocardiogram monitoring (Peterson 2013b). These tests should be repeated on a periodic basis to follow progression of envenomation and provide feedback regarding treatment success.

Complete blood counts often show hemoconcentration, leukocytosis, or thrombocytopenia (Buckley 2020). Increased creatine phosphokinase and myoglobinuria might be noted as a result of rhabdomyolysis from rattlesnakes equipped with neurotoxins (Peterson 2013b). Hematuria can be noted as well (Buckley 2020). Transient hypokalemia that responds to intravenous fluid and antivenin treatment may be evident following pit viper snake envenomation (Peterson 2013b). Coagulation profiles often reveal increased ACT, PT, and PTT as well as increased fibrinogen degradation products.

Differential Diagnoses

Rule‐outs for pit viper snake bite include trauma, insect bites or stings, animal bites, draining abscess, and penetrating wound (Buckley 2020; Peterson 2013b).

Diagnostics

There are no specific antemortem or postmortem tests to confirm pit viper snake envenomation (Peterson 2013b).

Management of Exposures

Development of significant signs, other than the immediate pain felt at the time of bite, can be delayed. It is imperative that treatment be sought as soon as possible because major irreversible complications can develop if too much time has elapsed (Peterson 2013b). It is important to keep the animal calm after being bitten because physical activity and anxiousness could promote more rapid uptake of the venom. Additionally, if possible, the bite site should be kept below heart level and the animal should be transported to a veterinary medical facility as soon as possible so that treatment, including antivenin therapy, can be initiated (Peterson 2013b). Pit viper bite victims should be hospitalized for a minimum of 8 hours so that they can be closely monitored. A severity score sheet should be initiated on presentation and periodically updated (Peterson 2013b) (Table 26.1). The severity score is a more objective method for assessing the patient's condition at any given point in time or assessing trends over time. In addition, it is important to take circumferential measurements at, above, and below the bite area so development of swelling can be methodically tracked (Peterson 2013b). Mark areas with a permanent marker so the same spot is always measured.

Administration of a crystalloid fluid drip via intravenous catheter should be initiated. Antivenin therapy is the only proven therapy for pit viper envenomation. There are several FDA‐approved available antivenins on the market. They range from whole antibody to Fab 2 fragments which will affect antigenicity. See Chapter 8 and Appendix 1 for more information. Start with one vial and redose if needed.

Prognosis

Although pit viper envenomation varies in severity, most dogs and cats treated promptly and aggressively generally recover (Buckley 2020; Peterson 2013b). Administration of antivenin increases the likelihood of recovery but does not ensure recovery; some pets have died despite antivenin treatment (Buckley 2020). Smaller pets are at greater risk. The prognosis is poor in animals receiving high‐volume envenomation or in those that experience shock, severe cardiac arrhythmias, hematologic effects, and infection (Buckley 2020).

Table 26.1. Snakebite severity score

Pulmonary system |
0 | Signs within normal limits
1 | Minimal: slight dyspnea
2 | Moderate: respiratory compromise, tachypnea, use of accessory muscles
3 | Severe: cyanosis, air hunger, extreme tachypnea, respiratory insufficiency or respiratory arrest from any cause
Cardiovascular system |
0 | Signs within normal limits
1 | Minimal: tachycardia, general weakness, benign dysrhythmia, hypertension
2 | Moderate: tachycardia, hypotension (but tarsal pulse still palpable)
3 | Severe: extreme tachycardia, hypotension (nonpalpable tarsal pulse or systolic blood pressure <80 mmHg), malignant dysrhythmia or cardiac arrest
Local wound |
0 | Signs within normal limits
1 | Minimal: pain, swelling, ecchymosis, erythema limited to bite site
2 | Moderate: pain, swelling, erythema involves less than half of extremity and may be spreading slowly
3 | Severe: pain, swelling, ecchymosis, erythema involves most or all of one extremity and is spreading rapidly
4 | Very severe: pain, swelling, ecchymosis, erythema extends beyond affected extremity, or significant tissue slough
Gastrointestinal system |
0 | Signs within normal limits
1 | Minimal: abdominal pain, tenesmus
2 | Moderate: vomiting, diarrhea
3 | Severe: repetitive vomiting, diarrhea, or hematemesis
Hematologic system |
0 | Signs within normal limits
1 | Minimal: coagulation parameters slightly abnormal, PT <20 seconds, PTT <50 seconds, platelets 100,000–150,000/mm³
2 | Moderate: coagulation parameters abnormal, PT 20–50 seconds, PTT 50–75 seconds, platelets 50,000–100,000/mm³
3 | Severe: coagulation parameters abnormal, PT 50–100 seconds, PTT 75–100 seconds, platelets 20,000–50,000/mm³
4 | Very severe: coagulation parameters markedly abnormal with bleeding present or the threat of spontaneous bleeding, including PT unmeasurable, PTT unmeasurable, platelets <20,000/mm³
Central nervous system |
0 | Signs within normal limits
1 | Minimal: apprehension
2 | Moderate: chills, weakness, faintness, ataxia
3 | Severe: lethargy, seizures, coma
Total possible score | 0–20

PT, prothrombin time; PTT, partial thromboplastin time.

Source: Peterson (2013b) / with permission of ELSEVIER.

REFERENCES

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27
Food‐Associated Intoxications

Mindy Perez

INTRODUCTION

The adage that “dogs and cats are not small people and cats are not small dogs” is never more obvious than when dealing with food‐associated intoxications. Many things that are safe for humans can be problematic for our small animal patients.

ALLIUM SPECIES

Sources

There are a number of plants in the Allium genera. Some common examples include Allium cepa, cultivated onion; Allium validum and Allium canadense, wild onion; Allium sativum, garlic; Allium schoenoprassum, chives; and Allium porrum, leek (Figure 27.1). These plants are frequently used by humans as food, flavoring agents, and medicinal herbs. Cull onions have been used as livestock feed.

Companion animals may have access to Allium spp. in the yard or garden, from the feeding of table food, from foods left unattended, or when pet owners give the food or supplements to their pets directly. Regardless of the source of exposure, dogs, and especially cats, may demonstrate signs of toxicosis.

Kinetics

The crushing or chewing of Allium spp. produces changes leading to the production of allicin; this compound has pharmacologic and toxicologic properties, and produces the characteristic garlic odor. The oil, which contains the pharmacological and toxic components, is readily absorbed through the gastrointestinal tract. Garlic oil is eliminated both through the urine and through the lungs (Okuyama et al. 1989). The half‐life of alliin, which is converted to allicin, in rats who were given 30 mg/kg was approximately 0.7 hours (Guo et al. 1990).

Mechanism of Action

When crushed or chewed, the sulfur compounds in Allium spp. are hydrolyzed to thiosulfinates that then decompose to disulfides. These disulfide compounds are oxidating agents, which can cause hemolysis of erythrocytes. The most toxic disulfide is reported to be dipropenyl disulfide, also known as N‐propyl disulfide (Cheeke 1998). These disulfides oxidize erythrocyte membranes. The result is the formation of Heinz bodies, methemoglobinemia, and anemia (Ogawa et al. 1986). Cats are more sensitive to the effects of Allium spp. because their hemoglobin is more sensitive to oxidative damage than other species. They have eight free sulfhydryl groups on their hemoglobin, which is twice the amount that dogs have and four times the amount that humans have. In addition, feline hemoglobin dissociates into dimers 10 times more readily than other species (Robertson et al. 1998).

Toxicity

Pantoja et al. (1991) reported natriuresis, diuresis, and hypotension in anesthetized dogs that were given 2.5–15 mg/kg of encapsulated garlic powder. Transient bradycardia was present in dogs at doses of 15 and 20 mg/kg of encapsulated garlic. Erythrocyte effects and decreased hemoglobin concentrations were seen in dogs that were given an extract equal to 5 g of whole garlic per kg of body weight once a day for 7 days. Cats and some dog breeds, particularly Japanese breeds such as Akitas, Shibas, and Tosas, are at an increased risk for toxicosis to Allium spp. because their erythrocytes are more susceptible to oxidative damage (Christopher et al. 1990).

Figure 27.1. Onions, garlic, and shallot.

Photograph courtesy of Tim Williams.

Dogs that are exposed to less than 10 g/kg of garlic and 15 g/kg of onion are unlikely to show signs of toxicosis other than vomiting, but due to individual differences, it is beneficial to monitor for mucous membrane and urine color as well as weakness and lethargy. Doses greater than 10 g/kg for garlic and 15 g/kg for onion should be decontaminated if no contraindications exist and treated as indicated (American Society for the Prevention of Cruelty to Animals [ASPCA] Animal Poison Control Center [APCC], unpublished data). Cats that are exposed to less than 1 g/kg of garlic and 5 g/kg of onion should be monitored, and doses greater than that should be decontaminated if no contraindications exist and treated as indicated (ASPCA APCC, unpublished data).

Clinical Effects

Signs

Hematological changes may occur from 12 hours to 5 days postexposure. The primary concern in Allium spp. exposure cases is for Heinz body hemolytic anemia (peaks at 5 days) and methemoglobinemia. Secondarily, in serious cases renal damage occurs from hemoglobinuria. In dogs, the most common signs reported to the ASPCA APCC are depression, decreased hematocrit, vomiting, elevated white blood cell count, anorexia, hemolysis, and weakness. Less commonly reported signs include salivation, diarrhea, ataxia, hemolysis, hemoglobinuria, Heinz bodies, methemoglobinemia, abnormal breath, and abnormal feces. Cats most frequently exhibited vomiting, salivation, and anorexia. Ogawa et al. (1986) reported that hematocrits returned to normal in 10–14 days after oral exposure.

Differential Diagnoses

If Allium spp. ingestion is suspected but specific evidence is unavailable, other potential causes of hemolysis or Heinz body anemia should be ruled out. Other toxicoses that may produce similar signs include zinc, copper, propylene glycol in cats, phenothiazines, and mothballs. Additional differentials may include autoimmune hemolytic anemia, blood parasites (e.g., Haemobartonella felis, Babesia canis, and Eperythrozoon suis), and hereditary diseases that affect red blood cells.

Diagnostics

Antemortem

Hematological testing should be performed with evaluations for Heinz body hemolytic anemia, methemoglobinemia, reticulocytes, icterus, and bilirubin, and chemistry evaluation of renal values. Urine output and presence of hemoglobinuria should be evaluated.

Postmortem

If death occurs, postmortem findings can include onion odor in the gastrointestinal contents, hemoglobin in the urine, pale or icteric tissues, and renal tubular degeneration and necrosis.

Management of Exposures

Small animals presenting with significant exposure to Allium spp. should be decontaminated. Induction of vomiting may be induced if the exposure was recent, and the animal is asymptomatic. However, caution should be exercised in determining whether contraindications to vomiting exist and whether it is safe to have the pet owner induce vomiting at home. Activated charcoal may be given once vomiting is controlled if the exposure was extremely large. A cathartic such as sorbitol can be given with activated charcoal.

Symptomatic treatment should be provided and may include administration of oxygen, blood transfusion(s), intravenous fluids, and control of gastrointestinal signs. Antioxidants such as N‐acetylcysteine or ascorbic acid may be used but are unproven. Treatment should continue until clinical signs are resolved.

Prognosis

The prognosis is generally good for animals that are decontaminated and treated early. However, the prognosis may be compromised in animals that develop renal damage secondary to hemolytic anemia.

AVOCADO

Sources

Avocados are in the family Lauraceae. They originate from southern Mexico to Central America but are now also grown in the warm climate of the southern United States. The genus Persea includes approximately 150 species and is the only edible genus. Persea americana is the only species known to have toxicological significance (Burrows and Tyrl 2013a). P. americana includes three ecological races or varieties: Guatemalan, Mexican, and West Indian or Columbian. Of the avocado races, there are a number of hybrids.

Kinetics

The toxic compound in avocados, persin, is absorbed quickly from the gastrointestinal system. The peak plasma level of persin with oral ingestion is 1–2 hours. Elimination of persin can occur through the milk in lactating animals (Oelrichs et al. 1995). Other forms of elimination are unknown, but mice that were dosed orally with persin eliminated the persin within 24 hours (Burrows and Tyrl 2013a).

Mechanism of Action

The mechanism of action for avocado toxicosis is unknown (Pickrell et al. 2004).

Toxicity

The Guatemalan avocado and its hybrids have been shown to be toxic. Other races/varieties have not been implicated in toxicoses to date (Burrows and Tyrl 20013a). While some species can develop sterile mastitis (horse, cattle, rabbit, goat) or cardiac failures (rabbit, bird, goat), dogs and cats just develop mild gastrointestinal signs.

Clinical Effects

Signs

Gastrointestinal signs in dogs and cats are expected to occur within 1–3 hours of exposure.

Laboratory

Blood chemistries and electrolytes should be monitored in these cases when signs are more than mild.

Differential Diagnoses

Many other toxicoses and disease processes may produce similar signs and should therefore be considered, especially if there is no known history of P. americana exposure.

Diagnostics

Antemortem

A history of exposure along with expected clinical signs provide adequate diagnostic evidence (Pickrell et al. 2004).

Postmortem

No pathognomonic lesions.

Management of Exposures

Emesis may be induced in dogs and potentially cats with significant exposure if the exposure is recent, no signs are present, and no other contraindications to emesis exist. Caution should be exercised in determining whether contraindications to vomiting exist and whether it is safe to have the pet owner induce vomiting at home. Treatment is primarily symptomatic because no specific antagonist exists. Crystalloid or colloid fluid support and antiemetics may be required.

Prognosis

Good prognosis for dogs and cats.

GRAPES AND RAISINS

Sources

The grape family contains 11–13 genera and 700–735 species (see Figure 27.2). Most species grow on woody vines, but a few species grow on shrubs or small trees. Grapes (Vitis spp.) are an important crop because they are eaten for food in whole fresh form and are used for raisins, juice, and wine. In addition, some taxa are used as ornamentals (Burrows and Tyrl 2013b). Vitis spp. have been linked to acute kidney injury in dogs.

Kinetics

Grapes and raisins are ingested orally. The toxic component in dogs is tartaric acid. Tartaric acid has a high rate of gastrointestinal absorption in dogs (Underhill et al. 1931). It is eliminated from the body in the urine. Dogs poorly eliminate organic acids compared to other species (Coyne and Landry 2023).

Mechanism of Action

The specific mechanism of acute kidney damage is not confirmed, but tartaric acid does cause proximal renal tubular necrosis (Coyne and Landry 2023; Wegenast et al. 2021).

Toxicity

Grapes may contain varying amounts of tartaric acid, generally ranging from 0.35 to 1.1% (Wegenast et al. 2022). Due to the varying amount of tartaric acid in different varieties of grapes and the decrease that is seen as the fruit reaches maturity, it is recommended that decontamination occurs if greater than 1 grape/raisin per 5 kg is ingested (Wegenast et al. 2022). As cooking decreases the toxicity of tartaric acid (Chattaway and Ray 1921), the decontamination trigger changes to 2 raisins per 5 kg if the raisins are baked in cookies, bagels, or bread. It is possible that individual animals may be more susceptible to toxicosis than other animals because reports from pet owners indicate that some dogs never became ill with ingestions of grapes or raisins.

Figure 27.2. Grapes on a vine.

Clinical Effects

Signs

The typical presentation involves vomiting within 12–15 hours of ingestion. The grapes and raisins are often seen in the vomitus and may be seen in fecal material as well. The dogs may exhibit lethargy, abdominal pain, anorexia, polydipsia, and diarrhea. These signs may be present for a few days or, in some cases, weeks. The kidney damage may progress, leading to oliguria and finally to anuria.

Laboratory

Blood chemistry panels may begin to show changes as early as 12 hours after exposure, but changes may not be noted for several days. Elevations of calcium, blood urea nitrogen, creatinine, and phosphorus have been documented. Elevations of pancreatic and liver enzymes have been documented in some cases as well.

Differential Diagnoses

Other toxicoses and disease processes produce similar signs and should therefore be considered, especially if there is no known history of Vitis spp. exposure. Differentials include exposure to ethylene glycol, lilies in cats, and aminoglycosides as well as leptospirosis, bacterial pyelonephritis, and chronic renal failure. Diseases that increase the risk for acute renal failure may include pancreatitis, heat stroke, hepatic failure, Rickettsia, bacterial endocarditis, and disseminated intravascular coagulation (Lane and Stokes 2011).

Diagnostics

Antemortem

A history of exposure along with consistent clinical signs provide adequate diagnostic evidence for a diagnosis. Biopsy of the kidney might provide additional information relevant for determining the prognosis.

Postmortem

Histopathological evaluation of tissues in the retrospective study demonstrated that the most consistent renal changes involved diffuse renal tubular degeneration, particularly affecting the proximal renal tubules. Other renal lesions were present in some cases. In addition, histopathology in some cases revealed congestion or edema of the liver, lungs, spleen, pancreas, and abdominal lymph nodes and occasional fibrinoid vasculitis or vascular necrosis (Eubig et al. 2008).

Management of Exposures

Emesis may be induced in dogs that have ingested grapes or raisins if the exposure is recent, no signs are present, and no other contraindications to emesis exist. Caution should be exercised in determining whether contraindications to vomiting exist and whether it is safe to have the pet owner induce vomiting at home. Activated charcoal may be given to dogs once vomiting is controlled if decontamination was not fruitful.

Baseline chemistries, complete blood count, electrolytes, and urinalysis should be performed. Renal values should be monitored throughout the course of treatment. Treatment is primarily symptomatic because no specific antagonist exists. Fluid support is required. Dehydration should be corrected, and then fluid diuresis should be initiated. Hydration status, lung sounds, body weight, and urine output should be monitored. Diuretics such as mannitol and furosemide may be useful to treat oliguria. Dopamine has also been used in the treatment of oliguria. If hyperphosphatemia occurs, aluminum hydroxide may be beneficial. If uremia occurs, hemodialysis or peritoneal dialysis may be beneficial. Vomiting may be treated with antiemetics. Treatment should continue until signs are resolved.

Prognosis

In the retrospective study mentioned above, ataxia, decreased urine output, and weakness were associated with a negative prognosis. In the same study, 53% of the dogs fully recovered or had mild residual azotemia, 12% died, and 35% were euthanized (Eubig et al. 2008).

MACADAMIA NUTS

Sources

Macadamia integrifolia and Macadamia tetraphylla trees produce macadamia nuts. These trees have been cultivated in Hawaii since the late 1800s. These nuts are commonly eaten by humans. They may be eaten whole as snack foods, but they are also used in baking and in a variety of recipes.

Kinetics

Macadamia nuts are ingested orally. It is not known how the toxic component is absorbed, distributed, metabolized, or eliminated from the body.

Mechanism of Action

The mechanism of action for macadamia nut toxicosis is unknown.

Toxicity

Dogs are the only reported species to develop toxicosis from ingestions of macadamia nuts. Signs have been reported with macadamia nut ingestions of 2.4 g/kg of body weight to 62.4 g/kg of body weight. Signs may develop within 2–12 hours of ingestion and generally resolve within 48 hours (Hansen et al. 2000).

Clinical Effects

Signs

The most common signs include weakness, depression, vomiting, ataxia, tremors, and hyperthermia. A laboratory study involving four dogs confirmed the syndrome, which had been reported to the ASPCA APCC. Weakness, stiffness, and ataxia appear to be most apparent in the rear limbs. Dogs may be reluctant to stand and have difficulty walking (Hansen et al. 2000).

Laboratory

White blood cell counts were high for all four dogs listed in the study above. One dog maintained an elevated white blood cell count 48 hours after ingestion. Numbers of segmented neutrophils including immature forms were increased. A few toxic neutrophils containing vacuoles were noted. The only other laboratory abnormality was alkaline phosphatase. Three of the dogs had high values 24 hours after ingestion, and the values were still elevated 48 hours after exposure (Hansen et al. 2000).

Differential Diagnoses

Other toxicoses may produce similar signs and should therefore be considered, especially if there is no known history of Macadamia spp. exposure. Differentials include exposure to ivermectin, milbemycin, moxidectin, or other avermectins, ethylene glycol, 5‐hydroxytryptophan, benzodiazepines, barbiturate overdose, ethanol or other alcohols, and bromethalin.

Diagnostics

Antemortem

History of exposure along with expected clinical presentation provide adequate diagnostic evidence. Consistent laboratory findings may help to confirm diagnosis.

Postmortem

No deaths have been reported from Macadamia spp. exposures.

Management of Exposures

Emesis may be induced in dogs that have ingested macadamia nuts if the exposure is recent, no signs are present, and no other contraindications to emesis exist. Caution should be exercised in determining whether contraindications to vomiting exist and whether it is safe to have the pet owner induce vomiting at home.

Most cases of macadamia nut toxicosis do not require treatment. When treatment is needed, it is primarily symptomatic and supportive because no specific antagonist exists. If continued vomiting occurs, it may be treated with antiemetics. Subcutaneous or intravenous fluid support may be required if dehydration is present from vomiting and oral fluids are not tolerated. Close monitoring is required. Confinement may be necessary to prevent injury in ataxic animals and to reduce sensory stimuli. Body temperature should be monitored and thermoregulation provided if needed. Monitoring should continue until signs have resolved.

Prognosis

Dogs with macadamia nut toxicosis have a good prognosis. No deaths have been reported and no sequelae have been noted.

METHYLXANTHINES

Sources

Methylxanthines are naturally occurring alkaloids. They occur naturally in some foods. They are also used as medications. Theobromine and caffeine are the methylxanthines of toxicological significance in chocolate (Table 27.1). Caffeine is also naturally present in coffee and some teas, and is added to a number of commercial beverages. Pets are frequently attracted to these foods and beverages, and may ingest amounts significant to produce toxicosis. Most methylxanthine toxicoses in dogs occur as a result of chocolate ingestion so this chapter will focus on chocolate (Gwaltney‐Brant 2001).

Table 27.1. Approximate methylxanthine levels in different forms of chocolatea

Chocolate Type | Total Methylxanthinesb (mg/oz)
White chocolate | 1.1
Milk chocolate | 64
Semisweet chocolate chips | 160
Baker's chocolate (unsweetened) | 440
Dry cocoa powder | 800

a Levels of methylxanthines in chocolates vary due to natural variations in the methylxanthine content of the chocolate base, as well as differences in manufacturing processes.

b Includes levels of theobromine and caffeine.

Source: Adapted from Gwaltney‐Brant (2001).

Kinetics

Methylxanthines are well absorbed from the gastrointestinal tract (Barnes 2023). Signs can develop within 2 hours of exposure but onset may be longer, especially if the animal ingests the wrappers.

Methylxanthines are distributed throughout the body, cross the placenta, and are passed into the milk of lactating females. The liver metabolizes methylxanthines (Gwaltney‐Brant 2001). Enterohepatic recirculation and reabsorption from the urinary tract has been reported (Barnes 2023). The half‐lives of caffeine and theobromine in dogs are 4.5 and 17.5 hours, respectively (Gwaltney‐Brant 2001). Recovery generally occurs within 24–48 hours after exposure provided that the signs are controlled.

Mechanism of Action

A definitive mechanism of action has not been identified, but clinical signs in animals are believed to be related to competitive inhibition of cellular adenosine receptors. Other mechanism of actions may include cellular calcium reuptake inhibition and competition for benzodiazepine receptors (Barnes 2023; Gwaltney‐Brant 2001).

Toxicity

Both caffeine and theobromine are present in chocolate. The darker chocolates contain higher levels of methylxanthines than lighter chocolates such as milk chocolate on a per weight basis (see Figure 27.3). Toxicosis is dependent on the dose of methylxanthines ingested.

It is important to determine the combined dose of methylxanthines ingested. The worst‐case scenario should be utilized for dose calculations. At combined caffeine and theobromine doses of 10–20 mg/kg or less, signs of toxicosis generally do not occur. However, chocolate often contains a significant amount of fat so gastrointestinal upset and/or pancreatitis may occur with any chocolate exposure. Doses of 40 mg/kg or more may induce signs of cardiotoxicity, should be considered significant, and may require decontamination and/or treatment. Methylxanthine doses over 60 mg/kg can cause neurologic signs (tremors, seizures).

Clinical Effects

Signs

The most commonly observed signs associated with significant chocolate ingestion in dogs and cats include vomiting, restlessness, hyperactivity, tachycardia and other cardiac arrhythmias, tachypnea, polyuria, hyperthermia, tremors, and seizures. Weakness, coma, cyanosis, hypertension, bradycardia, and ataxia may also occur. Death occurs from heart rhythm disturbances or respiratory failure (Gwaltney‐Brant 2001).

Figure 27.3. Assorted chocolates; when calculating doses take into account whether chocolate is solid or filled.

Photograph courtesy of Tina Wismer.

Laboratory

Hypokalemia may coincide with diuresis and vomiting (Gwaltney‐Brant 2001). Chemistries associated with the pancreas may be elevated 1–3 days after the exposure, indicating pancreatitis.

Differential Diagnoses

Other toxicoses produce similar signs and should therefore be considered, especially if there is no known history of chocolate exposure. Differentials include exposure to caffeine tablets, other medications that contain methylxanthines, pseudoephedrine, amphetamines, antihistamines, cocaine, and other products that may cause seizures.

Diagnostics

Antemortem

History of exposure along with expected clinical presentation provide adequate diagnostic evidence. Some laboratories can test for methylxanthines in serum, plasma, and urine.

Postmortem

Stomach contents can be evaluated grossly for wrappers and may be collected and submitted for methylxanthine testing. Special request for methylxanthine or other toxicology testing is usually required (Dunayer 2014).

Management of Exposures

Emesis may be induced in dogs and cats that have ingested chocolate if the exposure is recent, no signs are present, and no other contraindications to emesis exist. Caution should be exercised in determining whether contraindications to vomiting exist and whether it is safe to have the pet owner induce vomiting at home. Gastric lavage may be indicated in rare cases with very large ingestions because chocolate may form a firm mass in the stomach, and lavage may break the mass down and allow for more complete removal than emesis. Activated charcoal may be given to dogs once vomiting is controlled and if the dose ingested is over the lethal dose of 100 mg/kg. Multiple doses of activated charcoal are generally not recommended due to possible electrolyte shifts. A cathartic such as sorbitol may be given if diarrhea is not present.

Close monitoring and nursing care should be provided. Intravenous fluid therapy should be initiated when significant exposure has occurred. Other treatments should be provided as needed based on signs that occur. Tremors may be controlled with diazepam or methocarbamol. Seizures may require diazepam, phenobarbital, or gas anesthesia. Beta‐blockers or lidocaine may be beneficial for treating tachyarrhythmias, and bradycardias can be treated with atropine (Gwaltney‐Brant 2001).

Prognosis

The prognosis is good for animals that receive timely decontamination and treatment.

TREMORGENIC MYCOTOXINS

Sources

Mycotoxins are secondary fungal metabolites that are toxic to species such as animals, plants, or other microbes. The effects of mycotoxins differ based on the toxin and its chemical structure (Boysen et al. 2002). Approximately 20 mycotoxins have been identified as tremorgens. The most frequently reported tremorgenic mycotoxins affecting pets are petitrem‐A and roquefortine C, both of which are produced by Penicillium species (Schell 2000).

Reports of tremorgenic mycotoxin exposures have involved moldy foods, including dairy foods, moldy walnuts or peanuts, stored grains, and moldy pasta, as well as compost material (Boysen et al. 2002; Schell 2000). Dogs may ingest moldy food from the garbage or from composting areas. Young et al. (2003) reported on two cases, one involving the ingestion of moldy cream cheese and the other involving the ingestion of moldy macaroni and cheese. Another report described an exposure that involved four dogs from one household that ingested material from a compost pile (Boysen et al. 2002).

Kinetics

Tremorgenic mycotoxins are rapidly absorbed from the gastrointestinal tract, with onset of action occurring from 15 minutes to several hours after the exposure (Young et al. 2003). Reports on distribution and elimination are not available.

Mechanism of Action

A definitive mechanism of action has not been identified, but several have been proposed. One potential mechanism of action is the interference of inhibitory neurotransmitters such as glycine and gamma‐aminobutyric acid (GABA) (Barker et al. 2013; Cole 1977). Additional studies will be required to determine a confirmed mechanism of action.

Toxicity

Severe tremors have been reported in dogs with penitrem A exposure to dosages of 0.175 mg/kg of body weight (Gil‐Serna et al. 2014). In a clinical environment, dosage calculation may not be possible so determining the risk based on dose may not occur.

Clinical Effects

Signs

Common signs include hyperthermia, salivation, vomiting, ataxia, tachycardia, hyperesthesia, diarrhea, mydriasis, trembling, fasciculation, tremors, seizures, and death. Signs from exposure often begin within 15 minutes to 2 hours after the exposure, but signs may occur after this time frame. Young et al. (2003) reported on an 11‐year‐old Labrador retriever exposed to moldy cream cheese from the garbage. Signs were noted to occur the morning after the dog ingested the food. In this case penitrem A and roquefortine C were identified by the laboratory when cream cheese from the wrapper was analyzed. Signs in this case included generalized muscle fasciculation and hyperextension of the extremities, blepharospasms, vocalization, weakness, tachypnea, hyperexcitation, and tachycardia.

A second case documented in this report involved a dog that developed status epilepticus associated with tremorgenic mycotoxin ingestion. Further complications occurred for this dog with the development of aspiration pneumonia potentially associated with emesis or the gastric lavage procedure performed on the dog (Young, et al. 2003). Signs from tremorgenic mycotoxins frequently resolve within 48 hours, but residual fasciculations or intention tremors may persist for longer periods (Young et al. 2003).

Laboratory

Diagnostic laboratories utilize chromatography or mass spectrometry to identify tremorgenic mycotoxins. Electrolytes and other blood values should be monitored based on presenting signs.

Differential Diagnoses

Other toxicoses can produce similar signs and should therefore be considered, especially if there is no known history of mold exposure. Differentials include exposure to strychnine, metaldehyde, ethylene glycol, cholinesterase inhibitors, methylxanthines, pseudoephedrine, amphetamines, and cocaine.

Diagnostics

Antemortem

A tentative diagnosis can be made based on the exposure history and the resulting signs. Confirmation of the diagnosis is dependent on the results of laboratory tests. Suspect food or vomitus may be collected and submitted for tremorgenic mycotoxin evaluation. Food samples should be sent chilled; vomitus should be frozen.

Postmortem

No characteristic postmortem lesions are expected. Suspect food, vomitus, or stomach contents may be submitted for tremorgenic mycotoxin evaluation. Food samples should be sent chilled; vomitus and stomach contents should be frozen.

Management of Exposures

Emesis may be induced in dogs that have ingested moldy food or compost if the exposure is recent, no signs are present, and no other contraindications to emesis exist. Caution should be exercised in determining whether contraindications to vomiting exist and whether it is safe to have the pet owner induce vomiting at home. Gastric lavage may be indicated in some cases. Since signs generally have a rapid onset, it is often not indicated to administer activated charcoal. Gastric lavage and enemas may also be considered.

Close monitoring and nursing care should be provided. The patient should be stabilized, and signs should be managed. Intravenous fluid therapy should be initiated to prevent or treat dehydration associated with vomiting and to help regulate electrolytes. Other treatments should be provided as needed based on signs that occur. Tremors may be controlled with diazepam or methocarbamol. Seizures may require diazepam, phenobarbital, phenobarbital, or gas anesthesia (Boysen et al. 2002; Young et al. 2003). Body temperature should be monitored, and thermoregulation provided.

Prognosis

The prognosis is good for animals that receive timely decontamination and treatment. Death may occur in untreated animals.

ETHANOL

Sources

Alcohol (ethanol) toxicosis most frequently occurs when animals are exposed to alcoholic beverages or raw yeast dough but may also occur with ingestion of certain drug formulations or rubbing alcohol.

Kinetics

Ethanol is fully and quickly absorbed from all parts of the gastrointestinal tract generally within 30–60 minutes (Mayfield and Mihic 2023; Wismer 2017; Yip 2019). Absorption may be enhanced if the stomach is empty, the concentration of the substance ingested is dilute, or the substance ingested is carbonated (Rangno et al. 1981; Yip 2019). Absorption may be delayed if there is food in the stomach, gastrointestinal disease is present, certain drugs are in the system, the concentration of alcohol is high, or if there is decreased gastrointestinal motility (Lin et al. 1976; Yip 2019). Peak plasma levels in humans are 30 minutes to 2 hours after ingestion (Yip 2019). Ethanol is primarily metabolized in the liver. The remainder is excreted unchanged in the breath, urine, feces, and sweat (Wismer 2017; Yip 2019).

Mechanism of Action

A definitive mechanism of action has not been identified, but the mechanism of action is believed to be related to dissolution of lipid membranes affecting ion channels and their proteins, which causes depressant effects on the central nervous system (CNS). Another potential mechanism of action suggests that ethanol can also augment GABA‐mediated synaptic inhibition as well as changes in chloride ions.

Toxicity

Any dose of alcohol has the potential to cause serious effects in pet animals. Effects will vary based upon the amount ingested and the absorption rate. The published lethal oral ethanol dose in dogs (100% ethanol) is 5.5–7.9 g/kg (Wimer et al. 1984). While ethanol levels may be determined from blood, serum, plasma, and urine, they are seldom performed in pets due to turnaround time to receive results. If you are unable to get a blood ethanol level, serum or plasma osmolality may be used to estimate blood ethanol levels. Blood alcohol content (g/L) = osmolal gap/27. In humans, blood ethanol concentrations between 150 and 300 mg/dl (32.6–65.2 mmol/L) will generally cause obvious signs and symptoms. Death is usually associated with blood ethanol levels greater than 400 mg/dl (86.8 mmol/L) (Yip 2019).

Clinical Effects

Signs

Alcohol intoxication leads to CNS depression (Mayfield and Mihic 2023). The signs most commonly reported include ataxia, lethargy, vomiting, recumbency, hypothermia, disorientation, and vocalization. Signs that have been reported but are less common include tremors, tachycardia, acidosis, diarrhea, dyspnea, coma, and seizures (Wismer 2017). Signs usually resolve within 12 hours of exposure.

Laboratory

Abnormal laboratory values may occur. Complete blood count, chemistry panel, and blood gases should be performed.

Differential Diagnoses

Other toxicoses produce similar signs and should therefore be considered, especially if there is no known history of alcohol exposure. Differentials include exposure to iron, isoniazid, lactic acidosis, diabetes, ethylene glycol, salicylic acid, toluene, and marijuana. Additional differentials may include uremia, diabetic ketoacidosis, or cardiovascular accident.

Diagnostics

Antemortem

Diagnosis may be determined based on the exposure history and the resulting signs. Blood alcohol levels can be obtained to confirm exposure.

Postmortem

Toxicology tests may be performed on blood or tissues to confirm exposure and cause of death.

Management of Exposures

Emesis may be induced in dogs and cats that have ingested ethanol if the exposure occurred within the previous 25 minutes, no signs are present, and no other contraindications to emesis exist. Caution should be exercised in determining whether contraindications to vomiting exist and whether it is safe to have the pet owner induce vomiting at home. Activated charcoal is not indicated (Wismer 2017).

Close monitoring and nursing care, including thermoregulation, should be provided. Confinement may be required to prevent injury. Heart rate, blood pressure, and electrocardiogram should be obtained. Intravenous fluid and electrolyte therapy should be initiated. Sodium bicarbonate should be included if metabolic acidosis occurs, and dextrose should be added if hypoglycemia occurs. Other treatments should be provided as needed based on signs that occur. Cardiac drugs that may be of benefit include epinephrine, atropine, lidocaine, and yohimbine. Ventilation and seizure control may be required.

Prognosis

The prognosis is good for animals that receive timely decontamination, supportive care, and treatment. Cases complicated by aspiration of gastric contents, co‐ingestants, or preexisting disease have a more guarded prognosis.

YEAST DOUGH

Sources

Dogs may ingest raw yeast dough if it is available (Thrall et al. 1984; Suter 1992). A commonly reported scenario involves a dog ingesting yeast bread or roll dough left out to rise on a countertop. Two potential syndromes may occur independently or concurrently, the first being ethanol intoxication and the second being bloat secondary to gas production in the gastrointestinal tract (Means 2003).

Kinetics

See Kinetics section for ethanol toxicosis.

Mechanism of Action

When yeast metabolizes sugar, it produces ethanol and carbon dioxide. This leads to drunk, bloated pets.

Toxicity

See the Toxicity section for ethanol toxicosis.

Clinical Effects

Signs

See the Clinical Effects section for ethanol toxicosis. In addition to signs of alcohol intoxication, the ingestion of bread dough can cause bloating due to gas production. Vomiting, abdominal pain, bloating, retching, and recumbency may occur.

Laboratory

See the Laboratory section for ethanol toxicosis.

Differential Diagnoses

See the Differential Diagnoses section for ethanol toxicosis. Other potential causes of gastrointestinal signs and bloat should be evaluated.

Diagnostics

Antemortem

History of exposure along with expected clinical presentation provide adequate diagnostic evidence. See the Antemortem section for ethanol toxicosis.

Postmortem

See the Postmortem section for ethanol toxicosis. Necropsy may reveal dough mass in the stomach.

Management of Exposures

See the Management of Exposures section for ethanol toxicosis. Emesis may be recommended with caution. Encourage the dog to drink ice water or lavage with cold water to help decrease fermentation. If bloat or gastric dilatation volvulus occurs, stabilization and standard treatment should be provided (Means 2003).

Prognosis

The prognosis is good for animals that receive timely decontamination, supportive care, and treatment.

XYLITOL

Sources

Xylitol, a sugar alcohol, is a natural sweetener found in plants. It is commonly obtained from birch bark. Xylitol has comparable sweetness to table sugar (Dunayer 2004). It is a nutritive sweetener that provides calories and is found in many human and pet products, e.g., sugar‐free gum, dental spray, dental lozenges, and toothpaste. It is also used as a sweetener in products for diabetics and is found in some dietary supplements and chewable vitamins, and in many other food products, such as high‐protein peanut butter, designed to be low in sugar or carbohydrates. In dogs, xylitol can cause hypoglycemia and liver necrosis.

Kinetics

When ingested, xylitol is absorbed readily from the gastrointestinal tract with peak plasma levels occurring 30 minutes after ingestion (Kuzuya et al. 1969). It may be converted to glucose and then glycogen in the liver. The liver is where 80% of xylitol metabolism occurs (Froesch and Jakob 1974).

Mechanism of Action

Xylitol stimulates insulin release in dogs leading to hypoglycemia. Xylitol is also metabolized intracellularly to D‐xylulose, which is then metabolized via the pentose‐phosphate pathway (PPP). The mechanism of action for liver effects is not known in the dog, but in other species the PPP bypasses adenosine triphosphate (ATP) production via the tricarboxylic acid cycle (Krebs cycle) (McCormick and Touster 1957). The lack of ATP results in cellular death due to lack of energy production.

Toxicity

Signs of hypoglycemia may occur at doses greater than 100 mg/kg of xylitol. Liver failure is seen at doses greater than 400 mg/kg.

Clinical Effects

Signs

Reported signs include hypoglycemia, vomiting, lethargy, and ataxia. The animal's condition may advance to include recumbency, seizures, and coagulopathy (Dunayer 2004; Dunayer and Gwaltney‐Brant 2006).

Laboratory

Abnormal laboratory values may include low potassium, low phosphate, elevated bilirubin, and elevated liver enzymes (Dunayer 2004; Dunayer and Gwaltney‐Brant 2006).

Differential Diagnoses

Additional differentials may include insulinoma, insulin overdose, oral hypoglycemic agents (e.g., sulfonylureas), hunting dog hypoglycemia, juvenile hypoglycemia, and prolonged starvation.

Diagnostics

Antemortem

History of exposure along with expected clinical presentation provide adequate diagnostic evidence.

Postmortem

Xylitol is not expected to remain in the tissues since it is metabolized quickly.

Management of Exposures

Emesis may be induced in dogs that have ingested xylitol‐containing products if the exposure was within 15–30 minutes, no signs are present, and no other contraindications to emesis exist. Caution should be exercised in determining whether contraindications to vomiting exist and whether it is safe to have the pet owner induce vomiting at home. Activated charcoal is not expected to be of benefit.

Close monitoring is required. Glucose should be monitored every 2–4 hours for the first 12–24 hours, and blood chemistries and electrolytes should be monitored. Small meals may be fed if blood sugar remains normal. Confinement may be necessary to prevent injury in ataxic animals. Symptomatic and supportive care should be provided and may include administration of intravenous fluids with dextrose, nutritional support, and potassium supplementation. If liver enzymes begin to elevate, coagulation parameters should be monitored. Hepatoprotective agents such as S‐adenosylmethionine, silymarin (milk thistle), or N‐acetylcysteine may be given (Dunayer 2004). Monitoring and treatment should continue until signs have resolved.

Prognosis

When treatment is provided and doses that affect the liver are not achieved, the prognosis is good. When hepatic necrosis and coagulopathy occur, the prognosis is guarded.

REFERENCES

Barker, Andrew K, Stahl, Chase, Ensley, Steve M, and Jeffery, Nick D. 2013. Tremorgenic mycotoxicosis in dogs. Compendium Continuing Education for Veterinarians 35(2):E1–E6.

Barnes, Peter J. 2023. Pulmonary pharmacology. In Goodman & Gilman's the Pharmacological Basis of Therapeutics, 14th ed., edited by Laurence L Brunton and Bjorn C Knollmann, pp. 875–898. New York: McGraw‐Hill LLC.

Boysen, Soren R, Rozanski, Elizabeth A, Chan, Daniel L, Grobe, Terri L, Fallon, Michael J, and Rush, John E. 2002. Tremorgenic mycotoxicosis in four dogs from a single household. Journal of the American Veterinary Medical Association 221(10):1441–1444.

Burrows, George E and Tyrl, Ronald J. 2013a. Lauraceae juss. In Toxic Plants of North America, 2nd ed., edited by George E Burrows and Ronald J Tyrl, pp. 744–747. Ames, Iowa: John Wiley & Sons, Inc.

Burrows, George E and Tyrl, Ronald J. 2013b. Vitaceae juss. In Toxic Plants of North America, 2nd ed., edited by George E Burrows and Ronald J Tyrl, p. 1269. Ames, Iowa: John Wiley & Sons, Inc.

Chattaway, Frederick Daniel and Ray, Francis Earl. 1921. II. The decomposition of tartaric acid by heat. Journal of the Chemical Society, Transactions 119:34–37.

Cheeke, Peter R. 1998. Forage‐induced anemia. In Natural Toxicants in Feeds, Forages, and Poisonous Plants, 2nd ed., edited by Peter R Cheeke, pp. 305–306. Danville, Illinois: Interstate Publishers.

Christopher, Mary M, White, James G, and Eaton, John W. 1990. Erythrocyte pathology and mechanisms of Heinz body‐mediated hemolysis in cats. Veterinary Pathology 27(5):299–310.

Cole, Richard J. 1977. Tremorgenic mycotoxins. In Mycotoxins in Human and Animal Health, edited by JV Rodricks, CW Hesseltine, and MA Mehlman, pp. 583–595. Park Forest South, Illinois: Pathotox Publishers.

Coyne, Sean R and Landry, Greg M. 2023. Tartaric acid induces toxicity in Madin–Darby canine kidney cells, but not human kidney‐2 cells in vitro, and is prevented by organic anion transporter inhibition and human OAT‐4 transfection. Journal of Veterinary Emergency and Critical Care 33(3):298–304.

Dunayer, Eric K. 2004. Hypoglycemia following canine ingestion of xylitol‐containing gum. Veterinary and Human Toxicology 46(2):87–88.

Dunayer, Eric K. 2014. Human foods with pet toxicoses: alcohol to xylitol. In Current Veterinary Therapy XV, edited by John D Bonagura and David C Twedt, pp. 147–150. St. Louis: Philadelphia: Elsevier Saunders.

Dunayer, Eric K and Gwaltney‐Brant, Sharon M. 2006. Acute hepatic failure and coagulopathy associated with xylitol ingestion in eight dogs. Journal of the American Veterinary Medical Association 229(7):1113–1117.

Eubig, Paul A, Brady, Melinda S, Gwaltney‐Brant, Sharon M, Khan, Safdar A, Mazzaferro, Elisa M, and Morrow, Carla MK. 2008. Acute renal failure in dogs after the ingestion of grapes or raisins: a retrospective evaluation of 43 dogs (1992–2002). Journal of Veterinary Internal Medicine 19(5):663–674.

Froesch, ER and Jakob, Andrea. 1974. The metabolism of xylitol. In Sugars in Nutrition, edited by Horace L Sipple and Kristen W McNutt, pp. 241–258. New York: Academic Press.

Gil‐Serna, Jessica, Vasquez, Covadonga, Gonzalez‐Jaen, M Teresa, and Patino, Belen. 2014. Mycotoxins toxicology. In Encyclopedia of Food Microbiology, 2nd ed., edited by Carl A Batt, pp. 887–892. London: Elsevier.

Guo, Z, Muller, Dirk, Pentz, Ronaldo, Kress, G, and Siegers, Claus‐Peter. 1990. Bioavailability of sulphur‐containing ingredients of garlic in the rat. Planta Medica 56(6):692.

Gwaltney‐Brant, Sharon. 2001. Chocolate intoxication. Veterinary Medicine 96(2):108–111.

Hansen, Steven R, Buck, William B, Meerdink, Gavin, and Khan, Safdar A. 2000. Weakness, tremors, and depression associated with macadamia nuts in dogs. Veterinary and Human Toxicology 42(1):18–21.

Kuzuya, Takeshi, Kanazawa, Yasunori, and Kosaka, Kinori. 1969. Stimulation of insulin secretion by xylitol in dogs. Endocrinology 84(2):200–207.

Lane, India F and Stokes, Jennifer E. 2011. Treatment of urinary disorders. In Small Animal Clinical Pharmacology and Therapeutics, 2nd ed., edited by Dawn M Booth, pp. 640–671. St. Louis: Elsevier.

Lin, Yi‐Jong, Weidler, Donald J, and Garg, Dyal C. 1976. Effects of solid food on blood levels of alcohol in man. Research Communications in Chemistry, Pathology, and Pharmacology 13(4):713–722.

Mayfield, Jody and Mihic, S John. 2023. Ethanol. In Goodman & Gilman's the Pharmacological Basis of Therapeutics, 14th ed., edited by Laurence L Brunton and Bjorn C Knollmann, pp. 519–530. New York: McGraw‐Hill LLC.

McCormick, Donald B and Touster, Oscar. 1957. The conversion in vivo of xylitol to glycogen via the pentose phosphate pathway. Journal of Biological Chemistry 229(1):451–461.

Means, Charlotte. 2003. Bread dough toxicosis in dogs. Journal of Veterinary Emergency and Critical Care 13(1):39–41.

Oelrichs, Peter B, Pearce, Clive M, Zhu, Jin, and Filippich, Louis J. 1995. Isolation and identification of a compound from avocado (Persea americana) leaves which causes necrosis of the acinar epithelium of the lactating mammary gland and the myocardium. Natural Toxins 3(5):344–349.

Ogawa, Eri, Shinoki, Toshihiko, Akahori, Fumiaki, and Masaoka, Toshio. 1986. Effect of onion ingestion on anti‐oxidizing agents in dog erythrocytes. Nihon Juigaku Zasshi 48(4):685–691.

Okuyama, Toru, Fujita, K, Shibata, Shoji, Hoson, Masayuki, Kawada, Tadanori, Masaki, Mika, and Yamate, Noboru. 1989. Effects of Chinese drugs “Xiebai” and “Dasuan” on human platelet aggregation (Allium bakeri, A. sativum). Planta Medica 55(3):242–244.

Pantoja, Carmen V, Chiang, Luciano C, Norris, Beryl C, and Concha, Juan B. 1991. Diuretic, natriuretic and hypotensive effects produced by Allium sativum (garlic) in anaesthetized dogs. Journal of Ethnopharmacology 31(3):325–331.

Pickrell, John A, Oehme, Fred, and Mannala, Shajan A. 2004. Avocado. In Clinical Veterinary Toxicology, edited by KH Plumlee, pp. 424–425. St. Louis: Mosby.

Rangno, Robert E, Kreeft, JH, and Sitar, Daniel S. 1981. Ethanol dose dependent elimination: Michaelis–Menten v classical kinetic analysis. British Journal of Clinical Pharmacology 12:667–673.

Robertson, Jane E, Christopher, Mary M, and Rogers, Quinton R. 1998. Heinz body formation in cats fed baby food containing onion powder. Journal of the American Veterinary Medical Association 212(8):1260–1266.

Schell, Mary M. 2000. Tremorgenic mycotoxin intoxication. Veterinary Medicine 95(4):283–286.

Suter, Robert J. 1992. Presumed ethanol intoxication in sheep dogs fed uncooked pizza dough. Australian Veterinary Journal 69(1):20.

Thrall, Mary Anna, Freemyer, FG, Hamar, Dwayne W, and Jones, RL. 1984. Ethanol toxicosis secondary to sourdough ingestion in a dog. Journal of the American Veterinary Medical Association 184(12):1513–1514.

Underhill, Frank P, Leonard, Clifford S, Gross, Erwin G, and Jaleski, Thomas C. 1931. II. The behavior of tartrate in the organism of the rabbit, dog, rat and guinea pig. The Journal of Pharmacology and Experimental Therapeutics 43(2):359–380.

Wegenast, Colette A, Meadows, Irina D, Anderson, Rachele E, Southard, Teresa, Barrientos, Cristy Rocio, Gonzalez, and Wismer, Tina A. 2022. Acute kidney injury in dogs following ingestion of cream of tartar and tamarinds and the connection to tartaric acid as the proposed toxic principle in grapes and raisins. Journal of Veterinary Emergency and Critical Care 32(6):812–816.

Wegenast, Colette, Meadows, Irina, Anderson, Rachele, and Southard, Teresa. 2021. Letter to the editor: unique sensitivity of dogs to tartaric acid and implications for toxicity of grapes. Journal of the American Veterinary Medical Association 258(7):706–707.

Wimer, William W, Russel, John A, and Kaplan, Harold L. 1984, pp. 8–76. Park Ridge, NJ: Noyes Data Corp.

Wismer, Tina A. 2017. Ethanol toxicosis: A review. Today's Veterinary Practice Mar/Apr:74–76.

Yip, Luke. 2019. Ethanol. In Goldfrank's Toxicologic Emergencies, 11th ed., edited by Lewis S Nelson, Mary Ann Howland, Neal A Lewin, Silar W Smith, Lewis R Goldfrank, and Robert S Hoffman, pp. 1143–1156. New York: McGraw‐Hill Education.

Young, Kristen L, Villar, David, Carson, Thomas L, Ierman, Paula M, Moore, Ronda A, and Bottoff, Michael R. 2003. Tremorgenic mycotoxin intoxication with penitrem A and roquefortine in two dogs. Journal of the American Veterinary Medical Association 221(1):52–53.

28
Mycotoxins and Mushrooms

Lizzy Stone‐Lawrence

INTRODUCTION

Mushroom poisonings are common in dogs and infrequent in cats. Poisonings probably occur more frequently because ingestions may not be observed by owners and few analytical laboratories can confirm mushroom toxicosis. Therefore, many mushroom‐induced toxicoses are likely attributed to other causes.

When dealing with a possible mushroom toxicosis, it is important to verify whether the mushroom was purchased from a store for medicinal or ingestion purposes or if it was obtained from mushroom hunting. If the owner suspects mushrooms, request a description of the mushroom (size, color) and whether the dog or cat ate the cap or stem. Whenever possible, the mushroom should be positively identified as to genus and species (see Figures 28.1 and 28.2). If the owner has access to the mushroom, it should be placed in a paper bag and refrigerated. The best way to bag it is to place the mushroom with the cap down on a white sheet of paper that has the site and the conditions written on it. It is sometimes important to include known trees in the environment because certain mushrooms are associated with specific trees (Puschner 2013). There are several social media sites that can attempt to identify mushrooms from photographs.

There are many different types of mushrooms containing a variety of toxins that cause differing clinical signs. The mushrooms that will be covered in this chapter include the mushrooms affecting the gastrointestinal (GI) system; muscarine‐containing mushrooms, which cause classic cholinergic signs (SLUDD); isoxazole‐ and psilocybin‐containing mushrooms, which cause hallucinogenic signs; and amanitin‐ and gyromitrin‐containing mushrooms, which are hepatotoxic (Table 28.1). Each category of mushroom, their mechanisms of action, their associated clinical signs, and medical management of intoxications will be covered separately because they have widely varying symptoms and degrees of toxicity.

MUSHROOMS CAUSING GASTROINTESTINAL SIGNS

Sources

Many mushrooms cause GI upset in animals. The species involved are members of the genera Agaricus, Albatrellus, Armillaria, Boletus, Chlorophyllum, Entoloma, Gomphus, Hebeloma, Laccaria, Lactarius, Laetiporus, Meripilus, and Omphalotus. The specific toxins for many of them have not been identified. Some possible toxins include monoterpenes (Albatrellus spp.), norcaperatic acid (Gomphus spp.), hebeleomic acid A (cytotoxic triterpene, Hefeloma crustuliniforme), cucurbitane triterpene glycosides (Hebeloma vinosphyllum), lectins (Laccaria amethystine), marasmane/lactarane sesquitrpenes (Russula spp. and Lactarius spp.), and phenylethylamines (Lactiprus sulphureus and Meripilus spp.) (Puschner 2013; Puschner and Wegenast 2018). These mushrooms are widely distributed throughout the United States and grow in a variety of substrates and environments.

Figure 28.1. It is not uncommon for owners to send a photograph of mushrooms found in the yard.

Photograph courtesy of Callie Heard.

Figure 28.2. Physical characteristics, such as gill pattern, can be helpful when identifying mushrooms.

Photograph courtesy of Callie Heard.

Kinetics

Kinetic information on these species has not been established because the toxic principle of most GI irritant mushrooms is not known. However, onset of signs is quick (15 minutes to 1 hour).

Mechanism of Action

A variety of mechanisms are thought to be responsible for causing clinical signs, including hypersensitivity, local irritation, and enzyme deficiencies (Puschner 2013).

Toxicity

The toxicity of these mushrooms varies. One‐half of a cap from an Agaricus spp. caused foaming, vomiting, diarrhea, and disorientation in a 1‐year‐old cat (Puschner 2013). An unknown species of Russula was eaten by a cat that subsequently developed hematemesis (Puschner 2013). Precise toxicity information specific to pet animals is not available.

Clinical Signs

The most common clinical effect seen is GI upset, including vomiting and diarrhea (possibly bloody), salivation, abdominal discomfort, and lethargy. The GI effects can result in dehydration and rarely cause electrolyte imbalances, hypovolemia, collapse, and death. The onset of signs is within 15 minutes to several hours and the duration is a few hours to several days. Typically, no long‐term effects are expected. If the onset of GI signs is 6–24 hours after ingestion there is a possibility that the animal ingested an amanitin‐containing mushroom, which is a much more serious intoxication.

Differential Diagnoses

The differential diagnoses for the GI class of mushrooms include bacterial or viral gastroenteritis, dietary indiscretion, pancreatitis, hepatotoxic mushroom ingestion, irritant plant ingestion, or tremorgenic mycotoxin ingestion.

Diagnostics

In a live animal, the vomitus should be examined for evidence of mushrooms, and at a necropsy, mushrooms may be found in the gastric contents. Fragments of mushrooms found in vomitus or gastric contents might be suitable for identification purposes. If the client can provide fresh, intact samples of the suspected mushrooms, they can be sent to qualified mycologists for identification.

Table 28.1. Mushrooms of veterinary importance in North America

Mushroom | Toxin | Clinical Signs
Agaricus, Albatrellus, Armillaria, Boletus, Chlorophyllum, Entoloma, Gomphus, Hebeloma, Laccaria, Lactarius, Omphalotus, Rhodophyllus, Ramaria, Suillus | No specific toxin identified | Gastrointestinal irritation
Vomiting
Abdominal pain
Diarrhea
Lethargy
Weakness
Dizziness
Inocybe spp. | Muscarine | Salivation
Clitocybe spp. | Lacrimation
Entoloma | Urination
Diarrhea
Miosis
Tachycardia
Hypotension
Bronchoconstriction
Vomiting
Amanita muscaria (fly agaric) | Isoxazole: ibotenic acid, muscimol | Behavioral changes (disoriented, agitated, depression)
Aminata pantherina (panther or warted agaric) | Somnolence/coma
Lethargy
Vomiting
Ataxia/paresis
Dyspnea
Hyperactivity
Salivation
Diarrhea
Miosis
Tremors/seizures
Second‐degree atrioventricular block
Psilocybe | Psilocybin | Central nervous system derangement
Conocybe | Psilocin | Altered behavior
Gymnopilus, Panaeolus | Agitation
Stropharia (hallucinogenic or magic mushrooms) | Aggression
Vocalization
Weakness/ataxia
Tachycardia
Hyperreflexia
Mydriasis
Seizures
Hyperthermia
Hypertension
Drowsiness
Gyromitra spp. (false morels) | Monomethylhydrazine | Vomiting
Helvella spp. | Watery diarrhea
Verpa bohemica | Dehydration
Abdominal pain
Lethargy
Fever
Liver and renal damage
Hemolysis
Methemoglobinemia
Hypoglycemia
Seizures
Amanita spp. (A. phalloides or death cap) | Cyclopeptides: | Irreversible cytotoxicity of liver and kidney
Galerina | amatoxins | Severe hypoglycemia
Lepiota | (α‐, β‐, γ‐, ε‐amanitins), phallotoxins, virotoxins | Gastroeneteritis
Death

Management of Exposures

The medical management of a GI toxin mushroom consists of inducing emesis if vomiting has not already occurred. Emesis can be achieved by having the owners use 3% hydrogen peroxide at home with the dose based on the weight of the animal, or a veterinarian can induce emesis with apomorphine or ropinirole. Activated charcoal may be administered if the mushroom is unable to be identified. A complete blood count, liver/renal panels, electrolytes, and acid/base evaluation should be obtained if hepatotoxic mushroom ingestion has not been ruled out. Parenteral fluid administration to combat dehydration due to excessive vomiting may be needed along with stomach protectants and antiemetics. Symptomatic and supportive care should be provided as needed.

Prognosis

Ingestion of these mushrooms is rarely fatal, but it is essential to differentiate GI‐toxic mushrooms from hepatotoxic ones.

MUSCARINIC MUSHROOMS

Sources

The agent in muscarinic mushrooms is muscarine, which is heat stable; only the L(+) isomer is active. Inocybe spp. and Clitocybe spp. species of mushrooms contain this agent and are nondescript small brown mushrooms. Very low concentrations of muscarine can be found in many other genera, including Entoloma and Mycena. These mushrooms are found throughout the United States and Canada, and prefer to grow in hardwood and coniferous forests, parks, lawns, and gardens.

Kinetics

The oral absorption of muscarine is poor, but some species (e.g., rabbits) have negligible absorption of muscarine (Benjamin 1995). Muscarine is not affected by digestive enzymes. It does not cross the blood–brain barrier so any central nervous system (CNS) signs are attributed to secondary effects from hypoxia due to hypotension.

Mechanism of Action

Muscarine binds muscarinic (acetylcholine) receptors in the parasympathetic nervous system, stimulating postsynaptic neurons. It is not degraded by acetylcholinesterase so the action is prolonged. The specific target organs are gland cells, cardiac nodal muscle fibers, and smooth muscle. Effects are peripheral, not central (Puschner 2013).

Toxicity

Species differ in their sensitivity to intoxication. Rabbits are relatively resistant due to poor oral absorption of muscarine. Cat and mouse cardiovascular systems are particularly sensitive to muscarine. In cats, as little as 0.01 mg/kg IV can cause hypotension (Benjamin 1995).

Clinical Signs

The clinical signs are typically cholinergic signs (e.g., salivation, lacrimation, urination, defecation, dyspnea, and emesis, or SLUDDE) without nicotinic or significant CNS effects. The most common signs seen are hypersalivation (with thick ropy saliva), vomiting, diarrhea, lacrimation, and wet bronchial sounds. There is frequently abdominal pain, urinary incontinence, and anxiety; occasionally, tachycardia, miosis, hypotension, and dyspnea; and, rarely, animals exhibit respiratory and cardiac arrest. The onset of signs is usually within 5–30 minutes of ingestion. Occasionally, signs may be delayed for up to 2 hours post‐ingestion Signs can persist for several hours if not treated, but they quickly subside when atropine is administered. There are no laboratory abnormalities expected.

Differential Diagnoses

The differential diagnoses include organophosphorus or carbamate insecticide, amatoxin‐a, or slaframine intoxications.

Diagnostics

Muscarine can be detected in urine and this has been used to confirm exposure, but the best diagnostic parameter is response to treatment (i.e., administration of atropine).

Management of Exposures

Induction of emesis is advised if the animal has not already vomited and the time from ingestion to presentation is not prolonged. Emesis can be achieved by having the owners use 3% hydrogen peroxide at home with a dose based on the body weight of the animal if no symptoms are present, or a veterinarian can induce emesis using apomorphine or ropinirole. Symptomatic and supportive care is always needed. Oxygen can be administered if dyspnea is noted. Intravenous (IV) fluid therapy can be administered for possible hypotension. The specific antagonist for muscarine is atropine. Atropine competitively dislodges muscarine from receptor sites without stimulating postsynaptic neurons. A preanesthetic atropine dose should be administered and, if no signs of atropinization occur (increased heart rate, mydriasis), additional atropine may be given to effect. The starting dose is 0.04 mg/kg (quarter IV with the remainder IM). The end point is not mydriasis, but cessation of secretions (Puschner 2013).

Prognosis

The prognosis is usually good since ingestions are rarely fatal.

HALLUCINOGENIC MUSHROOMS

Sources

Hallucinogenic mushrooms or “magic mushrooms” contain psilocybin and psilocin. Psilocin is the dephosphorylated form of psilocybin and can be the primary form present in the bloodstream. It is a methyltryptamine derivative and is heat stable and resists drying. Psilocybe spp., Panaeolus spp., Conocybe spp., Gymnophilus spp., and some Stropharia spp. also contain this type of toxin. Stems of some psilocybin‐containing mushrooms will turn blue when handled.

These mushrooms are found in North America, especially in the Pacific Northwest and Gulf Coast. They thrive in manure although some prefer mulch and rotting wood (Benjamin 1995). They will grow in lawns, gardens, parks, roadsides, and open woods. These mushrooms are used recreationally for hallucinogenic effects. Their sale and use are illegal in the majority of the United States, but the sale of the mycelia of the “magic mushrooms” is not illegal. The mushrooms have been put in capsules in a powdered form and added to soups, stews, milkshakes, and other edible products to mask the bitter taste (Benjamin 1995). Incidence of ingestion is increasing with the legalization of these mushrooms in several areas of the United States.

Kinetics

The bioavailability of psilocybin is ~50% in rats (Benjamin 1995). It is widely distributed throughout the body and it crosses the blood–brain barrier, concentrating in the liver and adrenals. Within 4 hours of ingestion, it cannot be detected in blood, but it remains in the liver and adrenals for up to 48 hours (Benjamin 1995). It does not appear to be metabolized via monoamine oxidase. Approximately 66% is excreted in urine within the first 24 hours while the remainder in the liver and adrenals is gradually eliminated over 7 days (Benjamin 1995). Some mushrooms in this group also contain serotonin and tryptophan.

Mechanism of Action

The chemical acts as a serotonin agonist. It is thought to stimulate serotonin receptors (e.g., 5‐hydroxytryptamine [2A is the subtype of receptor]) within the CNS and peripheral nervous system. The mechanism may also involve norepinephrine‐mediated pathways (Benjamin 1995).

Toxicity

Doses of about 4–8 mg psilocybin/2 g of dried mushrooms or 20 fresh mushrooms can produce signs. In humans the initial signs consist of relaxation and detachment, and can occur at a psilocybin dose of 4 mg. In humans, 6–12 mg psilocybin results in perceptual alteration and visual distortions. Greater than 12 mg psilocybin or one to four large fresh mushrooms can cause hallucinations in humans (Benjamin 1995).

Clinical Signs

The most common clinical effects from ingestion of these mushrooms are alteration of behavior and mentation, ataxia, and vocalization. Frequently, there will also be mydriasis and hyperthermia, and possibly tachycardia, seizures, and muscle weakness. Rarely, death has occurred. There are no specific laboratory abnormalities expected.

Differential Diagnoses

Differentials include serotonergic/psychotropic drug, alcohol, marijuana, or LSD intoxications.

Diagnosis

Tests are available to detect psilocybin, but the signs will probably have subsided by the time test results are obtained. No specific laboratory or necropsy/histopathologic alterations are expected.

Management of Exposures

Decontamination via emesis and lavage can be performed and activated charcoal given for recent ingestions. Emesis can be induced by having the owners use 3% hydrogen peroxide at home with a dose based on the weight of the animal if no symptoms are present, or a veterinarian can induce emesis using apomorphine or ropinirole. Aspiration is a risk that needs to be taken into consideration in animals showing neurologic signs. Gastric emptying can be followed by administration of one dose of activated charcoal. Seizures can be controlled with diazepam or, if no response, barbiturates, propofol, or isoflurane can be used as needed. The body temperature needs to be regulated and all sensory stimuli need to be kept to a minimum. Cyproheptadine, while not an antagonist, can block the effects of serotonergic drugs and may also be helpful for hyperthermia.

Prognosis

The prognosis is generally good, and most animals survive with supportive and symptomatic care.

IBOTENIC ACID AND MUSCIMOL‐CONTAINING MUSHROOMS

Sources

Ibotenic acid and muscimol are isoxazoles. Muscimol is the decarboxylation product of ibotenic acid (Benjamin 1995). Amanita gemmata, Amanita muscaria (fly agaric mukhomor, woodpecker‐of‐Mars), Amanita pantherina (panther mushroom), Amanita smithiana, Amanita strobilformis, and Tricholoma muscarium. A. muscaria and A. pantherina are responsible for most animal and human poisonings (Benjamin 1995).

A. muscaria has a cap that ranges from bright orange to bright crimson. It grows from summer to fall and fruiting most commonly occurs in fall and early winter. In the eastern United States, it can fruit in the summer and again in late fall. It is found primarily in coniferous and deciduous forests, but can also be found on roadsides, in parks and open forests, and on edges of pastures (Benjamin 1995; Puschner 2013). It is abundant in the Pacific Northwest in association with Douglas fir trees and is widespread throughout the United States and Canada. It is often found in association with beech and aspen. A. muscaria has been used as a fly attractant/poison (Benjamin 1995) and as an inebriant for recreational and religious purposes. A. pantheris is found more commonly in the western United States, especially the western coastal plain (Benjamin 1995). It fruits in the spring and early summer and again in the fall and is associated with conifers and sometimes hardwoods.

Kinetics

Muscimol and ibotenic acid cross the blood–brain barrier.

Mechanism of Action

Isoxazoles cause fluctuating CNS excitation and depression due to opposing effects of muscimol and ibotenic acid. The mechanism of action for the cholinergic‐like effects is not known. Muscimol is formed by the decarboxylation of ibotenic acid, which binds gamma‐aminobutyric acid (GABA) receptors in the CNS. This binding is irreversible and leads to prolonged activity, which results in CNS depression. Ibotenic acid acts on glutamate receptors in the brain, which results in CNS stimulation. It may also have direct neurotoxic effects, which can cause neuronal necrosis (Romano et al. 2019). Tricholomic acid from Tricholoma muscarium has a similar structure and mechanism of action as ibotenic acid.

Toxicity

The toxicity of these mushrooms can be difficult to quantify because it depends on many factors. Six millligrams of muscimol causes CNS effects in adult humans (Benjamin 1995). This amount is found in a single cap of A. pantherina and some A. muscaria. A lethal dose (human) is approximately 15 caps. Spring and summer fruiting caps may have higher levels of toxins. Ibotenic acid is five to 10 times less potent than muscimol in humans (Benjamin 1995). Drying mushrooms containing ibotenic acid results in spontaneous decarboxylation to muscimol. Dried mushrooms are more toxic than fresh, but prolonged storage results in degradation of the toxins so they become less toxic over time (>1 year).

Clinical Signs

The most common clinical signs are vomiting, ataxia, and disorientation. Frequently one can see hallucinations, vocalizations, alternating lethargy and agitation, hyperesthesia, recumbency, somnolence, and fasciculations. This range of clinical effects is known as pantherine syndrome. Within a few hours, recumbency and unconsciousness can develop. There is also the possibility of tremors, seizures, bradycardia, hypotension, and hypothermia. Rarely, one can see respiratory depression and death. The onset of signs is almost always within 30 minutes to 2 hours, but can sometimes be delayed for up to 6 hours. The duration of signs can be 8–24 hours. There are no long‐term sequela expected and no laboratory abnormalities expected, but if the vomiting and diarrhea are prolonged there can be electrolyte abnormalities (Puschner and Wegenast 2018).

Diagnosis

There are no diagnostic tests available and there are no diagnostic lesions that develop.

Differential Diagnoses

Differential diagnoses include ethylene glycol, alcohol, marijuana, serotonergic or dopaminergic drug, opiate, barbiturate, or other CNS depressants intoxications, and viral or bacterial encephalitis.

Management of Exposures

Decontamination is useful in asymptomatic animals and consists of induction of emesis if ingestion has been within 4 hours. Emesis can be achieved as previously discussed followed by activated charcoal. Symptomatic and supportive care is required. IV fluids are needed for cardiovascular support. Caution must be used if giving any CNS depressants as they have been linked to apnea (Puschner and Wegenast 2018). Non‐GABA sedatives such as acepromazine and dexmedetomidine can be considered. If seizures develop, diazepam and barbiturates can be used. Injectable methocarbamol is best for tremors. Providing an environment that minimizes external stimuli can reduce the tendency to seizure or tremor. Thermoregulation is needed and antiemetics and GI protectants are part of the supportive care needed. Atropine is contraindicated because it may worsen the clinical effects of isoxazoles (Benjamin 1995).

Prognosis

The prognosis is generally excellent provided good supportive care is provided.

GYROMITRIN‐CONTAINING MUSHROOMS

Sources

Gyromitrin is heat‐labile, volatile, and water soluble (Puschner and Wegenast 2018). Cooking mushrooms causes a decrease in toxicity, although the cooking liquid is toxic. Species containing gyromitrin include Gyromitra spp. (false morels), Helvella crispa, and H. lacuose. These mushrooms grow throughout North America, usually near conifers, aspens, and melting snowbanks. They are commonly found in the spring.

Kinetics

Gyromitrin is metabolized to methyl‐formylhydrazine and then to monomethylhydrazine. The mushrooms contain a monomethylhydrazine precursor that is toxic (Puschner 2013). Monomethylhydrazine inhibits GABA synthesis with decreased GABA inhibition. The monomethylhydrazine also reacts with pyridoxal 5‐phosphate to form a hydrazone. Depletion of tissue pyridoxal 5‐phosphate results in decreased glutamic acid decarboxylase inhibition and GABA synthesis. Decreased GABA synthesis predisposes to seizures. The inhibition of a diamine oxidase in the intestinal mucosa may be responsible for the GI signs. The mechanism of hepatic damage is hypothesized to involve inhibition of certain mixed function oxidases in the liver, resulting in the formation of free radicals and causing lipid peroxidation. The mechanism of hemolysis is not clearly defined but might be secondary to other metabolic disruptions (Benjamin 1995).

Toxicity

There is a wide variation of gyromitrin in individual mushrooms and species of mushrooms, and thus mushroom toxicity varies. Monomethylhydrazine precursor varies from 50 to 300 mg/kg and gyromitrin varies from 0.06 to 1.6 g/kg in fresh mushrooms. Cooking removes over 99% of the gyromitrin and drying also removes it. Monomethylhydrazine doses at 5 mg caused vomiting in monkeys and 7 mg caused death (Benjamin 1995).

Clinical Signs

The mushrooms cause a GI effect followed by neurologic, hepatorenal, and/or hemolytic syndromes. Onset of signs can be delayed from 6 to 24 hours after ingestion, but in some cases the signs occur as late as 53 hours post ingestion. There is a 2–8‐hour latent period following spore inhalation. The onset of GI signs is often sudden and may last for 2 days (Puschner 2013). The GI phase involves nausea, vomiting, watery and possibly bloody diarrhea, along with abdominal discomfort, lethargy, and possibly fever. No additional signs might occur and there may be spontaneous recovery in a few days to a week.

For hepatorenal syndrome, signs may develop in 36–48 hours and consist of icterus, hepatomegaly, and possibly splenomegaly. Rarely renal failure develops secondary to hypotension, dehydration, and hemolysis. The hemolytic syndrome occurs rarely and appears to be more prevalent in dogs, who appear to be more susceptible to hemolysis and methemoglobinemia (Benjamin 1995). Sometimes there is methemoglobinemia without hemolysis.

There can be a neurologic syndrome that is a terminal phase. This phase consists of delirium, fasciculations, mydriasis, stupor that progresses to coma, circulatory collapse, and respiratory arrest. Rabbits intoxicated with gyromitrin developed loss of activity, seizures, anorexia, hemoglobinuria, and weight loss (Puschner 2013). In one case, a dog developed vomiting 2–3 hours after chewing on Gyromitra esculenta and in 6 hours developed lethargy, followed by coma and death.

The most common signs are vomiting, diarrhea, and abdominal pain with fever. More severe signs can occur but are very rare and occur mainly in dogs. The duration of signs varies. The GI effects can last for up to a week; hepatic and renal signs can last for weeks before recovery or, conversely, deterioration and death. Hemolytic, liver, and kidney effects can be chronic.

Differential Diagnoses

Differential diagnoses include Amanita toxicosis, zinc, iron, and acetaminophen toxicosis.

Diagnosis

Diagnostically one must rely on the history of ingestion of mushrooms and any clinical signs consistent with exposure (i.e., latent period followed by GI, and/or hepatic and renal signs and hemolysis). Clinical pathology tests can show elevations in prothrombin time (PT), aspartate aminotransferase (AST), alanine aminotransferase (ALT), blood urea nitrogen, serum bilirubin, and creatinine (Puschner 2013). On postmortem, histopathology can show renal tubular necrosis, periacinar hepatic degeneration and necrosis, and cerebral edema (Benjamin 1995; Puschner and Wegenast 2018).

Management of Exposures

Management starts with early decontamination using emesis and activated charcoal. Emesis can be achieved as specified previously. It is necessary to correct fluid and electrolyte imbalances so it is important to monitor electrolytes, acid/base balance, hydration, PCV, and renal and liver function. Hemolysis and methemoglobinemia can also be factors and need to be monitored (Puschner 2013). Antiemetics can be used to control vomiting and antiseizure medications, such as diazepam, for control of seizures (Puschner and Wegenast 2018). IV fluid therapy at twice the maintenance rate might be required; a blood transfusion might be required for patients experiencing hemolysis. For liver and renal damage, antibiotics, lactulose, and S‐adenosylmethionine (SAMe) can be employed. Pyridoxine (vitamin B₆; 25 mg/kg IV over 15–30 minutes) is a specific antagonist (Puschner and Wegenast 2018). It is used to counter the neurologic signs caused by gyromitrin (Puschner 2013).

Prognosis

The prognosis is guarded in patients progressing beyond GI effects.

HEPATOTOXIC MUSHROOMS

Sources

Hepatotoxic mushrooms, Amanita, Galerina, and Lepiota genera, contain amanitins. There are nine amatoxins of which α‐, β‐ and γ‐amanitins are of major importance (Puschner 2018). The highest concentration of toxin is in the gills (46%) followed by the stems (23%) and cap (23%). The most frequently reported poisoning results from ingestion of Anthomastus phalloides (Puschner and Wegenast 2018). A. phalloides (death cap, deadly amanita) is found most commonly in California and New Jersey but can be found throughout the United States. It fruits from August to January in California and from August to November in the eastern states. A. phalloides requires tree roots to grow so it is not often found in grassy areas unless they contain mature trees with an extensive root system (Puschner and Wegenast 2018). A. phalloides mushrooms are most often associated with birch and oak trees and can be in woodlands, parks, and golf courses. This mushroom species is the most toxic of the amatoxin‐containing mushrooms and responsible for about 90–95% of human deaths from mushroom poisonings worldwide (Zilker and Faulstich 2017).

Other varieties have different patterns of growth. Amanita bisporigera (destroying angel) can be found across the northern tier states and in eastern Canada (Benjamin 1995). It is found in hardwood forests and mixed woodlands and is associated with oaks, birches, and aspens. Amanita verna (spring destroying angel, spring amanita, white death cap, fool's mushroom) is associated with oak trees and fruits in spring, summer, and early fall. Amanita virosa is found throughout southeast Canada and the eastern coastal United States and is especially abundant along Lake Ontario shores. It is found in hardwood and mixed forests. Amanita ocreata is found primarily along the coast of California, fruits in the spring, and is associated with oak trees. The remaining Amanita spp. are found primarily in southern and southeastern United States.

Galerina sp. are typically small and brown, and fruit in the late summer and early fall (the G. autumnalis, “deadly Galarina” can fruit in the spring). They may grow on wood that is decayed or buried. Galerina venenatia (deadly lawn Galerina) primarily inhabits lawns.

Lepiota sp. are primarily fall fruiting mushrooms with a wide distribution throughout the United States. They live in varied habitats, including woods, roadsides, lawns, meadows, parks, and gardens.

Kinetics

The bioavailability of amanitins in dogs and cats ranges from 10 to 20% (Benjamin 1995). Amanitins are taken up by epithelial cells of the GI tract and by hepatocytes, where they cause injury to GI mucosa and liver, respectively. Uptake into the hepatocytes can be blocked by bile salts, prednisolones, antanamide, octreotide, and silibinin. There is no evidence of the amanitins crossing the placental barrier. They undergo extensive enterohepatic recirculation, and excretion occurs in dogs via the urine. Within 6 hours 90% of the amanitins are eliminated via the kidneys. The concentration of amanitins may be 100–150 times higher in the urine than in the blood (Benjamin 1995). Urinary excretion can continue for up to 72 hours due to the persistence of the mushrooms in the GI tract and extensive enterohepatic recirculation.

Mechanism of Action

Amanitins inhibit nuclear RNA polymerase II and interfere with DNA and RNA transcription (Benjamin 1995), which results in inhibition of ribosomal protein synthesis. Cells that have a high rate of metabolism are affected the most, such as hepatocytes and intestinal crypt cells, but all cells in the body are susceptible. Blocking uptake by the hepatocytes might predispose other cells to damage through increased circulating amanitin concentration. The kidneys can be damaged in a similar way.

Toxicity

Toxicity varies with species. Rodents and rabbits seem to be unaffected by ingestion of the amanitins. The oral LD₅₀ (lethal dose 50, the amount it takes to kill 50% of the population) for a dog is approximately 1 mg amanitin (Benjamin 1995). This is about equivalent to one “decent‐sized” mushroom cap. The IV LD₅₀ for α‐amanitin is 0.1 mg/kg. The lethal dose of Galerina spp. is approximately 100–150 g of fresh mushrooms.

Clinical Effects

Signs

Signs typically occur in phases (Puschner 2018). Following a latent period of 6–12 hours, there is a triphasic syndrome (Table 28.2). Phase 1 consists of GI signs: vomiting, diarrhea, abdominal pain, dehydration, and lethargy. Anorexia may also be seen. Phase 2 is characterized by severe GI upset manifested as nausea, vomiting, bloody diarrhea, and severe abdominal pain. In this phase there is hepatotoxic damage with signs and laboratory values that point to liver failure leading to coagulopathy. These signs can include icterus, tachycardia, acidosis, hypotension, and hypoglycemia. This can be followed by another latent phase in which the animal appears to have recovered. This latent period requires diligent monitoring of liver and renal values to determine whether damage is being done and to assess liver and kidney function. Phase 3 involves hemorrhages, seizures, fulminant hepatic failure, and renal failure leading to death in 4–7 days (Enjalbert et al. 2002). Fifty percent of dogs given amanitins in lethal doses died from hypoglycemia within 1–2 days of exposure. The onset of signs is generally 6–12 hours for GI signs and 24–72 hours for hepatic failure. The duration of signs can be a few days for mild cases and in severe cases death in 4–10 days. In beagles experimentally given sublethal doses of amanitins, vomiting, and diarrhea began in 16 hours and subsided 60 hours later. In beagles given lethal doses, initial hyperglycemia was followed by hypoglycemia. Glucose was administered, which culminated in hepatic dystrophy and was fatal in 1–2 days (Puschner 2013).

Table 28.2. Typical clinical phases of cyclopeptides or Amanita phalloides toxicosisa

| Description | Time Period | Clinical Effects
Initial | Latent period | 6–12 (to 24) hours after exposure |
Phase I | Gastroenteritis (can detect amanitins in serum and urine) | ±12–24 hours duration | Nausea
Vomiting
Bloody diarrhea
Abdominal pain
Lethargy
Twitching
Dehydration
Elevated liver values
Phase II | Severe gastroenteritis | ±18–24 hours duration | Bloody diarrhea
Hemolysis
Electrolyte imbalance
Hyperthermia
Tachycardia
Bradycardia
Latency | Latent period (continue monitoring liver and kidney function) | 2–48 hours duration | Apparent recovery
Phase III | Final/terminal | Begins 36–84 hours after exposure | Liver, kidney, and multiorgan failure
Severe hypoglycemia
Icterus
Coagulopathy
Encephalopathy
Seizures
Azotemia
Anuria
Metabolic acidosis
Cerebral edema
Coma
Sepsis
Death

a Note that with large amanitin ingestions or ingestions by puppies, death may occur within 2 hours postexposure.

Laboratory

Significant elevations in serum AST, ALT, alkaline phosphatase, and bilirubin are commonly observed. Severe hypoglycemia is also characteristic (Tegzes and Puschner 2002). Coagulopathy as evidenced by prolonged clotting times occurs in a high percentage of affected dogs.

Differentials

Differentials include blue‐green algae, acetaminophen, cycad, iron, aflatoxin, and phenolic compounds intoxications, leptospirosis, infectious hepatitis, and hepatic neoplasia.

Diagnosis

Antemortem

Liver values begin to rise within 12 hours post exposure. Liver biopsies can be done to detect evidence of hepatic injury; hepatic necrosis would be the expected finding. Urine samples can be tested for the presence of amanitin. An amatoxin test (http://AMATOXtest.com) is available and can be run using vomit or urine from the patient.

Postmortem

On necropsy one would expect to find evidence of hepatic necrosis, GI mucosal injury, and renal tubular necrosis. Acute tubular necrosis is believed to be the result of reabsorption of the toxins by renal tubules after glomerular filtration (Puschner 2018). Liver and kidney samples can be tested for amanitin to confirm exposure (Puschner 2018).

Management of Exposures

Early detection appears to be critical because survival rates were greatly improved with prompt therapeutic intervention (Puschner 2018; Tegzes and Puschner 2002). The goal of therapy is to stop amatoxins from being absorbed from the GI tract or leaving the gall bladder and causing liver damage. Standard decontamination is recommended if initiated soon after exposure. Emesis can be achieved as previously specified. After gastric emptying, activated charcoal should be administered only if the exposure has happened in the previous 1–2 hours. Later implementation of charcoal can cause bile acid release and can worsen toxicosis.

Baseline serum chemistries, complete blood count, acid/base, and electrolytes, especially Na, should be obtained, and glucose, liver enzymes, renal values, and coagulation parameters should be monitored. Coagulation abnormalities have occurred in animals that develop GI signs within 24–48 hours of ingesting mushrooms. Levels are expected to be normal for the first 12 hours. ALT and AST begin to elevate and peak within 72–96 hours, with severe elevation evident within 72 hours. Supportive and symptomatic care is needed consisting of fluid therapy (diuresis without use of diuretics), temperature management, GI protectants, vitamin K₁, blood replacement therapy, special dietary food, and diazepam for seizures. No food or medication should be given orally for at least the first 12 hours after exposure. This can help sequester bile containing amatoxin into the gallbladder by limiting stimulus for gallbladder contraction. If liver values are elevating, continue to withhold any food or medication until liver values are improving. Water can be allowed as it minimally stimulates gallbladder contraction. Octreotide can be given as a bolus IV and then as a constant rate infusion and should be started as soon as possible, if able. This inhibits gall bladder contraction and increases muscle tone to minimize bile release (Goupil et al. 2021).

Percutaneous biliary drainage may also be considered if liver values are elevated or if amatoxin test is positive. A coagulation profile should be checked, and any abnormalities corrected prior to attempting percutaneous drainage. If liver values are not improving, the procedure can be repeated in 24–48 hours. Amatoxin containing bile is typically red to black in color (Goupil et al. 2021).

Liver protectants are recommended. N‐acetylcysteine and injectable silibinin (or silymarin, an herbal milk thistle protectant) appear to be equally efficacious. N‐acetylcysteine and silibinin are free radical scavengers (Benjamin 1995). SAMe has also been recommended because it acts as a membrane stabilizer, hinders amatoxins penetration of cells, scavenges free radicals, and favors regeneration of damaged livers (Enjalbert et al. 2002). Oral silibinin has poor bioavailability.

Both silibinin and penicillin G interfere with enterohepatic recirculation of amatoxins. Cephalosporins may also be as, or even more, effective (Enjalbert et al. 2002). Table 28.3 lists some of the therapeutic agents and dosages used for hepatotoxic mushroom toxicosis in pets.

Prognosis

The prognosis is poor, especially if there is a short latent period with an early rise in liver enzyme concentrations, presence of coagulopathy, and persistent hypoglycemia.

MYCOTOXINS

Mycotoxins are secondary chemical metabolites produced by various species of fungi in numerous commodities, foods, and feed. These compounds have diverse chemical structures and may cause biological and pathological changes in animals. Numerous fungi do not produce mycotoxins, and the presence of mold in feed or food does not guarantee that mycotoxins were or will be produced. Once produced, mycotoxins are stable compounds, are not readily destroyed by processing, and can be found in cereal by‐products (e.g., corn and wheat gluten, distiller's grains, etc.) and pet foods. Three genera of fungi – Fusarium, Penicillium, and Aspergillus – are primarily responsible for invasion of crops, particularly cereal grains, in the field and during harvest, transportation, processing, and storage of foods and feeds. Each fungus has specific requirements for matrix, oxygenation, temperature, and moisture for mold growth and subsequent mycotoxin development.

Table 28.3. Potential treatments for hepatotoxic mushroom ingestion

Treatment
Recommendation
Dose

Emesis (dogs)
Apomorphine
0.02–0.04 mg/kg IV, IM, or subconjunctival sac in the dog

3% hydrogen peroxide
Ropinirole
1–5 ml/kg PO (do not exceed 45 ml for dogs)

Ocular administration based on weight

Gastric lavage
Water at body temperature
10 ml/kg body weight, use large bore tube

Adsorbent
Activated charcoal
1–2 g/kg body weight PO once if within 2 h post exposure

Cathartic
Sorbitol
3 ml/kg (70%) PO with charcoal

Dehydration
Crystalloid fluids
As needed

Glucose

Hepatic damage
Acetylcysteine
140 mg/kg PO followed by 70 mg/kg

NPO
PO q 6 h

Sequesters amatoxins in gall bladder

Octreotide
10–20 mcg/kg bolus, then 10 ug/h. Constant rate infusion

Bile aspiration
Keeps amatoxins in gall bladder
Ultrasound guided; q 24–48 h

Penicillin G
300,000–40 million U/day (human dose)

Silymarin (herbal milk thistle, check label for concentration)
1.4–4.2 g/day PO for 4–5 days

Seizures
Diazepam
0.5–2 mg/kg IV

Phenobarbital
6 mg/kg IV to effect

Propofol
0.1 mg/kg/min IV constant rate infusion

Dyspnea
Oxygen

Mechanical ventilation

Sepsis
Broad‐spectrum antibiotics
Parenteral as needed

Severe hemorrhage
Vitamin K₁
2.5–5 mg/kg daily

Packed red blood cells
As needed

Whole blood

Tremors
Methocarbamol
50 mg/kg IV q 8 h

Mycotoxins frequently associated with pet food contamination include aflatoxins, Fusarium mycotoxins – particularly vomitoxin or deoxynivalenol (DON) – and ochratoxin A (Table 28.4). The tremorgenic mycotoxins associated with moldy food (bread, walnuts, cream cheese, and garbage), such as penitrem A and roquefortine, are discussed in Chapter 27.

Cereal grains, cereal by‐products, and nuts are often incorporated into commercial food for dogs and cats. These commodities can be contaminated with mycotoxins and may be diverted from use in human food to use in animal feeds. Many larger pet food companies test commodities for mycotoxins prior to incorporation into pet food; however, deviations in testing protocols may not detect mycotoxins and smaller, local mills may not test pet food ingredients prior to use. The result can be pet food contamination with mycotoxins.

In a worldwide review of the prevalence of mycotoxins in pet foods, most reported mycotoxin outbreaks in pets were related to aflatoxins, a few cases were related to tremorgenic mycotoxins, and several in Europe and the United Kingdom were associated with ochratoxin A (Leung et al. 2006) and trichothecenes (Glanemann et al. 2023). No natural outbreaks of aflatoxicosis have been reported in cats (Böhm and Razzazi‐Fazeli 2005).

Table 28.4. Mycotoxins in pet food

Source: Adapted from CAST (2003).

Mycotoxin | Fungi | Environment for Mold Growth | Commodity | Effects in Animals
Aflatoxins (B₁, B₂, G₁, G₂, M₁, M₂) | Aspergillus flavus and A. parasiticus | Warm days and nights (78–90 °F), high grain moisture (16–28%), drought stress, insect damage | Corn | Liver damage
Rice | Liver tumors
Peanuts/nuts | Hemorrhage
Cottonseed | Death
Vomitoxin (trichothecene mycotoxin) | Fusarium spp. | Alternating warm days and cool nights (40–80 °F), and humid | Cereals (wheat, corn, barley, oats) | Digestive disorders (vomiting, feed refusal, diarrhea)
Zearalenone | Fusarium graminearum (primarily) | Moderating temps (45–70 °F) and high grain moisture (22–25%) | Cereals (wheat, corn, barley) | Estrogenic effects (edema of vulva, vagina, uterus)
Fumonisin | Fusarium veriticilliodes (syn. Moniliforme) | Drought during growing season followed by cool, wet weather during pollination | Corn | Liver insult
Corn screenings |
Ochratoxin A | Aspergillus ochraceus | Cooler weather (54–77 °F) and grain moisture >16% | Corn | Kidney tubular necrosis
Penicillilum verrucosum | Wheat
Dried beans
Dried fruits
Roquefortine | Penicilium roqueforti and others | Walnuts | Tremors
Cream cheese | Incoordination
Penitrem A (tremorgens) | Penicillium crustosum | Bread | Death
Rice
Cheese
Garbage

AFLATOXINS

Aflatoxins are polycyclic furan compounds produced by Aspergillus molds both in the field prior to harvest and in storage. Aflatoxins are hepatotoxic and potent liver carcinogens. Cases of fatal hepatitis in dogs during the 1950s and turkeys in 1960, termed “hepatitis X” and “X disease,” respectively, were likely caused by aflatoxins.

Sources

Aspergillus flavus, A. parasiticus, and A. nomius can produce several aflatoxins. Aflatoxins identified include B₁ and B₂ (fluoresce blue in ultraviolet light), G₁ and G₂ (fluoresce green in ultraviolet light), and M₁ and M₂ (animal metabolites from hydroxylation of aflatoxins B₁ and B₂, respectively). Aflatoxin B₁ is the most toxic mycotoxin in this group, generally found at the highest concentration, and the most important member of the aflatoxins for analytical purposes in feeds. Aflatoxins M₁ and M₂ can be found in tissues, meat, milk, and eggs. Fungal growth and aflatoxin production are favored when grain moisture is >15%, relative humidity is >75%, and temperatures are warm (78–90+ °F). Aflatoxins may occur in corn, nuts, cottonseed, rice, and other crops during years of drought, warm‐to‐hot temperatures, and insect damage to crops. Large portions of crops in a region can be affected by widespread aflatoxin contamination in animal feeds.

Kinetics

Aflatoxin absorption is by passive diffusion from the small intestine (Meerdink 2004). Absorption is rapid and complete in numerous animal species, with a higher rate of absorption in young animals. Aflatoxins are eliminated from the body through the bile, urine, and feces, and into milk and eggs. Aflatoxins can undergo enterohepatic circulation. Generally, most of the toxin is excreted within 24 hours after exposure. Dogs given a single oral 100 mcg aflatoxin B₁/kg body weight dose in corn oil showed some vomiting postdosing, but no additional adverse effects, and over 90% of total aflatoxin M1 was found in the urine 12 hours postdosing; by 48 hours postdosing aflatoxin M1 was almost undetectable in urine (Bingham et al. 2004). Aflatoxins do not accumulate in body tissues, but repeated exposure may result in lasting adverse effects in tissues.

Most of the aflatoxin is biotransformed in the liver, with smaller amounts transformed in the kidney and small intestine. A critical metabolic step is the transformation of aflatoxin B₁ to a reactive epoxide intermediate by the cytochrome P450 system. Rapid formation of the reactive 8,9‐epoxide of aflatoxin B1 can overwhelm detoxification mechanisms by depleting intracellular glutathione (Dereszynski et al. 2008). Dogs as a species have low liver glutathione concentrations, compared with other species. The unstable aflatoxin epoxides can bind covalently to intracellular molecules such as DNA, RNA, and proteins forming adducts, which can result in cellular damage and hepatic necrosis. As mentioned earlier, aflatoxin M₁ is formed from hydroxylation of aflatoxin B₁ and is the major excretion product in several species via urine and milk (Meerdink 2004).

Mechanism of Action

The epoxide of aflatoxin B₁ binds cellular macromolecules, nucleic acids, subcellular organelles, and regulatory proteins that disrupt normal cellular processes and organ function. The outcome may result in cellular necrosis, cancer, immunosuppression (both humoral and cell‐mediated immunity), mutagenesis, and teratogenesis.

Toxicity

In naturally occurring cases, the concentration of aflatoxin in the feed (dose) and the duration of exposure may not be known. It is very important to retain a sample of the suspect pet food that the animals have been consuming and test for aflatoxins in an analytical laboratory. Dogs are considered sensitive to aflatoxins, with a LD₅₀ from 0.5 to 1.0 mg/kg body weight, and death may occur within 3 days after exposure. The LD₅₀ of aflatoxins in cats ranges from 0.3 to 0.6 mg/kg body weight. Following consumption of aflatoxin contaminated food, dogs can show peracute to acute, subacute, and chronic clinical signs. In a subacute study, young beagle dogs were orally dosed with an aflatoxin mixture (37.5% B₁, 5.4% B₂, 17.1% G₁, and 1.0% G₂) at dosages of 1, 5, and 20 mcg/kg body weight, with the duration of dosing lasting for 10 weeks at 5 days a week (Armbrecht et al. 1971). Clinical signs of icterus, inappetence, yellow‐orange colored urine, and increased prothrombin time were noted in dogs at the high dosage of 20 mcg/kg body weight. Histological changes were observed in only the high‐dosed group and consisted of moderate bile duct proliferation, bile pigment accumulation in the liver portal areas, and multiple vascular channels around central and portal liver veins. Therefore, the toxic dose for aflatoxins in dogs is estimated to be less than 20 mcg/kg body weight.

Clinical Signs

Clinical features of aflatoxicosis in dogs are not unique to this condition and may not be recognized antemortem. Pathological changes in the liver are more indicative of aflatoxicosis, and analytical detection of elevated aflatoxins B₁ in the feed and M₁ in hepatic tissue can confirm aflatoxicosis. Sudden deaths in kennel dogs fed a similar pet food may serve as sentinels of aflatoxicosis (Dereszynski et al. 2008). Dogs may be reluctant to eat contaminated food (aflatoxins are considered odorless and tasteless) but may consume noncontaminated feeds. The clinical signs of aflatoxicosis are related to liver damage and failure, which may be acute or chronic in nature. In a retrospective case study of dogs exposed to aflatoxin‐contaminated pet food in 2005–2006, the order of onset of clinical signs was anorexia, lethargy, vomiting, jaundice, diarrhea frequently associated with melena progressing to hematochezia, abdominal effusion (usually a transudate), peripheral edema, and terminal encephalopathy associated with hemorrhagic diathesis (Table 28.5) (Dereszynski et al. 2008). Dogs may develop polyuria and polydipsia and show depression. The severity of clinical signs can vary among dogs, probably related to differences in dose and duration of aflatoxin exposure, biotransformation of aflatoxins, nutritional status, and preexisting health conditions. Poor survival of dogs affected by aflatoxins in pet food was linked with severe enteric hemorrhage. Aflatoxicosis in dogs may induce disseminated intravascular coagulation that can deplete coagulation factors.

Table 28.5. Clinical signs and clinicopathologic changes in dogs associated with aflatoxin exposure

Source: Adapted from Dereszynski et al. (2008).

Clinical Signs | Clinicopathologic Changes
Sudden death | Coagulopathic disturbances: low plasma anticoagulant proteins (protein C, antithrombin)
Anorexia | Hypocholesterolemia
Lethargy | Hypoproteinemia (↓ total protein and albumin)
Vomiting | ↑ serum liver enzyme activities
Jaundice | Hyperbilirubinemia
Diarrhea (melena, hematochezia) | ↓ serum electrolytes (Na⁺, Ca⁺)
Dehydration | Granular casts in urine (cylindruria or renal casts)
Abdominal effusion, peripheral edema | Liver needle aspirates cyto prep: diffuse hepatocyte lipid vacuolation
Polyuria, polydipsia |
Terminal encephalopathy |
Hemorrhagic diathesis |

Good early markers of aflatoxicosis in dogs are hypocholesterolemia and lower plasma protein C and antithrombin activities (Dereszynski et al. 2008). Commonly, dogs have coagulopathies, such as prolonged activated partial thromboplastin time (aPTT)and PT, and lower fibrinogen concentrations and plasma coagulation factor VII. Because of vomiting, diarrhea, or abnormal body fluid distribution (i.e., abdominal effusion), electrolyte disturbances occur, such as lower serum concentrations of sodium and calcium and elevated serum phosphate. Dogs also had lowered serum albumin and total protein, and increased liver enzyme activities and hyperbilirubinemia. The magnitude of liver enzyme activities did not correlate with the severity of hepatocellular damage noted at necropsy (Dereszynski et al. 2008). No significant differences were observed in urine specific gravity (between survivor and nonsurvivor dogs), but dogs with granular casts, specifically with cylindruria (renal casts or tiny, tube‐shaped particles) died from aflatoxicosis, while few of these dogs were azotemic (Dereszynski et al. 2008). The presence of granular casts in the urine of dogs dying from aflatoxicosis could be related to aflatoxin adduct injury to tissue, altered redox status, or impaired renal perfusion from systemic effects of aflatoxins; the cause‐effect relationship is only speculated.

Needle aspirates of liver from dogs that died from aflatoxicosis were processed for cytology examination and revealed diffuse hepatocyte lipid vacuolation, hepatocyte degeneration, and minor inflammatory cell infiltrates. These findings are not pathognomonic for aflatoxins and a full necropsy is recommended.

Diagnosis

Diagnosis is based on compatible clinical signs and clinical pathology changes, particularly related to liver failure or sudden death. A complete necropsy is recommended in suspected aflatoxicoses. Histopathologic findings consistent with aflatoxicoses include hepatic lipidosis, portal fibroplasias, megalocytosis of hepatocytes, biliary hyperplasia, and, in chronic hepatopathy cases, marked lobular atrophy, bridging portal fibrosis, and regenerative hepatocellular nodules (Newman et al. 2007).

Suspect food consumed by the animal should be tested in analytical laboratories for aflatoxins, in particular aflatoxin B₁, for confirmation of exposure to aflatoxins. Aflatoxins are notorious for occurring in localized hot spots in feeds; multiple samples of the suspect food should be taken and can be held and frozen for future analysis. If the animal has been consuming the suspect food recently, liver samples can be frozen for subsequent analysis for aflatoxin M₁; however, the half‐life of aflatoxins in dogs has not been determined and is thought to be very short. Aflatoxin M₁ may be cleared from the liver within 7 days after a suspect food has been discontinued in the diet, so analysis of liver tissue may be of value only with recent exposure to a suspect food (Newman et al. 2007). Dog foods associated with recent outbreaks of aflatoxicosis had 60–579 mcg aflatoxin/kg of feed (Leung et al. 2006; Newman et al. 2007; Wall 2021). The US Food and Drug Administration's (FDA) action level for maximum aflatoxin in feed for pets (dogs, cats) is 20 mcg/kg or ppb (FDA 2000).

Differential Diagnoses

Differential diagnoses would include acetaminophen, cyanobacterial toxin—microcystins, iron, phenolic compounds, Penicillium islandicum mycotoxin—leutoskyrin, and pyrrolizidine alkaloid intoxications, leptospirosis, infectious hepatitis, and hepatic neoplasia from other causes.

Treatment

If aflatoxin is suspected from food exposure, identify the potential aflatoxin‐contaminated food source(s) and stop further exposure. Ensure that possible contaminated food sources are retained and frozen for analytical testing for aflatoxins. There is no antidote for aflatoxin.

There is no definitive treatment protocol for aflatoxicosis in animals. General supportive treatment and care are the main focus. Dogs may require IV fluids and blood component treatment; vitamins K and E may be administered to replenish coagulation cofactors and to inhibit membrane lipid peroxidation, respectively (Dereszynski et al. 2008). The dose of vitamin E was limited to ≤10 U/kg/d (≤4.5 U/lb/d) because of concerns that higher dosages may inhibit gamma‐carboxylation of vitamin K‐dependent coagulants. In the 2005/2006 outbreak of aflatoxicosis in dogs, one therapeutic approach was to provide hepatic supportive care with thiol donors for 2 months after the initial aflatoxin diagnosis; glutathione was considered important for aflatoxin detoxification mechanisms (aflatoxin metabolites undergo enterohepatic circulation) and glutathione can be depleted in dogs with spontaneous liver disease (Dereszynski et al. 2008). Initial thiol replacement was by IV N‐acetylcysteine but was changed to oral S‐adenosylmethionine when the dogs could tolerate oral treatment. Dogs with persistent vomiting were given antiemetics, but gastric atony, detected in several affected dogs, did not respond to antiemetic or prokinetic treatment and some dogs were euthanized.

Dogs suspected of developing gastric ulcers and esophagitis secondary to protracted vomiting were treated with a histamine‐2 receptor blocking agent famotidine and a gastric cytoprotective drug sucralfate. Silybin, considered a hepatic protective flavonoid from herbal milk thistle, was given to enhance glutathione‐S‐transferase activity and promote glutathione synthesis (Dereszynski et al. 2008). Broad‐spectrum antibiotics are recommended to protect against systemic infections from possible immunosuppression. L‐carnitine was provided to dogs to combat hepatic lipidosis, which has been shown to be beneficial in experimental aflatoxicosis in several species. Treated dogs frequently deteriorated despite treatment (Dereszynski et al. 2008).

Prognosis

The prognosis depends on the severity of liver damage. Severe liver damage suggests a guarded to poor prognosis. Monitoring coagulation (particularly aPTT and PT, plasma protein C, and antithrombin activity), serum liver enzyme activities, serum biochemistry panel, and electrolytes can be indicative of hepatic damage. The presence of granular casts, specifically for cylindruria, has been associated with fatality. The finding of enteric blood has been associated with the onset of hepatic encephalopathy and terminal stages of aflatoxicosis and death.

VOMITOXIN OR DEOXYNIVALENOL (DON)

Fusarium molds invade a variety of cereal plants, resulting in widespread plant diseases, such as “Fusarium head blight” or “scab” in wheat and barley and “Giberella ear rot” of corn. Moderate temperatures during flowering and higher humidity favor Fusarium growth in cereals and mycotoxin production in the field (see Table 28.4). A group of mycotoxins produced by Fusarium spp. are the trichothecenes, sesquiterpenoid compounds with an epoxy ring at C12–13 that is considered essential for toxicity. The trichothecenes include a number of mycotoxins, vomitoxin, 15‐ and 3‐acetyldeoxynivalnol, nivalenol, scirpenol, T‐2 toxin, HT‐2 toxin, diacetoxyscirpenol, etc., with a broad range of toxicity. Reports of adverse effects in dogs and cats are not common from trichothecene‐contaminated pet food.

Sources

Trichothecenes are produced by several genera of fungi, including Fusarium, Stachybotrys, Myrothecium, Trichothecium, and others. Trichothecene production by Fusarium fungi is heavily dependent on oxygen, environmental pH, osmotic tension, and temperature. For example, vomitoxin is produced under conditions of low oxygen tension, whereas zearalenone production by the same fungi requires oxygen saturation, usually occurring after field crops senesce. F. graminearum, the primary producer of vomitoxin in North America, has an optimum temperature range for growth of 78–82 °F (26–28 °C) at a water activity (aW) greater than 0.88. Vomitoxin is a stable chemical and is not destroyed by high temperatures and pressure treatments.

Kinetics and Toxicity

The kinetics of vomitoxin have not been described in dogs and cats. In other monogastric animals, vomitoxin is rapidly and nearly completely absorbed in the stomach and proximal small intestine after oral exposure. Distribution to all body tissues is fairly rapid, and most of the vomitoxin is eliminated in the urine and feces in less than 24–48 hours. Vomitoxin is not accumulated in tissues. In a feeding trial with mature Brittany and beagle dogs and American shorthair cats, naturally contaminated wheat was incorporated into pet foods at increasing concentrations of vomitoxin from 0 to 10 mg/kg or ppm (parts per million) (Hughes et al. 1999). Dogs previously exposed to vomitoxin‐contaminated pet food preferentially selected uncontaminated food. When the vomitoxin concentration in feed was >4.5 ± 1.7 mg/kg in dog food and >7.7 ± 1.1 mg/kg in cat food, feed intake was reduced in dogs and cats, respectively. Vomitoxin concentrations greater than 8–10 mg/kg in the diet caused vomiting in dogs and cats.

Mechanism of Action

Trichothecene mycotoxins have multiple effects on eukaryotic cells, including inhibition of protein, RNA, and DNA synthesis, alteration of membrane structure and mitochondrial function, stimulation of lipid peroxidation, induction of programmed cell death or apoptosis, and activation of cytokines and chemokines. Typical effects from trichothecene exposure are anorexia, vomiting, GI irritation, and immunosuppression.

Clinical Signs

The predominant clinical signs from vomitoxin exposure in pet food are feed refusal, vomiting, and weight loss in dogs (Table 28.6). In a study of mature beagle dogs fed Fusarium mycotoxin‐contaminated diets (2.7 and 3.9 ppm vomitoxin with low concentrations [<0.5 ppm] of 15‐acetyldeoxynivalenol and zearalenone, and 8–10 ppm fusaric acid), rapid onset of reduced feed intake was reported (Leung et al. 2007). Only one dog vomited on these diets; however, weight loss was reported in dogs fed the vomitoxin‐contaminated diets. Vomitoxin has been reported to delay gastric emptying through peripheral action at serotonin receptors in rodents (Fioramonti et al. 1993). Additional clinical signs from vomitoxin exposure could include GI irritation and diarrhea, and poor feed conversion. Dogs can show individual susceptibility to mycotoxins, and younger animals may be more susceptible to adverse effects at lower concentrations of vomitoxin in food.

Table 28.6. Clinical signs in dogs associated with vomitoxin exposure

Food refusal

Vomiting

Weight loss

Diarrhea

Poor feed conversion

Gastrointestinal irritation

Diagnosis

The clinical signs associated with vomitoxin exposure are common to many conditions and generally no significant changes are observed in clinicopathologic parameters. Vomitoxin, and other trichothecene mycotoxins, can be analyzed in pet foods by numerous veterinary diagnostic laboratories. The US FDA's advisory levels for vomitoxin on grains and grain by‐products for pets are not greater than 5 mg/kg (ppm) and not to exceed 40% of the diet or not to exceed 2 mg/kg (ppm) of their final diet (FDA 2010).

Differential Diagnoses

Clinical signs of food refusal, vomiting, weight loss, and diarrhea could be attributed to bacterial or viral intestinal infections and garbage or irritant plant ingestion.

Treatment

As with any mycotoxin exposure in feed, the first recommendation is to stop the exposure and switch to a diet with low or nondetectable concentrations of vomitoxin. Feed samples can be taken of the suspect pet food, frozen, and submitted to veterinary diagnostic laboratories for analysis. Generally, treatment is not required; if the animals are dehydrated from fluid loss through vomiting or diarrhea, fluid therapy should be instituted.

Prognosis

After exposure to the vomitoxin‐suspect diet is discontinued, rapid recovery to normal status should occur. The prognosis is good for recovery.

T‐2, HT‐2, AND DIACETOXYSCIRPENOL

An outbreak of pancytopenia occurred in the UK in 2021 (Glanemann et al. 2023). It was linked to potato flakes in three different commercial brands of cat food that were contaminated with T‐2, HT2, and diacetoxyscirpenol (DAS). These are all trichothecene mycotoxins produced by Fusarium. T‐2, HT‐2, and DAS are all hemato‐ and myelotoxic. They are generally associated with grain products and cases are much more common in herbivores.

OTHERS

Numerous mycotoxins can be produced in natural infections of mold in grains, feed, and food. Zearalenone, a resorcyclic acid lactone, is a mycotoxin produced by Fusarium species in corn and other crops, and it is often found with vomitoxin. Zearalenone, and related metabolites zearalenols and zearalanols, are estrogenic compounds that can affect the reproductive system, causing edema of the vulva and uterus, enlargement of mammary glands, and possibly ovarian dysfunction. The concern for adverse reproductive effects in dogs would be the breeding bitches; however, no case reports of zearalenone toxicosis have been adequately documented in dogs. Additional mycotoxins produced by Fusarium species are the fumonisins, particularly fumonisin B₁. Dogs and cats are not considered sensitive to fumonisins and toxicoses have not been reported for dogs and cats; on the other hand, horses are very sensitive to fumonisins and can develop brain malacia and necrosis. All species have the potential to have some liver damage from fumonisins. The FDA guidance levels for total fumonisins in corn and corn by‐products intended for pets are not greater than 10 mg/kg (ppm) and not to exceed 50% of the diet or not to exceed 5 mg/kg (ppm) of their final diet (FDA 2001).

Particularly in Europe and the United Kingdom, ochratoxin A is an important nephrotoxin mycotoxin. The molds Aspergillus ochraceus and Penicillium verrucosum produce ochratoxins in cereal grains under cooler weather, 54–77 °F, and moist conditions. Dogs are sensitive to ochratoxin A and can develop anorexia, vomiting, polyuria, polydipsia, bloody feces, and paralysis and die (Böhm and Razzazi‐Fazeli 2005). Daily oral doses of 0.2–0.3 mg ochratoxin A/kg body weight can be lethal to dogs within 10–14 days. Necropsy lesions related to ochratoxin A exposure include necrosis of proximal renal tubules, hemorrhagic enteritis, and necrosis of lymphoid tissue. No cases of ochratoxin A toxicosis in pets have been reported in North America.

Acknowledgements

The author would like to acknowledge Joyce Eisold and Michelle Mostrom for their work on a previous version of this chapter.

REFERENCES

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FDA (Food and Drug Administration). 2010. Guidance for Industry and FDA: Advisory Levels for Deoxynivalenol (DON) in Finished Wheat Products for Human Consumption and Grains and Grain By‐products Used for Animal Feed. Revised 7/2010. https://www.fda.gov/regulatory‐information/search‐fda‐guidance‐documents/guidance‐industry‐and‐fda‐advisory‐levels‐deoxynivalenol‐don‐finished‐wheat‐products‐human

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29
Household and Industrial Toxicants

Rhian Cope

INTRODUCTION

While there are many household and industrial toxicants there are only a few that animals will have access to. In many cases the biggest risk with these compounds is aspiration. Aspiration is the accidental introduction of liquid into the lungs. It may occur either directly or as a consequence of vomiting or regurgitation. It is a common complication of ingestion of many low viscosity household products.

Aspiration may occur silently and insidiously (most commonly) or occur secondarily to vomiting/regurgitation. Aspirated hydrocarbons (and other potential aspirants) impair lung fluid surfactant function, leading to alveolar damage and subsequent hypoxemia. Many aspirated materials can also directly damage pulmonary capillaries, producing pathological findings ranging from chemical pneumonitis, hemorrhages, and bronchopneumonia to gross pulmonary edema (Stice et al. 2018).

Many patients who aspirate low viscosity materials are often initially asymptomatic and may not be presented for treatment until significant respiratory compromise is present. In relatively rare instances, patients may present with initial symptoms such as gagging, choking, coughing, and dyspnea. Examination of the patient may show tachypnea, intercostal retractions, diminished breath sounds, tachycardia, and fever.

Patients with a history of ingestion of a potentially aspiratible material should always be monitored for aspiration pneumonia/pneumonitis and other respiratory system complications by continuous monitoring of peripheral hemoglobin oxygen saturation by pulse oximetry/co‐oximetry. Radiographic evidence may lag behind at least 6–12 hours. A proportion of patients with aspiration (particularly of hydrocarbon distillates) will develop acute respiratory distress syndrome (ARDS) (Stice et al. 2018).

In cases where the patient has ingested material and is at risk of aspiration, induction of vomiting and gastric lavage, even with a secure airway, are contraindicated. There is no specific treatment for hydrocarbon aspiration. Treatment is symptomatic and supportive. Conservative fluid management is critical in minimizing the effects of ARDS that may develop. The prognosis for confirmed cases of aspiration is always guarded, particularly if acute respiratory distress is present.

ALCOHOLS

Ethanol

Synonyms include alcohol, ethyl; denatured alcohol; distilled spirits; ethyl alcohol, undenatured; ethanol; ethyl alcohol; ethylcarbinol.

Sources

Ethanol is a ubiquitous household and industrial chemical. A partial list of common sources of ethanol in households includes alcoholic beverages, fermenting organic waste materials (particularly fruit, food waste in garbage), yeast bread dough and related fermenting yeast doughs, automotive deicers, window cleaners, antifogging solutions, dental mouthwashes, toothpastes, perfumes, fragrances, aftershaves, cosmetics, paints, varnishes, polishes, shellacs, sealers, degreasers, design and sketch art markers, paints, tinctures (e.g., tincture of iodine), cough syrups, cosmetics, adhesive removers, liquid detergents, stain removers, disinfectants, deodorizers, shampoos, hair conditioners, antiperspirants, thermometers, and insect repellents. Alcohol content in household products can be surprisingly high. It should be noted that the percentage of ethanol in distilled alcoholic beverages is half of its “proof” value. It follows that 80‐proof vodka is 40% alcohol (Stice et al. 2018). Fermenting fruits, grains, and vegetable matter can also produce ethanol and cause clinical signs if ingested. In industrial situations, ethanol is extensively used as a solvent and transport intermediate. Industrial‐grade ethanol is typically high purity (>98% by mass). In the context of veterinary medicine, acute poisoning is the most common of the various ethanol toxidromes.

Kinetics

The most common route of exposure in domestic animals is via ingestion, although inhalation exposures can occur under some rare circumstances (prolonged inhalation of ethanol vapors). Ethanol is rapidly absorbed from the gastrointestinal tract and the onset of clinical signs is generally correlated with blood ethanol concentration. The presence of food in the stomach or small intestine delays systemic absorption, as can the type of formulation containing ethanol. However, the onset of clinical signs will typically occur within an hour following ingestion (Richardson 2013; Stice et al. 2018).

Ethanol is metabolized by three basic mechanisms: (1) first‐pass metabolism of ethanol to acetaldehyde by gastric alcohol dehydrogenase; (2) first‐pass metabolism of ethanol to acetaldehyde by liver alcohol dehydrogenase 1B followed by conversion of the acetaldehyde to acetic acid by liver aldehyde dehydrogenase, and acetic acid is then converted to acetyl coenzyme A that is consumed as an energy source via the citric acid cycle or for the synthesis of lipids; and (3) conversion of ethanol to acetaldehyde by hepatic CYP 2E1. In domestic animals that are not normally regularly exposed to ethanol, mechanisms (1) and (2) are usually the most important. Clearance of ethanol from the bloodstream is mostly via hepatic metabolism, but small amounts of ethanol (<10% of the ingested amount) are exhaled or excreted in urine. Elimination time is increased with higher blood concentration (saturable metabolic enzymes) (Richardson 2013: Stice et al. 2018).

Mechanism of Action

Ethanol, particularly concentrated ethanol, is a skin, respiratory, eye, and gastrointestinal irritant. Its irritancy on the gastric mucosa is associated with its well‐known capacity to induce vomiting. Consumption of concentrated industrial ethanol produces significant damage to the gastric mucosa and bleeding into the stomach.

Within the central nervous system (CNS), ethanol and many of the anesthetics and narcotic hydrocarbon solvents appear to have a common site of action on CNS neurotransmitter receptors. Ethanol has agonist‐like effects on CNS GABA‐aminobutyric acid A and glycine receptors and inhibitory effects on glutamate N‐methyl‐D‐aspartate receptors (particularly in the hippocampus). These mechanisms help to explain the CNS depressive, anesthetic‐like effects and its amnesic actions. Importantly, the CNS depressive effects also include the loss of central cardiovascular/respiratory drive and the loss of normal airway‐protective reflexes. This increases the risk of aspiration (Richardson 2013; Stice et al. 2018).

Ethanol suppresses the release of antidiuretic hormone (arginine vasopressin) by the posterior pituitary. This reduces water reabsorption in the distal convoluted tubules and collecting tubules in the nephrons of kidneys, and causes increased urine production.

Doses of ethanol that produce inebriation typically sensitize the myocardium to the effects of catecholamines and fatal cardiac arrhythmias may develop. The hypothermia that is common in ethanol intoxication exacerbates these effects and increases the difficulty of treating any cardiac arrhythmias that develop. Hypothermia develops in ethanol poisoning due to a combination of peripheral vasodilation (increased heat loss) and a central loss of the ability to thermoregulate (Wismer 2017). Acute ethanol poisoning may also trigger acute pancreatitis. Ethanol is a proven teratogen in animals.

Toxicity

The lowest dosage expected to produce death in dogs following ingestion is around 5.5 g/kg. However, clinical signs of toxicity may occur at much lower dosages (Richardson 2013).

Clinical Effects

Signs

Clinical signs of acute ethanol poisoning in companion animals resemble the classical signs in humans: vomiting, an initial period of paradoxical behavioral excitation followed by CNS depression, ataxia, lethargy, and sedation. Significant ingestions are associated with coma and hypothermia. Signs of abdominal pain may be present due to ethanol's irritant effects on the gastric mucosa and its ability to trigger acute pancreatitis. Dehydration may occur because of an inability to concentrate urine due to decreased antidiuretic hormone. Pupillary reflexes may be variable in their response. Tachycardia or myocardial depression and hypotension may be present. Death is typically from cardiovascular respiratory arrest combined with hypothermia. Cardiac arrhythmias are common. Hypoglycemic seizures may occur, particularly in young animals. Importantly, many patients lose their airway protective reflexes. Thus, aspiration of vomitus is an important delayed effect of ethanol poisoning. Sequential diagnostic imaging should be performed if aspiration is suspected (Richardson 2013; Stice et al. 2018).

Laboratory

Determination of whole blood or serum alcohol concentration is the most effective method of confirming the diagnosis. However, ethanol levels can be determined in most body fluids and vomitus. Osmolar gap metabolic acidosis is a common finding in acute ethanol poisoning. An elevated anion gap may also be occasionally present in acute ethanol poisoning (Wismer 2017). Hypoglycemia, serum electrolyte disturbances, and evidence of hemoconcentration are common. Blood pCO₂ (partial pressure of carbon dioxide) measurement may be useful if respiratory depression is present. Evidence of acute pancreatitis such as elevated serum amylase and lipase may be present.

Differential Diagnoses

The most critical differential diagnosis is ethylene glycol poisoning. Other alcohols (methanol, isopropyl alcohol), hydrocarbon solvents, marijuana, macrolide antiparasitics, and amitraz produce similar effects to ethanol in domestic animals, as do most benzodiazepine, barbiturate, antipsychotic, antiseizure, and antidepressant human prescription drugs.

Diagnostics

Antemortem

The patient's history plus the presence of the typical clinical signs/laboratory findings of the ethanol toxidrome are usually the best diagnostic clues. Definitive diagnosis typically requires the determination of whole blood or serum ethanol. Alternatively, ethanol levels can be determined in most body fluids and in vomitus. Aspirating stomach contents using a small‐bore nasogastric tube can often yield useful samples for ethanol testing if performed within about 1 hour following ingestion. Samples of the material suspected of being ingested, preferably in the original container, are always particularly valuable.

Postmortem

Ethanol levels can be measured in most body fluids and in the gastric contents. Detection of significant amounts of ethanol provides the most definitive diagnosis. Hyperemia and inflammation of the gastric mucosa may be present. Inflammation of the esophagus and bleeding from the gastric mucosa may be present if concentrated ethanol solutions have been ingested (Richardson 2013). The presence of pneumonia is strongly suggestive of aspiration.

Management of Exposures

Given that absorption of ethanol from the gastrointestinal tract is rapid, attempts at decontamination of the upper intestinal tract are usually ineffective. Because of the potential loss of airway reflexes, induction of vomiting should only be used with extreme caution in asymptomatic patients with a history of very recent ingestion (within 15 minutes). Gastric lavage is no longer used in cases of human ethanol poisoning since it has been shown to be ineffective and to increase the risk of severe complications (Stice et al. 2018). Activated charcoal does not bind ethanol and is ineffective. Evacuation of stomach contents using a small‐bore nasogastric tube may be of some value if the patient presents within 1 hour of ingestion.

Intravenous fluid therapy should be used to correct/prevent dehydration, support kidney function, maintain circulation and blood pressure, correct/prevent hypoglycemia (dextrose intravenous fluids), and correct any electrolyte/acid base disturbances present. Treatment of acidosis may include sodium bicarbonate administration. Regular monitoring of the patient's blood pressure, serum electrolytes, and acid base status is recommended. Vasopressors, such as dopamine, and plasma expanders may be useful if significant hypotension is present (Richardson 2013).

Regular monitoring of cardiac electrical activity, particularly if the patient is hypothermic, is recommended. Hypothermia is a common and serious problem in ethanol toxicoses, and supplementary heat may be required. Given that animals with ethanol toxicoses have poor thermoregulation, it is also important to avoid iatrogenic hyperthermia.

Prognosis

Most cases in domestic animals are relatively mild and involve consumption of relatively dilute alcoholic materials. In this situation, most uncomplicated cases will recover within 24–48 hours provided close monitoring and supportive care is available. The prognosis for patients with severe CNS signs, significant hypothermia, significant cardiovascular respiratory depression, or metabolic acidosis is much more guarded. The presence of aspiration pneumonia always warrants a guarded prognosis (Richardson 2013; Stice et al. 2018).

Methanol

Synonyms include alcohol, methyl carbinol, methyl alcohol, and wood alcohol.

Sources and Formulations

Methanol is typically used in the same range of household products as ethanol. It is no longer used in cosmetics or personal care products in most jurisdictions. Most automotive windshield washer products and deicers contain from 20% to 86% methanol; dogs are commonly exposed when they chew on the plastic bottles.

Kinetics

The kinetics of methanol resemble that of ethanol. Importantly, significant toxicoses have been reported following exposure of the skin, as well as following ingestion and inhalation. Methanol is rapidly metabolized by alcohol dehydrogenase to formaldehyde that is then oxidized to formic acid by formaldehyde dehydrogenase. In all domestic nonprimate animals, formic acid rapidly converts to CO₂ and water. Formic acid is metabolized much more slowly in humans, leading to blindness and other effects (Stice et al. 2018). These effects do not occur in domestic companion or production animals.

Mechanism of Action

The mechanisms of action of methanol in the CNS in nonprimates are presumed to be similar to those of ethanol. However, methanol is generally a less potent inebriant than ethanol. Methanol is generally more irritating to the gastrointestinal tract than ethanol. Acute pancreatitis is common in acute methanol poisoning. Methanol is a proven teratogen.

Toxicity

The minimum lethal dosage in dogs is between 5.0 and 11.25 mg/kg. Methanol is far more toxic to primates, where blindness and neuronal necrosis can occur after exposure to relatively small amounts (Stice et al. 2018).

Clinical Effects

The effects of methanol in nonprimate companion animals essentially resemble those of ethanol. Importantly, methanol does not produce blindness in nonprimates. Unlike ethanol, an increased anion gap is typically present in methanol toxicoses.

Differential Diagnoses

Important differential diagnoses are like those of ethanol, but also include other potential causes of anion gap metabolic acidosis. Common causes of anion metabolic acidosis can be memorized using the following mnemonic AT MUD PILES: Alcohols, Toluene; Methanol, Uremia, Diabetic ketoacidosis (alcoholic ketoacidosis, starvation ketoacidosis; Paraldehyde (phenformin), Iron (isoniazid), Lactic acidosis, Ethylene glycol and Salicylates (nonsteroidal anti‐inflammatory drugs).

Diagnostics

Ante‐ and postmortem diagnostic techniques are essentially the same as for ethanol.

Management of Exposures

In nonprimate companion animals, the management of methanol poisoning resembles that of ethanol poisoning.

Prognosis

In nonprimate domestic animals, the prognosis is like ethanol toxicoses.

Isopropanol

Synonyms include 1‐methylethanol, 2‐hydroxypropane, 2‐propanol, 2‐propyl alcohol, dimethylcarbinol, isopropyl alcohol, isopropyl alcohol, and rubbing alcohol.

Sources and Formulations

Isopropanol is typically used in the same range of household and industrial products as ethanol. Seventy percent aqueous isopropanol is extensively used in medicine as an antiseptic and cleansing agent, and isopropanol is used as the base in alcohol‐based flea and tick sprays.

Kinetics

Isopropanol is rapidly absorbed from the gastrointestinal tract: approximately 80% of an oral dose is absorbed within 30 minutes. Except in the case of massive overdose, absorption is usually complete within 2 hours. Isopropanol is rapidly metabolized to acetone via alcohol dehydrogenase. Acetone is metabolized relatively slowly compared with the metabolites of ethanol and methanol.

Mechanism of Action

Isopropanol is a potent CNS depressant and its metabolite, acetone, potentiates this effect. Acetone, by itself, is also a CNS depressant. The mechanisms of action of isopropanol in the CNS are assumed to be similar to that of ethanol (Stice et al. 2018).

Toxicity

Isopropanol is approximately two times more toxic than ethanol. This is due to a combination of the innate properties of isopropanol, plus the potentiating effect and long half‐life of its main metabolite, acetone.

Clinical Effects

Acute isopropanol toxicosis following voluntary consumption is relatively uncommon in domestic animals because of its bitter taste. The clinical effects resemble those of ethanol. Given an identical dose, CNS signs will generally be more severe in isopropanol poisoning compared with ethanol poisoning.

Differential Diagnoses

Differential diagnoses are as per ethanol.

Diagnostics

Ante‐ and postmortem diagnostic techniques are essentially the same as for ethanol.

Management of Exposures

The management of isopropanol poisoning resembles that of ethanol poisoning. If the exposure is dermal (flea and tick spray), a warm bath with liquid hand‐washing detergent should be performed. Do not let the patient get chilled afterwards.

Prognosis

In nonprimate domestic animals, the prognosis is similar to ethanol toxicoses.

Benzyl Alcohol (Benzoic Acid, Sodium Benzoate, Potassium Benzoate)

Synonyms include benzyl alcohol, benzenemethanol, alphahydroxytoluene, phenol carbinol, phenyl carbinol, phenylmethanol, and phenylmethyl alcohol.

Sources and Formulations

Benzyl alcohol is most commonly encountered in veterinary medicine as an excipient and antibacterial preservative in pharmaceutical preparations, particularly those designed for intravenous delivery. Significant exposures may occur during repeated drug infusions or when bacteriostatic water or sodium chloride solutions are used to flush IV lines.

Benzoic acid and its benzoate salts are common food additives/preservatives. Benzyl alcohol is a natural constituent of a number of plants. It occurs, for example, in some edible fruits (up to 5 mg/kg) and in green and black tea (1–30 and 1–15 mg/kg, respectively). Benzyl alcohol is added as a flavoring substance to some foods and beverages at a level up to about 400 mg/kg (chewing gum 1254 mg/kg) (Johnson et al. 2017). Benzyl alcohol is extensively used as a preservative in cosmetics and personal care products. Among domestic animals, toxicity has most commonly been reported in cats receiving intravenous solutions containing benzyl alcohol as a preservative.

Kinetics

Benzyl alcohol is rapidly metabolized to benzyl aldehyde by alcohol dehydrogenase. Alcohol dehydrogenase then converts benzyl aldehyde to benzoic acid. In all domestic species except cats, benzoic acid is either glucuronidated to form benzyl glucuronide or conjugated to glycine to form hippuric acid. These metabolites are then largely excreted in urine (Johnson et al. 2017).

Mechanism of Action

Domestic cats lack the ability to rapidly glucuronidate benzoic acid and primarily slowly metabolize benzoic acid to hippuric acid. Under these circumstances, benzoic acid accumulates, resulting in anion‐gap metabolic acidosis. Benzoic acid has been shown to be extremely toxic to cats.

Toxicity

Benzyl alcohol is relatively toxic in cats. Lactated Ringer's solution containing 1.5% benzyl alcohol can cause severe signs of toxicosis in this species (Cullison et al. 1983).

Clinical Effects

Antemortem

Clinical signs in cats include hyperesthesia, followed by depression, coma, and finally death. In humans, respiratory distress (gasping syndrome), CNS depression, seizures, and hemolysis are regarded as highly suggestive of benzyl alcohol poisoning. Surprisingly, hemolysis has not been reported in cats. The clinical chemistry picture is dominated by the presence of anion gap metabolic acidosis.

Postmortem

There are no specific findings.

Differential Diagnoses

Differential diagnoses are as per ethanol.

Diagnostics

Apart from a history of exposure, the most effective method of confirming the diagnosis is detection of elevated levels of benzyl alcohol, benzoic acid, and/or hippuric acid in blood, serum, urine, or aqueous humor.

Management of Exposures

Treatment resembles that of ethanol poisoning. Hemodialysis has been used in humans, but its effectiveness remains unknown.

Higher Alcohols

These include butanols, pentanols, hexanols, heptanols, octanols, paraffinic alcohols, aliphatic alcohols, and amyl alcohol (n‐pentanyl alcohol), among others.

Sources and Formulations

Higher alcohols are largely used in industrial settings as solvent for paints, lacquers and varnishes, natural and synthetic resins, gums, vegetable oils, and dyes and alkaloids. They are used as intermediates in the manufacture of pharmaceuticals and chemicals and employed in industries producing artificial leather, textiles, safety glass, rubber cement, shellac, raincoats, and photographic films. They are also used as fragrances and solvents in perfumes, cosmetics, and personal care products.

Kinetics

Generally speaking, the shorter‐chain higher alcohols are well absorbed through skin, the respiratory tract, and the gastrointestinal tract. Glucuronidation is a common pathway of metabolism for many of these chemicals. Excretion in urine is usually the major route of excretion (Stice et al. 2018).

Mechanism of Action

The mechanism of action of the higher alcohols in the CNS is assumed to be similar to that of ethanol and the hydrocarbon solvents. Given that glucuronidation is important in the metabolism and excretion of these alcohols, it is likely that cats are significantly more sensitive to toxicity (cats have relatively inefficient glucuronidation of metabolites).

Butanols and amyl alcohols are irritants. All of the higher alcohols will produce defatting injuries to the skin with repeated exposures (Stice et al. 2018). There are not many cases in animals, but amyl alcohol exposure results in hearing impairment in humans and most of these chemicals will produce dyschromatopsias (alterations in color vision) in humans.

Toxicity

As a general rule, as the alcohol's carbon chain lengthens, its toxicity decreases. Branched chain alcohols are generally more toxic than the straight chained alcohols of similar carbon number. Longer chain alcohols are absorbed more slowly, are less able to penetrate the skin, and are less likely to be inhaled. Importantly, many of the higher alcohols are significant aspiration hazards.

Clinical Effects

Antemortem

Acute exposure to higher alcohols may result in CNS depression, hypotension, nausea, vomiting, and diarrhea. Butanols and amyl alcohols are irritants. Most of these materials are significant aspiration hazards. If aspirated, hemorrhagic pneumonitis is common. Other effects resemble those of ethanol.

Postmortem

Postmortem effects resemble those in ethanol poisoning. Chemical hemorrhagic aspiration pneumonitis is likely.

Differential Diagnoses

Differential diagnoses are as per ethanol.

Diagnostics

A history of potential exposure is the most important diagnostic tool. Tests for the presence of these materials in biological samples are not routinely available. The presence of chemical pneumonitis is strongly suggestive of post‐ingestion aspiration.

Management of Exposures

General symptomatic management as per ethanol poisoning is recommended.

Prognosis

Given their generally lower toxicity, for a given identical dose, the prognosis can usually be expected to be better than ethanol toxicity.

GLYCOLS

Ethylene Glycol

Synonyms include 1,2‐dihydroxyethane, 1,2‐ethandiol, 1,2‐ethane‐diol, 2‐hydroxyethanol, ethylene alcohol, ethylene dihydrate, glycol, and monoethylene glycol (MEG).

Sources

Ethylene glycol is a ubiquitous household chemical found in adhesives, sealers, deicers, radiator coolants, hydraulic fluids, some brake fluids, cleaners, wood preservatives, grouting mixtures, inks, caulks, and paints. One of the most common sources of ethylene glycol poisoning in domestic animals is automotive radiator coolant/antifreeze.

Kinetics

Ethylene glycol is rapidly and nearly completely absorbed from the digestive tract. Peak blood concentrations occur within about 1–4 hours following ingestion. Ethylene glycol is oxidized by alcohol deydrogenase to glycoaldehyde and then subsequently converted to glycolic acid, glyoxylic acid, and oxalic acid (Figure 29.1). Glyoxylic acid is metabolized in intermediary metabolism to malate, formate, and glycine. Ethylene glycol, glycolic acid, calcium oxalate, and glycine (and its conjugate, hippurate) are excreted in urine (Stice et al. 2018; Thrall et al. 2013).

Mechanism of Action

Ethylene glycol poisoning has three basic mechanisms of action: (1) CNS depression and inebriating effects that resemble those of the alcohols; (2) the metabolism to glycoaldehyde, glycolic acid, glyoxylic acid, oxalic acid, malate, formate, and glycine results in an anion gap metabolic acidosis; and (3) free calcium in the blood and tissues reacts with oxalic acid to form calcium oxalate, which then crystallizes out of solution in the proximal tubules of the kidney and in and around small blood vessels (particularly in the brain). This results in kidney failure (Thrall et al. 2013).

Figure 29.1. Metabolism of ethylene glycol.

Toxicity

The minimum lethal dosage of pure ethylene glycol in dogs is around 6.6 ml/kg. Cats are significantly more sensitive, with a minimum lethal dosage of around 1.5 ml/kg (Thrall et al. 2013).

Clinical Effects

Signs

The ethylene glycol toxidrome occurs in three sequential stages. Stage 1 is the CNS depression phase. CNS depression begins soon after exposure and lasts up to 12 hours after ingestion. This depression appears similar to ethanol intoxication but is typically more severe on a consumed volume‐to‐volume basis compared with ethanol consumption. The effects are due to unmetabolized ethylene glycol. Frequent urination and excessive thirst are common signs in dogs during this early stage. Cats typically do not develop this polydipsia.

Stage 2 is the cardiopulmonary phase. It is characterized by cardiorespiratory signs that typically consist of tachycardia, tachypnea, and hypotension or hypertension. After the glycoaldehyde metabolite forms at 4–12 hours post‐consumption, anion gap metabolic acidosis develops and the following effects may occur: seizures, myoclonic jerks, cerebral edema (in some cases), coma, and gastrointestinal irritation (vomiting). Cerebral edema, deposition of calcium oxalate crystals in the walls of small blood vessels in the brain, and exposure of the metabolically active deep gray matter nuclei of the brain basal ganglia to ethylene glycol metabolites contribute to the CNS toxicity. Depending on dose, cardiac arrhythmias, pulmonary edema, pneumonitis, congestive heart failure, and circulatory shock may develop during this phase.

Metabolism of the glycoaldehyde to oxalic acid often results in the appearance of calcium oxalate crystal precipitates in the meninges, blood vessel walls, lung, myocardium, and associated tissue injury. The formation of calcium oxalate crystal precipitates in tissues may be associated with hypocalcemia. Death may occur during this stage in some cases (Thrall et al. 2013).

Stage 3 is the renal failure phase. Kidney damage due to formation of calcium oxalate crystals in the renal tubules usually develops 24–72 hours after exposure. The subsequent decline in kidney function and oliguria exacerbates the anion gap metabolic acidosis and other serum chemistry disturbances.

Oliguric renal failure characterizes the third phase. Prolonged, rarely permanent, kidney failure is distinguished by proteinuria, hematuria, crystalluria, and increased serum blood urea nitrogen (BUN) and creatinine. Calcium oxalate crystals may appear in the urine as early as stage 1, but absence of these crystals does not rule out the diagnosis of ethylene glycol poisoning. Seizure development is a poor prognostic indicator (Thrall et al. 2013).

Laboratory

Ethylene glycol test kits are available that will accurately detect blood ethylene glycol down to a level of 20 mg/dl. These tests unfortunately have a lot of false positives (ethanol, methanol, xylitol, propylene glycol, etc.). Furthermore, in patients that present in the late stages of the toxicosis (after 12 hours), blood ethylene glycol levels may fall below the limit of detection due to its catabolism (Thrall et al. 2013).

An osmolar gap, without metabolic acidosis, or an anion gap can be detected before significant metabolism of ethylene glycol occurs. As ethylene glycol is metabolized, the osmolar gap, if present, will decrease and an anion gap metabolic acidosis evolves. Patients who present late may have renal failure with normal osmolar and anion gaps and no acidosis or measurable ethylene glycol levels.

Isosthenuria, due to an osmotic diuresis produced by urinary excretion of unmetabolized ethylene glycol is common in the early stage of the toxicosis in dogs. Decrease in urine specific gravity may also occur in cats during this stage, but isosthenuria rarely develops. Calcium oxalate monohydrate crystals (clear, six‐sided, prism‐like crystals) can be detected within 3–6 hours post ingestion in dogs. Urinary crystals can take many forms such as dumbbells, envelopes, and needles (most commonly). Importantly, the absence of urinary crystals, however, does not rule out poisoning. Urinary pH is usually decreased in ethylene glycol poisoning (Thrall et al. 2013).

Many radiator fluid formulations that contain ethylene glycol also contain fluorescein (a fluorescent green or red dye, depending on pH). In occasional cases, the dye (which fluoresces with UV light exposure) may be detectable in the urine. It may also be useful to examine any vomitus, the mouth, the face, and the animal's paws with a Wood's lamp to determine whether they appear fluorescent.

Once oliguric or anuric renal failure has developed (typically 24–48 hours following ingestion), large increases in serum BUN and creatinine will occur. Elevated serum potassium usually develops during this phase. About 50% of patients will also have decreased serum calcium due to the formation of calcium oxalate. Likewise, about 50% of patients will have elevated blood glucose. During the period of recovery from renal failure, patients will typically be isosthenuric. Urinalysis during this phase will typically reveal calcium oxalate monohydrate crystals, hematuria, proteinuria, and glucosuria.

Differential Diagnoses

The most critical differential diagnosis in the early stages of the toxidrome is poisoning by the various alcohols. Hydrocarbon solvents, marijuana, macrolide antiparasitics, and amitraz produce similar effects to the alcohols, as do most benzodiazepine, barbiturate, antipsychotic, antiseizure, and antidepressant human prescription drugs. During the later stages of the toxidrome, other causes of renal failure are the major differential diagnoses.

Diagnostics

Antemortem

The patient's history plus the presence of the typical clinical signs/laboratory findings of the ethylene glycol toxidrome plus detection of ethylene glycol in vomitus, urine, or blood are usually the best diagnostic clues. The level of ethylene glycol or its metabolites can be measured in most body fluids and in the gastric contents. Definitive diagnosis typically requires the determination of blood ethylene glycol. Aspirating stomach contents using a small‐bore nasogastric tube can often yield useful samples if performed within about 30–60 minutes following ingestion. Samples of the material suspected of being ingested, preferably in the original container, are always particularly valuable. It is important to communicate other possible exposures to the testing laboratory since 2,3‐butanediol, often found in the plasma of following ethanol ingestion, can be mistakenly identified as ethylene glycol when the analysis is performed by gas chromatography. Propylene glycol can also interfere with some ethylene glycol assays (Thrall et al. 2013).

Recent studies have demonstrated usefulness of glycolic acid analysis in ethylene glycol poisoning cases. Measuring glycolic acid in ethylene glycol poisonings has certain advantages: findings correlate better with ethylene glycol toxicity than ethylene glycol levels, findings determine how much ethylene glycol has metabolized to glycolic acid, the presence of glycolic acid objectively indicates toxicity, and the test confirms that the metabolic acidosis was due to ethylene glycol poisoning rather than another cause.

Postmortem

Signs of gastritis or enteritis (gastric and intestinal mucosa is hemorrhagic and hyperemic) are typically present, as are pulmonary edema and hyperemia. The kidneys are usually swollen, tan‐colored, and have intermittent gray or yellow streaks at the corticomedullary junction. Histologically, calcium oxalate crystals are found in and around the proximal convoluted tubules of the kidneys. In animals that survive, regenerating renal tubules may be seen. Similar crystals may be seen in the adventitia and perivascular spaces of the brain blood vessels.

Management of Exposures

Decontamination of the upper digestive tract either by inducing vomiting or dosing with activated charcoal has been proven to be ineffective. Aspiration of stomach contents with a small‐bore nasogastric tube may be of some benefit and may yield valuable diagnostic samples if performed within about 30–60 minutes post ingestion.

There are three critical objectives in the treatment of ethylene glycol poisoning: (1) prevention of conversion of ethylene glycol to its toxic metabolites, (2) correction of the anion‐gap metabolic acidosis and maintenance of renal glomerular filtration rate, and (3) adjunctive and supportive care. Except for hemodialysis, which is rarely available in veterinary practice, the older practices of increasing the excretion of ethylene glycol and its toxic metabolites by forced dieresis and/or urinary alkalinization have been proved to be ineffective. Furthermore, these techniques have been demonstrated to increase the serious complication rate and the death rate (Thrall et al. 2013).

The single most important factor associated with survival and reduction of morbidity in ethylene glycol poisoning is preventing conversion of ethylene glycol to its toxic metabolites by the prompt administration of the specific antidote fomepizole (4‐methylpyrazole). Fomepizole (dogs: loading dose of 15 mg/kg IV followed in 12 hours by 10 mg/kg every 12 hours for 4 doses) is the first‐choice antidote and is highly effective even in cases of massive poisonings and substantially reduces the risk of significant CNS and renal complications. Fomepizole is also highly effective following oral dosing. Fomepizole acts as a competitive inhibitor of the metabolism of ethylene glycol to glycolaldehyde metabolite and thus limits the formation of oxalate and associated tissue crystallization of calcium oxalate. Fomepizole greatly reduces the severity of the cardiopulmonary and renal failure stages of the poisoning. Fomepizole has a high therapeutic index and a very low risk of serious side effects. Fomepizole will not prevent the inebriation and CNS effects induced by unmetabolized ethylene glycol (and any other alcohols present) and may prolong this state in poisoned individuals. In cats, much higher doses (125 mg/kg slow IV then 31.25 mg/kg at 12, 24, 36 hours) are needed and sedation and ataxia will occur (Connally et al. 2010).

The second‐choice antidote is ethanol. There are several published methods for administration. Regardless of route of administration the objective is to rapidly achieve and maintain a blood ethanol concentration of at least 100 mg/dl to provide adequate competitive inhibition of ethylene glycol metabolism. Ethanol must be diluted before IV administration as it is hyperosmotic and can cause osmotic dehydration, hyponatremia, and venous irritation. A 20% ethanol solution can be given to both dogs and cats as bolus doses. Dogs require 5.5 ml/kg every 4 hours for 5 treatments, then every 6 hours for 4 treatments. Cats receive 5 ml/kg every 6 hours for 5 treatments, then every 8 hours for 4 treatments. The disadvantages of this dosing schedule include further CNS depression, acidosis, ethanol‐related toxicity such as hepatitis, pancreatitis, hypoglycemia, increased cardiovascular/respiratory depression, and hypothermia. To avoid this, a lower concentration of ethanol can be administered as a 7% aqueous solution intravenously. When using a 7% ethanol solution, administer 600 g/kg (8.6 ml/kg) slow IV followed by 100 g/kg/h (1.43 ml/kg/h) IV. This should be given in addition to a diuretic dose of IV fluids.

In extreme circumstances where ethanol infusion is not possible, pharmaceutical‐grade material can be administered orally or by small‐bore nasogastric tube. The oral loading dose is 750 mg/kg body weight administered slowly over the first hour, with a maintenance dose of 150 mg/kg body weight per hour thereafter. Always administer the ethanol slowly to reduce the risk of vomiting. If there is a high risk of vomiting, secure the airway using a cuffed endotracheal tube. If pharmaceutical‐grade ethanol is not available, distilled alcoholic beverages can be administered by small bore nasogastric tube as summarized in Table 29.1.

Administration of thiamine hydrochloride (promotes the metabolism of ethylene glycol to ketoadipate) and the administration of vitamin B6 (pyridoxine; promotes the metabolism of ethylene glycol to glycine and ultimately to hippuric acid) may be beneficial.

Detailed discussion of the treatment of acute oliguric renal failure and anion‐gap metabolic acidosis is beyond the scope of this chapter. However, reestablishment of a near‐normal renal glomerular filtration rate by the use of intravenous crystalloids and/or diuretics, such as mannitol, and/or vasopressors, such as dopamine, is often the most effective method of correcting the anion‐gap metabolic acidosis and other electrolyte disturbances associated with ethylene glycol poisoning. Care must be taken to avoid exacerbating electrolyte disturbances such as hyperkalemia and/or hypernatremia. The administration of bicarbonate may be useful in the initial control of metabolic acidosis.

Table 29.1. Distilled alcoholic beverages and doses that can be administered by small‐bore nasogastric tube to treat ethylene glycol exposure

Name of Alcoholic Beverage | Typical Proof | Typical Percentage of Ethanol by Volume | Typical Grams of Ethanol per 100 ml of Beverage | Typical ml/kg of Beverage Required for Loading Dose | Typical ml/kg of Beverage Required for Maintenance Dose
Brandy | 40–60 | 20–30 | 15.8–23.7 | 3.2–4.7 | 0.64–0.94
Cognac | 80 | 40 | 31.6 | 2.4 | 0.5
Gin | 90–110 | 45–55 | 35.6–43.5 | 1.7–2.1 | 0.3–0.4
Grain alcohol | 190 | 95 | 75.0 | 1 | 0.2
Rum | 151 | 75.5 | 59.6 | 1.3 | 0.25
Schnapps | 30–100 | 15–50 | 11.8–39.5 | 1.9–6.4 | 0.4–1.3
Tequila | 80–100 | 40–50 | 31.6–39.5 | 1.9–2.4 | 0.4–0.5
Vodka | 80–100 | 40–50 | 31.6–39.5 | 1.9–2.4 | 0.4–0.5 ml/kg
Whisky | 80–100 | 40–50 | 31.6–39.5 | 1.9–2.4 | 0.4–0.5 ml/kg

Prognosis

The prognosis for ethylene glycol poisoning in domestic animals is always guarded. Early aggressive treatment, particularly with fomepizole, is associated with an improved prognosis.

Propylene Glycol

Synonyms include 1,2‐dihydroxypropane, 1,2‐propylene glycol, 2,3‐propanediol, isopropylene glycol, 1,2‐propanediol, and trimethyl glycol.

Sources and Formulations

Propylene glycol is a ubiquitous ingredient in cosmetic and personal care products. It is also a Generally Recognized as Safe food additive, except in cat foods. In food, it is primarily used as a humectant to keep things moist. It can also be found in paints, cleaning agents, sealants, inks, and caulking agents. Propylene glycol is progressively replacing the use of ethylene glycol in radiator coolants, deicing solutions, and hydraulic fluids. It is also a ubiquitous excipient and solvent in pharmaceutical preparations.

Kinetics

Propylene glycol is rapidly and relatively completely absorbed from the gastrointestinal tract. Propylene glycol undergoes metabolic oxidation to pyruvic acid, acetic acid, lactic acid, and propionaldehyde. These metabolites are then consumed, primarily by the citric acid cycle. Propylene glycol is rapidly converted to proprionic acid, a volatile fatty acid, in the rumen. The volatile fatty acid is then rapidly absorbed and converted to glucose via gluconeogenesis. For this reason, administration of propylene glycol via an ororumen tube has been used as an emergency energy supplement in debilitated sheep and cattle (Stice et al. 2018).

Mechanism of Action

The CNS is the main target organ in acute propylene glycol toxicoses. The effects are similar to ethanol and other alcohols. The rapid metabolism of propylene glycol to lactic acid may also result in metabolic acidosis. A high level of dietary propylene glycol produces oxidative damage to erythrocytes and decreases red cell lifespan in cats. For this reason, propylene glycol is no longer used in cat foods.

Toxicity

The oral lethal dose 50 (LD₅₀) of propylene glycol (100%) in dogs is about 22 g/kg (Stice et al. 2018).

Clinical Effects

CNS depression is the primary manifestation of acute propylene glycol poisoning. Other effects include anion gap metabolic acidosis and blood hyperosmolality, and frequent urination due to osmotic dieresis. Propylene glycol does not cause direct damage to the kidneys.

Propylene glycol is a common diluent for injectable medications, most notably phenytoin. Toxicity following intravenous injection of pharmaceuticals containing high levels of propylene glycol may cause hypotension and cardiac arrhythmias.

Differential Diagnoses

Important differential diagnoses are similar to those of ethanol and ethylene glycol but also include other potential causes of anion gap metabolic acidosis.

Diagnostics

A history of consumption and the presence of anion gap metabolic acidosis are key diagnostic pointers. Detection of propylene glycol in vomitus or samples obtained by small‐bore nasogastric aspiration and/or in blood or other body fluids is usually conclusive. As always, samples of the ingested material are always particularly useful.

Management of Exposures

Antidotal therapy with fomepizole or ethanol is not required. Care is largely supportive. Intravenous bicarbonate and fluid therapy may be necessary to correct acidosis and prevent dehydration.

Prognosis

Propylene glycol is normally unpalatable to domestic animals. Thus, voluntary ingestions usually result in mild intoxication. Sere anion gap metabolic acidosis is indicative of a more guarded prognosis.

Butylene Glycol

Synonyms include 1,3‐butanediol and 1,3‐butylene glycol.

Sources and Formulations

Butylene glycol is commonly used in cosmetics and personal care products. Butylene glycol is a relatively common drug of abuse and has been sold in health food stores as a supplement.

Kinetics

Butylene glycol is rapidly and nearly completely absorbed from the gastrointestinal tract. It is rapidly metabolized to acetoacetate and gamma‐hydroxybutyrate (Stice et al. 2018).

Mechanism of Action

Gamma‐hydroxybutyrate is a CNS GABA agonist and this produces pronounced CNS depression and anesthetic/narcotic like effects.

Clinical Effects

The primary effects resemble those of alcohol intoxication.

Differential Diagnoses

Differential diagnoses are similar to ethanol.

Diagnostics

Detection of the material in the ingested substance, stomach contents or body fluids, plus a history of exposure are the key diagnostic steps.

Management of Exposures

Management is largely supportive and is similar to ethanol poisoning.

Prognosis

The prognosis is dependent on the severity of the CNS depression. The presence of unconsciousness or significant cardiovascular/respiratory depression is always associated with a more guarded prognosis.

BRAKE FLUID AND GLYCOL ETHERS

Sources

Brake fluid is a common household item. The main chemical constituents are high boiling point and high molecular weight polyalkylene glycol ethers. Some brands may also contain small amounts of ethylene and/or diethylene glycol. These products also contain small amounts of additives (e.g., corrosion inhibitors, antioxidants). These materials are usually mobile, water miscible liquids. Color ranges from colorless to amber; in some cases they may also contain dyes.

Kinetics

The main routes of exposure are ingestion and skin contact. In general, these materials are relatively poorly absorbed from the intestinal tract. Ingestion of large amounts can result in systemic effects.

Mechanism of Action

Ingestion of small amounts is unlikely to cause systemic toxicity; transient gastrointestinal effects may, however, be experienced. Swallowing of larger amounts may result in nausea, vomiting, and possibly signs of CNS depression. Kidney damage may also occur with some products due to the presence of diethylene glycol. The viscosity of the products is such that aspiration of product into the lung is unlikely. Brake fluids contain small amounts of additives. Although some of these may be hazardous in their own right, the amount of each present, typically less than 1%, is unlikely to contribute significantly to the acute toxicity of the product.

Clinical Effects

Signs

Following ingestion, the main clinical signs will most commonly relate to gastrointestinal upset, i.e., salivation, vomiting, and diarrhea. If ingestion of large amounts has occurred, there is a possibility of CNS depression and/or kidney damage. In rare cases, kidney failure and death may result.

Laboratory

Laboratory findings (if any) will most commonly reflect hemoconcentration. In very rare cases, evidence of kidney failure may be present (i.e., elevated blood urea nitrogen and creatinine, oliguria). Occasionally, the brake fluid may be visually detectable in the feces.

Differential Diagnoses

The most common differential diagnoses will be virtually any cause of acute diarrhea. If CNS depression is present, differential diagnoses are similar to those listed in the section on ethanol.

Diagnostics

A history of exposure and consumption is the most common method of diagnosis. Aspiration of stomach contents via small‐bore nasogastric tube may yield valuable diagnostic samples if performed within about an hour following ingestion.

Management of Exposures

Management of ingestions is most commonly symptomatic and supportive. If the diarrhea is severe, fluid therapy may be required.

Contamination of the skin and coat is best managed by gentle washing in a body‐temperature solution of dilute, mild, neutral hand‐dishwashing detergent followed by rinsing with clean water. Several rinse/wash cycles over a 5–10 minute period may be required. Alternatives to dishwashing detergents include pharmaceutical‐grade PEG 400, PEG 300, and polyvinyl pyrrolidone solutions (Besenhofer et al. 2010).

Due to their skin barrier disruptive effect, the use of solvents, petroleum distillates (such as baby oil, Stoddard solvent, engine degreasers, naphthas, kerosene, petrol, diesel etc.), mechanic's hand degreasers, strong cationic detergents, strong anionic detergents, and abrasive materials is contraindicated in dermal decontamination. These materials are known to be ineffective and to increase systemic absorption.

Prognosis

Prognosis is good to guarded.

ACIDS

Sources

Acids are compounds with a pH below 7. Products containing acids include cleaning agents (e.g., toilet bowl cleaners), anti‐rust compounds, etching compounds, automotive batteries, and pool sanitizers. The toxicity of an acid increases with increasing concentrations and lower pH. Common acids include acetic acid (vinegar), citric acid, glycolic acid (facial peels), and hydrochloric acid.

Kinetics and Mechanism of Action

Acids produce localized coagulative tissue necrosis and generally produce immediate pain on exposure, which helps to limit ingestion (Gwaltney‐Brant 2013).

Toxicity

Acids with a pH below 2 can cause tissue injury and corrosive damage. Acids with a pH above 2 only cause tissue irritation.

Clinical Effects

Signs

Clinical signs occur almost immediately on exposure. Oral exposure results in pain, vocalization, dysphagia, vomiting (with or without blood), and irritation or ulceration of oral and/or esophageal mucosa. Lesions often appear milky white to gray initially, then gradually turn black. Esophageal lesions are less common than with alkaline products. Dermal exposure results in dermal irritation or ulceration, accompanied by intense local pain. Ocular exposure may result in corneal erosion or ulceration (Gwaltney‐Brant 2013).

Laboratory

No specific abnormalities are expected. Can see elevated white count with secondary infection.

Differential Diagnoses

Other corrosives such as alkalis and cationic detergents. Nontoxic causes can include calicivirus and electrical burns.

Management of Exposures

Attempts to chemically neutralize acids with a weak alkali are contraindicated, as this may stimulate an exothermic reaction. Treatment of oral exposure includes immediate dilution with water or milk. Gastric lavage and induction of emesis are contraindicated due to the risk of increasing corrosive injury. Activated charcoal is ineffective for caustic agents and should not be used. Treatment of oral lesions is symptomatic and should include pain management (opioids), sucralfate slurries to treat oral, esophageal or gastric ulcers, intravenous fluids to maintain hydration, provisions for nutritional support (e.g., gastrostomy tube), and antibiotics if needed. The use of corticosteroids to decrease inflammation and esophageal stricture formation is controversial, as steroids will delay wound healing and may increase susceptibility to infection. Dermal and ocular exposures should be treated with copious flushing with clear water for 15 minutes. Fluorescein staining of the eyes should be performed, and corneal erosion or ulceration should be treated as needed (Gwaltney‐Brant 2013).

Prognosis

Prognosis in most cases is good. It can decrease if there are perforating ulcers in the stomach or of the esophagus.

ALKALIS

Sources

Alkaline products include sodium or potassium hydroxide, ammonium hydroxide, and potassium permanganate. Common sources of alkaline products include drain openers, automatic dishwasher detergents, alkaline batteries, toilet bowl cleaners, swimming pool products, and radiator cleaning agents.

Kinetics and Mechanism of Action

Alkaline agents penetrate local tissue rapidly and deeply, causing liquefactive necrosis. Unlike acidic products, very little pain may be evident on initial contact, which may encourage further contact and ultimately result in more extensive exposures (Gwaltney‐Brant 2013).

Toxicity

Agents with pH > 11 are capable of causing significant corrosive injury.

Clinical Effects

Signs

Clinical signs may not develop immediately, and it may require up to 12 hours for the full extent of tissue damage to become apparent. Acute signs include depression, hypersalivation, anorexia, oral inflammation or ulceration, dysphagia, vomiting (with or without blood), abdominal pain, and melena. Significant hyperthermia (>104 °F) may accompany oral inflammation. Esophageal and/or pharyngeal ulceration may occur. Sequelae can include esophageal perforations or strictures and pleuritis or peritonitis from leakage of ingesta through perforated mucosa (Gwaltney‐Brant 2013).

Differential Diagnosis

Other corrosives such as acids and cationic detergents. Nontoxic causes can include calicivirus and electrical burns.

Management of Exposures

As with oral acid exposures, emesis should NOT be induced and activated charcoal should not be given. Complete evaluation of the oral cavity for ulceration or irritation should be performed, although with very recent exposures the oral cavity may appear normal. Evidence of oral discomfort and inflammation generally develop within 2–4 hours, although the full extent of injury may not be evident until 12 hours post exposure. Endoscopy may be performed in cases in which esophageal damage is a concern. Should mucosal burns develop, treatment is the same as with an acid exposure (Gwaltney‐Brant 2013).

Prognosis

Esophageal lesions may take weeks to heal and there is risk of stricture formation, leading to impairment of esophageal function.

DETERGENTS

Sources

Detergents are ubiquitous materials in most households. There are four basic types.

Anionic Detergents

The detergent property of these materials is due to its anionic properties. The anion is neutralized with an alkaline or basic material to produce full detergency. There are three main groups: the alkyl aryl sulfonates, the long‐chain (fatty) alcohol sulfates, and other sulfonates (olefine sulfates and sulfonates, alpha olefine sulfates and sulfonates, sulfated monoglycerides, sulfated ethers, sulfosuccinates, alkane sulfonates, phosphate esters, alkyl isethionates, sucrose esters). These materials commonly contain water‐softening agents such as sodium phosphate, sodium carbonate, and sodium silicate. Laundry detergents (liquid and powdered) and shampoos are the most common sources of these materials in the home.

Nonionic Detergents

The materials are ionically inert and are the largest and most chemically diverse member of the detergent chemical family. Typical nonionic detergents include alkyl and aryl polyether sulfates, alcohols or sulfonates, polyglycol ethers, polyethylene glycol, and sorbitan monostearate. Common household sources of these materials include soaps, laundry detergents, and dishwashing detergents.

Cationic Detergents

The detergency of these materials is dependent on their cationic properties. However, these have poor detergency and are more commonly used as germicides, fabric softeners, and specialist emulsifiers; liquid potpourri products are also sources of cationic detergents. Typically, these materials are large halogenated (i.e., contain bromine, iodide, or chlorine) molecules. Common examples include benzethonium chloride, benzalkonium chloride, methyl benzethonium, cetylpyridinium chloride, and halogenated quaternary ammonium compounds. These are commonly found in disinfectants used in the veterinary clinic (see Figure 29.2).

Amphoteric Detergents

These contain both acidic and basic groups in their molecules and can act as cationic or anionic detergents, depending on the pH of the solution. These materials are commonly found in shampoos, skin cleaners, and carpet shampoo. They are very stable in strong acidic conditions and often used in conjunction with hydrofluoric acid in industrial settings.

Figure 29.2. Quaternary ammonium general cleaner.

Photograph courtesy of Tina Wismer.

Kinetics and Mechanism of Action

The main site of action of most of these materials is local, i.e., at the site of contact. In most cases, this means the skin, the oral mucous membranes or the gastrointestinal tract. The systemic toxicity of most domestic detergents is usually relatively low. The notable exceptions to this generalization are the cationic detergents and those detergents that contain citronella extract (fragrance), pine oil extracts (fragrance), or phenol‐based disinfectants.

Toxicity

In most circumstances, detergents formulated for general household use are specifically designed to have a low toxic potential. The exception to this is often machine dishwashing detergents, which are notoriously alkaline and capable of producing serious caustic burns to mucous membranes and the gastrointestinal tract.

As a general rule, ionic detergents are more irritating than nonionic detergents and anionic detergents are less irritating than cationic detergents. Household anionic detergents are rarely irritant or toxic, even following ingestion. Cationic detergents (particularly quaternary ammonium compounds) are irritating to the gastrointestinal tract, skin, and mucous membranes and may be potent systemic toxicants.

Clinical Effects

Signs

Repeated exposure of the skin to detergents results in cumulative irritant dermatitis, typically due to defatting injury to the skin. Relevant clinical signs include thickening of the skin with weeping, cracking, scaling, and possibly blistering. Splash injuries to the eyes with nonionic or anionic detergents usually produce transient signs of irritation. Splash injuries of the eyes by cationic detergents are potentially serious and may result in significant damage to the cornea and surrounding eye structures. Ingestion of many ionic detergents often results in signs of gastrointestinal disturbance, i.e., salivation, vomiting, nausea, diarrhea, and gastrointestinal distension. Ingestion of anionic detergents may result in intravascular red cell hemolysis in patients with impaired liver function. This is thought to be due to the reduced metabolism and excretion of the detergent.

Quarternary ammonium compounds are frequently corrosive to the mouth and gastrointestinal tract, and ingestion may result in serious vomiting (including vomiting of blood (appears like coffee grounds due to partial digestion in the stomach), diarrhea, vascular shock, collapse, and possibly death. Ingestion of cationic detergents, particularly those containing quaternary ammonium compounds, is associated with a systemic toxidrome consisting of CNS and respiratory depression, fever, seizures, collapse, and coma (Rubini et al. 2024; Wipond et al. 2023).

Laboratory

Since most of the effects of detergent are local, few laboratory signs can be expected in most cases. Clinical pathology signs that reflect dehydration may occur in cases where significant diarrhea is present. Alkaline dishwashing detergents will cause coagulative to liquefactive necrosis at the sites of contact.

Differential Diagnoses

The most common differential diagnoses will be virtually any cause of acute diarrhea or cumulative skin irritation. Systemic cationic detergent poisoning (particularly quaternary ammonium compounds) may resemble several types of pesticide poisoning.

Diagnostics

A history of exposure and consumption is the most common method of diagnosis.

Management of Exposures

Splash injuries to the eyes should be initially treated by copious flushing of the affected eye(s) with water or a specialist eye flush solution for 10–15 minutes. Specialist treatment may be required, particularly for eye injuries due to cationic detergents or machine dishwashing detergents. Washing with hand soaps (technically a mild anionic detergent) are generally effective at neutralizing and removing cationic detergents on the skin.

Administration of milk, egg whites, or water as diluents has been recommended for treatment of ingestion of anionic and cationic detergents provided there is no corrosive injury to the gastrointestinal tract. Induction of emesis is generally contraindicated because of the potential corrosive action of these materials. Activated charcoal use is also commonly recommended, although its efficacy is unknown. Simple aspiration of stomach contents using a fine‐bore nasogastric tube may also be beneficial if performed within about 60 minutes post ingestion.

Management of ingestions is most commonly symptomatic and supportive. If the diarrhea is severe or if vascular shock is present/likely, intravenous fluid therapy may be required. If significant damage to the mouth and/or esophagus has occurred, placement of a percutaneous esophageal gastric tube may be required for adequate nutritional support.

Prognosis

With ingestion of nonionic and anionic detergents, prognosis is usually good. With ingestion of cationic detergents, prognosis is often guarded.

BLEACH

Sources

There are several different types of bleaches. Household liquid bleach is usually 3–6% sodium hypochlorite. Powdered chlorine bleaches generally contain calcium hypochlorite, trichloroisocyanuric acid, or dichlorodimethyhydantoin. Color‐safe bleaches contain sodium peroxide, sodium perborates, or enzymatic detergents.

Kinetics and Mechanism of Action

Powdered chlorine bleaches change to hypochlorite when they come into contact with water. Color‐safe bleaches may change to hydrogen peroxide when they contact water.

Toxicity

Depending on the concentration and duration of exposure, sodium hypochlorite and related compounds can be irritating to corrosive to mucus membranes (Gwaltney‐Brant 2013) (see Figure 29.3). Most household bleaches are mild to moderate mucosal irritants. Alkaline bleach has a pH of 11–12 and can cause chemical burns.

Figure 29.3. Cat with tongue tip irritation from licking household bleach.

Photograph courtesy of Katrina Nolan.

Clinical Effects

Signs

The most common signs after exposure are gastrointestinal, skin, eye, and/or respiratory irritation. If the bleach concentration is greater than 6%, mucosal burns can develop. Color safe bleaches tend to cause protracted vomiting as they release hydrogen peroxide when they contact water. Inhalation of fumes can cause wheezing, coughing, and dyspnea (Gwaltney‐Brant 2013).

Management of Exposures

Remove animals to fresh air with inhalation exposures. Orally exposed animals should be given milk or water for dilution and monitored for gastrointestinal upset. Dermal irritation can be seen and animals should be bathed with liquid dishwashing detergent until they no longer smell like bleach (Gwaltney‐Brant 2013).

Prognosis

Generally good.

PHENOLS

Sources

Dilute phenol solutions (0.1–4.5%) are found in over‐the‐counter sore‐throat lozenges, throat sprays, gargles, gels, ointments, and lotions. Phenol is used as a local anesthetic.

Kinetics

Phenol is readily absorbed after inhalation or after oral or dermal exposure. Peak tissue concentrations are achieved within 1 hour (Wismer 2004).

Mechanism of Action

In dilute solutions, phenol is an irritant and tissue damage and inflammation may be seen at the site of contact. In concentrations above 5%, phenol is corrosive and denatures proteins (Wismer 2004).

Toxicity

Cats are more susceptible to toxicosis than dogs due to their inability to metabolize phenol.

Clinical Effects

Signs

Pain and blanching of the area along with blisters and burns can occur with dermal exposures. Oral exposures can cause oral, esophageal, and gastric ulcers. Large doses can lead to muscle tremors, seizures, coma, and death.

Laboratory

Phenols can cause methemoglobinemia and anemia, along with elevated liver values.

Management of Exposure

Ocular exposures should have the eyes flushed for 30 minutes with water or saline. Before washing any contaminated skin, blot the area first to remove as much phenol as possible. Then bathe with plenty of water and liquid dishwashing detergent until the product can no longer be smelled (Wismer 2004).

Prognosis

If no signs in 2–4 hours, none will occur.

ESSENTIAL OILS

Essential oils (see also Chapter 21) are fragrant hydrophobic plant extracts produced by distillation or solvent extraction of plant material. Common alternative names include “volatile oils,” “votive oils,” “ethereal oils,” or simply as the “oil of” the plant material from which they were extracted, such as oil of clove. These oily plant extracts are considered “essential” if they carry a distinctive scent or essence of the plant source. These materials do not have any specific chemical properties other than their characteristic fragrances.

Sources and Toxicity

Common essential oils found in many household products and herbal medicine products are listed in Table 29.2.

ISOCYANATE ADHESIVES

Sources

Any polyurethane glue, tile adhesive, or expanding foam insulation that contains isocyanates has the possibility to expand in the gastrointestinal tract.

Toxicity and Treatment

As the glue dries, it will expand to three to four times its original volume. Thus, when the glue is swallowed, it will potentially cause an acute gastric obstruction. Surgical removal of the gastric foreign body is usually required (Horstman et al. 2003).

DEICING SALTS

Sources

Common deicing salts may contain one of the following: calcium carbonate, calcium magnesium acetate, urea, potassium chloride, magnesium chloride, and sodium chloride.

Table 29.2. Common essential oils found in many household and herbal medicine products

Name of Essential oil
Plant of Origin
Chemical Properties
Key Toxic Effects

Camphor oil
Cinnamomum camphora
Camphor, a terpinoid
Pure material is an aspiration hazard

Local irritant to skin, eye, and gastrointestinal tract; central nervous system manifestations may range from an altered mental status to seizures to coma

Cardamom oil
Elettaria cardamomum
1,8‐cineole (eucalyptol) and alpha‐terpinyl acetate
Pure material is an aspiration hazard

Low potential for toxicity

Carnation oil
Dianthus caryophyllus
Eugenol, phenethyl alcohol, linalool, benzyl benzoate, (Z)‐3‐hexenyl benzoate and benzyl salicylate
Pure material is an aspiration hazard

Low potential for toxicity

Carrot seed oil
Daucus carota (carrot)
50% carotol, a sesquiterpene alcohol
Pure material is an aspiration hazard

Like most sequiterpene‐containing materials it is an irritant to the gastrointestinal tract, respiratory tract, skin, and eyes. Possibly central nervous system effects may occur at high doses

Cedar oil
Cedar wood oils: Juniperus spp., Cupressus spp.
30% (+)‐cedrol, alpha‐cedrene, and other sesquiterpenes
Pure material is an aspiration hazard

Skin, eye, and gastrointestinal irritant

Cedar leaf oil: Thuja occidentalis
Long‐term high exposure to vapor may result in lung and liver damage

Cedrol is a sedative

Citral (syn = lemonal)
Present in the oils of several plants, including lemon myrtle (90–98%), Listsea citrata (90%), Litsea cubeba (70–85%), lemongrass (65–85%), lemon tea‐tree (70–80%), Ocimum gratissimum (66.5%), Lindera citriodora (~65%), Calypranthes parriculata (~62%), petitgrain (36%), lemon verbena (30–35%), lemon ironbark (26%), lemon balm (11%), lime (6–9%), lemon (2–5%), and oranges
Bi‐terpenoid
Pure material is an aspiration hazard

Low toxicity in laboratory animal studies

May produce contact hypersensitivity in some individuals

DL‐limonene
Purified chemical substance from orange or lemon oils

Pure material is an aspiration hazard

Can have a phototoxic effect on bare skin

Citrus oil flea dips have been associated with poisoning in cats, clinical signs include hypersalivation, muscle tremors, ataxia, coma, and death

Eucalyptus oil
Eucalyptus globulus
1,8‐cineole and alpha‐pinene (bicyclic terpene)
Poisoning affects the nervous system (loss of consciousness, hypoventilation, depression of reflexes, and convulsions), the gastrointestinal system (abdominal pain, vomiting, and diarrhea), and the respiratory system (respiratory depression, dyspnea, pneumonitis, and bronchospasm). Gastrointestinal effects are frequently the initial effects, although drowsiness may occur in a few minutes and coma within 10 minutes. The patient may vomit while drowsy or unconscious and aspiration is a major risk. Tachycardia and weak irregular pulse have been noted. Muscle weakness and ataxia may occur. Nephritis is rare but has been recorded. Both miosis and mydriasis can occur (miosis being more common). Central nervous system depression or vomiting have been delayed up to 4 hours. Recovery or death is often within 24 hours.

It is a mild skin irritant

Lemon oil
Citrus limon (lemon tree)
>90% D‐limonene (a cyclic terpene).
Pure material is an aspiration hazard

Can have a phototoxic effect on bare skin

Citrus oil flea dips have been associated with poisoning in cats, clinical signs include hypersalivation, muscle tremors, ataxia, coma, and death

Menthol
Purified chemical substance from peppermint or spearmint
Aromatic alcohol
Pure material is an aspiration hazard

Has low toxicity

Pure material is a moderate skin, eye, and gastrointestinal irritant

Oil of citronella
Cymbopogon sp. (Citronella grasses)
Ceylon type: (obtained from Cymbopogon nardus Rendle) consists of geraniol (18–20%), limonene (9–11%), methyl isoeugenol (7–11%), citronellol (6–8%), and citronellal (5–15%)
Pure material is an aspiration hazard

Skin irritant in some individuals

Java type: (obtained from Cymbopogon winterianus Jowitt) consists of citronellal (32–45%), geraniol (11–13%), geranyl acetate (3–8%), limonene (1–4%)

Oil of cloves
Syzygium aromaticum
60–90% eugenol, eugenyl acetate, caryophyllene
Pure material is an aspiration hazard

Large oral doses may produce vomiting, sore throat, seizure, sedation, pulmonary edema, vomiting of blood, decreased blood clotting, kidney failure, and liver damage or failure

May produce hypoglycemia

Undiluted clove oil has a high risk of causing contact dermatitis, skin irritation, and burns

Allergic reactions to clove, its component eugenol, have been reported, including possible severe reactions (anaphylaxis)

Oil of spearmint
Mentha spicata
R‐carvone, a terpinoid
Pure material is an aspiration hazard

Considered nontoxic

May be a gastrointestinal irritant

Oil of wintergreen
Gaultheria procumbens
Menthyl salicylate and gaultherilene
Pure material is an aspiration hazard

See salicylate poisoning in the relevant section of this book

Orange oil (syn = sweet orange)
Citrus sinensis (sweet orange tree)
>90% D‐limonene (a cyclic terpene)
Pure material is an aspiration hazard

Can have a phototoxic effect on bare skin

Citrus oil flea dips have been associated with poisoning in cats, clinical signs include hypersalivation, muscle tremors, ataxia, coma, and death

Pennyroyal oil
Mentha pulegium
Pulegone, menthone, iso‐menthone, and neomenthone
Pure material is an aspiration hazard

Causes abortion in humans

Produces acute liver damage

Peppermint oil
Mentha × piperita, a cross between the watermint (Mentha aquatica) and spearmint (M. spicata)
Menthol, an aromatic alcohol
Pure material is an aspiration hazard

Carvone, a terpinoid
Peppermint oil is nontoxic and nonirritant in low concentrations

Pure material is irritant to the skin, mucous membranes, eyes, and gastrointestinal tract

Pine oil
Pinus sylvestris
Mainly bicyclic terpene alcohols, but may also contain terpene hydrocarbons, ethers, and esters
Pure material is an aspiration hazard

Skin irritant at high concentration

Potential for contact hypersensitivity

Sandalwood oil
Santalum sp.
Alpha and beta santalol, aromatic alcohols
Pure material is an aspiration hazard

Considered nontoxic and not irritating

Sassafras oil
Brazilian sassafras oil, obtained from the trunkwood of Ocotea pretiosa, and Chinese sassafras oil from C. camphora
>80% safrole, 5‐menthoxy‐eugenol, asarone, coniferaldehyde, camphone, and traces of thujone, anethole, apiol, and eugenol
Pure material is an aspiration hazard

Safrole is carcinogenic and hepatotoxic

Irritant to skin, eyes, and gastrointestinal tract

Central nervous system effects such as depression, hallucinations, and coma may occur

Tea tree oil
Melaleuca alternifolia
Mixture of terpenoids and sesquiterpenoids, with terpinene‐4‐ol (36%), gamma‐terpinene (20%), alpha‐terpinene (8%), and 1,8‐cineole (4%) as the major components
Pure material is an aspiration hazard

Can produce anaphylaxis in some individuals

Can be toxic in cats and dogs following topical exposure and ingestion. Toxidrome consists of ataxia, central nervous system depression, muscle tremors, coma. Evidence of liver damage has been reported in cats.

Toxidrome following oral exposure resembles that of eucalyptus oil

Toxicity and Treatment

Calcium carbonate, calcium magnesium acetate, and urea are primarily gastric irritants and will produce vomiting and diarrhea. Sodium chloride can produce serious hypernatremia (muscle tremors, acidosis, seizures) and osmotic diuresis. Muscle weakness and cardiac rhythm/electrical abnormalities can result from ingestion of potassium chloride or magnesium chloride (Foss 2002). Treatment is symptomatic and supportive.

REFERENCES

Besenhofer, Lauren M, Adegboyega, Patrick A, Bartels, Michael, Filary, Mark J, Perala, Adam W, McLaren, Marie C, and McMartin, Kenneth E. 2010. Inhibition of metabolism of diethylene glycol prevents target organ toxicity in rats. Toxicological Sciences 117(1):25–35.

Connally, Heather E, Thrall, Mary Anna, and Hamar, Dwayne W. 2010. Safety and efficacy of high‐dose fomepizole compared with ethanol as therapy for ethylene glycol intoxication in cats. Journal of Veterinary Emergency and Critical Care 20(2):191–206.

Cullison, RF, Menard, PD, and Buck, William B. 1983. Toxicosis in cats from use of benzyl alcohol in lactated Ringer's solution. Journal of the American Veterinary Medical Association 182(1):61.

Foss, Tamara S. 2002. The hazards of ice melts. Veterinary Technician 104:94–95.

Gwaltney‐Brant, Sharon M. 2013. Miscellaneous indoor toxicants. In Small Animal Toxicology, 3rd ed., edited by Michael E Peterson and Patricia A Talcott, pp. 291–308. St. Louis: Saunders.

Horstman, Christopher L, Eubig, Paul A, Cornell, Karen K, Khan, Safdar A, and Selcer, Barbara A. 2003. Gastric outflow obstruction after ingestion of wood glue in a dog. Journal of the American Animal Hospital Association 39(1):47–51.

Johnson, Jr, Wilbur, Bergfeld, Wilma, F et al. 2017. Safety assessment of benzyl alcohol, benzoic acid and its salts, and benzyl benzoate. International Journal of Toxicology 36(3S):5S–30S.

Richardson, Jill A. 2013. Ethanol. In Small Animal Toxicology, 3rd ed., edited by Michael E Peterson and Patricia A Talcott, pp. 547–549. St. Louis: Saunders.

Rubini, Silva, Rubini, Roberto, Bertocchi, Silvia et al. 2024. A case of severe benzalkonium chloride intoxication in a cat. Acta Veterinaria Scandinavica 66(1):18.

Stice, Szabina, Thrall, Mary A, and Hamar, Dwayne W. 2018. Alcohols and glycols. In Veterinary Toxicology: Basic and Clinical Principles, 3rd ed., edited by Ramesh C Gupta, pp. 647–657. London: Elsevier.

Thrall, Mary Anna, Connally, Heather E, Grauer, Gregory F, and Hamar, Dwayne W. 2013. Ethylene glycol. In Small Animal Toxicology, 3rd ed., edited by Michael E Peterson and Patricia A Talcott, pp. 551–567. St. Louis: Saunders.

Wipond, Marley, Prittie, Jennifer, Mastrocco, Alicia, and Donovan, Taryn A. 2023. Fatal exposure to quaternary ammonium disinfectant in 2 dogs. Journal of Veterinary Emergency and Critical Care 33(3):380–387.

Wismer, Tina. 2004. Phenols. In Clinical Veterinary Toxicology, edited by KH Plumlee, pp. 164–167. St. Louis: Mosby.

Wismer, Tina. 2017. Ethanol toxicosis: A review. Today's Veterinary Practice March/April:74–76.

30
Miscellaneous Toxicants

Elisha Argo

INTRODUCTION

This chapter will focus on the evaluation and advised treatment protocol for several different compounds or toxicants. In a clinical case assessment, it is important to note that exposure to a toxicant may not initially be known or observed. In some cases, clinical signs are reported prior to the identification of the causative agent or toxicant. In other cases, exposure to a toxin may be witnessed or direct evidence may be left behind identifying exposure has occurred, but the exact dose or amount may be unknown. Frequently veterinary professionals must provide supportive care to a patient who has ingested an unknown substance. In addition to this, the presentation in the clinic of some toxicology cases may not be according to the textbook description. In these cases, it is vital that veterinary professionals obtain a detailed history and proper signalment. Evaluating the circumstances and symptoms related to possible toxicant ingestion is sometimes the only approach at hand for plausible diagnosis and instigation of a proper treatment plan. A presumptive diagnosis can be founded on both historical information and clinical observations (smell, vomitus contents, evidence on hair or in teeth, or access to the substance along with evidence of that substance being disturbed in some way). It can be very difficult to confirm the diagnosis due to a lack of testing procedures for certain toxicants. Contact your local or state diagnostic laboratory or to check for available tests go to the American Association of Veterinary Laboratory Diagnosticians website (www.aavld.org).

PETROLEUM‐BASED TOXICANTS

Petroleum is a complex chemical structure containing a mixture of hydrocarbons. Crude oil intoxication is more common in large animals and poses a serious environmental issue (Coppock and Christian 2018). Petroleum‐based agents are a common household exposure to companion animals as well, but in these cases the products are more likely to be refined hydrocarbons such as gasoline, motor oil, waxes, or asphalt. These items are commonly found in hobby or work areas (garage storing paint and paint thinners), outdoor environments (BBQ areas with lighter fluid), vehicles (leaking oil or gasoline), cleaning compounds or topical creams (detergents, diaper rash creams, and topical prescription medications), and pest control products (insecticides, herbicides). In most cases, animals are exposed via oral (ingestions), inhalation (high concentration of fumes in surroundings), ocular (splash back), or dermal routes (rolling in toxicant and laying in toxicant). See Chapter 29 for more information.

Petroleum products are produced from the distillation of crude oil and comprise aliphatic and aromatic hydrocarbons. Most products are in a liquid state and have a strong, distinct odor (gasoline and paint thinner are great examples). Other products will form gases that are highly flammable such as gasoline, methane, and propane. These gases can act as simple asphyxiants when proper ventilation is not provided (Coppock and Christian 2018).

Aromatic hydrocarbons have been associated with certain neurological signs, and even potential bone marrow toxicity. When inhaled in high enough concentrations or in sufficient amounts, compounds that are aromatic hydrocarbons (benzene, toluene, ethylbenzene, xylene) can have both acute and chronic effects different from other hydrocarbons that are in gas and oil. For instance, benzene is hemotoxic and is a carcinogen at high levels, toluene can cause neurologic signs and neurologic damage at high dosages, and n‐hexane can cause peripheral neuropathy over time (Coppock and Christian 2018).

In all cases, clinical toxicosis develops rapidly after exposure, and most petroleum hydrocarbon‐based products will contain additional compounds such as anionic or cationic surfactants, metals, and proprietary products (such as pesticides) that should be considered when identifying risks to the patient.

Mechanism of Action

Quantifying dose ranges or verifying the cumulative amount of a petroleum product that was ingested by a pet can be very difficult to achieve. Unless the exposure was witnessed, estimates may be required to verify concerns and probable effects from the cumulative amount ingested more precisely. The chemical properties of the agent in question can help to identify its clinical effects. High volatility or the greater likelihood for the product to vaporize as well as lower viscosity or the product's lower resistance to flow can pose a significant risk for inhalation or aspiration into the lungs. In general, the lower the viscosity of a hydrocarbon the larger the risk for aspiration during ingestion or during emesis. Products with a viscosity score of <35 SUS (Saybolt Universal Seconds at a specified temperature) will pose a severe aspiration risk (Raisbeck 2013). The risk for pneumo‐toxicity is a direct result of viscosity and surface tension. Low viscosity allows the product to be more readily absorbed by the surrounding tissue. Low surface tension allows the product to spread over larger areas of the pulmonary tissues. Hydrocarbon vapors can displace alveolar oxygen, leading to cyanosis. In addition to the displacement of oxygen, hydrocarbons can dissolve natural lipids that serve as the pulmonary surfactant, leading to the rapid onset of signs. Inhalation or aspiration of fewer than 5 mL of a refined petroleum product can lead to fatal aspiration pneumonia in small animals (see Table 30.1) and as small as 0.1 ml of a low‐viscosity hydrocarbon (such as mineral spirits) when aspirated directly can result in severe respiratory symptoms. Hydrocarbon products with a viscosity of 35–100 SUS pose a moderate risk for aspiration and products with a viscosity of >100 SUS pose a minimal risk for aspiration (Raisbeck 2013).

Table 30.1. Petroleum hydrocarbon products listed by relative viscosity (lower to higher)a

| Saybolt Universal Seconds (SUS) at 100 °F
Lighter fluid (naptha) |  <32
Degreasers |  <32
Carburetor cleaner |  <32
Kerosene |  32
Gasoline treatment |  35
Diesel fuel 2D |  32–45
Fuel oil 2 |  33–40
Mineral seal oil |  36–42
Furniture polish |  40
Turpentine |  <60
Baby oil |  70
No. 4 fuel oil |  80
Paint thinners |  <100
Stoddard solvent (white spirits) |  <100
Transmission fluids |  <138
Heavy mineral oil |  180
Machine lubricant #10 |  160–235
Motor oil (10 W30) |  325
Tar, pine |  200–300
Tar, road RT‐6 |  250–400

a Adapted in part from 16 CFR Part 1700: https://www.cpsc.gov/s3fs‐public/pdfs/foia_resist.pdf

Exposure to petroleum products may result in gastrointestinal, respiratory, and central nervous system (CNS)‐associated symptoms (see Tables 30.2 and 30.3). There are also risks for more diverse clinical effects to occur depending on the hydrocarbon ingested. Polycyclic aromatic hydrocarbons are a widespread environmental concern due to their carcinogenic capabilities; they are also being researched as a cause of congenital heart diseases in humans. Certain halogenated hydrocarbons (anesthetic gases like halothane, fire‐extinguishing agents, and refrigerants) will sensitize the myocardium to circulating catecholamines and can lead to cardiac arrhythmias (Himmel 2008). Environmental oil exposures and chronic exposures have resulted in mild perivascular hemorrhage of the pia mater and white mater of the cerebellum and cerebrum. Larger separations between the pia‐mater and arachnoid membranes have been observed. Lesions and edema due to hypoxic damage are also common (Raisbeck 2013).

Table 30.2. Clinical signs related to petroleum hydrocarbon product ingestion

Inhalation | Aspiration pneumonia
Dyspnea
Coughing
Bronchospasms
Fever
Cyanosis
Depression
Dermal/ocular | Blisters
(grooming can lead to oral exposure) | Burns
Inflammation
Corneal ulcers
Oral | Salivation
Pawing at mouth/shaking head
Oral irritation/ulceration
Severe vomiting
Abdominal tenderness
Diarrhea
Anorexia
Systemic | Tachycardia/dysrhythmias
Ataxia
Tremors
Weakness
Depression
Agitation
Seizures
Aspiration pneumonia
Dyspnea/tachypnea
Hepatic insult
Renal degeneration

A variety of clinical signs can develop due to petroleum product ingestion, including gastrointestinal, respiratory, integumentary, and CNS. Other systemic effects can include sensitizing of the myocardium to catecholamines, resulting in cardiac arrhythmia and in the case of benzene (an aromatic hydrocarbon and carcinogen), bone marrow suppression, and pancytopenia.

Turpentine and other petroleum distillates or solvents made from hydrocarbons can cause irritation on contact with any tissue. Ocular and dermal irritation are very common in cases of prolonged skin contact or inadequate ventilation. These products have lipid solvent properties and can cause erythema, dermatitis, and epithelial necrosis in severe cases. If an animal is covered over a large percentage of their body surface area systemic toxicity can occur (Wismer 2004). Matting can contribute to trapping the product close to the skin, increasing the exposure area.

Clinical Effects

Signs

Signs can develop rapidly as soon as within minutes of exposure, but signs may also take up to 8 hours post‐exposure. This is most evident in cases when pets have ingested a hydrocarbon and remain clinically normal until the product is produced in vomitus and unintentionally inhaled or aspirated. In addition to ingestion, animals may be exposed by walking through spills or being confined in a poorly ventilated environment with petroleum products that are not stored properly.

Respiratory signs can include coughing, rhonchi, crackles, aspiration pneumonia, fever, depression, bronchospasms, hypoxia, and cyanosis. If direct contact with petroleum products occurs with alveolar surfaces, signs can include hemorrhage, pulmonary edema, fibrosis, and thrombosis leading to atelectasis, hypoxia, and pneumonitis. Small animals confined with large amounts of improperly stored petroleum solvents can develop chronic bronchitis and seizure activity (Coppock and Christian 2018).

A common route of exposure in dogs and cats would be dermal exposure resulting in oral exposure from grooming. Dermal exposures can cause blisters or chemical burns as well as irritation. Exposure of the oral tissue directly with petroleum products can cause buccal irritation, reduced respiratory function, hypersalivation, severe vomiting, oral and esophageal ulcerations, diarrhea (sometimes with oily residue), anorexia or inappetence, and abdominal tenderness or discomfort. Ocular exposures can cause severe irritation, producing inflammation, corneal damage, and corneal ulcers. Systemic toxicosis associated with petroleum‐based products can include tachycardia, arrhythmias (associated with hypoxia or myocardial sensitization to catecholamines), ataxia, weakness, CNS stimulatory effects such as agitation or seizures, or CNS depressive effects, tachypnea, hyperthermia, aspiration pneumonia, cyanosis, and hepatic and renal damage (Coppock and Christian 2018).

Diagnostics

Diagnosis is most often based on the history of direct exposure or possible exposure to petroleum‐based products as well as clinical presentation or symptoms. Often the product will have a characteristic odor that can be detected on the patient's coat, breath, vomitus or gastrointestinal contents, or urine. Very few diagnostic laboratories perform testing for petroleum hydrocarbons in gastrointestinal contents, but it is recommended that any samples stored for possible testing be kept in airtight, clean, glass containers. Tissue samples such as lung, liver, or kidney samples should be stored in aluminum foil and airtight containers, and then frozen to preserve them. Local veterinary diagnostic laboratories can direct veterinary professionals to a laboratory location that offers hydrocarbon testing (Coppock and Christian 2018). Commercial environmental laboratories may also perform petroleum testing depending on the toxicant involved. Quick on‐site testing at a veterinary facility can be obtained by placing a sample of the stomach contents in warm water and mixing vigorously while monitoring the sample for oily bubbles or oil film collecting on the surface of the water. This is not considered definitive testing due to natural fatty acids producing an oily film as well. During necropsies, postmortem lesions may involve pulmonary congestion and edema, fatty changes in hepatic tissues, renal degeneration, and necrosis. Ulcerations of the oral and tracheal mucous membranes may also be evident with the presence of oily substances on the tissue or leaching from the tissue when placed in solution. More severe clinical signs, including pulmonary edema, have been associated with more volatile or highly refined products due to their high risk for aspiration and resulting pneumonia (see Table 30.4).

Table 30.3. Some common hydrocarbons and signs of acute toxicosis

Compound
Dose
Clinical Signs

Acetone
LD₅₀ (oral): 5–10 mg/kg
CNS depression, narcosis, coma

Benzene
LD₅₀ (oral): 4 ml/kg
CNS depression, narcosis, bone marrow suppression

Carbon disulfide
LD₅₀ (oral): 5–10 mg/kg
LC₅₀ (inhalation): 15 mg/L
Tremors, cyanosis, vascular collapse, coma

Cyclohexane
LD₅₀ (oral): >8 ml/kg
CNS depression, ataxia, narcosis, coma

Diesel fuel
LD₅₀ (oral): 9 ml/kg
Relatively nontoxic; diarrhea, GI upset

Gasoline
LD₅₀ (oral): 18 ml/kg
Moderate topical and GI irritant, aspiration pneumonia

Home heating oil
LD₅₀ (oral): 18 ml/kg
Relatively nontoxic; diarrhea, GI upset if dose is sufficient

Isopropanol
LD₅₀ (oral): 6–13 g/kg
CNS depression, ataxia, acidosis, coma

Jet fuel A
LD₅₀ (oral): >20 ml/kg
Relatively nontoxic; diarrhea, GI upset if dose is sufficient

Motor oil
LD₅₀ (oral): >22 ml/kg
Relatively nontoxic; diarrhea, GI upset if dose is sufficient

Toluene
LD₅₀ (oral): 6–8 ml/kg
CNS depression, ataxia, liver and kidney damage

Turpentine
Minimum lethal dose: 15 ml/kg
Strong irritant, readily absorbed dermally and inhalation

Xylene
LD₅₀ (oral): 4 ml/kg
Strong topical irritant, CNS depression, tremors, coma

CNS, central nervous system; GI, gastrointestinal.

Table 30.4. Postmortem lesions reported following ingestion or aspiration of petroleum hydrocarbons

Ulcerations in oral, gastrointestinal, or tracheal mucosa

Oily contents in the gastrointestinal tract or lung

Pulmonary edema and congestion (lesions generally bilateral and caudoventral in the lung)

Hepatic fatty change and centrilobular necrosis

Renal degeneration and necrosis

Differential Diagnosis

Evaluation of clinical signs should also rule out possible exposures to organophosphates, caustic or corrosive compounds or cleaners, and trauma. The bronchial and alveolar reactions of necrosis, edema, and infiltration can be very hard to distinguish between inhalation exposures and infectious agent responses. Acute neurological signs may result from sodium ion toxicity. Ocular and respiratory irritation differential diagnoses consist of dry, dusty, and windy conditions combined with irritation from feed particles as well as infectious pinkeye.

Management of Exposures

The process of treating hydrocarbon exposures can be very challenging. Generally in these cases, exact amounts or doses of the agent ingested are simply not available. In addition, there is a lack of proven treatment recommendations or guidelines for specific hydrocarbon exposures. For example, if an otherwise healthy animal is exposed to small amounts of a high‐viscosity hydrocarbon, minimal treatment or cage rest and observation for 12–24 hours may be required. In cases where large volumes of low‐viscosity hydrocarbon have been ingested and the patient has complicating factors, full blood work and repeat laboratory work along with symptomatic treatment, cage rest, radiographs (possibly repeated), and other supportive care may be required (see Table 30.5).

Inducing emesis and performing gastric lavage in these cases should be avoided. Even with proper measures, such as a cuffed endotracheal tube, it is not thought to be enough of a protective measure against aspiration of these agents. Adsorbent product administration such as activated charcoal is also not appropriate and is generally not effective in absorbing the product and can also increase the overall risk for aspiration of the petroleum product in the event of vomiting. Evaluation of the use of gastric lavage and potential aspiration should always be weighed against overall toxicity risk. In the event of hydrocarbon exposures containing additional toxicants (such as insecticides, heavy metals, chlorine‐containing compounds, and other proprietary blended products) these treatments may be necessary. It is not advisable to dilute any petroleum product with mineral oil (Raisbeck 2013).

Treatment for aspiration pneumonia may be required. This includes repeated laboratory tests to evaluate hepatic and renal function (serum chemistries and complete blood count [CBC]), blood gases, and radiographs. If the animal presents with aspiration pneumonia, treatment begins with hospitalization and intravenous fluids paired with cage rest. Oxygen therapy may also be required for stabilization. In severe inhalation exposures, any use of a positive end‐expiratory pressure ventilation system should be used with caution. This is due to the risk of pneumothorax and pneumomediastinum. Bronchospasms may also require treatment and respond well to beta‐2 selective agonists (such as nebulizer treatments) but epinephrine should be avoided. Secondary infections may require antibiotic therapy. Renal as well as hepatic functions should be evaluated well before selecting the proper antibiotic treatment.

Ideally, postexposure thoracic radiographs should be taken within 2 hours of the initial exposure, then repeated 2–4 days postexposure to evaluate any pulmonary damage. CBC should be monitored for hemoconcentration (increased packed cell volume and hemoglobin concentrations) and inflammatory response. Serum biochemistry should be used to evaluate blood urea nitrogen, blood glucose, and hepatic enzyme values associated with possible systemic toxicity (acute renal and hepatic injury). Pulmonary performance should be monitored using a combination of oxygen saturation and blood gases. Respiratory symptoms can take days to weeks to resolve. Patients showing a rapid progression of respiratory symptoms have a guarded prognosis (Coppock and Christian 2018).

Table 30.5. Therapy recommendations for petroleum hydrocarbon exposure

Clinical Sign | Recommendation | Dose
Respiratory | Oxygen | Based on blood gas data
Positive end‐expiratory pressure ventilation
Antibiotics | As needed
Chest radiographs
Bronchospasm | Terbutaline (beta‐2 selective agonist) | Dogs: 0.003 to 0.005 mg/kg SQ q 4 h
Cardiac dysrhythmia | Electrocardiogram | Cats: 0.005 to 0.01 mg/kg SQ q 4 h
Dehydration | Crystalloid Fluids | As needed
Gastrointestinal irritation | Omeprazole | 1 mg/kg PO q 12 h
Sucralfate | Dogs: 0.5 to 1 g PO q 8–12 h
Cats: 0.25 g PO q 8–12 h
Seizures | Diazepam | 0.5 to 2 mg/kg IV
Dermal contact | Mild detergents/cool water
Topical antibiotics

IV, intravenous; PO, per os (orally); q, every; SQ, subcutaneous.

Animals with signs of oral irritation or buccal injury can be offered milk and consideration given to placing the patient on oral and gastro‐protectant medications such as sucralfate or omeprazole. For chronic symptoms associated with oral injury, such as anorexia, follow‐up care consisting of intravenous fluid therapy, bland soft diet options, or a feeding tube may be required to aid in adequate nutrition during recovery. Ideally, animals presenting with abnormal cardiac rhythm should be monitored with electrocardiograms and provided with supportive care as needed. Seizure activity caused by systemic hydrocarbon toxicity can be controlled with the administration of barbiturates or diazepam.

Dermal decontamination should be provided as soon as possible to patients with dermal exposure. Washing in mild, nonsolvent‐based soaps is ideal (such as dilute dish soap) due to petroleum distillates' inability to form a homogenous mixture with water. Topical ointments and/or antibiotics may be required for dermal injuries depending on the level of disruption to the skin barrier. Dermal decontamination with heavier chain hydrocarbons such as asphalt or tar may require clipping of the affected hair and an Elizabethan collar to prevent further grooming exposures and subsequent oral exposures (Raisbeck 2013).

Ocular exposures should be treated first by flushing the eyes with copious amounts of warm saline or warm water for 15 minutes. Stain can then be used to assess if ocular exposure has resulted in corneal damage or ulcers. These patients should be monitored for a minimum of 12 hours via cage rest to ensure no further effects. This is most important with possible respiratory injury or symptoms to ensure the patient is provided with oxygen supplementation quickly in the event symptoms develop.

FERTILIZERS

Fertilizers are widely available and used to provide nutrients to the soil to aid in plant growth. These products will commonly contain a nitrogen, phosphorus, and potassium blend and will also contain trace elements such as magnesium, manganese, molybdenum, sulfur, zinc, boron, calcium, copper, and iron. Fertilizers containing high iron concentrations of >1% may cause iron intoxication or severe irritation of the gastrointestinal system (Chapter 22). Generally, the iron in fertilizers is in a form that is very poorly absorbed from the gastrointestinal tract and is not anticipated to cause systemic iron toxicity. The most common additives in fertilizer are listed clearly on packaging. These are nitrogen, phosphorus, and potassium compounds reported in numbers as N%‐Phos%‐K% with the concentration of each compound indicated. For instance, a fertilizer with 5% nitrogen 5% potassium, and 3% phosphorus would have the label 5‐5‐3. Fertilizer product formulations can be liquids (prediluted or concentrated and requiring dilution prior to use), powders, granules, or solid sticks. Common sources for nitrogen in these products can vary and include potassium nitrate, ammonium, urea, blood meal or more organic forms (blood meal contains 12–13% nitrogen), canola meal, and fish powder. Sources for phosphorus can include inorganic sources such as potassium phosphate or ammonium, or organic forms such as blood meal, which can contain 12% phosphorus or even fish emulsions. Potassium is often added as potassium chloride or potash, which are salts of potassium carbonate, potassium oxide, or potassium chloride (Albretsen 2004).

Other fertilizer products may contain Epsom salts or magnesium sulfate, cocoa bean hulls, pesticides, herbicides, and fungicides. A thorough history of exposure and information on the exact product ingested is needed to further evaluate risk due to the variations available for the listed ingredients involved.

Signs

Ingredients listed in the product along with the amount ingested will determine clinical signs. Fertilizer products that only contain nutrients for plants are normally low toxicity and therefore do not pose a significant risk (Albretsen 2004). Typically, patients that have ingested fertilizer products will experience gastrointestinal irritation. Signs are usually observed within 2 hours of exposure and will begin with hypersalivation, vomiting, lethargy, and diarrhea. Gastrointestinal signs may last as long as 12–24 hours. With very large exposures to fertilizer products, more significant symptoms associated with the CNS have been noted, but these are less common. CNS signs include stiffness, rear limb weakness, and tremors. Hypersensitivity reactions have also been noted and included signs such as developing facial edema or facial swelling paired with hives, pruritis, and rash. These signs are more common in products containing zinc compounds. Cases where dogs have been inclined to ingest large volumes of blood or bone meal could result in more severe gastrointestinal irritation and upset and pancreatitis.

Management of Exposures

Asymptomatic animals with recent exposure to large volumes of fertilizer should be induced to vomit on presentation as a precaution. If the patient has already vomited the product this is not needed. Once successful decontamination has been achieved further medical care may not be needed. Symptomatic and supportive care may be required, and depending on the severity of the clinical signs present, monitoring or hospitalization may be required for adequate treatment. If large volumes of fertilizer have been ingested and cause severe stomach upset the animal may require intravenous fluid therapy for dehydration (Albretsen 2004). Fertilizer products should always be evaluated for additional risks and necessary treatments for herbicide, insecticide, or iron toxicosis. (see Chapters 18, 19, and 22 for further information).

Prognosis

Animals that receive proper supportive care in the event of fertilizer exposure have a good prognosis. Additional ingredients can drastically change this prognosis and can cause much more severe signs.

Minimize Risk of Exposure

When using spray applications of fertilizer products, the treated area should be allowed to fully dry before the animal is allowed access. For granules or powders, it is recommended to fully incorporate the product into the soil to minimize contact with the patient. All fertilizer products should be stored in airtight containers in a secure location. Always follow label directions.

MULCH

Animals are attracted to mulch products due to various different possible ingredients. Common products can be classified as either organic or inorganic. Examples of organic mulch products include grain straw, fresh or old hay, chipped brush, wood shavings, tree leaves, rice and buckwheat hulls, and even recycled newspapers. Organic mulches generally are considered nontoxic unless very large volumes are ingested. Organic mulches pose a risk for an acute gastrointestinal upset (vomiting, inappetence, and diarrhea or constipation), gastrointestinal irritation, and foreign body obstruction. It is always best to verify the actual product involved with the exposure to verify the ingredients involved. For instance, some organic mulches can contain cocoa bean mulch, which is made of cocoa bean shells. Dogs are very attracted to cocoa bean mulch due to its strong, chocolate‐like aroma. Cocoa bean mulch can contain 0.25–2.98% theobromine (860–13,500 mg of theobromine per pound of mulch and 54–850 mg of theobromine per ounce) (Drolet et al. 1984). These concentrations could lead to chocolate toxicosis. If large volumes of cocoa mulch are ingested, acute vomiting and muscle tremors can develop along with other signs associated with methylxanthine toxicosis (see Table 30.6). Inorganic mulches are also widely available and consist of synthetic type materials such as plastics, fabrics (geotextiles), stones, rocks (lava rock), and processed or pulverized rubber. These are typically just foreign body concerns.

Table 30.6. Clinical signs in dogs consuming cocoa bean mulch

Commonly Reported
Polydipsia
Vomiting
Muscle tremors

Less frequently reported
Pancreatitis
Tachycardia
Arrhythmia
Hyperactivity
Diarrhea

Management of Exposures

Treatment is dependent on the amount and type of mulch consumed, the overall timeline of ingestion or possible exposure, and the symptoms present. Generally, with small exposures to mulch close monitoring and symptomatic treatment are advised for 24 hours. When a large volume of mulch is ingested, and the exposure has been identified within 3–4 hours of ingestion, induction of emesis can be used to decontaminate as much as possible. Induction of emesis should only be used if the patient has normal mentation to ensure no further complications (such as aspiration) develop. Emesis can be induced with apomorphine, ropinirole, or unexpired 3% hydrogen peroxide (Table 30.7). One dose of activated charcoal with a cathartic can be used if decontamination is not productive. If CNS signs are severe gastric lavage can be performed with a cuffed endotracheal tube in place. CNS stimulatory effects such as hyperactivity, agitation, or seizures are well controlled with diazepam. Cardiac function should be monitored closely in dogs. Electrocardiogram should be checked for any persistent tachyarrhythmias, or premature ventricular contractions. Treatment with lidocaine and beta‐blockers may be required to stabilize the patient. Intravenous fluid therapy can aid in the urinary excretion of methylxanthines and urinary bladder catheterization should be considered (decrease the resorption of theobromine from retained urine in the bladder). Tachyarrhythmias are more frequently reported than bradycardia. Death is not common with the ingestion of mulches, including cocoa bean mulches (see Chapter 27) (Gwaltney‐Brant 2001).

Table 30.7. Treatment of mulch/cocoa bean mulch (theobromine) ingestion

Treatment
Recommendation
Dose

Emesis
Apomorphine (dog)
0.01–0.04 mg/kg SC, 0.03 mg/kg IV, or 0.04 mg/kg IM, or a 6.25 mg tablet or portion of tablet placed into the conjunctival sac

Ropinirole (dog)
Ocular administration: administer the appropriate drops to deliver a target dose of 3.75 mg/m²; a second dose may be administered if dog does not vomit within 20 min of first dose

3% hydrogen peroxide (dog)
2.2 ml/kg (1 ml/lb) PO up to a maximum of 45 ml for any patient
If no vomiting after 15–20 min can repeat once
Not recommended in felines due to the risk for severe esophagitis or gastritis with erosions

Adsorbent
Cathartic
Activated charcoal
Sorbitol
1–2 g/kg body weight PO
1–2 ml/kg PO (70%)
If activated charcoal does not contain a preexisting cathartic

Tremors
Diazepam
0.5–2 mg/kg IV

Methocarbamol
50–220 mg/kg IV slowly

Seizures
Diazepam
0.5–2 mg/kg IV

Tachyarrhythmia
Phenobarbital
2–6 mg/kg IV slowly

Propranolol
0.02–0.06 mg/kg IV slowly

Metoprolol
0.04–0.06 mg/kg IV slowly

Bradycardia
Lidocaine
1–2 mg/kg IV slowly, and then CRI 30–50 mcg/kg/min

Atropine
0.01−0.02 mg/kg IV

Atenolol
Dogs: 0.25–1.25 mg/kg PO q 12–24 h

Tachycardia with hypertension
Lidocaine
Dogs: 1–2 mg/kg IV, followed by 0.1% solution administered
at 30–50 mcg/kg/min (can be used for ventricular tachyarrhythmias in dogs not responding to beta‐blockers)
Cats: Use with caution due to concerns for lidocaine toxicosis. Initially IV bolus of 0.25–0.5 mg/kg given very slowly; can repeat at 0.15–0.25 mg/kg in 5–20 min if needed. If the original bolus is effective can start 10–20 mcg/kg/min IV CRI (0.6–1.2 mg/kg/h)

CRI, constant rate infusion; IM, intramuscular; IV, intravenous; PO, per os (orally); q, every; SC, subcutaneous.

Minimize Risk of Exposure

The best way to minimize the risk of potential exposures is by using a safer alternative mulch product. Cedar mulch and pine needle straw are very safe alternatives. Pine bark and cypress mulch can be used if larger plants are in the mulching area. Mulch types to avoid in pet households include cocoa mulch, eucalyptus mulch, dyed/chemically treated mulch, and mulch made from salvaged wood.

COMPOST PILES

Compost piles are used in households to reduce food waste through controlled decomposition. Compost piles can contain a variety of toxicants, including leftover or spoiled food, mold, toxic fruits, plant clippings, leaves, and compostable paper products. Most homes will avoid adding dairy, meat, bones, grease, and fat to compost but not always. It is very important to review the list of all possible items involved in compost exposure cases (Davis and Stern 2018). Many compost exposures involve dogs due to their natural scavenging behavior. When composting a succession of different bacterial populations develops. Species include Bacillus, Staphylococcus, and Streptococcus. These bacteria can cause gastroenteritis. Populations of yeast and mold may also be present and aid in the decomposition process. Various mold species, such as Penicillium, Aspergillus, and Claviceps, are likely to grow on dairy, grain, bread, pasta, and walnut products and may produce tremorgenic mycotoxins (Schell 2000). Tremorgenic mycotoxins can cause tremors and seizures (see also Chapter 27). Some chemicals are also added to help drive the compost to decompose, such as nitrogen (inorganic ammonium nitrate or organic manure or blood meal) and lime (alkalinizing agent for the compost pile).

Clinical Effects and Toxicity

Compost piles generally are low toxicity but this does directly depend on the probable items ingested. For instance, grapes and raisins or tremorgenic mycotoxins may require emergency treatment for the best prognosis (see Chapter 27). If tremorgenic mycotoxins are ingested in the compost material, they will rapidly be absorbed from the gastrointestinal tract. Signs can occur within 30 minutes to several hours after ingestion and include irritability or agitation, tremors (starting in the head and neck), weakness, panting, seizures, nystagmus, opisthotonos, recumbency, and death. Common tremorgenic mycotoxins are roquefortine and penitrem A (Schell 2000).

Common clinical signs include vomiting, diarrhea, and gastroenteritis. Some compost material that contains fruits, grains, and sources of sugar will ferment and create ethanol as a byproduct. If fermented fruit or ethanol has been ingested symptoms can include ataxia, depression, hypothermia, recumbency, and acidosis (Wismer 2017). Dehydration and fever may occur as well. Signs develop quickly after ingestion, around 1–4 hours depending on the volume ingested and the exact items ingested (see Table 30.8).

In more severe cases, such as hemorrhagic gastroenteritis, endotoxic shock, and CNS depression, more intensive treatment and intravenous fluids are required for stabilization (Unterer and Busch 2021). Some bacterial species present in compost account for these more severe signs, including Salmonella, Escherichia coli, and Clostridium (including Clostridium botulinum). Ingestion of botulinum toxin from the C. botulinum bacterium could result in drooling, weakness in the rear limbs and tail, poor ocular/ laryngeal/limb reflexes, respiratory paralysis, and death. Fortunately, dogs and cats are reported as less sensitive to botulinum toxin than cattle, horses, and birds.

Table 30.8. Clinical signs of compost ingestion

Bacterial | Vomiting
Diarrhea
Dehydration
Fever
Depression
Shock
Botulism | Drooling
Limb and tail weakness
Poor reflexes of eyes and throat
Respiratory paralysis
Death
Tremorgenic mycotoxins (roquefortine and penitrem A) | Irritability
Salivation
Vomiting
Ataxia
Tachycardia
Muscle tremors
Panting
Hyperthermia
Nystagmus
Seizures
Death
Ataxia
Ethanol (fermented fruit) | Depression
Hypothermia
Acidosis
Vomiting
Recumbency
Aspiration
Ropinirole (dog)Grapes/raisins (Vitis spp.) | Vomiting
Anorexia
Polydipsia, polyuria
Lethargy
Acute renal injury

Management of Cases

If exposure has occurred recently, emesis induction can be considered. Small ingestions of compost material may only require monitoring and symptomatic treatment for 12–24 hours. However, if the patient is symptomatic and not neurologically normal, inducing vomiting is not appropriate. If any clinical signs such as tremors or seizures are present these should be managed first. Methocarbamol, a centrally acting muscle relaxant, can be very useful in controlling tremors (see Table 30.9) and pentobarbital is also effective in the management of tremor and seizure activity in cases of tremorgenic mycotoxin exposure (Schell 2000). Diazepam may not be effective alone for the treatment of tremors and seizure activity resulting from compost exposure. When dealing with especially large exposures to compost, gastric lavage can be considered if vomiting has not occurred and CNS signs are preventing proper emesis induction.

Table 30.9. Treatment of compost ingestion (with the potential of tremorgenic mycotoxins and botulism exposure)

Treatment
Recommendation
Dose

Emesis
Apomorphine (dog)
0.01 − 0.04 mg/kg SC, 0.03 mg/kg IV, or 0.04 mg/kg IM, or a 6.25 mg tablet or portion of tablet placed into the conjunctival sac

Ropinirole (dog)
Ocular administration: administer the appropriate drops to deliver a target dose of 3.75 mg/m²; a second dose may be administered if dog does not vomit within 20 min of first dose

3% hydrogen peroxide (dog)
2.2 ml/kg (1 ml/lb) PO up to a maximum of 45 ml for any patient
If no vomiting after 15–20 min can repeat once
Not recommended in felines due to the risk for severe esophagitis or gastritis with erosions

Gastric lavage
Water at body temperature
10 ml/kg body weight by gravity installation; continue until lavage fluid runs clear

Adsorbent
Activated charcoal
1–2 g/kg body weight PO

Cathartic
Sorbitol
1–2 ml/kg PO (70%)
If activated charcoal does not contain a preexisting cathartic

Dehydration
Crystalloid fluids
As needed

Acid base imbalance
Sodium bicarbonate
As needed

Seizures
Diazepam
0.5–5 mg/kg IV (can be repeated at 10‐min intervals up to three times)

Seizures
Muscle tremors
Phenobarbital
6 mg/kg IV to effect

Pentobarbital
3–15 mg/kg IV slowly to effect

Methocarbamol
55–220 mg/kg IV to effect at a rate of no more than 2 ml/min

Botulism
Antitoxin
5 ml IV

Botulism
Artificial respiration
As required

IM, intramuscular; IV, intravenous; PO, per os (orally); SC, subcutaneous.

Gastric lavage should be performed under general anesthesia and the animal intubated with a cuffed endotracheal tube to protect the respiratory tract. During this process monitoring the patient's temperature is very important and body temperature fluids (10 ml/kg) should be used to remove the toxicant. Only gravity should be utilized to instill and drain the water used to lavage. Ideally one should repeat this process until the lavage fluid is clear. Large tubes should be used to obtain the best recovery of the compost material and prevent backflow blockages.

After emesis or lavage has been completed activated charcoal with the addition of a cathartic may be needed to aid in the excretion of mycotoxins. CBC, serum chemistry panel, urinalysis, and arterial blood gas measurements are useful in monitoring these cases.

Cases with excess vomiting or that receive activated charcoal should be given intravenous fluids during treatment and electrolytes should be monitored closely. If the patient develops an acid–base imbalance during treatment sodium bicarbonate should be given. Vital signs, including body temperature, should be monitored for hyperthermia in the event of tremor or seizure activity (Davis and Stern 2018).

Suspected ingestion of botulism and botulinum toxin should be treated in the same way. Application of either gastric lavage or induction of emesis should be achieved as soon as possible after ingestion. Activated charcoal therapy and antitoxin treatment should be started early in the treatment process, especially if botulinum toxin is suspected due to clinical signs. Supportive care will be required and possibly artificial respiration.

Prognosis

Prognosis is good in cases where prompt gastric decontamination has occurred and symptomatic treatment is applied over the initial 24–48 hours after the exposure. If a patient ingests a large volume of material containing tremorgenic mycotoxins and no gastrointestinal decontamination has occurred, the prognosis is poor. If the patient is symptomatic for botulinum toxin exposure prognosis is guarded to poor.

CHARCOAL BRIQUETTES

Common charcoal briquette products are considered a low‐toxicity exposure. There is potential for foreign body obstruction, gastrointestinal irritation, and respiratory irritation. The briquette itself is made from charred wood or animal bone, or even proprietary blends. These compounds do not pass well through the gastrointestinal tract and do not break down well. The dust found on the briquettes can cause respiratory and ocular irritation as well as gastrointestinal irritation after being ingested. Some products also contain accelerants and pose a risk for hydrocarbon toxicity. Self‐starting or quick‐lighting briquettes contain 10–20% hydrocarbon solvent, char dust, and limestone (<15%). Hydrocarbon‐containing briquettes can not only be irritating to the eyes, respiratory system, and gastrointestinal tract but can cause vomiting, diarrhea, anorexia, depression ataxia, and even CNS signs such as seizures in large exposures. Signs are expected to be self‐limiting in smaller exposures (see the previous section on petroleum products for therapy recommendations).

FIRE LOGS

Fire logs are compressed proprietary blends that are flammable and designed to replace natural wood. Logs are composed of combustible materials like sawdust, wood chips, peanut shells, and petroleum wax to bind products (up to 65%), coffee grounds can be used but in very low concentrations, and sometimes combinations of metals to produce specific‐colored flames. Color‐changing fire logs can contain a variety of chemicals such as ammonium chloride, calcium, sodium chloride, potassium nitrate, copper sulfate, boric acid, lead, arsenic, antimony, and selenium. Oxidizing agents are also used to improve burning (perborates, persulfates). Silica, clay, and coal dust along with other fire retardants are also used to extend the burning time. These exposures are considered nontoxic but do pose a risk for foreign body obstruction and gastrointestinal irritation (see Table 30.10) (Farrell 2024).

Most exposures occur in dogs attracted to the waxes that bind the log into its compressed shape. Common clinical signs are gastroenteritis, vomiting, diarrhea, and constipation. When larger exposures have occurred depression, hypotension, and rarely renal failure from the added metal salts have been observed. Early treatment should focus on decontamination by induction of emesis (ideally within 2–3 hours), but this is only if the animal is without altered mentation. Depending on the amounts ingested and clinical signs present antiemetics, intravenous fluid therapy and monitoring of renal function may be needed.

MATCHES

The ignition end of a match generally consists of potassium chlorate and is an oxidizing agent. Matches are considered low toxicity, but with large amounts of potassium chlorate, and the oxidizing effect can cause methemoglobinemia (cats are more sensitive). If a full box or book of matches is ingested (or >1 match per 10 lb) serious signs can develop within several hours of ingestion. Signs include vomiting, abdominal pain, CNS depression, hypotension, hemolysis, cyanosis, and possibly methemoglobinemia. If exposure has happened within the last 3–4 hours and the patient is not having CNS symptoms, oral decontamination with emesis is recommended. Supportive care may also be required, including intravenous fluid therapy, gastro‐protectant medications, and antiemetic/antidiarrheal medications. Treatment for methemoglobinemia consists of oxygen therapy, cardiovascular support/monitoring, and methylene blue (Gahagan and Wismer 2018). Ascorbic acid treatment in feline patients may be too slow to be used as a treatment therapy with these exposures.

Table 30.10. Products involving ignition

Product | Chemical | Clinical Signs
Charcoal briquettes | Char dust (wood, coal, starch, lime) | Vomiting
10–20% hydrocarbon solvent | Diarrhea
Mucous membrane irritation
Lethargy
Fire logs | Cellulose/lignin: sawdust, wood flour, coal dust, ground nut shells, silica | Vomiting (severe)
Diarrhea
Petroleum‐based wax | Constipation
Vegetable/plant wax | Depression
Potassium nitrate | Renal failure (rare)
Sodium chloride
Heavy metals
Match head | Potassium chlorate | Methemoglobinemia
Striking surface | Red phosphorus | Cyanosis
Powdered glass | Vomiting
Hypotension
Depression
Hemolysis
Sparklers | Potassium nitrate | Gastroenteritis
Fireworks | Oxidizing agents (potassium nitrate, chlorates) | Vomiting (severe)
Abdominal pain
Potassium perchlorates (produces white flash and noise) | Bloody feces
Shallow breathing
Methemoglobinemia
Colors produced by heavy metal salts (mercury, antimony, copper, strontium, lithium, barium, phosphorus) | Additional signs could be associated with heavy metals
Black powder:
75% potassium nitrate | Vomiting
15% charcoal | Diarrhea
10% sulfur | Methemoglobinemia
Watusi or dancing firecracker | Yellow phosphorus | Acute liver toxicity and organ failure
Signaling or illuminating flares | Metal nitrates or sodium nitrate | Gastroenteritis
Hydrocarbons | Methemoglobinemia

FIREWORKS AND FLARES

Fireworks commonly contain oxidizing agents, including potassium nitrate, potassium chlorate as well as potassium perchlorates, metal salts like silver fulminate, and gunpowder (potassium nitrate and saltpeter, charcoal, and sulfur) (see Table 30.10). Sparklers consist of potassium nitrate adhered to a thin metal wand. Flares are made from sulfur, hydrocarbons, and metal nitrates or sodium nitrate. The toxicity level of these exposures is low. The main risk with these exposures is gastrointestinal irritation resulting in vomiting, abdominal pain, hypersalivation, and diarrhea. Sometimes symptoms are more severe than anticipated. Occasionally bloody feces and gastrointestinal ulcerations can occur. Exposures causing hemolysis and seizures are very rare. Treatment consists of symptomatic and supportive therapy. In the case of an especially large exposure or feline exposure methemoglobinemia may develop and if signs occur treatment with oxygen and methylene blue should be instigated (Gahagan and Wismer 2018).

Fireworks made with yellow phosphorus are considered a severe exposure. Yellow phosphorus is found commonly in “Dancing firecrackers” or “Watusi” fireworks that are made in Asia, and is also found in South American fireworks known as “diabillos.” These products are extremely toxic. Yellow phosphorus is readily absorbed from the gastrointestinal tract and is a general protoplasmic toxin that affects multiple organ systems. The use of yellow phosphorus is restricted in the United States but some of these products are imported. Clinical signs include acute hepatic injury and/or hepatic failure, upper gastrointestinal hemorrhage, disseminated intravascular coagulation, bone marrow suppression, cerebral edema, and death. Treatment consists of early and aggressive decontamination of the gastrointestinal tract, monitoring of hepatic function, acid–base balance monitoring, and intravenous fluid therapy with glucose and possibly fresh frozen plasma. N‐acetylcysteine administration did not affect treatment outcomes.

EXPLOSIVES

Plastic explosives are explosive compounds that will generally be the consistency of putty and that are capable of being shaped by hand. Examples include C‐4 or Royal Defense Explosive (RDX), trimethylene, cyclotrimethylenenitramine, hexahydro‐1,3,5‐trinitro‐S‐triazine, polymer‐bonded explosive (PBX), trimethylenetrinitramine, trinirocyclotrimethylene triamine, and 1,3,5‐trinitro‐1,3,5‐triazacyclohexane. These explosive products are designed to withstand friction and high temperatures without exploding. This allows otherwise volatile agents to be transported easily without excess precautions. Exposures or ingestions of these products are generally accidental exposures that occur in canines during detection training or working in the field for the military or police handlers (Bruchim et al. 2005).

During the Vietnam war documented accidental ingestions in soldiers were recorded after C‐4 was used to cook food. Military personnel developed seizures within 8–12 hours of consumption. Some cases developed delayed seizure activity at 24–36 hours postexposure. Another common chemical in plastic explosives is cyclonite or cyclotrimethylenetrinitramine. Crystalline forms of these chemicals are colorless and insoluble in water. Human workers exposed have been noted to develop tonic–clonic spasms after inhalation of cyclonite dust on a daily basis. Symptoms would last 5–10 minutes and would be intermittent, not continuous. These symptoms would persist after the worker was removed from the toxic environment.

Animals have been noted to develop the same symptoms after exposure. For example, a young neutered male Labrador working dog of approximately 35 kg was exposed during an explosive detection exercise and presented 20 minutes after ingestion, despite the administration of activated charcoal quickly after ingestion and the small amount ingested (estimated as the size of a grain of rice) the patient did develop tremors and subsequently tonic–clonic seizure activity (Bruchim et al. 2005).

Kinetics

Plastic explosives are very slowly absorbed from the gastrointestinal tract and from the alveoli of the lungs. Peak plasma levels will vary based on species; rats will plateau after several hours. Experimental studies have shown RDX in rats was rapidly cleared from the plasma and following this was deposited into the tissues. C‐4 is also distributed widely into the tissues and is deposited in the highest concentrations in the kidneys followed by the brain, heart, and lungs. Cyclonite is a corrosive irritant to the eyes, skin, mucous membranes, and respiratory tract. It can also act as a CNS depressant and toxicant, and studies have produced evidence that some limbic structures may participate in RDX‐induced seizure susceptibility. Cyclonite does not have nitrate‐like toxicity and therefore methemoglobinemia is not anticipated with this particular toxicant (Gahagan and Wismer 2018).

Toxicity

There are considerable variabilities of the LD₅₀ (lethal dose 50) depending on the chemical formulation or granulation of the agent ingested. For instance, the LD₅₀ of coarse granular cyclonite is up to three times higher than that of the fine powder formulation. The fatal dose ranges of plastic explosive number 4 (PE‐4) in canines are 14–34 mg/kg (postmortem lesions listed in Table 30.11). It should also be noted that exposures to cyclonite and other explosive products can have a lethal dose as low as 6 mg/kg. The lethal dose range of RDX in felines is 100 mg/kg. It has been noted that dogs can be far more sensitive than cats with explosive exposures (Gahagan and Wismer 2018).

Table 30.11. Explosives and clinical signs

Name | Chemical | Clinical Signs
RDX (Royal defense explosive) | Cyclonite (cyclotrimethylenetrinitramine) | Confusion
Hyperesthesia
Hyperventilation
C‐4 | 91% cyclonite | Lethargy
5.4% plasticizer | Ataxia
2.1% polyisobutylene | Tremors/facial twitches
1.6% motor oil | Seizures
PE‐4 (plastic explosive number 4) | 88% RDX (cyclonite) | Transient blindness
12% plasticizer paraffin | Hyperthermia
Hematuria
Oliguria
Proteinuria
Salivation
Vomiting
Pale or congested mucous membranes
Petechial rash
Hepatic injury
Anemia
Urinary incontinence
Renal damage
Death
PETN (penthrite) | Pentaerythrityl tetranitrate | Vomiting
Ataxia
Collapse
Bradycardia
Dysrhythmia
Depression
Disorientation
TNT | 2,4,6‐trinitrotoluene | Methemoglobinemia
Anemia
Hepatic injury
Splenomegaly
Anorexia
Skin irritation (skin yellow‐orange color)
Mucous membrane irritation
Death
Dynamite | Nitroglycerin (glyceryl trinitrate) | Methemoglobinemia
Nitrate salts | Dyspnea
Diatomaceous earth or sawdust | Hypotension

Clinical Effect

Signs can develop within minutes to several hours after exposure. It is advised that due to this extended timeframe, animals that are stable and are considered clinically normal should continue to be monitored for a minimum of 4–6 hours. The clinical effects can be very severe and can quickly become serious, and early recognition of exposure and rapid treatment improves the outcome of treatment. Signs include lethargy, ataxia, disorientation or confusion, hyperesthesia, hypersalivation, gastrointestinal upset (vomiting and diarrhea), tremors, and seizure activity that can become prolonged (Gahagan and Wismer 2018).

Management of Exposures

Induction of emesis is controversial in explosive ingestion cases. Emesis is contraindicated if the animal is showing any neurological signs due to the risk of aspiration pneumonia. A large percentage of ingestions will vomit without assistance due to the irritating nature of the toxicant. Cyclonite has been shown to have a long retention time in the stomach and gastric lavage is strongly recommended in these cases. When performing gastric lavage, it is recommended to be performed within several hours of exposure and a cuffed endotracheal tube should be in place to prevent further complications (see Table 30.12). Activated charcoal should be administered following gastric lavage by orogastric tube or if the patient is normal neurologically, oral administration. C‐4 and other explosives can have caustic action throughout the gastrointestinal tract and gastrointestinal protectants are recommended during and after hospitalization. Atropine can be utilized in the event of copious hypersalivation (Gahagan and Wismer 2018).

Seizure activity in explosive exposures can be prolonged and have durations of several minutes separated by inactive or post‐ictal times of 20‐30 minutes characterized by a period of calm progressing into hyperesthesia and tremors prior to seizure activity reoccurring (Bruchim et al. 2005). Seizures are well controlled using sedatives such as diazepam and phenobarbital for up to 6–8 hours. Very severe prolonged convulsions may require deep anesthesia to control (such as propofol constant rate infusion administration), which may also be required for up to 6–8 hours. Once seizure activity has diminished or stabilized, patients can be well controlled by oral dosing of phenobarbital. Oral maintenance of phenobarbital may be required for days after exposure then properly reduced over time to control seizures and stimulate the possible production of cytochrome P450 enzyme activity and cyclonite metabolism. During the control of neurological signs in the clinic, if the animal experiences respiratory arrest mechanical ventilation may be required until normal respiratory function resumes. When removing anesthesia animals should be allowed to slowly return to consciousness and if seizure activity re‐occurs the anesthesia should then be resumed.

Table 30.12. Treatment for explosive ingestion

Treatment | Recommendation | Dose
Emesis | Apomorphine (dog) | 0.01–0.04 mg/kg IV, IM, or conjunctival sac in the dog
Ropinirole (dog) | Ocular administration: administer the appropriate drops to deliver a target dose of 3.75 mg/m²; a second dose may be administered if dog does not vomit within 20 min of first dose
Gastric lavage | Water at body temperature | 10 mg/kg body weight
Adsorbent | Activated charcoal | 1 to 2 g/kg body weight PO
Seizures | Phenobarbital | 4 mg/kg, IV q 4 h, 4 times for a total of 16 mg/kg
3 mg/kg PO, q 12 h as maintenance dose, and then tapering dose
Diazepam | 0.28 mg/kg rectally
0.34 mg/kg/h, IV
Propofol | 0.4 mg/kg IV
Gastrointestinal | Famotidine | 0.57 mg/kg PO q 12 h
protectant | Sucralfate | 28.5 mg/kg PO q 8 h
Omeprazole | 1.15 mg/kg PO q 12 h
Respiratory arrest | Oxygen | As needed
Positive pressure ventilation
Fluids | Isotonic crystalloid | 68.5 ml/kg/day IV reduced to 48 ml/kg/day IV
Hypoproteinemia | Fresh frozen plasma | 10 ml/kg IV at a rate of 5 ml/kg/h
Diuretic | Furosemide | 1 mg/kg
Liver insult | Vitamin K | 2 mg/kg PO q 24 h
Salivation | Atropine | 30–50 mcg/kg SQ
Methemoglobinemia | Oxygen therapy
Methylene blue | 1.5 mg/kg IV as a 10% solution in saline (monitor for Heinz bodies)

IM, intramuscular; IV, intravenous; PO, per os (orally); q, every; SQ, subcutaneous.

In one canine case, transient blindness and lack of menace response were noted for 12 hours after intensive hospitalization. Thiamine (8 mg/kg IM every 24 h) was administered to protect the CNS from insult and long‐term damage (Gahagan and Wismer 2018).

Fluid therapy consisting of lactated ringers or dextrose/saline infusions should be used to maintain hydration during treatment and will help manage acidotic patients. In a particular case, a canine patient developed facial and appendicular edema within 8 hours after admittance to the hospital. This patient was treated for hypoproteinemia with intravenous fresh frozen plasma followed by hydroxyethyl starch (1 ml/kg/h). To prevent pulmonary edema if the patient is sedated or anesthetized, it is recommended to turn or rotate the patient every 3–4 hours.

Laboratory results for the patient should be monitored for anemia via CBC and hepatic or renal damage via elevated enzyme values by serum chemistry (including blood urea nitrogen, bilirubin, and liver enzymes such as alanine aminotransferase (ALT) and alkaline phosphatase (ALP). It is recommended that bloodwork rechecks are performed days after exposure to ensure proper recovery. Reports of exposures have included liver damage indicated by multiple biochemistry panels up to 3 days after exposure to RDX. In the event of hepatic damage, the animal should be supplemented with vitamin K₁ and multivitamins. Urinalysis should also be performed to monitor urine protein and urine production. Following rehydration with intravenous fluids, the use of a diuretic is recommended to accelerate the elimination of metabolites in the urine.

Diagnostics and Prognosis

Some laboratories will be able to confirm the presence of explosives in gastric contents, but they are not commonly utilized. Despite such severe clinical signs evolving very quickly after ingestion, with prompt treatment death is not common. Recovery can take up to 48 hours (Gahagan and Wismer 2018). Prognosis is generally good in cases where exposure is detected rapidly, and treatment is instigated in a timely manner. Although renal toxicity has been noted, it is rare. See Table 30.13 for common lesions found on necropsy. In the case of the 2‐year‐old labrador mentioned earlier, after responding well to treatment for seizures he later developed polyuria, polydipsia, and renal insufficiency after exposure to C‐4 (cyclonite) and experienced a 70% reduction in glomerular filtration rate (Bruchim et al. 2005).

PENTAERYTHRITYL TETRANITRATE (PETN or PENTRHITE)

Pentaerythrityl tetranitrate (PETN) is a nitroglycerin compound that functions as a highly volatile explosive. PETN is more powerful and more sensitive to shock or friction than TNT or plastic explosives and structurally resembles nitroglycerin.

Clinical Signs

Clinical signs that commonly develop after ingestion of PETN are gastrointestinal upset, gastrointestinal irritation, and CNS depression. These symptoms are characterized by repetitive or frequent vomiting, nausea, decreased respiratory rate, depression, disorientation, miosis, weakness, ataxia, and dyspnea (see Table 30.12). Depending on the timeline of ingestion and clinical signs present, gastric lavage may be effective. In the majority of cases the patient may have vomited many times prior to presentation at the clinic. Signs that may develop after first‐pass metabolism include bradycardia, cyanosis, and respiratory failure. One canine patient was observed showing conscious proprioceptive deficits in the hindlimbs (Gahagan and Wismer 2018; Potocnjak et al. 2008).

Table 30.13. Postmortem lesions reported following ingestion of plastic explosives

Generalized congestion

Pulmonary edema

Petechial hemorrhages in the pancreas

Hepatic congestion and enlargement

Renal congestion and hydropic degeneration

Laboratory Analysis and Diagnostics

Patients should be monitored via serum chemistry and CBC for changes associated with hepatic damage, including elevated bilirubin, aspartate aminotransferase, ALT, ALP, and gamma‐glutamyl transferase. Heart rate and rhythm should be monitored using an electrocardiogram to identify and treat bradycardia and dysrhythmia as quickly as possible. The most common dysrhythmia includes sinus arrhythmia and periods of sinus arrest.

Veterinary diagnostic laboratories do not routinely analyze for plastic explosives. Presumptive diagnosis is based on history and compatible clinical signs. In one case report the analysis of canine serum using iron mobility spectrometry detected fragments consistent with PETN.

Management of Exposures

Treatment of exposures should start with decontamination, including, if appropriate (neurologically normal patient), emesis induction or alternatively gastric lavage. Intravenous fluid therapy is helpful in the stabilization of cases and the administration of drug therapy. Symptomatic treatment should be provided and includes antiemetics such as metoclopramide (0.5 mg/kg IV, IM, PO q 6–8 h) and gastroprotectants such as omeprazole (1 mg/kg PO q 12 h for 14 days) or ranitidine (2 mg/kg q 12 h). Vitamin supplementation, particularly thiamine to protect the CNS, as well as B₁, B₆, and B₁₂, are recommended. In one case, a canine patient was admitted and hospitalized for 7 days showing a gradual improvement of all signs present. Symptoms that resolved included ataxia, abnormal heart rate, and nausea/vomiting. The bradycardia associated with these exposures is thought to originate from the nitroglycerin increasing vagal tone (Gahagan and Wismer 2018).

DYNAMITE

Dynamite is composed of nitroglycerin absorbed into a porous material that often contains ammonium nitrate or cellulose nitrate, and nitrate salts. The clinical presentation and recommended treatment protocol of dynamite will be very similar to PETN. Signs include ataxia, vomiting, nausea, depression, dysrhythmia, and bradycardia. The nitrate salts in dynamite pose a risk for methemoglobinemia. Treatment for methemoglobinemia consists of oxygen supplementation or therapy and methylene blue (see Table 30.12).

2,4,6‐TRINITROTOLUENE

2,4,6‐Trinitrotoluene (TNT) is classified as a secondary explosive due to the requirement of an initiating factor (explosive or flame) required for ignition. TNT is a crystalline product with good chemical and thermal stability. It is also insoluble in water and not affected by acids. TNT is commonly mixed with other explosives such as RDX or HMX (high melting explosive) to make it easier to place and ignite. A common sign in long‐term human case exposures is yellowing of the skin or jaundice due to TNT causing hepatic damage. Ingestions by animals can result in methemoglobinemia, irritation of the mucous membranes of the eyes, respiratory tract as well as digestive tract, resulting in sneezing, coughing, cyanosis, muscular pain, erythema, pruritis, and dysrhythmia. Chronic exposures have resulted in anemia, peripheral neuritis, splenic injury, and hepatic and renal damage (Gahagan and Wismer 2018).

Management

Treatment following ingestion should start with decontamination by induction of emesis, if the patient is neurologically normal, or gastric lavage. This should be followed by activated charcoal administration with the use of a cathartic (see Table 30.12). CBC and serum chemistries should be monitored for any hepatic or renal damage. In the event of methemoglobinemia, treatment with oxygen therapy and methylene blue should be used. As in other cases supportive therapy should also be provided.

PAINT

Paint is a common exposure in dogs and cats. Both species may ingest wet or dry paint or walk through wet paint. There are a variety of different kinds of paints. Paints labeled with the AP (approved product) seal are considered to be non‐toxic. See Table 30.14 for types and risks. Houses in the United States painted before 1974 may contain lead paint (see Chapter 22).

Some paint containers for artwork or fabrics with be labeled with an ACMI seal indicating if it is considered non‐toxic. Care should be taken to evaluate the safety data information of paints whenever available to identify if any exposure to additional chemicals may have occurred such as ethylene glycol in low concentrations. Treatment is symptomatic and supportive. Severe signs can be seen when owners try to remove paint with hydrocarbons (turpentine, paint thinner). These can cause pain, skin irritation, and erythema. See petroleum‐based toxicants earlier in this chapter for treatment.

Table 30.14. Types of paints and potential risks

Type of Paint | Risksa
Acrylic | Water soluble; nontoxic
Artist oil paint | Oil based; GI upset, diarrhea; some contain toxic heavy metals (cadmium, lead)
Bituminous paint | Contains tar or asphalt; GI upset; see hydrocarbons
Cellulose paint | Oil based; high solvent content; see hydrocarbons
Chalk | Water soluble; GI upset
Enamel | Oil based; GI upset, diarrhea
Encaustic | Wax based; GI upset
Gouache | Water soluble; nontoxic
Latex | Water soluble; nontoxic; most common type
Oil‐based | Oil based; GI upset, diarrhea
Spray paint | Oil based; GI upset, diarrhea
Tempura | Water soluble; nontoxic
Watercolor | Water soluble; nontoxic

GI, gastrointestinal.

a Remember even nontoxic paint can cause mild stomach upset.

ACKNOWLEDGEMENTS

The author would like to acknowledge Michelle Mostrom for her work on a previous version of this chapter.

REFERENCES

Albretsen, Jay C. 2004. Fertilizers. In Clinical Veterinary Toxicology, edited by KH Plumlee, pp. 154–155. St. Louis: Mosby.

Bruchim, Yaron, Saragusty, Joseph, Weisman, A, and Sternheim, D. 2005. Cyclonite (RDX) intoxication in a police working dog. Veterinary Record 157(12):354–356.

Coppock, Robert W and Christian, Ralph G. 2018. Petroleum. In Veterinary Toxicology: Basic and Clinical Principles, 3rd ed., edited by Ramesh C Gupta, pp. 659–673. London: Elsevier.

Davis, Frank and Stern, Laura. 2018. Digging into compost intoxication. Today's Veterinary Nurse 1(4):14–17.

Drolet, Richard, Arendt, TD, and Stowe, CM. 1984. Cacao bean shell poisoning in a dog. Journal of the American Veterinary Medical Association 185(8):902.

Farrell, Kate S. 2024. Foreign objects. In Blackwell's Five‐Minute Veterinary Consult Clinical Companion Small Animal Toxicology, 3rd ed., edited by Lynn R Hovda, Ahna G Brutlag, Robert H Poppenga, and Steven E Epstein, pp. 503–507. Hoboken, NJ: Wiley Blackwell.

Gahagan, Patti and Wismer, Tina. 2018. Toxicology of explosives and fireworks in small animals. Veterinary Clinics of North America: Small Animal Practice 48(6):1039–1051.

Gwaltney‐Brant, Sharon. 2001. Chocolate intoxication. Veterinary Medicine 96(2):108–111.

Himmel, Herbert M. 2008. Mechanisms involved in cardiac sensitization by volatile anesthetics: general applicability to halogenated hydrocarbons? Critical Reviews in Toxicology 38(9):773–803.

Potocnjak, Dalibor, Baric‐Rafaj, Renata, Lemo, Niksa, Matijatko, Vesna, Kis, Ivana, Mrljak, Vladimir, and Harapin, Ivica. 2008. Poisoning of a dog with the explosive pentaerythrityl tetranitrate. Journal of Small Animal Practice 49(6):314–318.

Raisbeck, Merl F. 2013. Petroleum hydrocarbons. In Small Animal Toxicology, 3rd ed., edited by Michael E Peterson and Patricia A Talcott, pp. 755–761. St. Louis: Saunders.

Schell, Mary M. 2000. Tremorgenic mycotoxin intoxication. Veterinary Medicine 95(4):283–286.

Unterer, Stefan and Busch, Kathrin. 2021. Acute hemorrhagic diarrhea syndrome in dogs. Veterinary Clinics of North America: Small Animal Practice 51(1):79–92.

Wismer, Tina. 2004. Turpentine. In Clinical Veterinary Toxicology, edited by KH Plumlee, pp. 170–171. St. Louis: Mosby.

Wismer, Tina A. 2017. Ethanol toxicosis: A review. Today's Veterinary Practice Mar/Apr:74‐76.

Appendices

Appendix 1
Drugs Used in Toxicology

Catherine Dzienisiewski

Drug
Indication
Species
Dosage

Acepromazine
Sedation for agitation caused by psychotropic drugs (e.g., amphetamines, phenylpropanolamine, pseudoephedrine)
Dogs and cats
0.05–0.2 mg/kg IM or IV (start with lower dose and titrate up to effect). Doses as high as 1 mg/kg IM or IV have been used for treatment (Stowe et al. 1976)

N‐acetylcysteine (Mucomyst®, Acetadote®, Cetylev®, or ACC®)
Management of acetaminophen or phenazopyridine toxicosis; adjunct treatment for many liver toxins (e.g., mushrooms, xylitol)
Dogs and cats
Mucomyst®: Dilute to 5% solution; 140 mg/kg PO or IV loading dose, and then 70 mg/kg q 4–6 h for 7 treatments; if hepatic enzymes elevated, continue for additional 10 treatments. For patients that are showing signs of methemoglobinemia, 280 mg/kg IV or PO loading dose can be administered

Acetadote®: 150 mg/kg in 3 ml/kg diluent IV over 1 h; and then 50 mg/kg IV in 7 ml/kg diluent over 4 h, and then 100 mg/kg in 14 ml/kg diluent over 16 h (Cumberland Pharmaceuticals 2019)

Activated charcoal
Adsorption of toxicants (poor adsorption of many metals and minerals, small molecules [e.g., alcohols]). Generally administered with a cathartic—when administering multiple doses, cathartic is given every third dose
Dogs and cats
1 g/kg PO with or without sorbitol Additional doses may be administered for certain agents (bromethalin, modified‐release products, etc.) depending on dose

Albuterol
Bronchodilator for acute bronchoconstriction secondary to inhaled irritant
Dogs
0.02–0.05 mg/kg (20–50 mcg/kg) PO q 8–12 h
Using Aerodawg®, albuterol inhalers can be used as well

Cats
1–2 puffs (90 mcg) every 5–15 min using AeroKat®

Aluminum hydroxide
Antacid. Can be used for Zn phosphide ingestions to neutralize gastric pH to decrease formation of phosphine gas
Dogs and cats
1 ml/lb once prior to emesis

Aminocaproic acid
Hemostatic agent used to inhibit fibrinolysis and stabilize clot formation in hemorrhaging patients (Davis and Bracker 2016)
Dogs
Extra label dose for active hemorrhage: 100 mg/kg PO or 9–111 mg/kg IV

Aminophylline
Bronchodilator for acute bronchospasm
Dogs and cats
3–11 mg/kg IV or IM q 6–12 h (dogs may need higher end of dose range q 6–8 h. In cats, the low end of the dose range is used q 12 h)

Amiodarone
Class III antiarrhythmic (used for refractory ventricular tachycardia, supraventricular tachycardia, or atrial flutter)
Dogs
Use polysorbate 80‐free formulation, administer 2 mg/kg IV over 10 min followed by CRI of 0.8 mg/kg/h IV and then 0.5 mg/kg/h thereafter. A dedicated central venous catheter with an in‐line filter is recommended for IV administration

Antivenin Crotalidae Polyvalent Antiserum, Equine Origin, Antivenin®
Management of crotalid snake envenomation (rattlesnake, copperhead, water moccasin)
Dogs and cats
Administer 1–5 rehydrated vials IV depending on severity of bite; can be administered q 2 h as required depending on severity

Antivenin Crotalidae Polyvalent Antivenom, Equine Origin, Rattler Antivenin®
Management of crotalid snake envenomation (rattlesnake, copperhead, water moccasin)
Dogs and cats
Administer using a filtered IV set. Typically, 1–2 doses of antivenom (50–100 ml) are adequate for any body size. Administer slowly over 10 min and if no anaphylaxis, administer the remaining volume IV over 20–60 min. If adverse events develop, discontinue infusion for 10 min and restart a slower rate. If signs persist, discontinue use of product

Antivenin Polyvalent Crotalidae F(ab')2 (equine origin) Antivenom Injectable Solution Venom Vet®:
Management of crotalid snake envenomation (rattlesnake, copperhead, water moccasin)
Dogs and cats
Dilute 1 vial in 100–150 ml sterile saline and infuse over 1 h; monitor for anaphylaxis; repeat as necessary (VenomVet 2023)

Antivenin Polyvalent Crotalidae Immune F(ab) antivenom (ovine origin), human product
Extra label management of crotalid snake envenomation (rattlesnake, copperhead, water moccasin)
Dogs and cats
Dilute 1 vial in 250 ml of sterile saline and infuse over 1 h; monitor for anaphylaxis; repeat as necessary (CroFab 2018)

Antivenin Latrodectus (Lyovac®)
Management of envenomation by Latrodectus (black widow spider)
Dogs and cats
Contents of 1 vial diluted in 2.5 ml of horse serum IM or further dilute in 10–50 ml of sterile saline and administer IV over 15 min

After reconstitution, add contents of 1 vial to 100 ml of sterile saline and administer IV over 30 min. Consider pre‐medication with diphenhydramine (2–4 mg/kg SQ) to help prevent against allergic reactions (Merck and Co. Inc 2020)

Apomorphine
Induction of emesis; not effective in cats because they have few dopamine receptors within their emetic center in the CNS
Dogs
0.01–0.04 mg/kg IV, IM, SQ; however, induction of emesis is fastest IV (general dose: 0.03 mg/kg IV or 0.04 mg/kg IM)

Alternatively, a 6.25‐mg tablet may be crushed in a syringe and dissolved with few drops of sterile saline and administered into the conjunctival sac. After sufficient vomiting occurs, rinse conjunctival sac free of unabsorbed apomorphine

Ascorbic acid
Antioxidant; used to treat toxin‐induced methemoglobinemia; questionable efficacy
Dogs and cats
30 mg/kg PO or SQ q 6 h

Atenolol
Management of tachycardia
Dogs
0.25–1.5 mg/kg PO q 12 h; start at low end of dose and titrate up PRN

Cats
6.25 mg/CAT PO q 12 h; titrate up PRN

Atipamezole
Reversal of bradycardia, hypotension, and sedation from alpha‐agonists (e.g., amitraz, xylazine, clonidine, dexmedetomidine, imidazoline decongestants)
Dogs and cats
50 mcg/kg (give ¼ IV, and remainder IM); repeat dose in 30–60 min if hypotension has not improved. Doses may need to be repeated until resolution of clinical signs

Atropine
Test dose for suspected organophosphorus or carbamate toxicosis, or blue‐green algae intoxication
Dogs and cats
Obtain baseline heart rate, and then administer 0.02 mg/kg IV; recheck heart rate—if rate increases >5 bpm and mydriasis develops, this is not an organophosphate or carbamate toxicosis

Treatment of muscarinic mushroom toxicity
Dogs and cats
0.04 mg/kg; give ¼ dose IV, remainder IM or SQ. Titrate up PRN to control severe signs. Note: Atropine is contraindicated in management of ingestion of isoxazole mushrooms

Treatment of bradycardia or excessive bronchial secretions from organophosphorus or carbamate toxicosis
Dogs and cats
0.2–0.5 mg/kg, give ¼ dose IV, rest IM or SQ

Treatment of bradycardia from cardiac depressant drugs (e.g., digoxin)
Dogs and cats
0.02–0.04 mg/kg IM, IV, SQ prn

Bethanechol
Management of urinary retention due to anticholinergic toxicity
Dogs
2.5–25 mg/dog PO q 8–12 h

Cats
1.25 mg–7.5 mg/cat PO q 8–12 h

Bicarbonate, sodium
Management of acidosis
Dogs and cats
mEq required = 0.3 × body wt (kg) × (desired HCO₃ minus measured patient HCO₃); give ¼ to ⅓ calculated dose IV as a slow bolus, and the remaining amount IV over 4–6 h, and then recheck blood gases and status of patient

Blood, whole (transfusion)
Replacement therapy for anemia
Dogs and cats
20 ml/kg IV

Blood, pRBCs (transfusion)
Replacement therapy for anemia
Dogs and cats
10 ml/kg IV

Calcium gluconate
Treatment of hypocalcemia, hypermagnesemia, hyperkalemia, and calcium channel blocker toxicosis
Dogs and cats
For tetany: administer 0.54–1.61 ml/kg IV calcium gluconate 10% injection over 10–30 min, then CRI of 2.5–3.5 mg/kg/h of elemental calcium IV. Dilute in LRS or 0.9% saline

For hyperkalemic cardiotoxicity: 0.5–1 ml/kg 10% calcium gluconate IV slowly over 10–20 min. This will rapidly correct arrhythmias, but effects are short (10–15 min). IV calcium treatment can antagonize the cardiotoxic effects of potassium but will not reduce potassium concentrations

Calcium EDTA
Heavy metal chelator (lead and zinc toxicosis)
Dogs and cats
25 mg/kg (diluted in 5% dextrose to a concentration of 10 mg/ml) SQ q 8 h for 5 d

Chlorpromazine
Antiemetic
Dogs and cats
0.2–0.5 mg/kg IM or SQ q 6–8 h

Sedation for agitation caused by psychotropic drugs (e.g., amphetamines, phenylpropanolamine, pseudoephedrine)
Dogs
0.05–0.5 mg/kg IV q 6–8 h PRN

Cats
0.025‐0.5 mg/kg IV q 6‐8 h PRN

Cyproheptadine
Assistance in management of serotonin syndrome and serotonergic effects of psychotropic drugs
Dogs
1.1 mg/kg PO or per rectum q 6 h; usually requires 1–2 doses

Cats
2–4 mg per cat PO or per rectum q 6–8 h; usually requires 1–2 doses

Cholestyramine resin
Anion exchange resin that binds with bile acids in the intestine, preventing their reabsorption. Used in the management of enterohepatically recirculated agents that bind to bile acids (cholecalciferol, amiodarone, digoxin, NSAIDs, vincristine)
Dogs and Cats
300–500 mg/kg PO q 8 h with a meal; depending on the toxicity, length of administration will vary (NSAIDs 48 h, cholecalciferol 4 d or longer depending on severity of hypercalcemia)

Dantrolene
Management of malignant hyperthermia from hops
Dogs
3.5 mg/kg PO q 8 h or 2–3 mg/kg IV

Deferoxamine (Desferal®)
Chelator of iron
Dogs and cats
15 mg/kg/h IV slowly within 12–24 h of ingestion or 40 mg/kg IM q 4–8 h. Continue until serum iron levels are below 300 mcg/dL and pet is stable

Dexmedetomidine
Induction of emesis in cats
Cats
7 mcg/kg IM (6–18 mcg/kg IM; higher doses tend to cause sedation > emesis)

Dextrose
Management of hypoglycemia, hepatic protectant to decrease gluconeogenesis and therefore allow the liver to recover
Dogs and cats
Hypoglycemia: 0.5 g/kg 50% dextrose IV diluted 1:1, then CRI PRN. If CRI > 5% is needed to maintain BG, administration through a central line is required

Management of hyperkalemia (in conjunction with insulin)
Dogs and cats
Hyperkalemia: Dextrose 50% 1 ml/kg (0.5 g/kg) can be given as an IV bolus slowly. Regular insulin can be given at the same time at 0.25–0.5 units/kg slow IV. When using insulin and dextrose, it is imperative that dextrose be supplemented in the fluids at 2.5–5% to prevent secondary hypoglycemia

Diazepam
Sedation for CNS stimulation
CAUTION: avoid use or use with caution with sympathomimetic (e.g., amphetamine) intoxication because paradoxical excitation may occur
Dogs and cats
0.5–2 mg/kg slow IV

Management of mild tremors or seizures
Dogs and cats
0.5–2 mg/kg IV to effect

Management of metronidazole toxicity
Dogs and cats
0.5 mg/kg IV or PO q 8 h for 72 h (pets treated with diazepam seem to recover faster)

Digoxin immune Fab (Digibind® or DigiFab®)
Management of cardiac glycoside toxicosis (drugs, plants, toads) where life‐threatening arrhythmias have not resolved with symptomatic therapy or serum potassium levels >5 mmol/L in the setting of severe digitalis intoxication (Drugs.com 2023)
Dogs and cats
Dosage based on serum digoxin levels or amount of digoxin ingested (formulas on insert); if unknown exposure level, start with 1–2 vials over approximately 30 min. If the signs are life‐threatening, the product can be given as a bolus. The cardiac status should improve within 20–90 min of administration and complete resolution within 4 h; if significant improvement does not occur, additional vials may be needed (DeClementi 2018)

Dimercaprol (BAL)
Heavy metal chelator (arsenic, lead, mercury)
Dogs and cats
2.5–5 mg/kg IM; repeat q 4 h for 2 d and then q 12 h for 10 d or until recovery (5 mg/kg doses are typically only given on the first day of therapy and only to acutely affected patients)

Diphenhydramine
Management of acute allergic reactions
Dogs and cats
2–4 mg/kg PO q 8–12 h; 0.5–2 mg/kg IM, SQ, IV q 8–12 h

Management of acute extra‐pyramidal or dystonic signs (anxiety, agitation, facial fasciculations)
Dogs
2–4 mg/kg IM or 1 mg/kg IV not to exceed 40 mg total dose

Cats
2 mg/kg IM

Dopamine
Vasopressor used in severe hypotension
Dogs and cats
5–20 mcg/kg/min IV. Initially, 2.5–5 mcg/kg/min is recommended and then should be titrated upward to effect. Adequate volume replacement is required before use. A study in cats noted an initial CRI of 10 mcg/kg/min IV, with increases in increments of 2.5–5 mcg/kg/min IV (Licht et al. 2018)

Dobutamine
Vasopressor used in severe hypotension
Dogs and cats
2–20 mcg/kg/min IV CRI (use with caution in cats as doses >5 mcg/kg/min can cause CNS signs)

Epinephrine
Systemic treatment of acute anaphylaxis
Dogs and cats
0.01–0.02 mg/kg IV, IM, or SQ of a 1 mg/ml solution; repeat PRN

Erythropoietin
Adjunctive therapy for anemia secondary to bone marrow suppression
Dogs and cats
Initial dosage: 100 units/kg SQ three times/week. Continue with this frequency until target PCV has been achieved
Maintenance dosage: 50–100 units/kg SQ once to twice weekly

Esmolol
Management of ventricular arrhythmias; ultra‐short‐acting
Dogs and cats
Loading dose of 200–500 mcg/kg IV over 2–5 min followed by constant rate IV infusion of 10–200 mcg/kg/min

Ethanol
Management of ethylene glycol toxicosis; prevents formation of toxic metabolites
Dogs and cats
As 20% solution, administer 5.5 ml/kg IV q 6 h for 5 treatments, and then q 8 h for 4 treatments or 7% solution, load at 600 mg/kg slow IV (or 8.6 ml/kg), then maintain at 100 mg/kg/h (or 1.43 ml/kg/h) CRI IV, up to 200 mg/kg/h CRI IV (recommended rate during peritoneal dialysis). CRI preferred to avoid high blood ethanol levels

Filgrastim (Neupogen®)
Treatment for neutropenia
Dogs and cats
5–10 mcg/kg SQ q 24 h

Flumazenil
Benzodiazepine antagonist used to reverse severe benzodiazepine overdose
Dogs and cats
0.01 mg/kg IV and repeat PRN

Fluticasone
Inhaled glucocorticoid for inflammation secondary to inhalation of respiratory irritants
Dogs and cats
1–2 actuations every 12 h; adjust dose based on clinical response

Fomepizole
Management of ethylene glycol toxicosis; prevents formation of toxic metabolites
Dogs
20 mg/kg IV, and then 15 mg/kg IV at 12 and 24 h, and then 5 mg/kg at 36 h and q 12 h until no detectable EG in blood

Cats
125 mg/kg slow IV; then 31.25 mg/kg at 12, 24 and 36 h

Furosemide
Diuretic for use in management of pulmonary edema secondary to inhalation toxicity
Dogs
Initially, 2 mg/kg IV or IM; repeat q 1–2 h until respiratory rate/effort have improved or up to 8 mg/kg has been reached over 4 h

Cats
Initially, 1–3 mg/kg IV or IM; repeat q 1–2 h until respiratory rate/effort has improved

Diuretic to enhance calcium excretion in hypercalcemia (e.g., cholecalciferol toxicosis)
Dogs and cats
2–4 mg/kg PO, IV or IM q 8–12 h; ensure pet is appropriately volume expanded prior to use

Treatment for oliguric acute renal injury
Dogs
Initial bolus of 1–2 mg/kg IV (up to 4 mg/kg if no response seen in 30–60 min) followed by CRI of 0.1–2 mg/kg/h; adjust based on response to therapy

Cats
Initial bolus of 1–2 mg/kg IV followed by CRI of 0.25–1 mg/kg/h; adjust based on response to therapy

Ginkgo Biloba
May reduce the development of cerebral edema and brain lipid peroxidation in bromethalin toxicosis
Dogs and cats
100 mg/kg PO q 24 h (Dorman et al. 1992)

Glucagon
Manages severe cardiac arrhythmias (bradycardia, AV block) due to beta‐adrenergic blocker, calcium channel blocker, and tricyclic antidepressant overdoses
Dogs and cats
50 ng (nanograms)/kg IV bolus followed by CRI 10–15 ng/kg/min

Glycopyrrolate
Manage bradyarrhythmias in cases of cardiac glycoside toxicity
Dogs and cats
0.01 mg/kg IV

Adjunctive therapy for muscarinic signs associated with carbamate or organophosphorus intoxications
Dogs and cats
0.01–0.02 mg/kg IV; repeat PRN

H₂ blockers
Reduces gastric acid secretion
Dogs and cats
Cimetidine: 5–10 mg/kg PO, SQ, IM, IV q 6–8 h

Dogs
Famotidine: 0.5–1 mg/kg PO, IM, SQ, IV q 12–24

Cats
Famotidine: 0.5 mg/kg PO, SQ, IM, IV q 24 h Anecdotal reports of hemolysis when used IV in cats

Dogs
Ranitidine: 0.5–2 mg/kg PO, IV, IM q 8–12 h

Cats
Ranitidine: 2.5 mg/kg IV q 12 h or 3.5 mg/g PO q 12 h

Hydroxyethyl starch colloids (Hetastarch®, Vetstarch®)
Management of hypotension
Dogs
Rate of administration depends on individual patient requirements. Shock bolus is 10–20 ml/kg over 15–30 min; a CRI can follow at 1–2 ml/kg/h not to exceed 20 ml/kg/d

Cats
Rate of administration depends on individual patient requirements. Shock bolus is 5–10 mL/kg over 15–30 min; a CRI can follow at 1–2 mL/kg/h not to exceed 10 ml/kg/d

Hydralazine
Management of severe acute hypertension (phenylpropanolamine or any toxicity that results in severe acute hypertension)
Dogs
0.5–3 mg/kg IV q 12 h or 0.1 mg/kg loading dose IV followed by 1.5–5 mcg/kg/min CRI.
1 mg/kg PO initial dose. Recheck BP in 30–60 min; if no improvement, titrate up by 0.5–1 mg/kg to a maximum dose of 3 mg/kg

Cats
1–2.5 mg/cat SQ may be repeated in 15–30 min if systolic BP has not decreased
0.1 mg/kg IV loading dose followed by 1.5–5 mcg/kg/min IV CRI
2.5 mg/cat PO q 12 h

3% Hydrogen peroxide
Induction of emesis
Dogs
0.5 ml/kg PO to maximum of 45–50 ml; can repeat once in 10–15 min if vomiting is not achieved

Hydroxocobalamin
Management of cyanide toxicosis (including sodium nitroprusside or smoke inhalation)
Dogs
75–150 mg/kg IV over 7.5 min

Intravenous lipid solution (20%) (Liposyn®, Intralipids®)
Management of intoxication by highly lipid soluble compounds (e.g., avermectins, baclofen, calcium channel blockers); should be reserved for severe cases that are poorly responsive to other therapy
Dogs and cats
1.5 ml/kg IV administered over 5–15 min followed by 0.25 ml/kg/min IV for 1 h; repeat dosing can be given at 4 h intervals (or when serum no longer lipemic) for continued management of clinical signs

Isoproterenol
For severe bradyarrhythmias or as an alternative to calcium channel blocker overdose
Dogs and cats
0.02–0.5 mcg/kg/min IV CRI

Ketamine
Sedation; can be used in 5‐FU toxicities for refractory seizures
Dogs
5 mg/kg IV bolus

Lactulose
Laxative and reduces blood ammonia levels; helpful in cases of liver insufficiency
Dogs and cats
Orally: 1–3 ml/10 kg (NOT ml/kg) PO every 6–8 h; adjust dose to achieve 3–4 soft stools per day

Retention enema for acute hepatic encephalopathy: 1–10 ml/10 kg. After administering a cleansing enema, administer diluted lactulose solution (1 part lactulose to 2 to 3 parts warm water) as a retention enema for 30 min

Levetiracetam (Keppra®)
Anticonvulsant
Dogs
30–60 mg/kg IV bolus over 5–15 min

Cats
20–40 mg/kg IV q 8 h

Lidocaine
Management of ventricular arrhythmias
Dogs
Bolus 2 mg/kg slow IV up to 8 mg/kg; or rapid IV 0.8 mg/kg/min, and then CRI of 25–80 mcg/kg/min

Cats
Bolus 0.25–0.5 mg/kg slowly; repeat at 0.15–0.25 mg/kg in 5–20 min; CRI at 0.01–0.02 mg/kg/min
*Use with caution as cats are extremely sensitive and show CNS and CV depression in low doses

Magnesium hydroxide
Reduces gastric acid; used in Zn phosphide intoxications to slow conversion to toxic metabolites
Dogs and cats
5–15 ml q 12–24 h

Magnesium sulfate
Treatment of refractory ventricular arrhythmias or torsades des pointes
Dogs and cats
0.15–0.3 mEq/kg IV administered over 5–15 min

Mannitol
Osmotic diuretic for management of oliguric renal failure
Dogs and cats
0.25–0.5 gm/kg IV over 15–20 min; if substantial diuresis occurs, a CRI of 60–120 mg/kg/h IV or intermittent repeated boluses of 0.25–0.5 gm/kg IV can be administered q 4–6 h

Treatment of cerebral edema
Dogs and cats
0.5–1 gm/kg IV over 10–20 min; repeat q 6–8 h PRN

Maropitant
Antiemetic
Dogs and cats
1 mg/kg IV, SQ

Methocarbamol
Management of muscle tremors, rigidity, convulsive activity (e.g., permethrin, bifenthrin, tremorgenic mycotoxin, and metaldehyde toxicoses)
Dogs and cats
55–220 mg/kg IV; administer half rapidly, wait for the animal to relax, and then administer remainder to effect. Can exceed 330 mg/kg/day if patient does not develop severe CNS or respiratory depression

Methylene blue (not NEW methylene blue)
Treatment of methemoglobinemia secondary to toxin exposures (phenol, mothballs, hydroxyurea)
Dogs and cats
For refractory cases: using a 1% solution, a single dose of 1–1.5 mg/kg IV slow infusion over several minutes. Use with extreme caution, especially in cats

Metoclopramide (Reglan®)
Management of protracted vomiting and other dopaminergic signs secondary to ropinirole use (lethargy, muscle tremors)
Dogs
0.5 mg/kg IV or SQ

Metoprolol
Management of tachycardia
Dogs
0.2 mg/kg PO q 12 h, titrate upward PRN

Cats
2–15 mg/cat PO q 8–12 h

Midazolam
Management of anxiety, mild muscle tremors, or convulsive activity
Dogs and cats
0.1–0.3 mg/kg IV; titrate up to effect

Misoprostol
Used in the treatment of salicylate toxicosis to inhibit gastric acid and provide a cytoprotective effect on the mucosa
Dogs
3 mcg/kg q 8–12 h

Naloxone
Reversal of opioid toxicosis
Dogs and cats
0.001–0.4 mg/kg IV, IM, or SQ; repeat PRN
Can be administered transmucosal or intranasal (using the 0.4 mg/ml solution, administer ~ 0.2 mg/kg); repeat PRN

Neostigmine
Treatment of GI stasis secondary to anticholinergic toxicity
Dogs and cats
0.04 mg/kg IM q 6 h

Nitroprusside
Treatment of acute hypertension (systolic BP greater than 180 mm Hg)
Dogs and cats
Initial dose 0.5–1 mcg/kg/min; increase incrementally q 3–5 min until desired BP attained. Maximum CRI is 10–15 mcg/kg/min although most improve around 2–3 mcg/kg/min

Norepinephrine
Vasopressor used for severe hypotension refractory to adequate volume resuscitation
Dogs and cats
Initial dosage 0.05–0.1 mcg/kg/min IV CRI, then titrate up to effect. Maximum rate is 1–2 mcg/kg/min

Octreotide
Amatoxin toxicosis
Dogs
10–20 mcg/dog IV followed by a 10–20 mcg/dog/h (NOT mcg/kg/h) IV CRI

Omeprazole (or pantoprazole)
Proton pump inhibitor used for ulcer prevention and management
Dogs and cats
1 mg/kg PO (or IV) q 12 h

Ondansetron
Antiemetic
Dogs
0.5–1 mg/kg PO or IV slow q 8–12 h

Cats
0.1–1 mg/kg IV (slowly), SQ, IM, or PO q 6–12 h

Pamidronate (Aredia®)
Management of hypercalcemia due to intoxication by vitamin D or analogues
Dogs and cats
1.3–2 mg/kg diluted in 150–250 ml 0.9% NaCl slow IV over 2–3 h; may repeat in 3–7 d if needed

D‐penicillamine
Copper chelator (can be considered for lead toxicosis but other therapies are preferred)
Dogs and cats
10–15 mg/kg PO q 12 h on an empty stomach

Pentobarbital
Management of refractory seizures
Dogs and cats
3–15 mg/kg slow IV to effect

Phenobarbital
Management of seizures
Dogs
4–8 mg/kg IV to effect, then 4 mg/kg IV increments to a maximum dose of 20–24 mg/kg IV in a 24‐h period

Cats
3–6 mg/kg IV to effect, repeat PRN up to maximum dose of 24 mg/kg IV in 24 h period

Phenylephrine
Treatment of refractory hypotension to adequate volume resuscitation
Dogs
1–3 mcg/kg/min IV CRI; doses up to 10 mcg/kg/min have been used

Cats
1–2 mcg/kg/min IV CRI

Phenytoin
Treatment of refractory arrhythmias
Dogs
10 mg/kg slow IV in increments of 2–4 mg/kg; 30–50 mg/kg PO q 8 h

Physostigmine
Cholinesterase inhibitor; can be used as a diagnostic aid (temporarily reverses CNS effects) for ivermectin toxicity in dogs
Dogs
1–2 mg/DOG IV once
*Due to potential serious adverse effects, use is generally reserved for severe toxicity affecting the CNS. Otherwise, neostigmine or pyridostigmine

Plasma (FFP) transfusion
Coagulopathy; replacement of clotting factors
Dogs and cats
10–20 ml/kg over 1–4 h

Pralidoxime chloride (2‐PAM)
Treatment of organophosphorus insecticide intoxication; cholinesterase reactivator
Dogs and cats
20 mg/kg IM, IV, SQ q 6–12 h if no response after 3 doses, discontinue treatment. If signs worsen 2–4 h post administration, discontinue therapy as the signs could be due to carbamate insecticide toxicosis

Prednisone or prednisolone
Adjunct therapy in hypercalcemia due to vitamin D or analogue toxicosis
Dogs and cats
1–2 mg/kg PO q 12 h

Propranolol
Management of tachycardia (or other arrhythmias) with normotension
Dogs and cats
0.02–0.06 mg/kg slow IV; titrate up to effect; repeat PRN

Propofol
Management of refractory seizures
Dogs and cats
2–8 mg/kg IV bolus followed by CRI 0.1–0.25 mg/kg/min IV for maximum duration of 48 h

Protamine sulfate
Management of heparin overdoses with severe hemorrhage
Dogs and cats
Administer 1–1.5 mg slow IV to antagonize each 100 units heparin

Pyridostigmine
Management of toxicosis from non‐depolarizing neuromuscular blocking agents (botulism, atropine, avermectin, coral snake envenomation, and anticholinergics)
Dogs
1–3 mg/kg PO q 8–12 h

Pyridoxine
Used in management of seizures from penicillamine, Gyromitra mushroom, isoniazid, and hydrazine; adjunct therapy for ethylene glycol toxicosis
Cats
0.25 mg/kg/day (rarely used, but can be dosed similarly to dogs)

Dogs and cats
Administer milligram for milligram the dose of isoniazid/hydrazine; if not known, initial dose of 71 mg/kg as a 5–10% IV infusion over 30–60 min

Provide cofactors for the metabolism of ethylene glycol: 1–2 mg/kg IV q 6 h

Ropinirole (Clevor®)
Used in emesis induction in dogs; stimulates dopamine receptors in CRTZ
Dogs
Ocular administration: administer the appropriate drops to deliver a target dose of 3.75 mg/m²; a second dose may be administered if dog does not vomit within 20 min of first dose

SAMe (S‐adenosyl‐methionine)
Hepatoprotection
Dogs and cats
20 mg/kg/day PO q 24 h on an empty stomach

Silymarin
Hepatoprotection
Dogs and cats
20–50 mg/kg/day PO

Cats
200–400 mg/day (not mg/kg) PO

Sodium nitrite
Used in management of cyanide toxicosis; induces methemoglobinemia which combines with cyanide to form cyanomethemoglobin
Dogs
16 mg/kg IV of a 3% solution first, then followed by sodium thiosulfate

Sodium thiosulfate
Used in management of cyanide toxicosis; provides sulfur, which increases the rate of rhodanese reaction
Dogs and cats
150–500 mg/kg IV bolus or CRI of 25% solution. Monitor Na levels. In mild toxicosis, use of sodium thiosulfate may be used without sodium nitrite

Succimer (DMSA 2,3‐dimercaptosucinic acid)
Heavy metal chelator (lead, mercury, arsenic)
Dogs and cats
10 mg/kg PO q 8 h for 10 d; can be given rectally if patient is vomiting

Sucralfate
GI mucosal protectant to prevent and treat ulceration
Dogs and cats
250–500 mg/animal for small dogs and cats. 1 g/animal for large‐sized dogs. When using tablet formulations, it is recommended to crush the tablet then suspend it in a small amount of water prior to administration. Administer PO q 6–8 h for 14 d

Terbutaline
Bronchodilator to treat bronchospasm secondary to inhaled irritants
Dogs and cats
0.01 mg/kg IV, IM, SQ; positive response will usually be seen within 15–30 min

Theophylline
Bronchodilator to treat bronchospasm secondary to inhaled irritants
Dogs
5–20 mg/kg PO q 12–24 h

Cats
Using sustained release human formulation: 15–25 mg/kg PO q 24 h

Tranexamic acid
Inhibits fibrinolysis and stabilizes clot formation in actively hemorrhaging patients
Dogs
Extra label dose: 10 mg/kg IV bolus over 2 min followed by 10 mg/kg/h IV CRI for 3 h

Trientine
Chelator for copper hepatotoxicity
Dogs
5–7.5 mg/kg PO q 12 h given 1–2 h prior to meals

Ursodiol
Used in cases of hepatic injury where there is hyperbilirubinemia, evidence of cholestasis, or evidence of delayed hepatotoxicity
Dogs and cats
10–15 mg/kg PO with food q 24 h (or divided q 12 h)

Vasopressin
Treatment of refractory hypotension to adequate volume resuscitation or catecholamines
Dogs and cats
0.01–0.04 Units/min IV. Do NOT exceed 0.04 Units/min as there is a risk for myocardial ischemia

Vitamin K₁ (phytonadione)
Treatment of anticoagulant rodenticide coagulopathy
Dogs and cats
3–5 mg/kg PO divided q 12 h; treat for 7, 21, or 28 d according to type of rodenticide; check prothrombin time 48–72 h after last dose vitamin K₁

Xylazine
Emetic
Cats
0.44 mg/kg IM

Yohimbine
Reversal of bradycardia, hypotension, and sedation from alpha agonists (e.g., amitraz, xylazine), imidazole decongestants
Dogs
0.11 mg/kg IV

Cats
0.5 mg/kg IV

Zoledronate (zoledronic acid)
Management of hypercalcemia due to intoxication by vitamin D or analogues
Dogs and cats
0.25 mg/kg dilute in 50–100 ml D5W. Give over 15 min; if given more rapidly or at a slower infusion has been associated with AKI

Source: Adapted from Plumb (2022) unless otherwise noted.

REFERENCES

CroFab. 2018. Product information. https://www.fda.gov/media/74683/download (accessed January 24, 2024).

Cumberland Pharmaceuticals. 2019. Acetadote product insert. https://www.acetadote.com/New_Acetadote_Labeling_25OCT2019.pdf (accessed January 24, 2024).

Davis, Megan and Bracker, Kiko. 2016. Retrospective study of 122 dogs that were treated with the antifibrinolytic drug aminocaproic acid: 2010–2012. Journal of the American Animal Hospital Association 52(3):144–148.

DeClementi, Camille. 2018. Prevention and treatment of poisoning. In Veterinary Toxicology: Basic and Clinical Principles, 3rd ed., edited by Ramesh C Gupta, pp. 1151–1152. London: Elsevier.

Dorman, David C, Cote, L Marie, and Buck, William B. 1992. Effects of an extract of Gingko biloba on bromethalin‐induced cerebral lipid peroxidation and edema in rats. American Journal of Veterinary Research 53(1):138–142.

Drugs.com 2023. Digibind Prescribing Information. https://www.drugs.com/pro/digibind.html#:~:text=Diluting%200.1%20mL%20of%20reconstituted,be%20read%20at%2020%20minutes (accessed January 24, 2024).

Licht, Nikki, Rozanski, Elizabeth A, and Rush, John E. 2018. Vasopressor use in 41 critically ill cats (2007–2016). Canadian Veterinary Journal 59(11):1175–1180.

Merck & Co, Inc. 2020. Antivenin (Latrodectus mactans), Equine origin, product insert. https://www.merck.com/product/usa/pi_circulars/a/antivenin/antivenin_pi.pdf (accessed January 24, 2024).

Plumb, Donald C. Plumb's Veterinary Drugs Online (2022). https://app.plumbs.com (accessed 13 March 2023).

Stowe, CM, Werdin, RE, Barnes, DM et al. 1976. Amphetamine poisoning in dogs. Journal of the American Veterinary Medical Association 168(6):504–506.

VenomVet. 2023. Product information. https://venomvet.com/product‐insert (accessed January 24, 2024).

Appendix 2
Additional Toxic Plants and Associated System‐Based Effects

Charlotte Means

Common names may be the same for multiple different plants.

GASTROINTESTINAL

Abrus precatorius (Buddhist rosary bead, crab's eyes, Indian bead, jequirity bean, love bean, prayer bean, precatory bean, rosary pea, Seminole bead)

Acalypha hispida (bristly copperleaf, chenille plant, foxtail, Philippines medusa, red‐hot cattail)

Aconitum spp. (aconite, blue rocket, devil's helmet, helment flower, leopard's bane, monkshood, queen of poisons, wolfsbane, woman's bane) (see Figure A2.1)

Acorus calamus (sweet‐flag)

Adonis aestivalis (pheasant's eye, summer adonis, summer pheasant's eye)

Aesculus spp. (bottlebrush buckeye, buckeye, firecracker plant, horse chestnut, red buckeye)

Ageratina altissima (fall poison, richweed, tremetol, white snakeroot)

Ageratum houstonianum (ageratum, blue billygoat weed, bluemink, floss flower, Mexican ageratum)

Aglaonema spp. (Chinese evergreen, golden evergreen, painted drop tongue, Philippine evergreen, poison dart plant)

Allamanda cathartica (allamanda, golden‐trumpet, golden trumpet vine, yellow allamanda)

Alocasia spp. (elephant's ear, giant taro, Persian palm, Yucatan princess)

Aloe arborescens (candelabra aloe, krantz aloe, torch aloe)

Amaryllis spp. (amaryllis, belladonna lily, cape belladonna, naked lady, Saint Joseph lily)

Ananas comosus (pineapple)

Anemone spp. (anemone, crowfoot, meadow anemone, Pasque flower, thimbleweed, windflower)

Anthurium spp. (anthurium, flamingo flower, flamingo lily, fleabane, oilcloth flower, painter's pallet, pigtail plant, tailflower) (see Figure A2.2)

Apocynum spp. (amy root, bitter root, dogbane, dogbane hemp, Indian hemp, prairie dogbane)

Arisaema spp. (bog onion, brown dragon, Japanese cobra lily, dancing crane cobra lily, devil's ear, dragon arum, dragon root, green dragon, Indian cradle, Indian turnip, jack‐in‐the‐pulpit, lady‐in‐a‐chaise, lord‐and‐lady, memory root, parson‐in‐the‐pulpit, pepper turnip, starch wort, three‐leaved Indian turnip, wake robin, wild turnip)

Armoracia rusticana (horseradish, red cole)

Arnica montana (arnica, arnica root, leopard's bane, mountain arnica, mountain snuff, mountain tobacco, wolfbane)

Artemisia spp. (absinth, artemisia, boy's love, dragon plant, dragon sagewort, dusty miller, estragon, felon herb, garderobe, lad's love, madderwort, maid's love, mugwort, old man, sagebrush, sagewort, sitherwood, southernwood, tarragon, wormwood)

Arum spp. (Adam and Eve, arum, arum lilies, black calla, bobbins, cuckoo's pint, Italian arum, Italian lily, lords and ladies, orange candle flower, Solomon's lily, starch root, wake robin, wild arum, wild calla) (see Figure A2.3)

Figure A2.1. Aconitum spp.

Photograph courtesy of Tina Wismer.

Figure A2.2. Anthurium spp.

Photograph courtesy of Tina Wismer.

Figure A2.3. Arum spp. fruits.

Photograph courtesy of Tina Wismer.

Asclepias spp. (annual milkweed, asclepias, blood flower, blunt‐leaved milkweed, butterfly weed, chieger flower, chiggerflower, clasping milkweed, fleshy milkweed, green antelopehorn, Indian paintbrush, Indian root, marsh milkweed, milkweed, pleurisy root, poke milkweed, sand milkweed, scarlet milkweed, sunset flower, swallow wort, swamp butterfly weed, tropical milkweed, whorled milkweed)

Aucuba japonica (aucuba, blotched‐leaved laurel, gold dust, gold‐leaf plant, Japanese aucuba, Japanese laurel, Japan laurel, spotted laurel, variegated laurel) (see Figure A2.4)

Begonia spp. (angel wings begonia, begonia, Belgian begonia, climbing begonia, dragon wings begonia, elephant ear begonia, hardy begonia, iron cross begonia, maple leaf begonia, metallic leaf begonia, rex begonia, tuberous begonia, wax begonia)

Bowiea volubilis (climbing onion, Zulu potato)

Brunfelsia spp. (Brazil raintree, brunfelsia, Franciscan raintree, kiss‐me‐quick, lady‐of‐the‐night, morning‐noon‐and‐night, yesterday‐today‐and‐tomorrow)

Bryonia spp. (red bryony, white bryony)

Figure A2.4. Aucuba japonica.

Photograph courtesy of Tina Wismer.

Buxus sempervirens (American boxwood, boxwood, common box, common boxwood, European box)

Caesalpinia pulcherrima (Barbados flower fence, Barbados pride, dwarf Poinciana, Mexican bird of paradise, peacock flower, pride of Barbados, red bird‐of‐paradise)

Caladium spp. (angel wings, caladium, elephant's ear, exposition, fancy‐leaved caladium, mother‐in‐law plant, pai, pink cloud, stoplight, Texas wonder, via, via sori)

Caltha palustris (cowslip, kingcup, marsh marigold, yellow marsh marigold)

Capsicum annuum (cayenne pepper, chili pepper, ornamental pepper, pepper, sweet peppers)

Caryota mitis (Burmese fishtail palm, clustering fishtail palm, fishtail palm)

Cascabela thevetia (be‐still tree, lucky nut, yellow oleander)

Caulophyllum thalictroides (blue cohosh)

Cestrum spp. (cestrum, jessamine, night blooming jasmine, night blooming jessamine, orange peel, yellow cestrum, yellow shrub jessamine)

Chelidonium majus (celadine, greater celadine, rock‐poppy, St. John's wort)

Cicuta maculata (beaver poison, cowbane, poison parsnip, spotted hemlock, water hemlock)

Figure A2.5. Codiaeum variegatum.

Photograph courtesy of Tina Wismer.

Clematis spp. (blue jasmine, clematis, leatherflower, old man's beard, traveller's joy, vase vine, virgin's bower, woodbine)

Clivia spp. (bush lily, cape clivia, clivia lily, clivia, clivies, flame lily, kaffir lily, klivia, September lily)

Codiaeum variegatum (croton, fire croton, garden croton, Joseph's coat, variegated croton) (see Figure A2.5)

Colchicum spp. (autumn crocus, meadow saffron, mysteria, naked ladies, wonder bulb)

Convallaria spp. (lily of the valley)

Corydalis spp. (bulbous corydalis, fitweed, fumitory, golden corydalis, scrambled eggs, golden smoke)

Crinum spp. (cape lily, cemetery plant, crinum lily, seven sisters, Southern swamp lily, spider lily, string lily, swamp lily) (see Figure A2.6)

Cycas spp. (cycad, sago palm)

Cyclamen spp. (alpine violet, cyclamen, Persian violet, sowbread) (see Figure A2.7)

Cytisus spp. (common broom, English broom, Portuguese broom, Scotch broom, Scottish broom, striated broom)

Daphne spp. (daphne, dwarf bay, mezereon, paradise plant, spurge flax, spurge laurel, winter daphne)

Delphinium spp. (delphinium, larkspur, staggerweed)

Dicentra spp. (bleeding heart, dutchman's breeches, squirrel corn, steer's head, turkey corn) (see Figure A2.8)

Figure A2.6. Crinium spp.

Photograph courtesy of Tina Wismer.

Figure A2.7. Cyclamen spp.

Photograph courtesy of Tina Wismer.

Figure A2.8. Dicentra spp.

Photograph courtesy of Tina Wismer.

Dieffenbachia spp. (dieffenbachia, dumbcane, exotica, leopard lily, tropic snow)

Digitalis spp. (dead men's fingers, foxglove, long purples)

Dioscorea communis (black bryony, lady's‐seal, black bindweed)

Dioscorea polystachya (Chinese yam, cinnamon vine)

Dracaena spp. (African spear, Brazil Saint Barbara sword, Chinese water bamboo, corn plant, cornstalk plant, cylindrical snake plant, dracaena, dragon tree, Florida beauty, friendship bamboo, gold dust, golden birds nest, good luck plant, Janet Craig plant, lucky bamboo, mother‐in‐law's tongue, ribbon plant, snake plant, spear sansevieria, spotted dracaena, striped dragon palm, Warneckii, water bamboo)

Drimia maritima (maritime squill, red squill, sea onion, sea squill, squill)

Dryopteris spp. (autumn fern, buckler fern, evergreen wood fern, fancy fern, glandular wood fern, Goldie's fern, log fern, male fern, narrow swamp fern, shield fern, spinulose wood fern, toothed wood fern, wood fern)

Epipremnum aureum (devil's ivy, devil's vine, golden pothos, ivy arum, marble queen, pothos, taro vine)

Erythrina herbacea (cardinal‐spear, Cherokee‐bean, coral bean, red cardinal)

Eucalyptus spp. (argyle apple, eucalyptus, gum, lemon scented gum, silver dollar tree)

Euonymus spp. (burning bush, corky spindletree, hearts‐a‐bustin, Indian arrow wood, spindletree, strawberry bush, wahoo, winged euonymus, wintercreeper)

Euphorbia lactea (candelabra cactus, dragon bones, false cactus, milkstripe euphorbia, mottled candlestick, mottled spurge)

Euphorbia milii (Christ plant, Christ thorn, crown of thorns) (see Figure A2.9)

Euphorbia myrsinites (blue spurge, broad‐leaved glaucous spurge, creeping spurge, donkeytail, myrtle euphorbia, myrtle spurge)

Euphorbia pulcherrima (bird‐of‐paradise flower, Christmas flower, flame‐leaf flower, lobster flower, poinsettia) (see Figure A2.10)

Euphorbia resinifera (Africa spurge, euphorbium, resin spurge, staghorn coral)

Euphorbia tirucalli (African mild bush, azeloz, finger tree, Indian tree spurge, milkbush, pencil cactus, pencil tree, petroleum plant, rubber euphorbia, sticks of fire)

Euphorbia umbellata (African milk bush)

Ficus benjamina (Benjamin tree, Chinese banyan, fig, Indian rubber plant, weeping fig)

Figure A2.9. Euphorbia milii; crown of thorns is a fitting common name.

Photograph courtesy of Tina Wismer.

Figure A2.10. Euphorbia pulcherrima; plants can grow very large in tropical climates.

Photograph courtesy of Tina Wismer.

Figure A2.11. Galanthus spp.

Photograph courtesy of Tina Wismer.

Galanthus spp. (snowdrop) (see Figure A2.11)

Gloriosa spp. (cat's claw, climbing lily, flame lily, flame‐of‐the‐woods, gloriosa lily, glory flower, glory lily, superb lily, tiger's claw) (see Figure A2.12)

Gypsophila paniculata (baby's breath)

Hedera spp. (Algerian ivy, Baltic ivy, branching ivy, Canary Island ivy, Coney Island ivy, English ivy, glacier ivy, Madeira ivy, needlepoint ivy, Persian ivy, sweetheart ivy)

Helleborus spp. (Christmas rose, dungwort, hellebore, Lenten rose, setterwort, stinkwort, winter rose)

Heptapleurum spp. (Australian ivy palm, Hawaiian umbrella tree, octopus tree, parasol plant, schefflera, umbrella tree) (see Figure A2.13)

Hippeastrum spp. (amaryllis, dutch amaryllis, fire lily)

Hura crepitans (assacu, jabillo, monkey no‐climb, possumwood, sandbox tree, monkey pistol)

Hyacinthoides hispanica (Spanish bluebell, wood hyacinth)

Hyacinthus orientalis (common hyacinth, Dutch hyacinth, garden hyacinth, hyacinth)

Hydrangea spp. (blood‐on‐the‐snow, Chinese quinine, climbing hydrangea, French hydrangea, hills of snow, hortensia, hydrangea, mop head hydrangea, mountain hydrangea, oak‐leaf hydrangea, sevenbark, snowball plant, woodvamp) (see Figure A2.14)

Figure A2.12. Gloriosa spp.

Photograph courtesy of Tina Wismer.

Figure A2.13. Variegated Heptapleurum spp.

Photograph courtesy of Tina Wismer.

Figure A2.14. Panicle Hydrangea spp.

Photograph courtesy of Tina Wismer.

Hymenocallis spp. (basket flower, ismene, Peruvian daffodil, sea daffodil, spider lily) (see Figure A2.15)

Ilex spp. (Appalachian tea, baygall bush, big gallberry, inkberry, holly, possumhaw, tarajo, winterberry, yaupon)

Iris spp. (bearded iris, blackberry lily, butterfly flower, candy lily, Chinese leopard flower, flag, fringed iris, iris, kakitsubata, leopard lily, netted iris, orchid lily, pardancanda, shaga, Siberian flag, snake lily, water flag, winter iris) (see Figure A2.16)

Jatropha curcas (Barbados nut, bubble bush, physic nut, poison nut, purging nut)

Juniperus sabina (Calgary carpet juniper, savin juniper, savin)

Kalanchoe spp. (chandelier plant, devil's backbone, kalanchoe, mother‐in‐law‐plant, mother of millions, mother of thousands, silver teaspoons)

Kalmia latifolia (calico bush, ivy bush, laurel, mountain ivy, mountain laurel, sheepkill, spoonwood)

Laburnum anagyroides (common laburnum, golden chain tree, golden rain tree) (see Figure A2.17)

Lantana spp. (lantana, pole cat geranium, red sage, Sellow's lantana, shrub verbena, trailing lantana, trailing shrubverbena, wild verbena, yellow sage)

Figure A2.15. Hymenocallis spp.

Photograph courtesy of Tina Wismer.

Figure A2.16. Bearded iris.

Photograph courtesy of Tina Wismer.

Figure A2.17. Laburnum spp.

Photograph courtesy of Tina Wismer.

Laurus nobilis (bay laurel, bay leaf tree, bay tree, Grecian laurel, laurel, laurel tree, sweet bag, sweet bay, tree laurel, true laurel)

Ligustrum spp. (amur, common privet, privet, wax leaf)

Lilium spp. (Asiatic lily, Asian lily, Carolina lily, Easter lily, Formosa lily, Gray's lily, leopard lily, lily, Madonna lily, northern red lily, orange bell lily, Oriental lily, pine lily, red lily, regal lily, roan lily, royal lily, rubrum lily, spotted lily, tiger lily, trumpet lily, Turk's cap lily, wild lily, wood lily)

Lobelia spp. (blue cardinal flower, cardinal flower, Indian pink, Indian tobacco, lobelia)

Lonicera japonica (Chinese honeysuckle, gold‐and‐silver honeysuckle, Hall's honeysuckle, honeysuckle, Japanese honeysuckle) (see Figure A2.18)

Lophophora williamsii (mescal, mescal buttons, peyote)

Lupinus spp. (hairy lupine, lupine, spreading lupine, wild lupine) (see Figure A2.19)

Macadamia integrifolia (Australian nut, macadamia nut, Queensland nut)

Maianthemum spp. (Canadian mayflower, false lily‐of‐the‐valley, false Solomon's seal, false spikenard, feathery false lily of the valley, smilacina, Solomon's plume)

Melia azedarach (bead tree, China ball tree, Chinaberry, China tree, Japanese bead tree, Persian lilac, pride‐of‐India, syringa, Texas umbrella tree, white cedar)

Figure A2.18. Lonicera japonica.

Photograph courtesy of Jenny Schuett.

Mimosa pudica (action plant, humble plant, sensitive plant, shame plant, sleepy plant, touch‐me‐not)

Mirabilis jalapa (four‐o'clock, marvel‐of‐Peru)

Monstera spp. (ceriman, cutleaf philodendron, hurricane plant, Mexican breadfruit, split‐leaf philodendron, swiss cheese plant) (see Figures A2.20 and A2.21)

Figure A2.19. Seed pods of a Lupinus spp.

Photograph courtesy of Tina Wismer.

Narcissus spp. (daffodil, jonquil, trumpet narcissus) (see Figure A2.22)

Nerium oleander (kaner, oleander, rosebay, rose laurel)

Nicotiana spp. (flowering tobacco, jasmine tobacco, mustard tree, nicotiana, sweet tobacco, tobacco, tree tobacco, white shooting stars, white tobacco) (see Figure A2.23)

Ornithogalum spp. (Cape hyacinth, spire lily, star‐of‐Bethlehem, summer hyacinth)

Oxalis spp. (clover, good luck plant, lemon clover, love plant, lucky clover, oxalis, pickle plant, shamrock, sorrel, sourgrass, sours, wood sorrel)

Paris quadrifolia (herb Paris, true lover's know)

Phaseolus vulgaris (bean, green bean)

Philodendron spp. (heart leaf philodendron, parlor ivy, philodendron, sweetheart plant) (see Figure A2.24)

Physalis spp. (bladder cherry, cape gooseberry, Chinese lantern, ground cherry, husk tomato, jamberries, Jerusalem cherry, Mexican green tomato, miltomates, strawberry tomato, tomatillo)

Phytolacca americana (garnet, pigeon berry, poke, pokeberry, pokeweed, scoke) (see Figure A2.25)

Pieris spp. (fetterbush, lily‐of‐the‐valley shrub, mountain andromeda, pieris)

Figure A2.20. Monstera spp.

Photograph courtesy of Tina Wismer.

Figure A2.21. Fruit of Monstera spp.; it is edible when ripe.

Photograph courtesy of Tina Wismer.

Figure A2.22. Narcissus spp.

Photograph courtesy of Tina Wismer.

Figure A2.23. Nicotiana spp.

Photograph courtesy of Tina Wismer.

Figure A2.24. Philodendron spp.

Photograph courtesy of Tina Wismer.

Figure A2.25. Phytolacca americana.

Photograph courtesy of Ginger Watts Brown.

Plumbago spp. (leadwort, plumbago)

Podophyllum spp. (American mandrake, devil's apple, duck's foot, dysosma, hog apple, Indian apple, mandrake, mayapple, pixie-parasol, raccoonberry, umbrella-leaf, wild lemon) (see Figure A2.26)

Polygonatum spp. (Solomon's seal) (see Figure A2.27)

Primula obconica (German primrose, poison primrose, primrose)

Prunus spp. (apricot, bitter almond, cherry, cherry laurel, choke cherry, English laurel, flowering almond, hog plum, nectarine, peach, plum, sand cherry, skip cherry laurel, sloe plum, sour cherry)

Pulsatilla vulgaris (meadow anemone, pasque flower, wind flower)

Pyracantha spp. (Egyptian thorn, everlasting thorn, fire bush, firethorn, Formosan firethorn, lowdense pyracantha, scarlet firethorn, scarlet pyracantha)

Quercus spp. (oak)

Ranunculus spp. (buttercress, buttercup, burwort, Carolina buttercup, crowfoot, dusky maiden, figwort, lesser celandine, Persian buttercup, pilewort, ranunculus, spearwort)

Rhamnus spp. (buckthorn, common buckthorn)

Rheum rhabarbarum (pie plant, rhubarb)

Rhododendron spp. (azalea, rhododendron, rosebay)

Figure A2.26. Podophyllum spp.

Photograph courtesy of Tina Wismer.

Figure A2.27. Polygonatum spp.

Photograph courtesy of Tina Wismer.

Ricinus communis (African wonder tree, castor bean, castor oil plant, mole bean plant)

Robinia pseudoacacia (black locust, common locust, false acacia, green locust, pea flower locust, white locust, yellow locust)

Sambucus spp. (danewort, elder, elderberry, red elderberry, scarlet elder)

Scadoxus multiflorus (African blood lily, blood lily, cape tulip, pincushion flower, powderpuff lily)

Scilla spp. (autumn squill, blue squill, Cuban lily, Siberian squill, two‐leaved squill)

Sinapis arvensis (bazzocks, bread and marmalade, California rape, canola, charlock, charlock mustard, common mustard, crunch‐weed, field kale, field mustard, headridge, kedlock, rapeseed, wild kale, wild mustard)

Solanum dulcamara (bitter nightshade, bittersweet, bittersweet nightshade, blue blindweed, blue nightshade, climbing nightshade, devil's apple, European bittersweet, felonwort, felonwood, poisonous nightshade, scarlet berry, snakeberry, soda apple, violet bloom, wolfgrape, woody nightshade)

Solanum lycopersicum (tomato)

Solanum nigrum (blackberry nightshade, black nightshade, common nightshade, European black nightshade, garden nightshade, poisonberry)

Solanum pseudocapsicum (Christmas cherry, false Jerusalem cherry, Jerusalem cherry, Madeira cherry, Madeira winter cherry, natal cherry, winter cherry)

Solanum spp. (nightshade)

Solanum tuberosum (Irish potato, pomme de terre, potato, white potato)

Sophora spp. (Eve's necklace, David's mountain laurel, frijolillo, mescal bean, mountain laurel, necklace tree, pink sophora, sophora, Texas mountain laurel, Texas sophora)

Spathiphyllum spp. (peace lily, Mauna Loa, spathe flower, white sails)

Syngonium podophyllum (African evergreen, American evergreen, arrow‐head vine, green gold naphthysis, nephthytis, trileaf wonder) (see Figure A2.28)

Tagetes spp. (African marigold, American marigold, Aztec marigold, big marigold, French marigold, hierbanis, marigold, Mexican marigold, Mexican tarragon, pericon, sweet mace, yerbaniz) (see Figure A2.29)

Tanacetum vulgare (bitter buttons, common tansy, cow bitter, garden tansy, golden buttons, tansy)

Taxus spp. (yew)

Thuja occidentalis (American arborvitae, eastern white cedar, northern white cedar)

Tradescantia spathecea (boat lily, Moses in a basket, Moses in the cradle, oyster plant) (see Figure A2.30)

Tulipa spp. (tulip)

Figure A2.28. Syngonium podophyllum.

Photograph courtesy of Tina Wismer.

Figure A2.29. Tagetes spp.

Photograph courtesy of Jenny Schuett.

Urtica spp. (common nettle, stinging nettle)

Veratrum spp. (American white hellebore, corn lily, false hellebore, hellebore, Indian poke)

Vernicia fordii (tung nut, tung oil tree)

Viburnum spp. (arrowwood viburnum, black haw, blue haw, bracted viburnum, Chindo viburnum, Chinese snowball tree, cowberry, European cranberry bush, guelder‐rose, hobbleleaf, Koreanspice viburnum, limerock arrowwood viburnum, maple leaf viburnum, mirror leaf viburnum, moosewood, nannyberry, nanny plum, sheepberry, swamp haw, sweetberry, wild raisin, witch hobble, withered)

Figure A2.30. Tradescantia spp.

Photograph courtesy of Tina Wismer.

Vinca spp. (blue buttons, periwinkle, running myrtle, vinca)

Viscum spp. (European mistletoe)

Wisteria spp. (wisteria) (see Figure A2.31)

Zamia spp. (cardboard palm, chigua, coontie, cycad, fern palm, Florida arrowroot, koo, maw'‐ti‐ree‐na, sago palm)

Zantedeschia spp. (African lily, altar lily, arum lily, calla lily, Egyptian lily, lily of the Nile, pig lily, trumpet lily)

Zephyranthes spp. (atamasco lily, fairy lily, rainflower, rain lily, zephyr lily)

Zigadenus glaberrimus (camas, large death camus, large‐flowered Zigadenus, sandbog deathcamas, snakeroot)

Figure A2.31. Wisteria spp.

Photograph courtesy of Tina Wismer.

CENTRAL AND PERIPHERAL NERVOUS SYSTEM

Pinpoint Pupils

Clivia spp. (bush lily, cape clivia, clivia lily, clivia, clivies, flame lily, kaffir lily, klivia, September lily)

Eschscholzia californica (bottlestopper, California poppy, desert trumpet, golden poppy, sunlight poppy)

Kalmia latifolia (calico bush, ivy bush, laurel, mountain ivy, mountain laurel, sheepkill, spoonwood)

Papaver spp. (blue Himalayan poppy, blue poppy, corn poppy, field poppy, Flanders poppy, Oriental poppy, poppy, red poppy) (see Figure A2.32)

Paris quadrifolia (herb Paris, true lover's know)

Pieris spp. (fetterbush, lily‐of‐the‐valley shrub, mountain andromeda, pieris)

Rhododendron spp. (azalea, rhododendron, rosebay)

Dilated Pupils

Asclepias spp. (annual milkweed, asclepias, blood flower, blunt‐leaved milkweed, butterfly weed, chieger flower, chiggerflower, clasping milkweed, fleshy milkweed, green antelopehorn, Indian paintbrush, Indian root, marsh milkweed, milkweed, pleurisy root, poke milkweed, sand milkweed, scarlet milkweed, sunset flower, swallow wort, swamp butterfly weed, tropical milkweed, whorled milkweed)

Atropa bella‐donna (belladonna, deadly nightshade)

Brugmansia spp. (angel's trumpet, tree datura)

Conium maculatum (deadly hemlock, poison fool's parsley, poison hemlock, poison parsley, spotted hemlock) (see Figure A2.33)

Datura spp. (angel's trumpet, death angel, devil's trumpet, downy thornapple, horn of plenty, jimsonweed, metel, prickly burr, stinkweed, thornapple, tree datura)

Dracaena spp. (African spear, Brazil Saint Barbara sword, Chinese water bamboo, corn plant, cornstalk plant, cylindrical snake plant, dracaena, dragon tree, Florida beauty, friendship bamboo, gold dust, golden birds nest, good luck plant, Janet Craig plant, lucky bamboo, mother‐in‐law's tongue, ribbon plant, snake plant, spear sansevieria, spotted dracaena, striped dragon palm, Warneckii, water bamboo)

Euphorbia lactea (candelabra cactus, dragon bones, false cactus, milkstripe euphorbia, mottled candlestick, mottled spurge)

Figure A2.32. Papaver spp.

Photograph courtesy of Tina Wismer.

Euphorbia resinifera (Africa spurge, euphorbium, resin spurge, staghorn coral)

Euphorbia tirucalli (African mild bush, azeloz, finger tree, Indian tree spurge, milkbush, pencil cactus, pencil tree, petroleum plant, rubber euphorbia, sticks of fire)

Hedera spp. (Algerian ivy, Baltic ivy, branching ivy, Canary Island ivy, Coney Island ivy, English ivy, glacier ivy, Madeira ivy, needlepoint ivy, Persian ivy, sweetheart ivy)

Helleborus spp. (Christmas rose, dungwort, hellebore, Lenten rose, setterwort, stinkwort, winter rose)

Heptapleurum spp. (Australian ivy palm, Hawaiian umbrella tree, octopus tree, parasol plant, schefflera, umbrella tree) (see Figure A2.13)

Hura crepitans (assacu, jabillo, monkey no‐climb, possumwood, sandbox tree, monkey pistol)

Hyoscyamus niger (black henbane, henbane, hog's bean, stinking nightshade, witches herb)

Ipomoea spp. (cardinal climber, Cypress vine, firecreacker vine, fire vine, flying saucers, grannyvine, hearts and honey vine, Indian potato, man‐of‐the‐earth, manroot, moonflower, moonvine, morning glory, redstar, scarlet creeper, Spanish flag, sweet potato, sweet potato vine, wild potato vine)

Figure A2.33. Conium spp.

Photograph courtesy of Jenny Schuett.

Lophophora williamsii (mescal, mescal buttons, peyote)

Polyscias spp. (aralia, coffee tree, dinner plate aralia, ming aralia, parsley aralia, wild coffee)

Solanum dulcamara (bitter nightshade, bittersweet, bittersweet nightshade, blue blindweed, blue nightshade, climbing nightshade, devil's apple, European bittersweet, felonwort, felonwood, poisonous nightshade, scarlet berry, snakeberry, soda apple, violet bloom, wolfgrape, woody nightshade)

Solanum lycopersicum (tomato)

Solanum nigrum (blackberry nightshade, black nightshade, common nightshade, European black nightshade, garden nightshade, poisonberry)

Solanum tuberosum (Irish potato, pomme de terre, potato, white potato)

Taxus spp. (yew)

Vernicia fordii (tung nut, tung oil tree)

Hyperexcitability, Muscle Twitches

Aesculus spp. (bottlebrush buckeye, buckeye, firecracker plant, horse chestnut, red buckeye)

Atropa bella‐donna (belladonna, deadly nightshade)

Brunfelsia spp. (Brazil raintree, brunfelsia, Franciscan raintree, kiss‐me‐quick, lady‐of‐the‐night, morning‐noon‐and‐night, yesterday‐today‐and‐tomorrow)

Cannabis sativa (bhang, bud, dope, doobie, ganja, grass, hash, hashish, marijuana, mary jane, pot, weed)

Coffea arabica (Arabian coffee, coffee, coffee plant)

Corydalis spp. (bulbous corydalis, fitweed, fumitory, golden corydalis, scrambled eggs)

Daphne spp. (daphne, dwarf bay, mezereon, paradise plant, spurge flax, spurge laurel, winter daphne)

Datura spp. (angel's trumpet, death angel, devil's trumpet, downy thornapple, horn of plenty, jimsonweed, metel, prickly burr, stinkweed, thornapple, tree datura)

Hyoscyamus niger (black henbane, henbane, hog's bean, stinking nightshade, witches herb)

Kalmia latifolia (calico bush, ivy bush, laurel, mountain ivy, mountain laurel, sheepkill, spoonwood)

Laburnum anagyroides (common laburnum, golden chain tree, golden rain tree) (see Figure A2.17)

Pieris spp. (fetterbush, lily‐of‐the‐valley shrub, mountain andromeda, pieris)

Rhododendron spp. (azalea, rhododendron, rosebay)

Hallucination, Behavioral Changes

Atropa bella‐donna (belladonna, deadly nightshade)

Brugmansia spp. (angel's trumpet, tree datura)

Cannabis sativa (bhang, bud, dope, doobie, ganja, grass, hash, hashish, marijuana, mary jane, pot, weed)

Catharanthus roseus (annual vinca, Madagascar periwinkle, periwinkle, rose periwinkle, running myrtle, vinca)

Datura spp. (angel's trumpet, death angel, devil's trumpet, downy thornapple, horn of plenty, jimsonweed, metel, prickly burr, stinkweed, thornapple, tree datura)

Dryopteris spp. (autumn fern, buckler fern, evergreen wood fern, fancy fern, glandular wood fern, Goldie's fern, log fern, male fern, narrow swamp fern, shield fern, spinulose wood fern, toothed wood fern, wood fern)

Helleborus spp. (Christmas rose, dungwort, hellebore, Lenten rose, setterwort, stinkwort, winter rose)

Hyoscyamus niger (black henbane, henbane, hog's bean, stinking nightshade, witches herb)

Ipomoea spp. (cardinal climber, Cypress vine, firecreacker vine, fire vine, flying saucers, grannyvine, hearts and honey vine, Indian potato, man‐of‐the‐earth, manroot, moonflower, moonvine, morning glory, redstar, scarlet creeper, Spanish flag, sweet potato, sweet potato vine, wild potato vine)

Laburnum anagyroides (common laburnum, golden chain tree, golden rain tree) (see Figure A2.17)

Lophophora williamsii (mescal, mescal buttons, peyote)

Myristica fragrans (nutmeg)

Sophora spp. (Eve's necklace, David's mountain laurel, frijolillo, mescal bean, mountain laurel, necklace tree, pink sophora, sophora, Texas mountain laurel, Texas sophora)

Trembling, Ataxia, Weakness, Depression

Aconitum spp. (aconite, blue rocket, devil's helmet, helment flower, leopard's bane, monkshood, queen of poisons, wolfsbane, woman's bane) (see Figure A2.1)

Aesculus spp. (bottlebrush buckeye, buckeye, firecracker plant, horse chestnut, red buckeye)

Ageratina altissima (fall poison, richweed, tremetol, white snakeroot)

Ageratum houstonianum (ageratum, blue billygoatweed, bluemink, floss flower, Mexican ageratum)

Albizia julibrissin (mimosa, silk tree)

Amaryllis spp. (amaryllis, belladonna lily, cape belladonna, naked lady, saint Joseph lily)

Asclepias spp. (annual milkweed, asclepias, blood flower, blunt‐leaved milkweed, butterfly weed, chieger flower, chiggerflower, clasping milkweed, fleshy milkweed, green antelopehorn, Indian paintbrush, Indian root, marsh milkweed, milkweed, pleurisy root, poke milkweed, sand milkweed, scarlet milkweed, sunset flower, swallow wort, swamp butterfly weed, tropical milkweed, whorled milkweed)

Brunfelsia spp. (Brazil raintree, brunfelsia, Franciscan raintree, kiss‐me‐quick, lady‐of‐the‐night, morning‐noon‐and‐night, yesterday‐today‐and‐tomorrow)

Bryonia spp. (red bryony, white bryony)

Buxus sempervirens (American boxwood, boxwood, common box, common boxwood, European box)

Caulophyllum thalictroides (blue cohosh)

Cicuta maculata (beaver poison, cowbane, poison parsnip, spotted hemlock, water hemlock)

Conium maculatum (deadly hemlock, poison fool's parsley, poison hemlock, poison parsley, spotted hemlock) (see Figure A2.33)

Corydalis spp. (bulbous corydalis, fitweed, fumitory, golden corydalis, scrambled eggs)

Cycas spp. (cycad, sago palm)

Cynoglossum amabile (blue showers, Chinese forget‐me‐not, hound's tongue)

Daphne spp. (daphne, dwarf bay, mezereon, paradise plant, spurge flax, spurge laurel, winter daphne)

Delphinium spp. (delphinium, larkspur, staggerweed)

Dicentra spp. (bleeding heart, dutchman's breeches, squirrel corn, steer's head, turkey corn) (see Figure A2.8)

Digitalis spp. (dead men's fingers, foxglove, long purples)

Dracaena spp. (African spear, Brazil Saint Barbara sword, Chinese water bamboo, corn plant, cornstalk plant, cylindrical snake plant, dracaena, dragon tree, Florida beauty, friendship bamboo, gold dust, golden birds nest, good luck plant, Janet Craig plant, lucky bamboo, mother‐in‐law's tongue, ribbon plant, snake plant, spear sansevieria, spotted dracaena, striped dragon palm, Warneckii, water bamboo)

Equisetum spp. (common horsetail, field horsetail, horsetail, scouring rush, western horsetail) (see Figure A2.34)

Erythrina herbacea (cardinal‐spear, Cherokee‐bean, coral bean, red cardinal)

Gloriosa spp. (cat's claw, climbing lily, flame lily, flame‐of‐the‐woods, gloriosa lily, glory flower, glory lily, superb lily, tiger's claw) (see Figure A2.12)

Heptapleurum spp. (Australian ivy palm, Hawaiian umbrella tree, octopus tree, parasol plant, schefflera, umbrella tree) (see Figure A2.13)

Hyacinthoides hispanica (Spanish bluebell, wood hyacinth)

Juglans nigra (black walnut) (see Figure A2.35)

Kalanchoe spp. (chandelier plant, devil's backbone, kalanchoe, mother‐in‐law‐plant, mother of millions, mother of thousands, silver teaspoons)

Lactuca virosa (bitter lettuce, opium lettuce, poisonous lettuce, wild lettuce)

Lantana spp. (lantana, pole cat geranium, red sage, Sellow's lantana, shrub verbena, trailing lantana, trailing shrubverbena, wild verbena, yellow sage)

Lilium spp. (Asiatic lily, Asian lily, Carolina lily, Easter lily, Formosa lily, Gray's lily, leopard lily, lily, Madonna lily, Northern red lily, orange bell lily, Oriental lily, pine lily, red lily, regal lily, roan lily, royal lily, rubrum lily, spotted lily, tiger lily, trumpet lily, Turk's cap lily, wild lily, wood lily)

Figure A2.34. Equisetum spp.

Photograph courtesy of Tina Wismer.

Lobelia spp. (blue cardinal flower, cardinal flower, Indian pink, Indian tobacco, lobelia)

Lupinus spp. (hairy lupine, lupine, spreading lupine, wild lupine) (see Figure A2.19)

Macadamia integrifolia (Australian nut, macadamia nut, Queensland nut)

Melia azedarach (bead tree, China ball tree, Chinaberry, China tree, Japanese bead tree, Persian lilac, pride‐of‐India, syringa, Texas umbrella tree, white cedar)

Narcissus spp. (daffodil, jonquil, trumpet narcissus) (see Figure A2.22)

Nicotiana spp. (flowering tobacco, jasmine tobacco, mustard tree, nicotiana, sweet tobacco, tobacco, tree tobacco, white shooting stars, white tobacco) (see Figure A2.23)

Papaver spp. (blue Himalayan poppy, blue poppy, corn poppy, field poppy, Flanders poppy, Oriental poppy, poppy, red poppy) (see Figure A2.32)

Pieris spp. (fetterbush, lily‐of‐the‐valley shrub, mountain andromeda, pieris)

Polyscias spp. (aralia, coffee tree, dinner plate aralia, ming aralia, parsley aralia, wild coffee)

Rhododendron spp. (azalea, rhododendron, rosebay)

Solanum dulcamara (bitter nightshade, bittersweet, bittersweet nightshade, blue blindweed, blue nightshade, climbing nightshade, devil's apple, European bittersweet, felonwort, felonwood, poisonous nightshade, scarlet berry, snakeberry, soda apple, violet bloom, wolfgrape, woody nightshade)

Figure A2.35. Juglans nigra still inside its hull.

Photograph courtesy of Jenny Schuett.

Solanum tuberosum (Irish potato, pomme de terre, potato, white potato)

Solanum nigrum (blackberry nightshade, black nightshade, common nightshade, European black nightshade, garden nightshade, poisonberry)

Sophora spp. (Eve's necklace, David's mountain laurel, frijolillo, mescal bean, mountain laurel, necklace tree, pink sophora, sophora, Texas mountain laurel, Texas sophora)

Urtica spp. (common nettle, stinging nettle)

Zamia spp. (cardboard palm, chigua, coontie, cycad, fern palm, Florida arrowroot, koo, maw'‐ti‐ree‐na, sago palm)

Zephyranthes spp. (atamasco lily, fairy lily, rainflower, rain lily, zephyr lily)

Paralysis

Aconitum spp. (aconite, blue rocket, devil's helmet, helmet flower, leopard's bane, monkshood, queen of poisons, wolfsbane, woman's bane) (see Figure A2.1)

Brugmansia spp. (angel's trumpet, tree datura)

Clivia spp. (bush lily, cape clivia, clivia lily, clivia, clivies, flame lily, kaffir lily, klivia, September lily)

Colchicum spp. (autumn crocus, meadow saffron, mysteria, naked ladies, wonder bulb)

Conium maculatum (deadly hemlock, poison fool's parsley, poison hemlock, poison parsley, spotted hemlock) (see Figure A2.33)

Cyclamen spp. (alpine violet, cyclamen, Persian violet, sowbread) (see Figure A2.7)

Cytisus spp. (common broom, English broom, Portuguese broom, Scotch broom, Scottish broom, striated broom)

Delphinium spp. (delphinium, larkspur, staggerweed)

Erythrina herbacea (cardinal‐spear, Cherokee‐bean, coral bean, red cardinal)

Hippeastrum spp. (amaryllis, dutch amaryllis, fire lily)

Kalmia latifolia (calico bush, ivy bush, laurel, mountain ivy, mountain laurel, sheepkill, spoonwood)

Karwinskia humboldtiana (coyotilla, cacachila, tullidora)

Pieris spp. (fetterbush, lily‐of‐the‐valley shrub, mountain andromeda, pieris)

Rhododendron spp. (azalea, rhododendron, rosebay)

Scadoxus multiflorus (African blood lily, blood lily, cape tulip, pincushion flower, powderpuff lily)

Veratrum spp. (American white hellebore, corn lily, false hellebore, hellebore, Indian poke)

Zigadenus glaberrimus (camas, large death camus, large‐flowered Zigadenus, sandbog deathcamas, snakeroot)

Convulsions

Albizia julibrissin (mimosa, silk tree)

Amaryllis spp. (amaryllis, belladonna lily, cape belladonna, naked lady, saint Joseph lily)

Asclepias spp. (annual milkweed, asclepias, blood flower, blunt‐leaved milkweed, butterfly weed, chieger flower, chiggerflower, clasping milkweed, fleshy milkweed, green antelopehorn, Indian paintbrush, Indian root, marsh milkweed, milkweed, pleurisy root, poke milkweed, sand milkweed, scarlet milkweed, sunset flower, swallow wort, swamp butterfly weed, tropical milkweed, whorled milkweed)

Bowiea volubilis (climbing onion, Zulu potato)

Brugmansia spp. (angel's trumpet, tree datura)

Brunfelsia spp. (Brazil raintree, brunfelsia, Franciscan raintree, kiss‐me‐quick, lady‐of‐the‐night, morning‐noon‐and‐night, yesterday‐today‐and‐tomorrow)

Buxus sempervirens (American boxwood, boxwood, common box, common boxwood, European box)

Cicuta maculata (beaver poison, cowbane, poison parsnip, spotted hemlock, water hemlock)

Colchicum spp. (autumn crocus, meadow saffron, mysteria, naked ladies, wonder bulb)

Corydalis spp. (bulbous corydalis, fitweed, fumitory, golden corydalis, scrambled eggs)

Cycas spp. (cycad, sago palm)

Cyclamen spp. (alpine violet, cyclamen, Persian violet, sowbread) (see Figure A2.7)

Cytisus spp. (common broom, English broom, Portuguese broom, Scotch broom, Scottish broom, striated broom)

Dicentra spp. (bleeding heart, dutchman's breeches, squirrel corn, steer's head, turkey corn) (see Figure A2.8)

Drimia maritima (maritime squill, red squill, sea onion, sea squill, squill)

Euphorbia lactea (candelabra cactus, dragon bones, false cactus, milkstripe euphorbia, mottled candlestick, mottled spurge)

Euphorbia resinifera (Africa spurge, euphorbium, resin spurge, staghorn coral)

Euphorbia tirucalli (African mild bush, azeloz, finger tree, Indian tree spurge, milkbush, pencil cactus, pencil tree, petroleum plant, rubber euphorbia, sticks of fire)

Galanthus spp. (snowdrop) (see Figure A2.11)

Gelsemium sempervirens (Carolina jessamine, yellow jessamine)

Hedera spp. (Algerian ivy, Baltic ivy, branching ivy, Canary Island ivy, Coney Island ivy, English ivy, glacier ivy, Madeira ivy, needlepoint ivy, Persian ivy, sweetheart ivy)

Heptapleurum spp. (Australian ivy palm, Hawaiian umbrella tree, octopus tree, parasol plant, schefflera, umbrella tree) (see Figure A2.13)

Hura crepitans (assacu, jabillo, monkey no‐climb, possumwood, sandbox tree, monkey pistol)

Laburnum anagyroides (common laburnum, golden chain tree, golden rain tree) (see Figure A2.17)

Melia azedarach (bead tree, China ball tree, Chinaberry, China tree, Japanese bead tree, Persian lilac, pride‐of‐India, syringa, Texas umbrella tree, white cedar)

Nicotiana spp. (flowering tobacco, jasmine tobacco, mustard tree, nicotiana, sweet tobacco, tobacco, tree tobacco, white shooting stars, white tobacco) (see Figure A2.23)

Polyscias spp. (aralia, coffee tree, dinner plate aralia, ming aralia, parsley aralia, wild coffee)

Ricinus communis (African wonder tree, castor bean, castor oil plant, mole bean plant)

Robinia pseudoacacia (black locust, common locust, false acacia, green locust, pea flower locust, white locust, yellow locust)

Scilla spp. (autumn squill, blue squill, Cuban lily, Siberian squill, two‐leaved squill)

Tanacetum vulgare (bitter buttons, common tansy, cow bitter, garden tansy, golden buttons, tansy)

Thuja occidentalis (American arborvitae, eastern white cedar, northern white cedar)

Vernicia fordii (tung nut, tung oil tree)

Zamia spp. (cardboard palm, chigua, coontie, cycad, fern palm, Florida arrowroot, koo, maw'‐ti‐ree‐na, sago palm)

Unconsciousness/Coma

Acorus calamus (sweet‐flag)

Ageratina altissima (fall poison, richweed, tremetol, white snakeroot)

Ageratum houstonianum (ageratum, blue billygoatweed, bluemink, floss flower, Mexican ageratum)

Amaryllis spp. (amaryllis, belladonna lily, cape belladonna, naked lady, Saint Joseph lily)

Armoracia rusticana (horseradish, red cole)

Atropa bella‐donna (belladonna, deadly nightshade)

Cicuta maculata (beaver poison, cowbane, poison parsnip, spotted hemlock, water hemlock)

Conium maculatum (deadly hemlock, poison fool's parsley, poison hemlock, poison parsley, spotted hemlock) (see Figure A2.33)

Cycas spp. (cycad, sago palm)

Daphne spp. (daphne, dwarf bay, mezereon, paradise plant, spurge flax, spurge laurel, winter daphne)

Datura spp. (angel's trumpet, death angel, devil's trumpet, downy thornapple, horn of plenty, jimsonweed, metel, prickly burr, stinkweed, thornapple, tree datura)

Eschscholzia californica (bottlestopper, California poppy, desert trumpet, golden poppy, sunlight poppy)

Hedera spp. (Algerian ivy, Baltic ivy, branching ivy, Canary Island ivy, Coney Island ivy, English ivy, glacier ivy, Madeira ivy, needlepoint ivy, Persian ivy, sweetheart ivy)

Hura crepitans (assacu, jabillo, monkey no‐climb, possumwood, sandbox tree, monkey pistol)

Hyoscyamus niger (black henbane, henbane, hog's bean, stinking nightshade, witches herb)

Kalmia latifolia (calico bush, ivy bush, laurel, mountain ivy, mountain laurel, sheepkill, spoonwood)

Lobelia spp. (blue cardinal flower, cardinal flower, Indian pink, Indian tobacco, lobelia)

Melia azedarach (bead tree, China ball tree, Chinaberry, China tree, Japanese bead tree, Persian lilac, pride‐of‐India, syringa, Texas umbrella tree, white cedar)

Nicotiana spp. (flowering tobacco, jasmine tobacco, mustard tree, nicotiana, sweet tobacco, tobacco, tree tobacco, white shooting stars, white tobacco) (see Figure A2.23)

Oxalis spp. (clover, good luck plant, lemon clover, love plant, lucky clover, oxalis, pickle plant, shamrock, sorrel, sourgrass, sours, wood sorrel)

Papaver spp. (blue Himalayan poppy, blue poppy, corn poppy, field poppy, Flanders poppy, Oriental poppy, poppy, red poppy) (see Figure A2.32)

Prunus spp. (apricot, bitter almond, cherry, cherry laurel, choke cherry, English laurel, flowering almond, hog plum, nectarine, peach, plum, sand cherry, skip cherry laurel, sloe plum, sour cherry)

Rhododendron spp. (azalea, rhododendron, rosebay)

Solanum tuberosum (Irish potato, pomme de terre, potato, white potato)

Sophora spp. (Eve's necklace, David's mountain laurel, frijolillo, mescal bean, mountain laurel, necklace tree, pink sophora, sophora, Texas mountain laurel, Texas sophora)

Taxus spp. (yew)

Zamia spp. (cardboard palm, chigua, coontie, cycad, fern palm, Florida arrowroot, koo, maw'‐ti‐ree‐na, sago palm)

Zantedeschia spp. (African lily, altar lily, arum lily, calla lily, Egyptian lily, lily of the Nile, pig lily, trumpet lily)

CARDIOVASCULAR

Aconitum spp. (aconite, blue rocket, devil's helmet, helment flower, leopard's bane, monkshood, queen of poisons, wolfsbane, woman's bane) (see Figure A2.1)

Amaryllis spp. (amaryllis, belladonna lily, cape belladonna, naked lady, Saint Joseph lily)

Apocynum spp. (amy root, bitter root, dogbane, dogbane hemp, Indian hemp, prairie dogbane)

Armoracia rusticana (horseradish, red cole)

Arnica montana (arnica, arnica root, leopard's bane, mountain arnica, mountain snuff, mountain tobacco, wolfbane)

Atropa bella‐donna (belladonna, deadly nightshade)

Bowiea volubilis (climbing onion, Zulu potato)

Brugmansia spp. (angel's trumpet, tree datura)

Cascabela thevetia (be‐still tree, lucky nut, yellow oleander)

Cestrum spp. (cestrum, jessamine, night blooming jasmine, night blooming jessamine, orange peel, yellow cestrum, yellow shrub jessamine)

Conium maculatum (deadly hemlock, poison fool's parsley, poison hemlock, poison parsley, spotted hemlock) (see Figure A2.33.)

Crocus sativus (autumn crocus, saffron, saffron crocus)

Cytisus spp. (common broom, English broom, Portuguese broom, Scotch broom, Scottish broom, striated broom)

Datura spp. (angel's trumpet, death angel, devil's trumpet, downy thornapple, horn of plenty, jimsonweed, metel, prickly burr, stinkweed, thornapple, tree datura)

Digitalis spp. (dead men's fingers, foxglove, long purples)

Drimia maritima (maritime squill, red squill, sea onion, sea squill, squill)

Euonymus spp. (burning bush, corky spindletree, hearts‐a‐bustin', Indian arrow wood, spindletree, strawberry bush, wahoo, winged euonymus, wintercreeper)

Galanthus spp. (snowdrop) (see Figure A2.11)

Gloriosa spp. (cat's claw, climbing lily, flame lily, flame‐of‐the‐woods, gloriosa lily, glory flower, glory lily, superb lily, tiger's claw) (see Figure A2.12)

Glycyrrhiza glabra (black sugar, common licorice, licorice, liquorice, mulaith, sweetwood)

Hedera spp. (Algerian ivy, Baltic ivy, branching ivy, Canary Island ivy, Coney Island ivy, English ivy, glacier ivy, Madeira ivy, needlepoint ivy, Persian ivy, sweetheart ivy)

Helleborus spp. (Christmas rose, dungwort, hellebore, Lenten rose, setterwort, stinkwort, winter rose)

Heptapleurum spp. (Australian ivy palm, Hawaiian umbrella tree, octopus tree, parasol plant, schefflera, umbrella tree) (see Figure A2.13)

Hippeastrum spp. (amaryllis, dutch amaryllis, fire lily)

Hyoscyamus niger (black henbane, henbane, hog's bean, stinking nightshade, witches herb)

Ipomoea spp. (cardinal climber, Cypress vine, firecreacker vine, fire vine, flying saucers, grannyvine, hearts and honey vine, Indian potato, man‐of‐the‐earth, manroot, moonflower, moonvine, morning glory, redstar, scarlet creeper, Spanish flag, sweet potato, sweet potato vine, wild potato vine)

Kalanchoe spp. (chandelier plant, devil's backbone, kalanchoe, mother‐in‐law‐plant, mother of millions, mother of thousands, silver teaspoons)

Kalmia latifolia (calico bush, ivy bush, laurel, mountain ivy, mountain laurel, sheepkill, spoonwood)

Ligustrum spp. (amur, common privet, privet, wax leaf)

Lobelia spp. (blue cardinal flower, cardinal flower, Indian pink, Indian tobacco, lobelia)

Lupinus spp. (hairy lupine, lupine, spreading lupine, wild lupine) (see Figure A2.19)

Narcissus spp. (daffodil, jonquil, trumpet narcissus) (see Figure A2.22)

Nerium oleander (kaner, oleander, rosebay, rose laurel)

Nicotiana spp. (flowering tobacco, jasmine tobacco, mustard tree, nicotiana, sweet tobacco, tobacco, tree tobacco, white shooting stars, white tobacco) (see Figure A2.23)

Ornithogalum spp. (Cape hyacinth, spire lily, star‐of‐Bethlehem, summer hyacinth)

Periploca sepium (Chinese silk vine, silk vine)

Persea americana (alligator pear, avocado)

Phaseolus vulgaris (bean, green bean)

Pieris spp. (fetterbush, lily‐of‐the‐valley shrub, mountain andromeda, pieris)

Polyscias spp. (aralia, coffee tree, dinner plate aralia, ming aralia, parsley aralia, wild coffee)

Rhododendron spp. (azalea, rhododendron, rosebay)

Ricinus communis (African wonder tree, castor bean, castor oil plant, mole bean plant)

Robinia pseudoacacia (black locust, common locust, false acacia, green locust, pea flower locust, white locust, yellow locust)

Scilla spp. (autumn squill, blue squill, Cuban lily, Siberian squill, two‐leaved squill)

Solanum tuberosum (Irish potato, pomme de terre, potato, white potato)

Tanacetum vulgare (bitter buttons, common tansy, cow bitter, garden tansy, golden buttons, tansy)

Taxus spp. (yew)

Tulipa spp. (tulip)

Urtica spp. (common nettle, stinging nettle)

Veratrum spp. (American white hellebore, corn lily, false hellebore, hellebore, Indian poke)

Vinca spp. (blue buttons, periwinkle, running myrtle, vinca)

Zephyranthes spp. (atamasco lily, fairy lily, rainflower, rain lily, zephyr lily)

Zigadenus glaberrimus (camas, large death camus, large‐flowered Zigadenus, sandbog deathcamas, snakeroot)

Respiratory

Dyspnea, Cyanosis

Alocasia spp. (elephant's ear, giant taro, Persian palm, Yucatan princess)

Anthurium spp. (anthurium, flamingo flower, flamingo lily, fleabane, oilcloth flower, painter's pallet, pigtail plant, tailflower) (see Figure A2.2)

Arnica montana (arnica, arnica root, leopard's bane, mountain arnica, mountain snuff, mountain tobacco, wolfbane)

Arum spp. (Adam and Eve, arum, arum lilies, black calla, bobbins, cuckoo's pint, Italian arum, Italian lily, lords and ladies, orange candle flower, Solomon's lily, starch root, wake robin, wild arum, wild calla) (see Figure A2.3)

Buxus sempervirens (American boxwood, boxwood, common box, common boxwood, European box)

Caladium spp. (angel wings, caladium, elephant's ear, exposition, fancy‐leaved caladium, mother‐in‐law plant, pai, pink cloud, stoplight, Texas wonder, via, via sori)

Cestrum spp. (cestrum, jessamine, night blooming jasmine, night blooming jessamine, orange peel, yellow cestrum, yellow shrub jessamine)

Corydalis spp. (bulbous corydalis, fitweed, fumitory, golden corydalis, scrambled eggs)

Dicentra spp. (bleeding heart, dutchman's breeches, squirrel corn, steer's head, turkey corn) (see Figure A2.8)

Dieffenbachia spp. (dieffenbachia, dumbcane, exotica, leopard lily, tropic snow)

Epipremnum aureum (devil's ivy, devil's vine, golden pothos, ivy arum, marble queen, pothos, taro vine)

Eschscholzia californica (bottlestopper, California poppy, desert trumpet)

Monstera spp. (ceriman, cutleaf philodendron, hurricane plant, Mexican breadfruit, split‐leaf philodendron, swiss cheese plant) (see Figures A2.20 and A2.21)

Philodendron spp. (heart leaf philodendron, parlor ivy, philodendron, sweetheart plant) (see Figure A2.24)

Prunus spp. (apricot, bitter almond, cherry, cherry laurel, choke cherry, English laurel, flowering almond, hog plum, nectarine, peach, plum, sand cherry, skip cherry laurel, sloe plum, sour cherry)

Solanum tuberosum (Irish potato, pomme de terre, potato, white potato)

Syngonium podophyllum (African evergreen, American evergreen, arrow‐head vine, green gold naphthysis, nephthytis, trileaf wonder) (see Figure A2.28)

Tulipa spp. (tulip)

Urtica spp. (common nettle, stinging nettle)

Veratrum spp. (American white hellebore, corn lily, false hellebore, hellebore, Indian poke)

Zantedeschia spp. (African lily, altar lily, arum lily, calla lily, Egyptian lily, lily of the Nile, pig lily, trumpet lily)

Respiratory Depression or Paralysis

Aconitum spp. (aconite, blue rocket, devil's helmet, helment flower, leopard's bane, monkshood, queen of poisons, wolfsbane, woman's bane) (see Figure A2.1)

Asclepias spp. (annual milkweed, asclepias, blood flower, blunt‐leaved milkweed, butterfly weed, chieger flower, chiggerflower, clasping milkweed, fleshy milkweed, green antelopehorn, Indian paintbrush, Indian root, marsh milkweed, milkweed, pleurisy root, poke milkweed, sand milkweed, scarlet milkweed, sunset flower, swallow wort, swamp butterfly weed, tropical milkweed, whorled milkweed)

Atropa bella‐donna (belladonna, deadly nightshade)

Brugmansia spp. (angel's trumpet, tree datura)

Bryonia spp. (red bryony, white bryony)

Buxus sempervirens (American boxwood, boxwood, common box, common boxwood, European box)

Cannabis sativa (bhang, bud, dope, doobie, ganja, grass, hash, hashish, marijuana, mary jane, pot, weed)

Colchicum spp. (autumn crocus, meadow saffron, mysteria, naked ladies, wonder bulb)

Conium maculatum (deadly hemlock, poison fool's parsley, poison hemlock, poison parsley, spotted hemlock) (see Figure A2.33)

Cytisus spp. (common broom, English broom, Portuguese broom, Scotch broom, Scottish broom, striated broom)

Datura spp. (angel's trumpet, death angel, devil's trumpet, downy thornapple, horn of plenty, jimsonweed, metel, prickly burr, stinkweed, thornapple, tree datura)

Delphinium spp. (delphinium, larkspur, staggerweed)

Erythrina herbacea (cardinal‐spear, Cherokee‐bean, coral bean, red cardinal)

Gloriosa spp. (cat's claw, climbing lily, flame lily, flame‐of‐the‐woods, gloriosa lily, glory flower, glory lily, superb lily, tiger's claw) (see Figure A2.12)

Hyoscyamus niger (black henbane, henbane, hog's bean, stinking nightshade, witches herb)

Laburnum anagyroides (common laburnum, golden chain tree, golden rain tree) (see Figure A2.17)

Lupinus spp. (hairy lupine, lupine, spreading lupine, wild lupine) (see Figure A2.19)

Nicotiana spp. (flowering tobacco, jasmine tobacco, mustard tree, nicotiana, sweet tobacco, tobacco, tree tobacco, white shooting stars, white tobacco) (see Figure A2.23)

Papaver spp. (blue Himalayan poppy, blue poppy, corn poppy, field poppy, Flanders poppy, Oriental poppy, poppy, red poppy) (see Figure A2.32)

Rhododendron spp. (azalea, rhododendron, rosebay)

Solanum dulcamara (bitter nightshade, bittersweet, bittersweet nightshade, blue blindweed, blue nightshade, climbing nightshade, devil's apple, European bittersweet, felonwort, felonwood, poisonous nightshade, scarlet berry, snakeberry, soda apple, violet bloom, wolfgrape, woody nightshade)

Taxus spp. (yew)

Veratrum spp. (American white hellebore, corn lily, false hellebore, hellebore, Indian poke)

RENAL

Bryonia spp. (red bryony, white bryony)

Cestrum spp. (cestrum, jessamine, night blooming jasmine, night blooming jessamine, orange peel, yellow cestrum, yellow shrub jessamine)

Crocus sativus (autumn crocus, saffron, saffron crocus)

Gloriosa spp. (cat's claw, climbing lily, flame lily, flame‐of‐the‐woods, gloriosa lily, glory flower, glory lily, superb lily, tiger's claw) (see Figure A2.12)

Glycyrrhiza glabra (black sugar, common licorice, licorice, liquorice, mulaith, sweetwood)

Lilium spp. (Asiatic lily, Asian lily, Carolina lily, Easter lily, Formosa lily, Gray's lily, leopard lily, lily, Madonna lily, Northern red lily, orange bell lily, Oriental lily, pine lily, red lily, regal lily, roan lily, royal lily, rubrum lily, spotted lily, tiger lily, trumpet lily, Turk's cap lily, wild lily, wood lily) – CATS ONLY

Quercus spp. (oak)

Rheum rhabarbarum (pie plant, rhubarb)

Ricinus communis (African wonder tree, castor bean, castor oil plant, mole bean plant)

Robinia pseudoacacia (black locust, common locust, false acacia, green locust, pea flower locust, white locust, yellow locust)

Thuja occidentalis (American arborvitae, Eastern white cedar, Northern white cedar)

Calcium Oxalate Crystalluria

Acorus calamus (sweet‐flag)

Aglaonema spp. (Chinese evergreen, golden evergreen, painted drop tongue, Philippine evergreen, poison dart plant)

Arum spp. (Adam and Eve, arum, arum lilies, black calla, bobbins, cuckoo's pint, Italian arum, Italian lily, lords and ladies, orange candle flower, Solomon's lily, starch root, wake robin, wild arum, wild calla) (see Figure A2.3)

Caladium spp. (angel wings, caladium, elephant's ear, exposition, fancy‐leaved caladium, mother‐in‐law plant, pai, pink cloud, stoplight, Texas wonder, via, via sori)

Epipremnum aureum (devil's ivy, devil's vine, golden pothos, ivy arum, marble queen, pothos, taro vine)

Heptapleurum spp. (Australian ivy palm, Hawaiian umbrella tree, octopus tree, parasol plant, schefflera, umbrella tree) (see Figure A2.13)

Monstera spp. (ceriman, cutleaf philodendron, hurricane plant, Mexican breadfruit, split‐leaf philodendron, swiss cheese plant) (see Figures A2.20 and A2.21)

Oxalis spp. (clover, good luck plant, lemon clover, love plant, lucky clover, oxalis, pickle plant, shamrock, sorrel, sourgrass, sours, wood sorrel)

Syngonium podophyllum (African evergreen, American evergreen, arrow‐head vine, green gold naphthysis, nephthytis, trileaf wonder) (see Figure A2.28)

Zantedeschia spp. (African lily, altar lily, arum lily, calla lily, Egyptian lily, lily of the Nile, pig lily, trumpet lily)

Hematuria, Azotemia

Abrus precatorius (Buddhist rosary bead, crab's eyes, Indian bead, jequirity bean, love bean, prayer bean, precatory bean, rosary pea, Seminole bead)

Allium spp. (camphor of the poor, chives, elephant garlic, false garlic, garlic, green onion, hard neck garlic, leek, meadow garlic, nodding onion, onion, ornamental onion, nectar of the gods, ramps, rocambole, rustic treacle, scallion, serpent garlic, shallot, soft neck garlic, spring onion, stinking rose, wild garlic, wild leek, wild onion, wood garlic)

Ricinus communis (African wonder tree, castor bean, castor oil plant, mole bean plant)

Robinia pseudoacacia (black locust, common locust, false acacia, green locust, pea flower locust, white locust, yellow locust)

LIVER DAMAGE

Amaryllis spp. (amaryllis, belladonna lily, cape belladonna, naked lady, Saint Joseph lily)

Amsinckia spp. (fiddleneck, tarweed fiddleneck, tarweed)

Atractylis gummifera (Mediterranean thistle)

Borago officinalis (borage, cool tankard, cover crop, starflower, tailwort, talewort)

Cestrum spp. (cestrum, jessamine, night blooming jasmine, night blooming jessamine, orange peel, yellow cestrum, yellow shrub jessamine)

Crotalaria spp. (crotalaria, devil‐bean, rattlebox, rattlepod, rattleweed, shake shake)

Cycas spp. (cycad, sago palm)

Cynoglossum amabile (blue showers, Chinese forget‐me‐not, hound's tongue)

Echium spp. (adderwort, blue devil, blue echium, blueweed, cat's tail, Lady Campbell weed, Patterson's curse, purple bugloss, purple plague, Riverina bluebell, salvation Jane, snake flower, viper's bugloss)

Galanthus spp. (snowdrop) (see Figure A2.11)

Heliotropium spp. (cherry pie flower, garden heliotrope, heliotrope, monkey tail)

Lantana spp. (lantana, pole cat geranium, red sage, Sellow's lantana, shrub verbena, trailing lantana, trailing shrubverbena, wild verbena, yellow sage)

Narcissus spp. (daffodil, jonquil, trumpet narcissus) (see Figure A2.22)

Quercus spp. (oak)

Senecio spp. (birdseed, chickenweed, common butterweed, dog standard, dusty miller, golden ragwort, groundsel, old‐man‐in‐the‐spring, ragwort, senecio, staggerwort, stinking willie, tansy, tansy ragwort)

Symphytum officinale (black wort, boneset, bruise wort, comfrey, common comfrey, consound, knitbone, slippery‐root)

Thuja occidentalis (American arborvitae, eastern white cedar, northern white cedar)

Zamia spp. (cardboard palm, chigua, coontie, cycad, fern palm, Florida arrowroot, koo, maw'‐ti‐ree‐na, sago palm)

EMACIATION, ASCITES, EDEMA OF DEPENDENT EXTREMITIES; JAUNDICE; HEPATOENCEPHALOPATHY

Amsinckia spp. (fiddleneck, tarweed fiddleneck, tarweed)

Borago officinalis (borage, cool tankard, cover crop, starflower, tailwort, talewort)

Crotalaria spp. (crotalaria, devil‐bean, rattlebox, rattlepod, rattleweed, shake shake)

Cynoglossum amabile (blue showers, Chinese forget‐me‐not, hound's tongue)

Echium spp. (adderwort, blue devil, blue echium, blueweed, cat's tail, Lady Campbell weed, Patterson's curse, purple bugloss, purple plague, Riverina bluebell, salvation Jane, snake flower, viper's bugloss)

Heliotropium spp. (cherry pie flower, garden heliotrope, heliotrope, monkey tail)

Senecio spp. (birdseed, chickenweed, common butterweed, dog standard, dusty miller, golden ragwort, groundsel, old‐man‐in‐the‐spring, ragwort, senecio, staggerwort, stinking willie, tansy, tansy ragwort)

Symphytum officinale (black wort, boneset, bruise wort, comfrey, common comfrey, consound, knitbone, slippery‐root)

CONTACT DERMATITIS, EYE IRRITANTS, ALLERGENS

Acalypha hispida (bristly copperleaf, chenille plant, foxtail, Philippines medusa, red‐hot cattail)

Agapanthus spp. (agapanthus, African lily, lily of the Nile)

Aglaonema spp. (Chinese evergreen, golden evergreen, painted drop tongue, Philippine evergreen, poison dart plant)

Allamanda cathartica (allamanda, golden‐trumpet, golden trumpet vine, yellow allamanda)

Allium spp. (camphor of the poor, chives, elephant garlic, false garlic, garlic, green onion, hard neck garlic, leek, meadow garlic, nodding onion, onion, ornamental onion, nectar of the gods, ramps, rocambole, rustic treacle, scallion, serpent garlic, shallot, soft neck garlic, spring onion, stinking rose, wild garlic, wild leek, wild onion, wood garlic)

Anemone spp. (anemone, crowfoot, meadow anemone, Pasque flower, thimbleweed, windflower)

Armoracia rusticana (horseradish, red cole)

Arnica montana (arnica, arnica root, leopard's bane, mountain arnica, mountain snuff, mountain tobacco, wolfbane)

Arum spp. (Adam and Eve, arum, arum lilies, black calla, bobbins, cuckoo's pint, Italian arum, Italian lily, lords and ladies, orange candle flower, Solomon's lily, starch root, wake robin, wild arum, wild calla) (see Figure A2.3)

Bryonia spp. (red bryony, white bryony)

Capsicum annuum (cayenne pepper, chili pepper, ornamental pepper, pepper, sweet peppers)

Chrysanthemum spp. (autumn mum, chrysanthemum, florist's chrysanthemum, florist's daisy, hardy chrysanthemum, hardy garden mums, heritage mums, mums)

Clematis spp. (blue jasmine, clematis, leatherflower, old man's beard, traveller's joy, vase vine, virgin's bower, woodbine)

Codiaeum variegatum (croton, fire croton, garden croton, Joseph's coat, variegated croton) (see Figure A2.5)

Dieffenbachia spp. (dieffenbachia, dumbcane, exotica, leopard lily, tropic snow)

Dioscorea communis (black bryony, lady's‐seal, black bindweed)

Dioscorea polystachya (Chinese yam, cinnamon vine)

Dryopteris spp. (autumn fern, buckler fern, evergreen wood fern, fancy fern, glandular wood fern, Goldie's fern, log fern, male fern, narrow swamp fern, shield fern, spinulose wood fern, toothed wood fern, wood fern)

Epipremnum aureum (devil's ivy, devil's vine, golden pothos, ivy arum, marble queen, pothos, taro vine)

Eucalyptus spp. (argyle apple, eucalyptus, gum, lemon scented gum, silver dollar tree)

Euphorbia lactea (candelabra cactus, dragon bones, false cactus, milkstripe euphorbia, mottled candlestick, mottled spurge)

Euphorbia milii (Christ plant, Christ thorn, crown of thorns) (see Figure A2.9)

Euphorbia myrsinites (blue spurge, broad‐leaved glaucous spurge, creeping spurge, donkeytail, myrtle euphorbia, myrtle spurge)

Euphorbia pulcherrima (bird‐of‐paradise flower, Christmas flower, flame‐leaf flower, lobster flower, poinsettia) (see Figure A2.10)

Euphorbia resinifera (Africa spurge, euphorbium, resin spurge, staghorn coral)

Euphorbia tirucalli (African mild bush, azeloz, finger tree, Indian tree spurge, milkbush, pencil cactus, pencil tree, petroleum plant, rubber euphorbia, sticks of fire)

Euphorbia umbellata (African milk bush)

Ficus benjamina (Benjamin tree, Chinese banyan, fig, Indian rubber plant, weeping fig)

Gypsophila paniculata (baby's breath)

Hedera spp. (Algerian ivy, Baltic ivy, branching ivy, Canary Island ivy, Coney Island ivy, English ivy, glacier ivy, Madeira ivy, needlepoint ivy, Persian ivy, sweetheart ivy)

Helenium spp. (sneezeweed)

Iris spp. (bearded iris, blackberry lily, butterfly flower, candy lily, Chinese leopard flower, flag, fringed iris, iris, kakitsubata, leopard lily, netted iris, orchid lily, pardancanda, shaga, Siberian flag, snake lily, water flag, winter iris) (see Figure A2.16)

Lactuca virosa (bitter lettuce, opium lettuce, poisonous lettuce, wild lettuce)

Laurus nobilis (bay laurel, bay leaf tree, bay tree, Grecian laurel, laurel, laurel tree, sweet bag, sweet bay, tree laurel, true laurel)

Monstera spp. (ceriman, cutleaf philodendron, hurricane plant, Mexican breadfruit, split‐leaf philodendron, swiss cheese plant) (see Figures A2.20 and A2.21)

Narcissus spp. (daffodil, jonquil, trumpet narcissus) (see Figure A2.22)

Pelargonium spp. (geranium, ivy geranium, scented geranium)

Philodendron spp. (heart leaf philodendron, parlor ivy, philodendron, sweetheart plant) (see Figure A2.24)

Physalis spp. (bladder cherry, cape gooseberry, Chinese lantern, ground cherry, husk tomato, jamberries, Jerusalem cherry, Mexican green tomato, miltomates, strawberry tomato, tomatillo)

Plumbago spp. (leadwort, plumbago)

Polyscias spp. (aralia, coffee tree, dinner plate aralia, ming aralia, parsley aralia, wild coffee)

Primula obconica (German primrose, poison primrose, primrose)

Pulsatilla vulgaris (meadow anemone, pasque flower, wind flower)

Ranunculus spp. (buttercress, buttercup, burwort, Carolina buttercup, crowfoot, dusky maiden, figwort, lesser celandine, Persian buttercup, pilewort, ranunculus, spearwort)

Spathiphyllum spp. (peace lily, Mauna Loa, spathe flower, white sails)

Tagetes spp. (African marigold, American marigold, Aztec marigold, big marigold, French marigold, hierbanis, marigold, Mexican marigold, Mexican tarragon, pericon, sweet mace, yerbaniz) (see Figure A2.29)

Thuja occidentalis (American arborvitae, eastern white cedar, northern white cedar)

Tolmiea menziesii (curiosity plant, mother of thousands, pick‐a‐back plant, pickaback plant, piggy back plant, youth on age)

Tradescantia spathecea (boat lily, Moses in a basket, Moses in the cradle, oyster plant) (see Figure A2.30)

Tulipa spp. (tulip)

Vernicia fordii (tung nut, tung oil tree)

Viscum spp. (European mistletoe)

Zantedeschia spp. (African lily, altar lily, arum lily, calla lily, Egyptian lily, lily of the Nile, pig lily, trumpet lily)

Primary Photosensitization

Ammi majus (bishop's weed, false Queen Anne's lace, greater ammi)

Dahlia spp. (bedding dahlia, dahlia)

Hypericum perforatum (common St. John's wort, goatweed, Klamath weed, St. John's wort)

Tagetes spp. (African marigold, American marigold, Aztec marigold, big marigold, French marigold, hierbanis, marigold, Mexican marigold, Mexican tarragon, pericon, sweet mace, yerbaniz) (see Figure A2.29)

SUDDEN DEATH

Digitalis spp. (dead men's fingers, foxglove, long purples)

Cascabela thevetia (be‐still tree, lucky nut, yellow oleander)

Cicuta maculata (beaver poison, cowbane, poison parsnip, spotted hemlock, water hemlock)

Laburnum anagyroides (common laburnum, golden chain tree, golden rain tree) (see Figure A2.17)

Nerium oleander (kaner, oleander, rosebay, rose laurel)

Taxus spp. (yew)

Veratrum spp. (American white hellebore, corn lily, false hellebore, hellebore, Indian poke)

Appendix 3
Plants Not Reported to be Toxic

Charlotte Means

Please note that many plants may have the same common name. These are considered non‐toxic for dogs and cats.

Abronia fragrans (fragrant sand verbena)

Achmea spp. (aechmea, silver vase plant, urn plant, vase plant)

Adonidia merrilli (Christmas palm, dwarf royal palm, Manila palm, Merrill palm)

Aeschynanthus spp. (lipstick plant, lipstick vine)

Alcea rosea (hollyhock)

Alsobia dianthiflora (chocolate soldier, episcia, lace flower, lace flower vine)

Alternanthera dentata (Joseph's coat, upright calico plant)

Anoectochilus setaceus (bristly Anoectochilus, golden jewel orchid, jewel orchid, king of the forest)

Ansellia africana (leopard orchid)

Antirrhinum majus (common snapdrapgon, garden snapdragon)

Aralia nudicaulis (wild sarsaparilla)

Arctotis stoechadifolia (African daisy, blue‐eyed African daisy, blue‐eyed daisy, cape daisy, South African daisy, white arctotis)

Aspidistra elatior (cast iron plant)

Asplenium bulbiferum (hen‐and‐chickens fern, mother fern, mother spleenwort, pikopiko)

Asplenium nidus (crispy wave fern)

Beaucarnea recurvata (bottle palm, ponytail palm)

Berberis aquifolium (creeping mahonia, holly‐leaved barberry, mountain grape, Oregon grape, Oregon holly, Oregon hollygrape, tall mahonia)

Bulbophyllum appendiculatum (cirrhopetalum, old world orchid, stinking bulbophyllum)

Calathea crotalifera (caeroba, calathea, maranta, peacock plant, prayer plant, rattle shaker, rattle snake plant, zebra plant)

Calendula officinalis (calendula, common marigold, garden marigold, gold bloom, holligold, marigold, Mary bud, pot marigold, ruddles)

Calochortus gunnisonii (butterfly tulip, cat ear, mariposa lily, star tulip)

Calochortus nuttalli (sego lily)

Callistephus chinensis (China aster)

Camellia japonica (camellia)

Canna edulis (achira, edible canna, tous‐les‐mois)

Canna generalis (canna lily, common garden canna)

Carya spp. (big shellbark hickory, bitternut, bitter pecan, bitter water hickory, broom hickory, hickory, king nut, mockernut hickory, pecan, pignut, pignut hickory, shagbark hickory, shellbark hickory, small‐fruited hickory, squarenut hickory, swamp hickory, water hickory, water pignut, white‐heart hickory)

Castanea spp. (sweet chestnut)

Cattleya forbesii (cocktail orchid, forbes cattleya)

Cattleya mossiae (crimson lipped cattleya, ruby lipped cattleya, Easter orchid)

Cattleya trianae (Christmas orchid, flor de mayo, may flower, winter cattleya)

Celosia spp. (celosia, cocks comb, fairy fountain, feathered amaranth, velvet flower) (see Figure A3.1)

Centaurea cyanus (bachelor's buttons, bluebottle, cornflower)

Figure A3.1. Celosia spp.

Photograph courtesy of Tina Wismer.

Cephalocereus senilis (bunny cactus, old man cactus, white Persian cat cactus)

Ceratonia siliqua (algaroba, carob, carob tree, kharoub, locust pods, Saint John's bread, sugar pod)

Ceratostigma plumbaginoides (blue leadwood, blue plumbago, dwarf plumbago, hardy plumbago, leadwort, perennial plumbago, plumbago, plumbago Larpentiae)

Ceratostigma willmottianum (Chinese leadwort, Chinese plumbago, hardy plumbago)

Chamaedorea spp. (bamboo palm, good luck palm, miniature fish tail palm, neanthe bella palm, neanthebella, parlor palm)

Chlorophytum comosum (spider plant)

Chlorophytum laxum (bichetti grass, false lily turf, Saint Bernard's lily, Siam lily, wheat plant)

Chrysojasminum floridum (flowering jasmine, showy jasmine)

Chrysojasminum fruticans (common yellow jasmine, wild jasmine)

Cissus alata (grape ivy, grape leaf ivy, oak leaf ivy, Venezuela treebine)

Clintonia umbellulata (Clinton's lily, speckled wood lily, white bluebead lily, white Clintonia)

Clintonia uniflora (bead lily, bride's‐bonnet, queencup, queen's cup)

Figure A3.2. Fruits of Crataegus ambigua (Russian hawthorn).

Photograph courtesy of Tina Wismer.

Cortaderia selloana (pampas grass, Uruguayan pampas grass)

Crataegus spp. (aubepine, black haw, black hawthorn, English hawthorn, haw apple, hawthorn, may bush, pirliteiro, thornapple, Washington hawthorn) (see Figure A3.2)

Crossandra infundibuliformis (crossandra, firecracker flower)

Cryptanthus spp. (color band, dwarf rose‐stripe star, earth star, pheasant tail, pheasant plant, pink starlite, silver star)

Cryptogramma crispa (parsley fern)

Cucumis anguria (bur gourd, maroon cucumber, West Indian gherkin)

Cucumis dipsaceus (Arabian cucumber, hedgehog gourd, teasel gourd)

Cucumis melo (cantaloupe, casaba melon, honeydew, melon, muskmelon)

Cucumis sativus (cucumber, gherkins)

Cuitlauzina pulchella (lily of the valley orchid, species orchid, beautiful cuitlauzina)

Cucurbita ficifolia (Asian pumpkin, black seed squash, chilacayote, cidra, fig‐leaf gourd, Malabar gourd)

Cucurbita maxima (banana squash, buttercup squash, Hubbard squash, kabocha squash, turban squash)

Cucurbita pepo cv var. turbinata (acorn squash)

Cymbalaria muralis (coliseum ivy, ivy‐leaved toadflax, Kenilworth ivy, mother‐of‐thousands, Oxford ivy, pennywort, wandering‐sailor)

Cyrtomium falcatum (fish tail fern, holly fern, Japanese holly fern)

Darlingtonia californica (California pitcher plant, cobra lily, cobra plant)

Davallia spp. (ball fern, deersfoot fern, hare's foot fern, shinobu fern, squirrel's foot fern, rabbit foot fern)

Delosperma nubigenum (cloud‐loving hardy ice plant, hardy ice plant)

Dendrobium monophyllym (lily of the valley orchid)

Dendrophylax lindenii (frog orchid, ghost leafless orchid, ghost orchid, leafless orchid, palm polly, white butterfly orchid, white frog orchid)

Deutzia gracilis (Japanese snow flower, slender deutzia)

Dichorisandra reginae (Queen's spiderwort)

Dichorisandra thyrsiflora (blue ginger)

Dionaea muscipula (Venus fly trap)

Dipterostemon capitatus (brodiaea, blue‐dicks, purplehead, wild hyacinth)

Echeveria agavoides (lipstick echeveria, molded wax agave)

Echeveria derenbergii (blue echeveria, copper rose, maroon chenille plant, painted lady, plush plant, wax rosette)

Echeveria elegans (Mexican gem, Mexican hens and chicks, Mexican snowball, white Mexican rose)

Echeveria multicaulis (copper rose, maroon, painted lady)

Echeveria secunda (blue echeveria, glaucous echeveria, old hen‐and‐chickens)

Echeveria setosa (firecracker echeveria, firecracker plant, hens and chicks, Mexican firecracker)

Echinops spp. (globe thistle)

Echinopsis spp. (Easter lily cactus)

Elaeagnus spp. (autumnberry, autumn olive, silver berry)

Encyclia tampensis (butterfly orchid, Florida butterfly orchid, Tampa butterfly orchid)

Epidendrum ibaguense (crucifix orchid, fiery reed orchid, reed‐stem orchid, spice orchid)

Epilobium ssp. (blooming‐sally, fire weed, willowherb)

Episcia reptans (acajou, cyrtudeira, flame, flame African violet, flame violet, frosty, lady lou, moss agate, pink brocade, red African violet)

Eriogonum alenii (umbrella plant)

Eriogonum inflatum (desert trumpet)

Eriogonum umbellatum (sulfur flower, sulphur flower, sulphurflower buckwheat)

Erythronium Americanum (adder's tongue, American trout lily, dog‐tooth violet, fawn lily, trout lily)

Exacum affine (Arabian gentian, German violet, Persian violet)

Fatsia japonica (big‐leaf paper plant, figleaf palm, Formosa rice tree, glossy‐leaved paper plant, Japanese aralia, Japanese fatsia, paper plant)

Felicia amelloides (blue daisy bush, blue felicia)

Fittonia spp. (mosaic plant, nerve plant, silver nerve plant)

Forsythia spp. (Easter tree, forsythia, golden bells, lian qiao)

Fragaria spp. (strawberry, wild strawberry)

Fuchsia magellanica (ladies ear drops, lady's ear drops) (see Figure A3.3)

Fuchsia triphylla (firecracker fuchsia, honeysuckle fuchsia)

Gardenia jasminoides (cape jasmine, gardenia)

Glechoma hederacea (alehoffs, cat's foot, creeping Charlie, field balm, gill‐over‐the‐hill, ground ivy, hay maids, runaway Robin) (see Figure A3.4)

Gleditsia triacanthos (honey locust, honey shucks locust, sweet bean tree, sweet locust, thorny locust)

Gloxinella lindeniana (gloxinia, tree gloxinia)

Figure A3.3. Fuchsia magellanica.

Photograph courtesy of Tina Wismer.

Figure A3.4. Glechoma hederacea.

Photograph courtesy of Jenny Schuett.

Gloxinia perennis (Canterbury bells)

Goeppertia micans (minature maranta, prayer plant)

Gomesa flexuosa (dancing doll orchid, dancing ladies orchid, golden shower)

Grammatophyllum speciosum (giant orchid, queen of the orchids, sugar cane orchid, tiger orchid)

Graptopetalum paraguayense (ghost plant, mother of pearl)

Guzmania lingulate (droophead tufted airplant, orange star, scarlet star, vase plant)

Guzmania musaica (mosaic vase)

Gynura spp. (purple passion, velvet plant)

Halesia carolina (Carolina silverbell, common silverbell, mountain silverbell, opossum wood, shittimwood, silver bell, snowbell tree)

Haworthia spp. (cushion aloe, pearl plant, star cactus, star window plant, zebra cactus, zebra Haworthia, zebra plant)

Hedychium coronarium (butterfly ginger, butterfly lily, cinnamon jasmine, garland flower, white garland lily, white ginger lily)

Hedychium gardneranum (ginger lily, Kahali garland‐lily, Kahali ginger)

Heuchera spp. (alumroot, coral bells)

Howea belmoreana (Belmore sentry palm, curly palm, kentia palm)

Howea forsteriana (Forster sentry palm, Kentia palm, palm court palm, paradise palm, thatch palm)

Hoya carnosa (curly rope plant, Hindu rope hoya, honey plant, krinkle kurl, porcelainflower, porcelain flower, variegated wax plant, wax plant)

Hoya kerrii (lucky heart plant, sweetheart hoya, sweetheart plant, sweetheart valentine hoya, valentine hoya, wax hearts)

Hoya pubicalyx (pink silver, porcelain flower, silver pink vine, wax plant)

Hylocereus undatus (dragon fruit, night blooming cereus, pitahayas, pitaya)

Hypoestes phyllostachya (baby's tears, flamingo plant, freckle face, measles plant, pink splash, polka dot plant)

Incarvillea delavaya (flowering fern, hardy gloxinia)

Iresine herbstii (Achyranthes verschaffeltii, beefsteak plant, chicken gizzard, blood leaf, Joseph's coat) (see Figure A3.5)

Ixora coccinea (flame of the woods, iron tree, ixora, jungle flame, jungle geranium, Maui sunset)

Ixora javanica (Javanese ixora, jungle flame, jungle geranium, red ixora)

Jacaranda copaia (bignonia, caaroba, caroba, carobhina, carob tree)

Figure A3.5. Iresine herbstii.

Photograph courtesy of Tina Wismer.

Jasminum spp. (common jasmine, jasmine, poet's jasmine, red jasmine, true jasmine, winter jasmine)

Kaempferia spp. (kaempferia, peacock ginger, peacock plant, resurrection lily)

Kniphofia spp. (red hot poker, torch lily)

Kohleria amabilis (tree gloxinia)

Lachenalia spp. (cape cowslip, leopard lily, wild hyacinth)

Lagerstromeria spp. (crape myrtle, crepe myrtle)

Leucocrinum montanum (mountain lily, sand lily, star lily)

Liriodendron tulipifera (canary whitehood, canoewood, lyre tree, North American whitewood, tulip popular, tulip tree, western popular, whitewood, yellow popular)

Liriope muscari (lilyturf)

Lithops naureeniae (kiawe, living stones, mesquite)

Lophospermum erubescens (creeping gloxinia)

Ludisia discolor (golden lace orchid, jewel orchid, tiger orchid)

Lysimachia nummularia (creeping Charlie, creeping Jenny, creeping Joan, creeping yellow loosestrife, moneywort, running Jenny, wandering Jenny, wandering sailor)

Mammillaria spp. (pincushion cactus, thimble cactus)

Maranta leuconeura (cathedral windows, herringbone plant, prayer plant, rabbit tracks)

Masdevallia spp. (Masd, tailed orchid)

Melaleuca citrina (crimson bottlebrush, lemon bottlebrush)

Melaleuca linearis (erect bottlebrush, stiff bottlebrush)

Melaleuca viminalis (crimson bottlebrush, prickly bottlebrush, weeping bottlebrush)

Miltoniopsis roezlii (pansy orchid)

Misopates orontium (calf's snout, lesser snapdragon, linearleaf snapdragon, weasel's snout)

Musa spp. (banana, edible banana) (see Figure A3.6)

Muscari spp. (grape hyacinth)

Nematanthus fornix (candycorn plant, gold‐fish plant, goldfish plant, hypocerta)

Neoregelia carolinae (aregelia, blushing bromeliad, crimson cup, fingernail plant, marbled fingernail, miniature marble plant, neoregalia, ossifragi vase, striped blushing bromeliad)

Nephrolepis biserrata (bold sword fern, crisped feather fern, giant sword fern, tall feather fern, Verona fern, Verona lace fern, Whitman fern)

Nephrolepis cordifolia (duffii fern, duffy fern, lemon button fern)

Nephrolepis exaltata (bold sword fern, Boston blue bell fern, Boston fern, Boston sword fern, Dallas fern, dwarf Boston fern, dwarf feather fern, dwarf Whitman fern, feather fern, fishbone fern, fluffy ruffles, sword fern, tuber ladder fern)

Figure A3.6. Edible bananas hanging on the tree.

Photograph courtesy of Tina Wismer.

Oncidium alexandrae (curled odontoglossum, lace orchid)

Oncidium sphacelatum (golden shower orchid, Kandyan dancer orchid)

Onychium japonicum (carrot fern)

Oscularia piquetbergensis (ice plant)

Pellaea spp. (button fern, cliff brake fern)

Peperomia argyreia (peperomia Peltifolia, peperomia Sandersii, watermelon begonia, watermelon peperomia, watermelon plant)

Peperomia caperata (emerald‐ripple peperomia, emerald ripple pepper, green‐ripple peperomia, little‐fantasy peperomia)

Peperomia clusiifolia (red edged peperomia, red edged radiator pant, red edge peperomia)

Peperomia fernandopoiana (leather peperomia)

Peperomia griseoargentea (ivy peperomia, ivy‐leaf peperomia, ivy leaf pepper, peperomia Hederifolia, plantinum peperomia, silver leaf peperomia)

Peperomia marmorata (silver heart)

Peperomia metallica (metallic peperomia)

Peperomia obtusifolia (American rubber plant, baby rubberplant, blunt‐leaved peperomia, oval leaf peperomia, pepper‐face)

Peperomia polybotrya (raindrop, rain drop plant)

Peperomia prostrata (string of turtles, trailing peperomia)

Peperomia rotundifolia (creeping buttons, jade necklace, peperomia Rotundifolia, round leaf peperomia, trailing jade, yorba linda)

Peperomia scandens (philodendron peperomia, variegated philodendron leaf peperomia)

Peperomia serpens (vining peperomia)

Peperomia verschaffeltii (sweetheart peperomia)

Phlox divaricate (blue phlox, Eastern blue phlox, Louisiana phlox, struggling phlox, wild sweet William, woodland phlox, wood phlox)

Phlox subulate (creeping phlox, flowering moss, ground pink, moss phlox, moss pink, mountain pink, rock phlox, thrift)

Phoenix canariensis (Canary Island date palm, pineapple palm)

Phoenix roebelenii (dwarf date palm, miniature date palm, pigmy date palm, robellini palm)

Phyllostachys aurea (fish‐pole bamboo)

Pilea cadierei (aluminum plant, watermelon pilea, watermelon plant)

Pilia involucrate (friendship plant, panamiga)

Pilea microphylla (artillery plant, pilea mucosa)

Pilea nummulariifolia (creeping Charlie, creeping pilea)

Pilea pumila (clearweed, coolwort, richweed)

Pittosporum tobira (Australian laurel, Japanese pittosporum, mockorange, pittosporum)

Plantanthera spp. (butterfly orchid)

Platanus spp. (buttonball tree, buttonwood, London planetree, maple‐leaved plane tree, plane tree, sycamore)

Platycerium bifurcatum (common staghorn fern, elkhorn fern, staghorn fern)

Plectranthus spp. (candle vine, cockspur flower, creeping Charlie, little spurflower, spur‐flower, Swedish ivy, white‐edged Swedish ivy)

Plerandra elegantissima (false aralia)

Pleiospilos bolusii (African living rock, kwaggavy, lewerplant, living rock cactus, mimicry plant)

Polystichum acrostichoides (Christmas dagger, Christmas dagger fern, Christmas fern)

Polystichum munitum (California sword fern, giant holly fern, imbricate sword fern, swordfern, western sword, western sword fern)

Potentilla spp. (barren strawberry, cinquefoil, five fingers, silverweed, tormentil) (see Figure A3.7)

Prosthechea prismatocarpa (prism‐shaped seedpod, rainbow orchid)

Figure A3.7. Potentilla atrosanguinea (dark crimson cinquefoil).

Photograph courtesy of Tina Wismer.

Psychilis atropurpurea (dark purple psychilis, dragon's mouth orchid, spice orchid)

Psychopsis spp. (butterfly orchid)

Pteris spp. (brake, brake fern, dish fern, silver table fern, table fern)

Raphanus rhaphinistrum (rabano de Maleza, wild radish)

Rhapis excela (bamboo palm, broadleaf lady palm fan tufted palm, lady palm)

Rhipsalis baccifera (mistletoe cactus)

Rubus spp. (Allegheny blackberry, American dewberry, ballon berry, blackberry, blackcap, black raspberry, bristly dewberry, common blackberry, common dewberry, creeping Rubus, dewberry, European raspberry, Graves' blackberry, Himalayan blackberry, hirsute raspberry, Japanese wineberry, northern blackberry, northern dewberry, raspberry, red raspberry, roseberry, salmon berry, sand blackberry, smooth blackberry, strawberryleaf raspberry, swamp dewberry, thornless blackberry, wineberry)

Sairocarpus multiflorus (chaparral snapdragon, multi‐flowered snapdragon, New World snapdragon, rose snapdragon, Sierra snapdragon, sticky snapdragon, wild snapdragon, withered snapdragon)

Salvia coccinea (blood sage, scarlet sage, Texas sage, tropical sage)

Sanvitalia procumbens (creeping zinnia, dwarf sunflower, gold trim floral, Mexican creeping zinnia, miniature sunflower)

Schlumbergera spp. (Christmas cactus, crab cactus, Easter cactus, holiday cactus, shrimp cactus, Thanksgiving cactus)

Sedum morganianum (burro's tail, donkey tail)

Selaginella spp. (club moss, cushion moss, highland moss, Irish moss)

Sempervivum spp. (hens and chicks, houseleeks)

Silene acaulis (cushion pink, moss campion)

Sinningia speciosia (Brazilian gloxinia, florist's gloxinia, gloxinia, violet slipper gloxinia)

Smilax glabra (cat brier, Chin‐Lao‐Shu, China root, greenbrier, Kuang‐Yen pa‐Hsieh, Leng‐Fen Tu'an, Lou‐Lang‐T'ou, Shan Ku'ei‐Lai, shiny leaf smilax, Ti Hu‐Ling, TuFu‐Ling)

Smilax herbacea (carrion flower, common carrion vine, Jacob's ladder, smooth carrion flower)

Smilax laurifolia (bamboo vine, blaspheme vine, laurel‐leaved greenbrier)

Smilax rotundifolia (bullbrier, catbrier, common greenbrier, horsebrier, round‐leaved greenbrier)

Smilax smallii (Jacksonbrier)

Smilax tamnoides (bristly greenbrier, hagbrier, hellfetter, hispida)

Soleirolia soleirolii (angel tears, baby tears, Corsican carpet, irish moss, Japanese moss, mind‐your‐own‐business, Paddy's wig, peace‐in‐the‐home, Pollyanna vine)

Sophronitis spp. (Brazilian orchid)

Stapelia spp. (African starfish flower, black bells, carrion flower, carrion plant, hairy stapelia, hairy toad plant, shaggy stapelia, starfish flower, star flower, toad spotted cactus)

Stephanotis floribunda (bride's flower, clustered wax flower, Hawaiian wedding flower, Madagascar jasmine, wax flower)

Streptocarpus spp. (cape primrose)

Streptocarpus sect Saintpaulia (African violet, Kenya violet, Usambara violet)

Stewartia spp. (orangebark stewartia, mountain camellia, mountain stewartia, silky camellia, summer dogwood, tall stewartia)

Strobilanthes alternata (purple waffle plant, waffle plant)

Tilia spp. (basswood, linden)

Tillandsia spp. (air plant, grandfather's whiskers, graybeard, long moss, Spanish moss, wool crepe)

Townsendia exscapa (Easter daisy, giant aster, stemless Townsend daisy)

Trachelospermum jasminoides (confederate jasmine, star jasmine)

Trachycarpus fortunei (fortunes palm, windmill palm)

Trichocentrum lanceanum (Lance's trichocentrum)

Tsuga spp. (Canadian hemlock, Carolina hemlock, hemlock tree)

Vriesea spp. (flaming sword, urn plant, vriesea)

Index

Note: Numbers in italics are in figures, Numbers in bold are in tables.

Abamectin 149; see also Macrocyclic lactone parasiticides

ABCB1 gene, 37, 149; see Macrocyclic lactone parasiticides, MDR1 p‐glycoprotein

Abronia fragrans, 373

Abrus precatoris, 120, 348, 369

Absinthe, see Artemisia absinthium

Acacia spp., 68

Acalypha hispida, 348, 370

ACE inhibitors, see Angiotensin‐converting enzyme inhibitors

Acepromazine, 70, 219, 227, 231, 331

Acetaminophen, 78, 109, 121, 213–215

Acetone, 294, 314

Acetylcholine (ACh), 67, 69, 93, 96, 139–140, 144, 228, 234, 241, 274

Acetylcholinesterase (AChE), 5, 69, 139, 250, 274

Acids, 119, 122, 301–302

Acokanthera oblongifolia, 66

Aconite, see Aconitum spp.

Aconitum spp., 348, 349, 362, 364, 366, 368

Acorn squash, see Curcurbita spp.

Acorus calamus, 348, 365, 369

Activated charcoal, 53, 58, 69, 105, 129, 131, 133–135, 138, 141, 144, 148, 151, 153, 155, 157, 167, 175, 176, 178, 180, 181, 200–208, 211, 215–217, 219, 220, 222, 223, 227, 228, 230–232, 235, 236, 259, 261, 264, 274, 276–278, 281, 282, 304, 317, 318, 320, 320, 321, 325, 325, 327, 331

Acute renal failure, see Kidney, failure, acute

Acute toxicity, classification, 3

Adenium obesum, 66, 164

Adonidia merrilli, 373

Adonis aestivalis, 348

Adonis macrocarpa, 66

Aechmea spp., 373

Aeschynanthus spp., 373

Aesculus spp., 348, 362

Aflatoxin, 109, 283, 283–286

Africa milk bush, see Euphorbia umbellata

African daisy, see Arctotis stoechadifolia

African violet, see Streptocarpus spp.

Agapanthus spp., 370

Agaricus spp., 271, 273

Ageratina altissiama, 71, 94, 348, 362, 365

Ageratum houstonianum, 348, 362, 365

Agkistrodon spp., 252

Aglaonema spp., 119, 348, 369, 370

Air plant, see Tillandsia spp.

Albizia julibrissin, 362, 364

Albuterol, 51, 53, 78, 99, 101, 198–199, 332

Alcea rosea, 373

Alcohol, 18, 50, 53, 66, 78, 95, 266–267, 290–295, 299

antidotal usage, 66, 298

higher alcohols, 295

proof, conversion, 291

Aldicarb, 67, 79, 140

Alimentary system, 117–118, 119–120

Alkalis, 117, 119, 122, 302

Allamanda cathartica, 348, 370

All‐heal, see Valeriana spp.

Allium spp., 8, 37, 121, 258–259, 259, 369, 370

Almond, see Prunus spp.

Alocasia spp., 68, 119, 348, 367

Aloe arborescens, A. barbadensis, A. vera, 159, 160, 348

Alpha‐2‐adrenergic agonists, 66, 69, 71, 99, 137, 138, 219, 220, 334, 347

Alphahydroxytoluene, see Benzyl alcohol

Alpha lipoic acid, 51, 176

Alpine golden chain, see Laburnum anagyroides

Alprazolam, 95, 201

Alsobia dianthiflora, 373

Alternanthera dentata, 373

Aluminum hydroxide, 262, 332

Aluminum plant, see Pilea spp.

Amanita spp., 273, 274, 276, 278, 279; see also Mushrooms

Amanitin, 271, 272, 274, 279, 280, 281

Amaryllis, see Amaryllis spp.; Hippeastrum spp.

Amaryllis spp., 348, 362, 364–366, 369

Amelanchier spp., 68

Aminocaproic acid, 332

Aminoglycoside antibiotics, 63, 114, 115

Aminophylline, 332

4‐Aminopyridine, 94

Amiodarone, 332, 335

Amitraz, 66, 69, 94, 99, 137–138, 334, 347

Amitriptyline, 52, 70, 95, 99, 201, 202; see also Antidepressants; Tricyclic antidepressants

Amlodipine, 80, 99, 100, 206, 207

Ammi majus, 371

Ammonia, 105

Amphetamines, 49, 52, 52, 53, 70, 78, 81, 95, 99, 199–200, 201, 226–227, 231, 331, 335, 336

Amphoteric detergents, 303

Amphotericin B, 114, 115

Amsinckia spp., 369, 370

Ananas comosus, 348

Anemia, 49, 50, 118, 129, 148, 182, 190, 217, 241, 249, 258–259, 305, 324, 326, 327, 334, 338

Heinz body, 8, 68, 195, 214, 258–259

hemolytic, 83, 118, 121, 195, 214, 249, 251, 258–259

Anemone spp., 348, 370

Angel dust, see PCP

Angel’s trumpet, see Brugmansia spp.; Datura spp.

Angiotensin‐converting enzyme (ACE) inhibitors, 99, 205

Angiotensin II receptor antagonists, 99, 101

Anionic detergents, 302–304

Anoectochilus setaceus, 373

Ansellia africana, 373

Anthurium spp., 119, 348, 349, 367

Antibiotic antineoplastics, 99

Anticholinesterase insecticides, see Organophosphate and carbamate insecticides

Anticoagulant rodenticides, 31, 33, 49, 51, 72, 78, 83, 99, 118, 121, 127–129, 132, 347

Antidepressants, 78, 200–203

atypical antidepressants, 201, 203

monoamine oxidase inhibitors, 201, 203

selective serotonin reuptake inhibitors (SSRIs), 200, 201, 202–203

serotonin norepinephrine reuptake inhibitors (SNRIs), 200, 201, 203

serotonin syndrome and, 200–203

tricyclic antidepressants, 52, 52, 63, 70, 71, 95, 99, 200, 201, 202

Antidotes, 62–76

antibodies, 64–66

antivenin, 64–65

black widow spider, 64, 248, 333

coral snake, 65, 252

Crotalidae, 64–65, 254, 332–333

chelators, 62–64

chemical, 62

functional, 62

pharmacologic, 62

Antifreeze 52, 66, 295–300; see also Ethylene glycol; Propylene glycol

Antihistamines, 70, 95, 143, 145, 178, 202, 213, 214, 215–216, 218, 220, 227, 242

Antirrhinum majus, 373

Antivenin/antivenom, see Antidotes

Apocynum spp., 348, 366

Apomorphine, 32, 57, 135, 274–276, 282, 317, 318, 320, 325, 333

Apoptosis, hepatic, 110, 111, 190, 287

Apple, see Malus spp.

Apricot, see Prunus spp.

Arabian cucumber, see Cucumis spp.

Aralia nudicaulis, 373

Aralia, see Polyscias spp.

Arborvitae, see Thuja occidentalis

Arctotis stoechadifolia, 373

Arisaema spp., 119, 348

Armillaria spp., 271, 273

Armoracia rusticana, 348, 365, 366, 370

Arnica montana, 348, 366, 367, 370

Arsenic, 7, 63, 64, 78, 109, 114, 115, 117, 119, 153, 184–186, 321, 337, 346

Arteglasin, 161

Artemisia absinthium, 180, 348

Artillery plant, see Pilea spp.

Arum spp., 119, 348, 349, 367, 369, 370

Asclepias spp., 66, 94, 349, 360, 362, 364, 368

Ascorbic acid, 63, 176, 192, 215, 259, 321, 333

Asian lady beetle, see Harmonia axyridis

Asparagus spp., 159

ASPCA Animal Poison Control Center, 17, 17, 18, 19, 20, 26, 27, 48, 77, 127, 131, 132, 173, 176, 199, 237, 259, 262

Aspidistra elatior, 373

Aspiration, 34, 56, 58, 59, 83, 105, 105, 117, 119, 134, 135, 138, 151, 155, 180, 181, 204, 209, 228, 230, 241, 252, 265, 267, 276, 290–293, 295, 298, 300, 301, 304, 306–309, 312, 313, 313, 314, 314, 315, 317, 319, 325

Aspirin, 7, 41, 42, 49, 114, 118, 121, 176, 216–218, 217

Asplenium spp., 373

Atenolol, 101, 206, 318, 333

Atipamezole, 57, 66, 71, 138, 220, 334

Atractylis gummifera, 369

Atropa belladonna, 69, 94, 360, 362, 365, 366, 368

Atropine, 66, 95, 142, 166, 206, 223, 249, 275, 277, 334

Atypical antidepressants, see also Antidepressants

Aucuba japonica, 349, 350

August lily, see Hosta spp.

Australian shepherd dogs, MDR1 p‐glycoprotein genetic polymorphism, 150

Avermectin, 20, 50, 63, 69, 94, 341, 345

Avitrol, see 4‐aminopyridine

Avocado, see Persea spp.

Azalea, see Rhododendron spp.

Baby rubberplant, see Peperomia spp.

Baby’s breath plant, see Gypsophila paniculata

Baby tears, see Soleirolia soleirolii

Baclofen, 20, 77–80, 78, 204–205, 341

Banana, see Musa spp.

Barbiturates, 52, 52, 58, 78, 95, 134, 144, 155, 177, 219, 227–229, 231, 235, 245, 276, 277, 316

Bath salts (illicit drug), 238, 238

Batteries, 53, 59, 117, 119, 122, 189, 193, 301, 302

Bay laurel, see Laurus nobilis

Beaucarnea recurvata, 373

Bee sting, see Hymenopteran insects; Venom, Apid (bee)

Begonia spp., 159–160, 160, 349

Benazepril, 99, 205

Benzenemethanol, see Benzyl alcohol

Benzocaine, 52, 68, 95, 121, 215

Benzodiazepines, 50, 52, 52, 67, 69, 95, 148, 155, 172, 175, 176, 179, 200, 201, 203–204, 227, 229–230, 233, 235, 237

Benzoic acid, 294–295

Benzyl alcohol, 294–295

Berberis aquifolium, 373

Bermuda buttercup, see Oxalis spp.

Beta‐adrenergic blocking agents, 53, 67, 99, 101, 199, 206, 227, 339

Bethanechol, 334

Bicarbonate, sodium, 70, 152, 157, 202, 267, 292, 299, 300, 320, 321, 334

Bichetii grass, see Chlorophytum spp.

Bioavailability, 10, 11, 64, 69, 72, 138, 181, 182, 184, 185, 187, 189, 191, 205, 206, 275, 279, 281

Biotransformation, 5, 10–12, 62, 66, 109, 184, 199, 228, 284

Bisaldolol, 178

Bismuth subsalicylate, 41, 42, 216, 218

Bitter lettuce, see Lactuca virosa

Bitter orange, see Citrus aurantium

Bittersweet, see Solanum dulcamara

Blackberry, see Rubus spp.

Black bryony, see Dioscorea communis

Black locust, see Robinia pseudoacacia

Black nightshade, see Solanum nigrum

Black walnut, see Juglans nigra

Black widow spider, see Latrodectus spp.

Bleach, 49, 119, 122, 304–305

Bleeding heart, see Dicentra spp.

Blood‐brain barrier, 8, 10, 11, 31, 93, 96, 98, 101, 130, 131, 149, 150, 177, 189, 198, 204, 206, 216, 226, 274–276

Blood leaf, see Iresine herbstii

Blood lily, see Scadoxus multiflorus

Blood transfusion, 129, 179, 259, 278

pRBC, 334

whole, 129, 215, 334

Blue cohosh, see Caulophyllum thalictroides

Blue daisy bush, see Felicia amelloides

Blue‐dicks, see Dipterostemon capitatus

Blue ginger, see Dichorisandra spp.

Blue‐green algae, 51, 78, 81, 94, 109, 110, 334

Blue leadwood, see Ceratostigma spp.

Blushing bromeliad, see Neoregelia carolinae

Boletus spp., 271, 273

Borage, see Borago officinalis

Borago officinalis, 369, 370

Borates, 119, 147–148, 321

Border collie dogs, MDR1 p‐glycoprotein genetic polymorphism, 150

Boric acid, see Borates

Botulism, 69, 78, 94, 319, 320, 321, 345

Bowiea volubilis, 349, 365, 366

Boxwood, see Buxus sempervirens

Brake fluid, 300–301

Brake, see Pteris spp.

Brazilian orchid, see Sophronitis spp.

Bread dough, raw yeast, 78, 267, 290

Bristly greenbrier, see Smilax spp.

Broadleaf lady palm, see Rhapis excela

Brodifacoum, 128, 130

Bromadiolone, 130

Bromethalin, 20, 33, 37, 49, 50, 58, 83, 94, 130–132, 130, 131, 132, 132, 331, 339

Bromide, 95

Brompheniramine, 216

Bronchodilators, 78, 99, 105, 198–199, 332, 346

Broom, see Cytisus spp.

Brown recluse spider, see Loxosceles spp.

Brugmansia spp., 360, 362, 364–366, 368

Brunfelsia americana, B. pauciflora, B. spp., 78, 94, 134, 135, 170, 170, 349, 362

Bryonia spp., 349, 362, 368, 370

Bryony, see Bryonia spp.

Bryophyllum, see Kalanchoe spp.

Buckeye, see Aesculus spp.

Buckthorn, see Rhamnus spp.

Bulbophyllum appendiculatum, 373

Bunchberry, see Lantana spp.

Buprenorphine, 69, 235

Bupropion, 52, 63, 95, 201

Burning bush, see Euonymus spp.

Burro’s tail, see Sedum morganianum

Buspirone, 52, 95, 201

Buttercup, see Ranunculus spp.

Butterfly orchid, see Plantanthera spp.; Psychopsis spp.

Butylene glycol, 300

Buxus sempervirens, 350, 362, 365, 367, 368

Cadmium, 11, 62–64, 115, 118, 119, 120, 328

Caesalpinia pulcherrima, 350

Caffeine, 20, 78, 95, 99, 101–102, 162, 174–176, 220, 263–264, 263

Caladium spp., 119, 350, 367, 369

Calathea crotalifera, 373

Calcifediol, 132

Calcipotriene, 132

Calcitriol, 71, 115, 132, 133

Calcium channel blockers, 51, 63, 67, 71, 80, 99, 100–101, 206–207, 335, 339, 341

Calcium chloride, 67, 119

Calcium disodium EDTA, 62–63, 191–192, 192, 196, 335

Calcium gluconate, 67, 100, 187, 335

Calcium homeostasis, 110

Calcium oxalate crystalluria, 114, 115, 160, 296–298, 369

Calcium, x phosphorus product, 132

Calcium salts, 67, 160, 207

Calculations, 37–47, 263

Calendula officinalis, 373

California pitcher plant, see Darlingtonia californica

California poppy, see Eschscholzia californica

Calla lily, see Zantedeschia spp.

Callistephus chinensis, 373

Calochortus spp., 373

Calotropis procera, 66

Caltha palustris, 350

Calycanthus spp., 94

Camellia japonica, 373

Camphor oil, 306

Canary Island date palm, see Phoenix spp.

Canavalia spp., 68

Cancer, 5, 284

Candelabra cactus, see Euphorbia lactea

Cannabis sativa, 50, 52, 53, 63, 94, 233–234, 362, 368

Canna spp., 373

Canterbury bells, see Gloxinia perennis

Cape cowslip, see Lachenalia spp.

Cape jasmine, see Gardenia jasminoides

Cape primrose, see Streptocarpus spp.

Capon’s tale, see Valeriana spp.

Capsaicin, 160

Capsicum spp., 160, 161, 350, 370

Captan, 151

Captopril, 205

Carbamate insecticides, 6, 10, 67, 69, 79, 81, 120, 139–142, 140, 334, 339, 344

Carbaryl, 10, 67, 140

Carbofuran, 140

Carbon dioxide, 104, 105, 121, 267

Carbon monoxide, 68, 78, 95, 102, 104, 105, 105, 118, 121

Cardamom oil, 306

Cardboard palm, see Zamia spp.

Cardiac glycoside

animal/insect, 65, 244, 337, 339

drugs, 65, 99, 101, 207–208, 337, 339

plants, 20, 49, 65, 66, 78, 99, 164–165, 207–208, 337, 339

Cardiovascular system, 9, 49, 98–103

Carissa laxiflora, 66

Carnation oil, 306

Caroba, see Jacaranda copaia

Carob, see Ceratonia siliqua

Carolina silverbell, see Halesia carolina

Carprofen 109, 110, 115, 221; see also Nonsteroidal anti‐inflammatory drugs

Carrionflower, see Smilax spp.; Stapelia spp.

Carrot fern, see Onychium japonicum

Carrot seed oil, 306

Carvediolol, 206

Carya spp., 373

Caryota mitis, 350

Cascabela thevetia, 350, 366, 372

Castanea spp., 373

Cast iron plant, see Aspidistra elatior

Castor bean plant, see Ricinus communis

Castor oil plant, see Ricinus communis

Catharanthus roseus, 70, 362

Cathartics, 58, 155, 175, 215, 217, 219, 236, 259, 264, 282, 317, 318, 320, 320, 327

bulk, 58

osmotic, 58

sorbitol, 58, 191, 259, 264, 282, 318, 320

saline, 58, 191

magnesium sulfate, 58, 191

sodium sulfate, 58, 191

Cationic detergents, 117, 119, 122, 301, 303–304, 312

Cats

amitraz toxicosis, 137

benzyl alcohol, 294

bromethalin toxicosis, 130

dermal reaction to pyrethrin‐based sprays, 143

lily toxicosis, 169

organophosphorus toxicosis, 141

permethrin toxicosis, 143–144

species differences, 8, 12, 274

Cattleya spp., 373

Caulophyllum thalictroides, 350, 362

Cavallia spp., 375

Cedar oil, 306

Celosia spp., 373, 374

Centaurea cyanus, 373

Centruroides spp., 249–250

Cephalocereus senilis, 374

Ceratonia siliqua, 373

Ceratostigma spp., 374

Cerbera manghas, 66

Cercocarpus spp., 68

Cestrum spp., 69, 350, 366–369

Cetirizine, 216

C‐4 explosive, 323, 324, 325, 326

Chamaedorea spp., 374

Chamaemelum nobile, see Chamomile

Chamomile, 178

Charcoal briquette, 321, 322

Chelidonium majus, 350

Chemical, interaction

additive, 5, 6

antagonistic, 5, 6, 6

potentiation, 6, 6

synergistic, 5, 6

Chenille plant, see Acalypha hispida

Chenopodium spp., 68

Cherokee‐bean, see Erythrina herbacea

Cherry, see Prunus spp.

China aster, see Callistephus chinensis

Chinaberry, see Melia azedarach

China root, see Smilax spp.

Chinese evergreen, see Aglaonema spp.

Chinese herbal medicine, 174, 182

Chinese plumbago, see Ceratostigma spp.

Chinese silk vine, see Periploca sepium

Chinese yam, see Dioscorea polystachya

Chinook, MDR1 p‐glycoprotein genetic polymorphism, 150

Chlorates, 121, 321, 322, 322

Chlorinated hydrocarbons, see Organochlorine insecticides

Chlorine, 105, 304, 315

Chloroform, 109

Chlorophacinone, 128

Chlorophyllum spp., 271, 273

Chlorophytum spp., 374

Chlorothalonil, 151

3‐Chloro‐p‐toluidine hydrochloride, 94

Chlorpheniramine, 216

Chlorphenoxy herbicides, see Herbicides, chlorphenoxy

Chlorpromazine, 52, 70, 95, 175, 200, 219, 223, 227, 231, 335

Chlorpyrifos, 67, 140, 141

Chocolate, see Methylxanthines

Chocolate soldier, see Alsobia dianthiflora

Cholecalciferol, 20, 33, 71, 99, 102, 114, 115, 132–133, 223, 335, 339

Cholestasis, 110, 111, 168, 346

Cholestyramine, 133, 335

Chondroitin, 181–182

Christmas cactus plant, see Schlumbergera spp.

Christmas fern, see Polystichum spp.

Christmas orchid, see Cattleya spp.

Christmas palm, see Adonidia merrilli

Chronic toxicity, 4, 100, 190

Chrysanthemum spp., 142, 161, 161, 370

Chrysojasminum spp., 374

Cicuta spp., 94, 350, 362, 365, 372

Cimetidine, 70, 176, 215, 339

Cinnamomnum spp., 176–177, 306

Cinnamon, see Cinnamomum spp.

Cinquefoil, see Potentilla spp.

Cirrhosis, 111

Cisplatin, 105, 109, 115

Cissus alata, 374

Citalopram 201; see also Selective serotonin reuptake inhibitors

Citral, 306

Citronella, see Cymbopgum nardus

Citrus spp., 174, 180, 307, 308

C. aurantium, 174

d‐limonene, 180, 307

Clearweed, see Pilea spp.

Clematis spp., 161, 350, 370

Cliff brake fern, see Pellaea spp.

Climbing onion, see Bowiea volubilis

Clinical toxicology, 3

Clintonia spp., 374

Clitocybe spp., 273, 274

Clivia spp., 350, 360, 364

Clomipramine 95, 99, 99, 201, 202; see also Tricyclic antidepressants

Clonazepam, 201

Clotting factors, 51, 72, 118, 128–129, 248, 344

Clove oil, 308

Club moss, see Selaginella spp.

Coagulation tests, 50, 51, 129, 249, 254, 255, 281

Coagulopathy, 33, 65, 118, 128, 155, 178, 200, 223, 241, 248, 249, 261, 268, 281, 285, 286, 323

Cocaine, 52, 52, 53, 78, 81, 95, 99, 101, 200, 201, 230–231

Cocktail orchid, see Cattleya spp.

Cocoa bean shell mulch, 316, 317, 317, 318, 318

Codeine, 52, 69, 95, 235

Codiaeum variegatum, 350, 350, 370

Coffea arabica, 101, 175, 263, 321, 362

Coffee, see Coffea arabica

Colchicine, 118, 120, 172

Colchicum autumnale, 120, 162, 172, 350, 364, 365, 368

Collie dogs, MDR1 p‐glycoprotein genetic polymorphism, 8, 31, 150, 150

Colorado River toad, see Incilius alvarius

Comfrey, see Symphytum officinale

Common greenbrier, see Smilax spp.

Common yellow jasmine, see Chrysojasminum

Compost, 33, 265, 318–321

Compound 1080, see Sodium fluoroacetate

Conium spp., 5, 94, 360, 361, 362, 364, 365, 366, 368

Conocybe spp., 273, 275

Convallaria majalis, 20, 66, 71, 164, 165, 207, 350

Conversion factors, 39, 39, 41, 42

Copperheads, 65, 65, 252, 332–333

Copper rose, see Echeveria spp.

Coral bells, see Heuchera spp.

Coral snakes, see Snakes, elapids

Cornflower, see Centaurea cyanus

Corrosives, see Acids; Alkalis; Cationic detergents

Cortaderia selloana, 374

Corticosteroids, 9, 111, 128, 132, 133, 218, 242, 244, 302

Corydalis spp., 350, 362, 363, 365, 367

Cotoneaster spp., 68

Cottonmouth, 65, 65, 252

Coumarin, 72, 125, 177

Coyotilla, see Karwinskia humboldtiana

Crataegus spp., 374, 374

Creeping Charlie, see Glechoma hederacea; Pilea spp.

Creeping gloxinia, see Lophospermum erubescens

Creeping Jenny, see Lysimachia nummularia

Creeping zinnia, see Sanvitalia procumbens

Crepe myrtle, see Lagerstromeria spp.

Crimson bottlebrush, see Melaleuca spp.

Crinum spp., 350, 351

Crispy wave fern, see Asplenium spp.

Crocus, autumn‐blooming, see Colchicum autumnale

Crocus spp., 119, 162–163, 366, 368

Crocus, spring‐blooming, see Crocus spp.

Crossandra infundibuliformis, 374

Crotalaria spp., 369, 370

Crotalidae polyvalent immune Fab, 65

cross reactivity, 65

Crotalus spp.; see Snakes, pit viper

Croton, see Codiaeum variegatum

Crown of thorns, see Euphorbia milii

Crucifix orchid, see Epidendrum ibaguense

Cryptanthus spp., 374

Cryptogramma crispa, 374

Crytostegia grandioflora, 66

Cucumber, see Cucumis spp.

Cucumis spp., 374

Cucurbita spp., 374–375

Cuitlauzina pulchella, 374

Curled odontoglossum, see Oncidium spp.

Curly palm, see Howea spp.

Cyanide, 49, 68, 71, 104, 105, 118, 121, 340, 346

plants, see cyanogenic glycosides

Cyanogenic glycosides, 68, 171–172, 340, 346

Cycas revoluta, C. spp., 18, 51, 79, 109, 119, 167, 167, 350, 363, 365, 369

Cycad palm, see Cycas revoluta

Cycasin, 167

Cyclamen spp., 161, 350, 351, 364, 365

Cyclophosphamide, 68, 109, 115, 115

Cymbalaria muralis, 375

Cymbopgum nardus, 180, 303, 308

Cynodon spp., 68

Cynoglossum amabile, 363, 369, 370

Cyproheptadine, 70, 95, 175, 177, 200, 201, 205, 219, 223, 230, 231, 233, 236, 276, 335

Cyrtomium falcatum, 375

Cytisus spp., 350, 364–366, 368

Cytoskeletal disruption, 96, 110

2, 4‐D, 151–152

Daffodil, see Narcissus spp.

Dahlia spp., 371

Dancing doll orchid, see Gomesa flexuosa

Dantrolene, 70, 172, 336

Daphne spp., 350, 362, 363, 365

Dark purple psychilis, see Psychilis atropurpurea

Darlingtonia californica, 375

Database, emergency

blood gases, 51

coagulation profile, 51

glucose, blood, 51

hematology, 50

PCV, 50

radiography, 53

serum chemistry, 50

total solids, 50

urinalysis, 51

Datura spp., 69, 94, 360, 362, 365, 366, 368

Day lily, see Hemerocallis spp.

DDT, 11, 94

Deadly nightshade, see Atropa belladonna

Decongestant, 79, 95, 174, 213, 214, 215, 218–220, 218, 226, 227; see also Pseudoephedrine

imidazoline, 66, 69, 99, 219–220, 334, 347

Decontamination, 55–61

contraindications, 32, 53, 57–58, 152, 159, 194, 215, 290, 302, 304, 325

emesis, 56–58

contraindicated emetics, 57

enemas, 53, 58, 155, 182, 202, 218, 265, 341

dermal, 53, 59, 301, 316

dilution, 53, 58, 58, 139, 149, 160, 302, 305

gastric lavage, 58–59, 134, 135, 141, 155, 176, 189, 191, 202, 204, 228, 231, 264, 265, 282, 317, 320, 320, 321, 325, 325, 326, 327

ocular, 53, 59, 149

DEET, see Diethyltoluamide

Deferoxamine, 63, 156, 189, 336

Deicing salts, 18, 119, 305–310

Delayed reaction, 5

Delosperma nubigenum, 375

Delphinium spp., 350, 363, 364, 368

Demographics, 17

Denatured alcohol, see Ethanol

Dendrobium monophyllum, 375

Dendrophylax lindenii, 375

Deoxynivalenol (DON), 282, 286–287

Deracoxib, 115, 221; see also Nonsteroidal anti‐inflammatory drugs

Desert rose, see Adenium obesum

Desert trumpet, see Eriogonum spp.

Desmethylbromethalin, 37, 130,

Desvenlafaxine, 201; see also Serotonin norepinephrine reuptake inhibitors

Detergents, 16, 17, 20, 56, 57, 59, 117, 119, 122, 301–304, 311

Deutzia gracilis, 375

Developmental toxicity, 9

Dexmedetomidine, 57, 66, 99, 219, 277, 334, 336

Dextromethorphan, 52, 69, 201, 236

Dextrose, 43, 65, 70, 135, 176, 186, 192, 210, 211, 267, 268, 292, 326, 335, 336

Diacetoxyscirpenol, 266, 287–288

Diazepam, 50, 95, 109, 138, 142, 144, 164, 170, 175–177, 181, 199–201, 201, 205, 209, 210, 215, 216, 218–220, 222, 229, 231, 234, 242, 245, 248, 264, 266, 276–278, 281, 282, 315, 316, 317, 318, 320, 320, 325, 325, 336

Diazinon, 67, 140

Dicentra spp., 350, 351, 363, 365, 367

Dichlorvos, 140

Dichorisandra spp., 375

Dicoumarol, 127

Dieffenbachia spp. 119, 162, 163, 351, 367, 370

Dieldrin, 79

Diesel fuel, 301, 312, 314

Diethyltoluamide (DEET), 94, 148–149

Difenacoum, 128

Difethialone, 127, 128

Digitalis purpurea, 20, 51, 53, 66, 100, 164, 165, 207, 351, 363, 366, 372

Digitoxin, 65, 100, 164, 207

Digoxin, 8, 65, 99, 100, 101, 164, 207–208, 334, 335, 337

Digoxin immune Fab, 65, 164, 208, 245, 337

cross reactivity, 66

Diltiazem, 52, 67, 80, 99, 100, 206

Dimenhydrinate, 64, 216

Dimercaprol (BAL), 63, 186, 191, 194, 337

Dinotefuran, 144, 144

Dionaea muscipula, 375

Dioscorea communis, 351, 370

Dioscorea polystachya, 351, 370

Diphacinone, 40, 128

Diphenhydramine, 52, 95, 205, 216, 250, 333, 337

Dipterostemon capitatus, 375

Diquat, 11, 114, 115, 153

Disodium methanearsenate (DSMA), 153, 185

Disseminated intravascular coagulopathy, see Coagulopathy

Disulfoton (disyston), 67, 79, 140

D‐limonene, see Citrus spp.

Dobutamine, 207, 337

Dogbane, see Apocynum spp.

Dogs

2, 4‐D toxicosis, 152

grape and raisin toxicosis, 260

macadamia nuts, 262

macrocyclic lactone parasiticide susceptibility, 149–150

MDR1–defective, 149–150

xylitol toxicosis, 267–68

Dopamine, 93, 101, 199, 200, 203, 207, 226, 232, 233, 236, 244, 262, 292, 299, 337

Doramectin, 149; see also Macrocyclic lactone parasiticides

Dosage, 4, 37

Dose, 4, 37

Dose‐response

individual, 7, 8

population, 7, 7

Doxepin, 52, 70, 201; see also Tricyclic antidepressants

D‐penicillamine, 63–64, 69, 154, 191, 196, 344, 345

Dracaena spp., 351, 360, 363

Drimia maritima, 351, 365, 366

Droophead tufted airplant, see Guzmania spp.

Drosera spp., 68

Dryopteris spp., 351, 362, 370

Duloxetine, 201

Dumbcane, see Dieffenbachia spp.

Dutchman’s breeches, see Dicentra spp.

Dynamite, see Explosives

Earth star, see Cryptanthuss pp.

Easter lily, see Lilium longiflorum

Easter lily cactus, see Echinopsis spp.

Easter orchid, see Cattleya spp.

Echeveria spp., 375

Echinacea purpurea, 177–178

Echinopsis spp., 375

Echinops spp., 375

Echium spp., 369, 370

Ecstasy (MDMA), 231, 238

ED50, 8

Edema, 163, 185, 241, 243, 250, 261, 283, 284, 285, 288, 312, 314, 370

cerebral, 132, 182, 191, 227, 278, 280, 296, 323, 339, 342

facial and paw, 214, 242, 250, 316, 326

myelin, 96

pulmonary, 56, 63, 79, 104, 105, 105, 175, 198, 199, 202, 204, 207, 208, 245, 290, 296, 298, 308, 313, 314, 326, 326, 338

Efudex, see 5‐Fluorouracil

Elaeagnus spp., 375

Elapids, see Snakes, elapids

Elderberry, see Sambucus spp.

Elephant’s ear, see Alocasia spp.

Elkhorn fern, see Platycerium bifurcatum

Emerald‐ripple peperomia, see Peperomia spp.

Enalapril, 101, 205

Encyclia tampensis, 375

Endectocide, 149

English ivy, see Hedera spp.

English shepherd, MDR1 p‐glycoprotein genetic polymorphism, 150

Enterohepatic recirculation, 12, 58, 109, 130, 132, 149, 175, 176, 202, 221, 263, 279, 281

Entoloma spp., 273, 371

Environmental Protection Agency (EPA, US EPA), 25, 127, 132, 137, 156

registration number, 33, 38, 127

EPA, see Environmental Protection Agency

Ephedra, 95, 174

Ephedra sinica, 174

Ephedrine, 52, 70, 101, 102, 174, 218, 227, 337

Epidendrum ibaguense, 375

Epilobium spp., 375

Epipremnum aureum,119, 162, 351, 367, 369, 371

Episcia repens, 375

Eprinomectin, 149; see also Macrocyclic lactone parasiticides

Equisetum spp., 363, 363

Erect bottlebrush, see Melaleuca spp.

Eriogonum spp., 375

Erythrina herbacea, 351, 363, 364, 368

Erythronium Americanum, 375

Erythropoietin, 338

Esafoxolaner, 138

Eschscholzia californica, 360, 365, 367

Escitalopram, 201; see also Selective serotonin reuptake inhibitors

Esmolol, 101, 206, 245, 338

Essential oils, 94, 119, 122, 180–181, 305, 306–309

Estrogen, 118, 121

Ethanol (ethyl alcohol), 66, 120, 226, 266–267, 290–293, 298, 338

for treatment of ethylene glycol toxicosis, 66, 338

Ethylene glycol, 78, 95, 115, 295–299

Etorphine, 235, 236

Eucalyptus oil, 307

Eucalyptus spp., 68, 307, 318, 352, 371

Euonymus spp., 352, 366

Euphorbia lactea, 353, 360, 365, 371

Euphorbia milii, 352, 352, 371

Euphorbia myrsinites, 352, 371

Euphorbia pulcherrima, 162, 352, 352, 371

Euphorbia resinifera, 352, 361, 365, 371

Euphorbia tirucalli, 352, 361, 365, 371

Euphorbia umbellata, 352, 371

Exacum affine, 375

Explosives, 323–327

dynamite, 324, 327

pentaerythrityl tetranitrate (PETN), 324, 326–327

plastic explosives, 324

2, 4, 6‐trinitrotoluene (TNT), 324, 327

Exposure

amount, 37

duration, 7

frequency, 7

route, 6, 55

site, 6

False aralia, see Plerandra elegantissima

False hellebore, see Veratrum spp.

False sago palm, see Cycas spp.

False Solomon’s seal, see Maianthemum spp.

Famotidine, 286, 325, 339, 340

Fatsia japonica, 375

Felicia amelloides, 375

Fenfluramine, 201

Fentanyl, 235

Fern palm, see Cycas spp.

Ferric molluscides, 154–156

Fertilizers, 18, 78, 81, 119, 120, 151, 159, 187, 316–317

Fexofenadine, 216

Ficus benjamina, 352, 371

Fiddleneck, see Amsinckia spp.

Fig‐leaf gourd, see Curcurbita spp.

Filgrastim, 209, 338

Fire ants, 240, 242–244

Firecracker flower, see Crossandra infundibuliformis

Firecracker fuchsia, see Fuchsia spp.

Fire logs, 321, 322

Firethorn, see Pyracantha spp.

Fireworks, 322, 322–323

sparklers, 322

Watusi (dancing) firecracker, 322

Fish‐pole bamboo, see Phyllostachys aurea

Fishtail palm, see Caryota mitis

Fittonia spp., 375

Fitweed, see Corydalis spp.

Flame violet, see Episcia reptans

Flamingo flower, see Anthurium spp.

Flaming sword, see Vriesea spp.

Flare, signaling or illuminating, 322–323, 322

Florida butterfly orchid, see Encyclia tampensis

Flowering jasmine, see Chrysojasminum spp.

Fluoride, 67, 184, 186–187

Fluoroquinalones, 122

5‐Fluorouracil, 78, 80, 95, 120, 121, 209

Fluoxetine, 52, 179, 200, 201, 202; see also Selective serotonin reuptake inhibitors

Fluralaner, 138

Flumazenil, 67, 203, 230, 338

Fluticasone, 338

Folinic acid, 67

Fomepizole, 66, 298–300, 338

Food and Drug Administration (US FDA), 26, 69, 72, 174, 181, 254, 285, 287, 288

Forsythia spp., 375

Four‐o’‐clock, see Mirabilis jalapa

Foxglove plant, see Digitalis purpurea

Fragaria spp., 375

Fragrant sand verbena, see Abronia fragrans

Franciscan rain tree plant, see Brunfelsia americana

Free radicals, 5, 102, 109–110, 120, 153, 188, 277, 281

Friendship plant, see Pilea spp.

Fuchsia spp., 375, 375

Fumonisin, 283, 288

Fungicides, 151, 316

Furosemide, 105, 132, 133, 262, 325, 338

GABA, 93, 138, 142, 150, 154, 203, 204, 228, 229, 233, 236, 265, 276, 277, 291, 300

Galanthus spp., 352, 353, 365, 366, 369

Galerina spp., 274, 278–279

Garbage poisoning, 78, 265, 282, 283, 290

Gardenia jasminoides, 375

Garlic, see Allium spp.

Gasoline, 55, 117, 184, 311, 312, 314

Gelsemium sempervirens, 365

General anesthetics, 95

Geranium, see Pelargonium spp.

German chamomile, see Chamomile

German shepherd dogs, 16, 17

MDRI p–glycoprotein genetic polymorphism, 150

Genetic polymorphism, 8, 149, 150, 150

Genetic testing, 149, 150

Geriatric patients, 8–9, 217, 243

GHB (gamma‐hydorxybutyric acid), 232

Ghost orchid, see Dendrophylax lindenii

Ghost plant, see Graptopetalum paraguayense

Giant sword fern, see Nephrolepis spp.

Ginkgo biloba, 339

Glaucous echeveria, see Echeveria spp.

Glechoma hederacea, 375, 376

Gleditsia triacanthos, 375

Glimepiride, 210

Glipizide, 210

Globe thistle, see Echinops spp.

Gloriosa superba, 120, 172, 353, 353, 363, 366, 368

Glory lily, see Gloriosa superba

Gloxinella lindeniana, 375

Gloxinia, see Gloxinella lindeniana; Sinningia speciosa

Gloxinia perennis, 376

Glucagon, 67, 339

Glucosamine, 181–182

Glue, expanding, see Isocyanate adhesives

Glyburide, 210

Glyceria spp., 68

Glycine, 93, 96, 133, 265, 291, 294, 296, 298

Glycol ethers, 300–301

Glycols, 20, 295–300, 303; see also Ethylene glycol; Propylene glycol

Glycopyrrolate, 339

Glycosides, 271

anthraquinone, 159

cardiac, 65, 66, 78, 99, 101, 164–166, 207, 244

cyanogenic, 171–172

Glycyrrhiza glabra, 366, 368

Goatweed, see St. John’s wort

Goeppertia micans, 376

Golden chain tree, see Laburnum anagyroides

Golden rain tree, see Laburnum anagyroides

Goldfish plant, see Nematanthus fornix

Gomesa flexuosa, 376

Gomphus spp., 271, 273

Grammatophyllum speciosum, 376

Grape, see Vitis spp.

Grape hyacinth, see Muscari spp.

Grape ivy, see Cissus alata

Graptopetalum paraguyense, 376

GRAS (generally regarded as safe), 179

Grayanotoxins, 99, 166–167

Greater celadine, see Chelidonium majus

Great laurel, see Rhododendron spp.

Green bean, see Phaseolus vulgaris

Griffonia simplicifolia, 177

Ground cherry, see Physalis spp.

Ground ivy, see Glechoma hederacea

Guarana, see Paullinia cupana

Guinea pigs

desmethylbromethalin and toxicity, 37, 130

LD50, 130

Guzmania spp., 376

Gynura spp., 376

Gypsophila paniculata, 162, 353, 371

Gyromitra spp., 274, 277–278

Halesia carolina, 376

Half‐life, 12

Hardy gloxinia, see Incarvillea delavaya

Hardy ice plant, see Delosperma nubigenum

Harmonia axyridis, 245–246

Haworthia spp., 376

Hawthorn, see Crataegus spp.

Hazard (risk), 4

Hebeloma spp., 271, 273

Hedera spp., 353, 361, 365, 366, 371

Helenium spp., 70, 371

Heliotrope, see Heliotropium spp.; Valeriana spp.

Heliotropium spp., 369, 370

Helleborus spp., 66, 353, 361, 362, 366

Hematopoietic system, 118, 121, 190

Hemerocallis spp., 169, 169

Hemlock, see Tsuga spp.

Henbane, see Hyoscyamus niger

Hepatobiliary system, 107–112

Hepatocellular degeneration, 110–111

Hepatocellular necrosis, 111

Hepatotoxic mushrooms, 78, 109, 278–281, 282; see also Mushrooms

Heptane, 104, 105

Heptapleurum spp., 353, 353, 361, 363, 365, 366, 369

Herbicides, 5, 18, 81, 119, 147, 151–154, 159, 184, 185, 311, 316

2, 4‐D, 151–152

chlorphenoxy herbicides, 70, 151–152

glyphosate, 152

paraquat, 105, 115, 152–153

Herb‐paris, see Paris quadrifolia

Hedychium spp., 376

Heroin, 235, 236

Heteromeles spp., 68

Heuchera spp., 376

Hexachlorophene, 109

Hickory, see Carya spp.

Hippeastrum spp., 353, 364, 367

History taking, 16, 29–36, 38, 48

agent information, 18, 29, 33, 38

client information, 29, 30

clinical status, 29, 32

environmental information, 29, 32

exposure information, 29, 33, 38

medical records, 29

patient information, 29, 31–32

patient presentation, 29

sudden death, 77, 81

Holly, see Ilex spp.

Hollyhock, see Alcea rosea

Honey locust, see Gleditsia triacanthos

Hops plant, see Humulus lupulus

Horse chestnut, see Aesculus spp.

Horseradish, see Armoracia spp.

Horsetail, see Equisetum spp.

Hosta spp., 162, 162

Hound’s tongue, see Cynoglossum amabile

Houseleeks, see Sempervivum spp.

Howea spp., 376

Hoya spp., 376

HT‐2, 286–288

Hubbard squash, see Curcurbita spp.

Humulus lupulus, 78, 80, 172, 172

Hura crepitans, 353, 361, 365, 366

Hyacinthoides hispanica, 353, 363

Hyacinthus spp., 119, 162, 353

Hydralazine, 99, 340

Hydrangea spp., 68, 353, 353

Hydrocarbons, see Petroleum distillates

Hydrocodone, 69, 95, 235

Hydrogen peroxide, 34, 56–57, 57, 274, 275, 282, 317, 318, 320, 340

Hydromorphone, 69, 235

Hydroxocobalamin, 68, 172, 340

25‐Hydroxycholecalciferol, 132

Hydroxycoumarins, 178

Hydroxyethyl starch, 326, 340

5‐Hydroxytryptophan, 78, 80, 177, 201, 201

Hylocereus undatus, 376

Hymenocallis spp., 354, 354

Hymenopteran insects, 240–244

Hyoscyamus spp., 69, 361, 362, 366–368

Hyperbaric oxygen, 68, 70

Hypercalcemia, 33, 71, 72, 114, 133, 335, 339, 343, 344, 347

Hyperglycemia, 51, 68, 188, 207, 232, 280

in amitraz toxicosis, 137, 138

in black widow spider envenomation, 247

in sodium fluoroacetate toxicosis, 157

Hypericum perforatum, 179, 371

Hyperkalemia, 53, 67, 152, 157, 206, 250, 299, 335, 336

in cardiac glycoside toxicosis, 165, 208, 245

Hyperphosphatemia, 262

Hyperthermia, 49, 78, 79, 156, 166, 175, 177, 179, 199, 200, 219, 221–223, 227, 230–232, 234, 237, 238, 241, 244, 250, 262, 263, 265, 302, 313, 319, 321, 324

in castor bean toxicosis, 163

in hops toxicosis, 70, 78, 81, 172, 336

in metaldehyde toxicosis, 78, 81, 154–155

in mushroom toxicosis, 273, 276, 280

in serotonin syndrome, 70, 78, 80, 201–203

Hypocalcemia, 63, 67, 152, 157, 160, 165, 170, 187, 191, 296, 335

Hypoestes phyllostachya, 376

Hypoglycemia, 51, 67, 70, 79, 96, 168, 176, 177, 206, 210–211, 223, 267, 268, 274, 279, 280, 280, 281, 292, 298, 308, 336

Hypoglycemics, 176–177, 210–211

metformin, 210–211

sulfonylureas, 210

Ibuprofen, 19, 31, 52, 95, 109, 114, 115, 213, 220–221, 220, 221, 222; see also Nonsteroidal anti‐inflammatory drugs

Ice melts, see Deicing salts

Ice plant, see Oscularia piquetbergensis

Idiosyncratic reaction, 5, 109, 110, 122, 142

Illicit drug, 174, 226–239

testing, 51, 52, 200, 202, 227–229, 231, 234, 236

Ilex spp., 162, 162, 354

Immediate reaction, 5

Imidacloprid, 144, 144

Imipramine, 52, 70, 201; see also Tricyclic antidepressants

Incarvillea delavaya, 376

Incilius alvarius, 244–245

Indian common mallow, see Sida cordifolia

Indigofera spp., 168

Information resources, 22–28

computer databases, 23

diagnostic laboratories, 24

internet sites, 23

peer‐reviewed journal, 23

poison control centers, 26

textbooks, 23

Inhalation, 6, 9, 17, 55, 56, 59, 68, 104, 149, 152, 193, 194, 198, 233, 278, 291, 293, 305, 311, 312, 313, 314, 315, 323, 338, 340

Initial assessment, 48

cardiovascular system, 49

central nervous system, 49

respiratory system, 49

Inocybe spp., 273, 274

Insoluble calcium oxalates, see Oxalates, insoluble

Integumentary system, 118–120, 122

Intoxication incidence, 16–21

Ionophores, 33, 78, 99, 122

Ipomoea spp., 94, 232, 361, 362, 367

Iresine herbstii, 376, 376

Iris spp., 119, 162, 354, 354, 371

Irish shamrock, see Oxalis spp.

Intravenous lipids, 63, 101, 134, 144, 151, 202, 205–207, 229, 234, 341

Iron, 5, 40, 63, 64, 68, 78, 108, 109, 120, 155–156, 187–189, 194, 223–224, 316, 317, 327, 336

percentage determination, 40, 41, 41, 188

Isocyanate adhesives, 305

Isoniazid, 69, 78, 95, 345

Isopropanol (isopropyl alcohol), 6, 293–294, 314

Isoproterenol, 207, 341

Isoxazolines, 20, 138–139

Ivermectin, 149, 150; see also Macrocyclic lactone parasiticides

Ivy‐leaf peperomia, see Peperomia spp.

Ixora spp., 376

Jacaranda copaia, 376

Jack‐in‐the‐pulpit, see Arisaema spp.

Jacksonbrier, see Smilax spp.

Jade necklace, see Peperomia spp.

Japanese holly fern, see Cyrtomium falcatum

Japanese honeysuckle, see Lonicera japonica

Japanese pieris plant, see Pieris japonica

Japanese showy lily, see Lilium lancifolium

Japanese yew, see Taxus spp.

Jasmine, see Jasminum spp.

Jasminum spp., 377

Jatropha curcas, 354

Jerusalem cherry, see Solanum pseudocapsicum

Jessamine, see Cestrum spp.

Jewel orchid, see Anoectochilus setaceus; Ludisia discolor

Jimsonweed, see Datura spp.

Joseph’s coat, see Alternanthera dentata

Juglans nigra, 362, 363

Juncus spp., 68

Jungle geranium, see Ixora spp.

Juniperus sabina, 306, 354

K2, 238

Kaempferia spp., 377

Kahali ginger, see Hedychium spp.

Kalanchoe spp., 165–166, 166, 354, 363, 367

Kalmia spp., 166, 354, 360, 362, 364, 366, 367

Kandyan dancer orchid, see Oncidium spp.

Karwinskia humboldtiana, 364

Kenilworth ivy, see Cymbalaria muralis

Kentia palm, see Howea spp.

Ketamine, 52, 101, 236, 341

Ketoconazole, 70, 109

Khat, 238

Kidney, see Urinary system

Klamath weed, see Hypericum perforatum

Kniphofia spp., 377

Kohleria amabilis, 377

Laboratory

diagnostic, 24, 52, 81, 82, 86–90

testing

antemortem, 87, 88

postmortem, 88, 88

sample types, 81–82, 87

toxicant, 86

Laburnum anagyroides, 170–171, 354, 354, 362, 365, 368, 372

Lachenalia spp., 377

Lactarius spp., 271, 273

Lactuca virosa, 363, 371

Lactulose, 278, 341

Lady‐of‐the‐night plant, see Brunfelsia americana

Lady’s ear drops, see Fuchsia spp.

Lagerstromeria spp., 377

Lamotrigine, 52, 80

Lance’s trichocentrum, see Trichocentrum lanceanum

Lantana spp., 168, 168, 354, 363, 369

Larkspur, see Delphinium spp.

Latrodectus spp., 64, 94, 247–248, 333

Laurel‐leaved greenbrier, see Smilax spp.

Laurus nobilis, 355, 371

Laxatives, 118, 120, 341

Lead, 4, 11, 32, 62–64, 87, 95, 115, 121, 184, 185, 189–193, 327, 335, 344

Leather peperomia, see Peperomia spp.

Lemon button fern, see Nephrolepis spp.

Lemon oil, 307

Leopard orchid, see Ansellia africana

Lepiota spp., 274, 278–279

Lethal dosage (LD), 4

Leucocrinum montanum, 377

Levetiracetam, 182, 200, 205, 341

Licorice, see Glycyrrhiza glabra

Lidocaine, 52, 78, 95, 121, 176, 208, 223, 264, 267, 317, 318, 341

Ligustrum spp. 355, 367

Lilium spp., 16, 18, 51, 115, 159, 168–169, 355, 363, 368

L. candidum, 168

L. lancifolium, 168

L. longiflorum, 168, 169

L. pardalinum, 168

L. speciosum, 168

L. tigrinum, 168, 169

Lily, see Lilium spp.

Lily of the Nile, see Agapanthus spp.

Lily‐of‐the‐valley, see Convallaria majalis

Lily of the valley orchid, see Cuitlauzina pulchella; Dendrobium monophyllum

Lilyturf, see Liriope spp.

Linalool, see Citrus spp.

Lindane, 79, 94

Linden, see Tilia spp.

Lipidosis, hepatic, 71, 110, 111, 285, 286

Lipstick plant, see Aeschynanthus spp.

Liriodendron tulipifera, 377

Liriope muscari, 377

Lisinopril, 99, 205

Lithium, 95, 322

Lithops naureeniae, 377

Liver, see Hepatobiliary system

Livestock protection collar (LPC), 156

Living stones, see Lithops naureeniae

Lobelia spp., 94, 355, 363, 366, 367

Local anesthetics, 63, 68, 78, 95, 230, 305

Longhaired whippet dogs, MDR1 p‐glycoprotein genetic polymorphism, 150

Lonicera japonica, 355, 355

Lophophora williamsii, 355, 361, 362

Lophospermum erubescens, 377

Loratadine, 95, 216

Lorazepam, 201

Lotilaner, 138, 139

Lotus spp., 68

Loxosceles spp., 247–249

LSD (lysergic acid diethylamide), 95, 201, 232–233, 238

L‐tryptophan, 201

Lucky heart plant, see Hoya spp.

Ludisia discolor, 377

Lung fibrosis in paraquat toxicosis, 11, 153

Lupine, see Lupinus spp.

Lupinus spp., 94, 355, 355, 363, 367, 368

Lycium spp., 69

Lysimachia nummularia, 377

Macadamia nuts, see Macadamia spp.

Macadamia spp., 94, 122, 159, 262–263, 355, 363

Macrocyclic lactone parasiticides (macrolides), 149–151

cats, 149

dog breed sensitivity to, 31, 150

MDR1 p‐glycoprotein and, 149–150

Macrolides, see Macrocyclic lactone parasiticides

Macrozamin, 167

Madagascar jasmine, see Stephanotis floribunda

Madagascar periwinkle, see Catharanthus roseus

Magnesium hydroxide, 133, 187, 342

Magnesium sulfate, 58, 191, 316, 342

Ma huang, see Ephedra sinica

Maianthemum spp., 355

Malicious poisonings, 17, 52, 77, 81, 127, 152

Malignant hyperthermia, 70, 78, 172, 336

Malus spp, 171–172

Mammillaria spp., 377

Mandragora spp., 69

Manihot spp., 68

Mannitol, 191, 262, 299, 342

in bromethalin toxicosis, 132

MAO inhibitors, see Monoamine oxidase inhibitors

Maranta leuconeura, 377

Margin of safety, 8, 80, 100, 101, 144, 149, 175, 178, 181, 203–205, 207, 208, 228, 229, 233

Marigold, see Tagetes spp.

Marijuana, see Cannabis sativa

Mariposa lily, see Calochortus spp.

Maroon cucumber, see Cucumis spp.

Maropitant, 105, 342

Marsh marigold, see Caltha palustris

Masd, see Masdevallia spp.

Masdevallia spp., 377

Matches, 121, 321–322, 322

Matricaria recutita, see Chamomile

Mayapple, see Podophyllum spp.

McNab, MDR1 p‐glycoprotein genetic polymorphism, 150

Meadow saffron, see Colchicum autumnale

Mebendazole, 109

Median lethal dosage (LD50), 4, 38

Mediterranean thistle, see Atractylis gummifera

Melaleuca spp., 180, 309, 377

Melaleuca, see Melaleuca spp.

Melamine, 115, 115

Melatonin, 95

Melia azedarach, 166–167, 355, 363, 365, 366

Meloxicam 221; see also Nonsteroidal anti‐inflammatory drugs

Mentha pulegium, see Pennyroyal oil

Menthol, 307, 309

Meperidine, 52, 179, 201

Mercury, 6–7, 63, 64, 115, 184, 193–194, 322, 337, 346

organic alkyl, 95, 193

Metabolism, see Toxicokinetics

Metaldehyde, 49, 70, 71, 78, 81, 94, 154–155, 342

Metallic peperomia, see Peperomia spp.

Metallothionein, 184, 195

Metformin, 210–211

Methadone, 52, 52, 69, 235

Methane, 104, 105, 121, 311

Methanol, 292, 293, 297

Methemoglobinemia, 8, 49, 50, 68, 78, 105, 121, 214–215, 223, 258, 259, 274, 278, 305, 321, 322, 323, 324, 325, 327, 331, 333, 342, 346

Methocarbamol, 71, 134, 143, 152, 155, 182, 219, 248, 264, 266, 277, 282, 318, 320, 320, 342

Methomyl, 67, 79, 81, 140

Methotrexate, 67, 120, 121

Methyl alcohol, see Methanol

Methylene blue, 68, 321, 323, 325, 327, 342

Methylxanthines, 7, 20, 42, 49, 53, 95, 99, 101–102, 175–176, 233, 263–264, 263, 264, 317, 318

Metoclopramide, 52, 57, 327, 342

Metoprolol, 101, 176, 206, 223, 227, 318, 342

Mexican firecracker, see Echeveria spp.

Mexican snowball, see Echeveria spp.

Microcystin, 81, 109, 110

Micruroides spp., see Snakes, elapids

Micrurus spp., see Snakes, elapids

Midazolam, 119, 200, 205, 210, 343

Milbemycin oxime, 149, 150; see also Macrocyclic lactone parasiticides

Milkweed, see Asclepias spp.

Miltoniopsis roezlii, 377

Mimicry plant, see Pleiospilos bolusii

Mimosa pudica, 355

Mineralization, soft tissue, 99, 100, 114, 115, 132–133

Miniature Australian shepherd dogs, MDR1 p‐glycoprotein genetic polymorphism, 150

Miniature maranta, see Goeppertia micans

Minimum lethal dosage (MLD), 4, 148

Minimum toxic dosage (MTD), 4

Minoxidil, 99, 100

Mirabilis jalapa, 355

Mirtazapine, 95, 201

Misopates orontium, 377

Misoprostol, 218, 222, 343

Mistletoe, see Viscum spp.

Mistletoe cactus, see Rhipsalis baccifera

Mitochondrial injury, 110, 188, 190, 287

Mock azalea, see Adenium obesum

Molded wax agave, see Echeveria spp.

Moldy food, see Mycotoxins, tremorgenic

Molluscicides, 81, 147, 154–156

Morning glory, see Ipomoea spp.

Monkshood, see Aconitum spp.

Monoamine oxidase inhibitors (MAOI) 70, 95, 176, 177, 179, 201, 203; see also Antidepressants

Monomethylhydrazine, 94, 274, 277–278

Monosodium methanearsenate (MSMA), 153, 185

Monstera spp., 119, 355, 356, 367, 369, 371

Morning‐noon‐and‐night plant, see Brunfelsia pauciflora

Morphine, 69, 95, 235, 236

Mosiac vase, see Guzmania spp.

Moss campion, see Silene acaulis

Moss phlox, see Phlox spp.

Mother‐of‐millions plant, see Kalanchoe spp.

Mother spleenwort, see Asplenium spp.

Motor oil, 122, 311, 312, 314, 324

Mountain laurel plant, see Kalmia spp.

Mountain rosebay, see Rhododendron spp.

Moxidectin 8, 94, 149, 150; see also Macrocyclic lactone parasiticides

Mulch, 275, 317–318, 317, 318

Musa spp., 377, 377

Muscarinic signs, 66, 67, 141, 142, 273, 339

Muscari spp., 377

Musculoskeletal system, 121, 122

Mushrooms, 26, 32, 33, 67, 69, 87, 87, 271–282, 272

gastrointestinal irritant, 271–274, 273

gyromitrin, 67, 69, 271, 277–278, 345

hallucinogenic, 94, 271, 273, 275–276

hepatotoxic, 68–71, 78, 109, 274, 278–281, 282, 331

ibotenic acid, 276–277

isoxazole, 94, 271, 273, 334

monomethylhydrazines, 94, 274

muscarinic, 67, 105, 271, 273, 274–275, 334

muscimol, 273, 276–277

Muskmelon, see Cucumis spp.

Mycotoxins, 281–288

nephrotoxin, 288

pet food associated, 281–282, 283, 284, 286–287

tremorgenic, 51, 71, 78, 94, 122, 264–266, 282, 319–321, 319, 320, 342

Myristica fragrans, 362

Myrtle spurge, see Euphorbia myrsinites

N‐acetylcysteine, 68, 215, 281, 282, 331

Naked lady, see Colchicum autumnale

Naloxone, 52, 69, 222, 236, 343

Nandina spp., 68

Naphazoline, 99, 219

Naphthalene, 68, 109, 118, 121

Naproxen, 12, 52, 70, 109, 220–221, 221, 228, 234; see also Nonsteroidal anti‐inflammatory drugs

Narcissus spp., 119, 162–163, 356, 356, 363, 367, 369, 371

National Pesticide Information Center (NPIC), 25, 147

Natural gas, 105

Nectarine, see Prunus spp.

Nefazodone, 52, 95, 201

Nemantanthus fornix, 377

Neonicotinoid insecticides, 144–145, 144

Neoregelia carolinae, 377

Neostigmine, 69, 343

Nephrolepis spp., 377

Nephthytis, see Syngonium podophyllum

Nerium oleander, 20, 66, 94, 164–165, 165, 207, 356, 367, 372

Nerve plant, see Fittonia spp.

Nervous system, 49, 53, 56, 79, 93–97, 94–95

Nettle, see Urtica spp.

Nicotiana spp., 5, 94, 171, 234, 356, 357, 363, 365–368

Nicotine, 79, 94, 171, 234–235, 235

Nicotinic acetylcholine receptor (nAChR), 144

Nicotinic signs, 69, 141, 142, 275

Night blooming cereus, see Hylocereus undatus

Nightshade plant, see Solanum spp.

Nifedipine, 100, 206

Nimodipine, 206

Nitenpyram, 144, 144

Nitrogen gas, 104, 105

Nitroprusside, 68, 71, 219, 223, 237, 340, 343

NOAEL (no observed adverse effect level), 38, 144

NOEL (no observed effect level), 181

Nonionic detergents, 303–304

Nonsteroidal anti‐inflammatory drugs (NSAIDs), 9, 12, 20, 31, 52, 109, 110, 111, 114, 115, 117, 119, 128, 162, 178, 191, 213, 218, 220–222, 221, 228, 230, 234, 249, 335

Norepinephrine, 71, 93, 154, 199, 200, 202, 203, 207, 218, 220, 226, 228, 230, 233, 237, 244, 275, 343

Nortriptyline, 70, 201; see also Tricyclic antidepressants

NSAID, see Nonsteroidal anti‐inflammatory drugs

Nutmeg, see Myristica fragrans

Oak, see Quercus spp.

Ochratoxin, 282, 283, 283, 288

Octreotide, 71, 279, 281, 282, 343

Old English sheepdogs, MDR1 p‐glycoprotein genetic polymorphism, 8, 150

Old man cactus, see Cephalocereus senilis

Old world orchid, see Bulbophyllum appendiculatum

Oleander, see Nerium oleander

Omeprazole, 164, 315, 316, 325, 327, 343

Omphalotus spp., 271, 273

Oncidium spp., 377

Ondansetron, 343

Onions, see Allium spp.

Onychium japonicum, 377

Opioids (opiates), 50, 52, 52, 69, 95, 118, 120, 235–237, 248, 249, 302, 343

Orange oil, 308

Oregon grape, see Berberis aquifolium

Organochlorine insecticides (OCs), 11, 79, 94, 142

Organophosphorus and carbamate insecticides, 5, 6, 53, 67, 67, 69, 70, 79, 81, 94, 96, 105, 118, 120, 139–142, 140, 334, 339, 344

Ornamental bulbs, 119, 162–163

Ornamental peppers, see Capsicum spp.

Ornithogalum spp., 66, 356, 367

Oscularia piquetbergensis, 377

Oxalates; see also Ethylene glycol

insoluble, 117, 119, 159–160, 162, 169

soluble, 67, 159–160, 169–170, 369

Oxalis spp., 18, 169, 356, 366, 369

Oxycodone, 69, 235

Oxymetazoline, 99, 219

Oxymorphone, 69, 235, 236

Oyster plant, see Tradescantia spathacea

Paint, 32, 59, 184, 189, 191, 290, 295, 296, 299, 311, 327, 328

Painted lady, see Echeveria spp.

Pamidronate (pamidronic acid), 71, 72, 133, 343

Pampas grass, see Cortaderia selloana

2‐PAM, see pralidoxime chloride

Panaeolus spp., 271, 275

Panicum spp., 68

Pansy orchid, see Miltoniopsis roezlii

Papaver somniferum, 235, 360, 361, 363, 366, 368

Paper plant, see Fatsia japonica

Paralysis, 50, 78, 81, 94, 95, 121, 122, 128, 130, 134, 140, 141, 161, 166–167, 171, 172, 204, 247, 251, 288, 319, 319, 364, 368

Paracelsus, 16, 37

Paraquat, 11, 63, 70, 88, 104, 105, 115, 152–153

Paris quadrifolia, 356, 360

Parlor palm, see Chamaedorea spp.

Paroxetine, 201; see also Selective serotonin reuptake inhibitors

Parsley fern, see Cryptogramma crispa

Partial thromboplastin time (PTT), 51, 129, 248, 254, 255, 285, 286

Parts per billion (ppb), 4, 39, 39

Parts per million (ppm), 4, 39, 39

Parts per trillion (ppt), 4

Pasque flower, see Pulsatilla vulgaris

Paullinia cupana, 175

PCP (phencyclidine), 52, 236–237

PE‐4 explosive, see Explosives

Peace lily, see Spathiphyllum spp.

Peach, see Prunus spp.

Peacock flower, see Caesalpinia pulcherrima

Peacock ginger, see Kaempferia spp.

Pears, see Pyrus spp.

Pecan, see Carya spp.

Pediatric patients, 8, 9

Pelargonium spp., 371

Pellaea spp., 377

Pencil cactus, see Euphorbia tirucalli

Penitrem A, 94, 265, 282, 283, 319, 319

Pennyroyal oil, 180–181, 309

Penthrite, see Explosives

Pentobarbital, 170, 179, 209, 227, 320, 344

Peperomia sp., 377–378

Peppermint oil, 307, 309

Peppers, chili, see Capsicum spp.

Peppers, ornamental, see Capsicum spp.

Periploca sepium, 367

Permethrin, 20, 53, 71, 143–144, 342

Persea spp., 260, 367

Persian lilac, see Melia azedarach

Persian violet, see Cyclamen spp.; Exacum affine

Pesticide, definition of, 5, 147

PETN explosive, see Explosives

Pet Poison Helpline, 17, 27, 48, 173

Petroleum distillates, 105, 119, 122, 301, 311–316, 312, 313, 314, 315, 321, 322

Peyote, see Lophophora williamsii

P‐glycoprotein, see Macrocyclic lactone parasiticides, MDR1 p‐glycoprotein and

Phalaris spp., 68

Phaseolus vulgaris, 356, 367

Pheasant’s eye, see Adonis aestivalis

Phenobarbital, 109, 175, 228, 264, 266, 282, 318, 320, 325, 326, 344

Phenol, 8, 68, 95, 109, 119, 121, 305, 342

Phenol carbinol, see Benzyl alcohol

Phenothiazines, 70, 71, 95, 200, 201, 223, 227, 233

Phenylbutazone, 114, 115, 121

Phenyl carbinol, see Benzyl alcohol

Phenylephrine, 52, 95, 101, 218–219, 344

Phenylmethanol, see Benzyl alcohol

Phenylmethylalcohol, see Benzyl alcohol

Phenylpropanolamine (PPA), 52, 71, 99, 100, 101, 175, 222–223, 331, 335, 340

Phenylzine, 201; see also Monoamine oxidase inhibitors

Phenytoin, 109, 300, 344

Philodendron peperomia, see Peperomia spp.

Philodendron spp., 119, 162, 356, 357, 367, 371

Phlox spp., 378

Phoenix spp., 378

Phosmet, 140

Phosphine gas, 57, 105, 134–135, 332

Phosphorus

serum, 102, 132–133, 169, 245, 261

yellow/white/red, 68, 108, 109, 322, 323

Phyllostachys aurea, 378

Physalis spp., 69, 356, 371

Physic nut, see Jatropha curcas

Physostigmine, 69, 151, 344

Phytolacca americana, 356, 357

Pieris japonica, 166, 356, 360, 362–364, 367

Piggyback plant, see Tolmiea menziesii

Pigmy date palm, see Phoenix spp.

Pilea spp., 378

Pimobendan, 99, 101, 208

Pincushion cactus, see Mammillaria spp.

Pineapple, see Ananas comosus

Pindone, 128

Pine oil, 105, 303, 309

Piperazine, 95

Pittosporum tobira, 378

Plane tree, see Platanus spp.

Plantanthera spp., 378

Plasma, 65, 86, 129, 148, 182, 285, 323, 325, 326, 344

proteins, 9, 11, 128

Platanus spp., 378

Platycerium bifurcatum, 378

Plectranthus spp., 378

Pleiospilos bolusii, 378

Plerandra elegantissima, 378

Plum, see Prunus spp.

Plumbago spp., 357, 371

Podophyllum spp., 357, 358

Poinsettia plant, see Euphorbia pulcherrima

Poison hemlock, see Conium maculatum

Poisoning incidence, 16–20, 82, 107

Pokeweed, see Phytolacca americana

Polka dot plant, see Hypoestes phyllostachya

Polygonatum spp., 357, 358

Polyscias spp., 361, 363, 365, 367, 371

Polystichum spp., 378

Ponytail palm, see Beaucarnea recurvata

Potassium benzoate, see Benzyl alcohol

Potassium chlorate, 321–322, 322

Potato, see Solanum tuberosum

Potentilla spp., 378, 378

Pothos, see Epipremnum aureum

Pralidoxime chloride (2‐PAM, protopam chloride), 69, 142, 344

Prayer plant, see Maranta leuconeura

Prednisone (prednisolone), 133, 279, 344

Primrose, see Primula obconica

Primula obconica, 357, 371

Privet, see Ligustrum spp.

Propiconazole, 151

Propofol, 95, 134, 144, 155, 219, 227, 276, 282, 325, 326, 345

Propoxur, 67, 140

Propoxyphene, 235

Propranolol, 63, 101, 166, 175, 176, 199, 202, 206, 219, 223, 227, 231, 245, 318, 344

Propylene glycol, 50, 52, 95, 121, 215, 297, 299–300

Prosthechea prismatocarpa, 378

Prothrombin time (PT), 51, 129, 214, 249, 254, 255, 278, 284

Protamine sulfate, 64, 345

Protoanemonin, 161

Protopam chloride, see pralidoxime chloride

Prunus spp., 68, 171–172, 357, 366, 368

Pseudoephedrine, 52, 52, 79, 95, 101, 174–176, 200, 216, 218–219, 218, 226, 227, 331, 335

Psilocybe spp., 273, 275–276

Psilocybin, 273, 275–276

Psilocin, 273

Psychilis atropurpurea, 378

Psychopsis spp., 378

Pteris spp., 378

Pulmonary fibrosis, see Lung, fibrosis

Pulmonary system, 104–106

Pulsatilla vulgaris, 357, 371

Purple passion, see Gynura spp.

Pyracantha spp., 68, 357

Pyrethrins, see Pyrethroid insecticides

Pyrethroid insecticides, 5, 51, 94, 122, 142–144

Pyrethrum, 142

Pyridostigmine, 69, 345

Pyridoxine, 69, 278, 298, 344, 345

Pyrus spp., 171

Queen Anne’s lace, see Ammi majus

Queen’s cup, see Clintonia spp.

Queen’s spiderwort, see Dichorisandra spp.

Quercus spp., 120, 357, 369

Rabbit foot fern, see Davallia spp.

Ragwort, see Senecio spp.

Rainbow orchid, see Prosthechea spp.

Raindrop, see Peperomia spp.

Rain lily, see Zephyranthes spp.

Raisins, see Vitis spp.

Ranunculus spp., 68, 357, 371

Raphanus rhapinistrum, 378

Raspberry, see Rubus spp.

Rattlesnakes, see Snakes, pit vipers

RDX explosive, see Explosives

Recluse spiders, 247–249

Red edged peperomia, see Peperomia spp.

Red hot poker, see Kniphofia spp.

Red laurel, see Rhododendron spp.

Red sage, see Lantana spp.

Reproductive toxicity, 9, 171, 288

Reserpine, 179, 201

Resin spurge, see Euphorbia resinifera

Rhamnus spp., 357

Rhapis excela, 378

Rheum rhabarbarum, 169–170, 170, 357, 369

Rhipsalis baccifera, 378

Rhododendron spp., 99, 166, 166, 357, 360, 362–364, 366–368

Rhodotypos spp., 68

Rhubarb, see Rheum rhabarbarum

Ricin, 163

Ricinus communis, 70, 78, 109, 120, 163–164, 164, 358, 365, 367, 369

Robinia pseudoacacia, 358, 365, 367, 369

Roman chamomile, see Chamomile

Ropinirole, 57, 135, 176, 274, 275, 282, 317, 318, 320, 325, 342, 345

Roquefortine, 94, 264, 265, 282, 283, 319, 319

Rosary pea, see Abrus precatorius

Rosin rose, see Hypericum perforatum

Rubbing alcohol, see Isopropanol

Rubrum lily, see Lilium lancifolium

Rubus spp., 378

Russula spp., 271

S‐adenyl‐methionine (SAMe), 71, 345

Sago palm, see Cycas revoluta

Sairocarpus multiflorus, 378

Salicylates, 41, 42, 70, 95, 216–218, 217, 306, 308, 343

Salt (sodium chloride), 34, 39, 57, 79, 95, 249, 305–310, 321, 322

Salvia coccinea, 379

Salvia divinorum, 237

Sambucus spp., 68, 358

Sandalwood oil, 309

Sandbog death camas, see Zigadenus glaberrimus

Sandbox tree, see Hura crepitans

Sand lily, see Leucocrinum montanum

Sanvitalia procumbens, 379

Saponins, 159, 161, 162, 164

Sarolaner, 20, 138

Sassafras oil, 309

Scadoxus multiflorus, 358, 364

Scarlet sage, see Salvia coccinea

Schefflera, see Heptapleurum spp.

Schlumbergera spp., 164, 379

Scilla hyacinthoides, 66, 358, 365, 367

Scorpions, 249–250

Scotch laburnum, see Laburnum anagyroides

Sedum morganianum, 379

Sego lily, see Calochortus spp.

Seizures, 31, 32, 38, 48, 49, 51, 56, 56, 58, 70, 79, 89, 94, 95, 96, 241, 244, 245, 247, 248, 255, 265, 266, 294, 296, 297, 304, 305, 308, 310, 313, 313, 315, 316, 317, 318, 321, 323, 324, 325, 325, 326, 336, 341, 344, 345

in drug toxicoses, 63, 67, 69, 70, 78, 80, 95, 176, 198–205, 207, 209, 210, 216–218, 222, 223, 227, 229–231, 234–237, 238

in food toxicoses, 79, 263, 264, 266–268, 292

in herbal toxicoses, 175–177, 179–182

in metal or mineral toxicoses, 190, 191

in pesticide toxicoses, 78, 79, 81, 94, 128, 130, 132, 134, 135, 137–139, 141–143, 148, 150, 153–157

in plant/fungi toxicoses, 78, 79, 81, 94, 161, 163, 164, 166, 167, 170–172, 273, 274, 276–279, 280, 281, 282, 319, 319, 320, 320, 321

Selaginella spp., 379

Selamectin, 149, 150; see also Macrocyclic lactone parasiticides

Selective serotonin reuptake inhibitors (SSRI), see also Antidepressants

Selegiline, 52, 201; see also Monoamine oxidase inhibitors

Sempervivum spp., 379

Senecio spp., 369, 370

Sensitive plant, see Mimosa pudica

Serotonin, 70, 154, 177, 179, 199–203, 201, 219, 226, 230–233, 250, 275, 287

Serotonin norepinephrine reuptake inhibitors (SNRIs), see also Antidepressants

Serotonin syndrome, 70, 80, 95, 175, 177, 179, 200–203, 231, 236, 335

Sertraline, 52, 179, 201, 204, 230; see also Selective serotonin reuptake inhibitors

Seville orange, see Citrus aurantium

Shamrock, see Oxalis spp.

Shetland sheepdogs, MDR1 p‐glycoprotein genetic polymorphism, 8,

Shrub verbena, see Lantana spp.

Sibutramine, 174

Sida cordifolia, 174

Silene acaulis, 379

Silica gel, 31

Silken windhound, MDR1 p‐glycoprotein genetic polymorphism, 150

Silk tree, see Albizia julibrissin

Silver berry, see Elaeagnus spp.

Silver heart, see Peperomia spp.

Silymarin, 69, 167, 168, 182, 268, 281, 282, 345

Sinapis arvensis, 358

Sinningia speciosa, 379

Sistrurus spp., 65, 252

Slender deutzia, see Deutzia gracilis

SLUDDE signs, 67, 79, 81, 141, 275

Smilax spp., 379

Smoke inhalation, 55, 79, 340

Snakes, 250–255,

elapids, 65, 69, 94, 250–252, 345

envenomation, 79, 94, 250–255

pit vipers, 62, 65, 65, 115, 115, 121, 121, 177, 252–255, 252, 253, 332, 333

snakebite severity scoresheet, 255

Snapdragon, see Antirrhinum majus

Sneezeweed, see Helenium spp.

Snowdrop, see Galanthus spp.

Spanish bluebell, see Hyacinthoides hispanica

Sodium benzoate, see Benzyl alcohol

Sodium fluoroacetate (1080), 94, 100, 156–157

Sodium nitrate, 322, 322

Sodium nitrite, 68, 171, 346

Sodium thiosulfate, 171, 346

Solanum dulcamara, 358, 361, 363, 368

Solanum lycopersicum, 171, 171, 358, 361

Solanum nigrum, 358, 361, 364

Solanum pseudocapsicum, 358

Solanum spp., 69, 171, 358

Solanum tuberosum, 358, 361, 364, 366–368

Soleirolia soleirolii, 379

Solenopsis spp., 240, 242

Solomon’s seal, see Polygonatum spp.

Solute, 43, 113, 114

Solution, 43

Solvent, 4, 10, 43, 53, 55, 120, 142, 180, 291, 295, 299, 301, 312, 313, 328

Sophora spp., 358, 362, 364, 366

Sophronitis spp., 379

Sorghum spp., 68

Sorphastrum spp., 68

Sorrel, see Oxalis spp.

Sotalol, 206

Soursob, see Oxalis spp.

Sow’s bread, see Cyclamen spp.

Sparklers, 322, 322

Spathiphyllum spp., 119, 162, 163, 169, 358, 371

Spearmint oil, 307, 308, 309

Species differences, 8, 11, 12, 172, 274

Spice, 238

Spider lily, see Crinum spp.; Hymenocallis spp.

Spider plant, see Chlorophytum spp.

Spiders, 64, 94, 246–249, 333

Spirea spp., 68

Split‐leaf philodendron, see Monstera spp.

Spur‐flower, see Plectranthus spp.

Squill, see Drimia maritima; Scilla spp.

SSRI, see Selective serotonin reuptake inhibitors

Stapelia spp., 379

Star jasmine, see Trachelospermum jasminoides

Star‐of‐Bethlehem, see Ornithogalum spp.

Stemless Townsend daisy, see Townsendia exscapa

Stephanotis floribunda, 379

Stewartia spp., 379

Stillingia spp., 68

St. Johns’s Wort, see Hypericum perforatum

Strawberry, see Fragaria spp.

Streptocarpus spp., 379

String of turtles, see Peperomia spp.

Strobilanthes alternata, 372

Strophanthus spp., 66

Strychnine, 71, 79, 94, 96, 133–134

Subacute toxicity, 3, 168, 178, 284

Subchronic toxicity, 3

Succimer, 64, 154, 184, 186, 191–192, 192, 346

Suckleya spp., 68

Sucralfate, 70, 152, 153, 164, 189, 194, 217, 222, 286, 302, 315, 316, 325, 346

Sudden death

investigation, 77, 79, 80

sample collection, 81–82

sample submission, 82

toxicants causing, 77–81, 78, 102, 133, 165, 167, 284, 285, 285, 372

Sulfonamides, 109, 121

Sulfonylurea diabetic medications, 67, 70, 210

Sulfur, 71, 139, 151, 172, 258, 316, 322, 322, 346

Sulfuryl fluoride, 105

Sulphurflower buckwheat, see Eriogonum spp.

Sumatriptan, 201

Sweet chestnut, see Castanea spp.

Sweet clover, moldy, 127

Sweet‐flag, see Acorus calamus

Sweetheart peperomia, see Peperomia spp.

Sword fern, see Nephrolepis spp.

Sycamore, see Platanus spp.

Sympathomimetics, 101, 174–175, 218–219, 222–223, 230–231

Symphytum officinale, 370

Syngonium podophyllum, 119, 358, 359, 368, 369

T‐2, 286–288

Tagetes spp., 358, 359, 371

Tanacetum vulgare, 358, 365, 367

Tansy, see Tanacetum vulgare

Tartaric acid, 114, 115, 260–261

Taxines, 99, 167

Taxus spp., 71, 167, 167, 359, 361, 366–368, 372

TD50, 8

Tea tree oil, see Melaleuca spp.

Terbufos, 67, 140

Terbutaline, 101, 105, 315, 346

Testing, see Laboratory

Tetanus, 71, 94

Tetrahydrozoline, 219

Tetrodotoxins, 69, 71, 79

Texas umbrella tree, see Melia azedarach

Thallium, 95

THC, see Cannabis sativa

Theobromine 20, 95, 101, 162, 175, 263, 263, 317, 318, 318; see also Methylxanthines

Theophylline, 95, 101, 175, 346

Therapeutic index, 7–8, 101, 298

Thevetia nerifolia, 66

Thiotic acid, see Alpha lipoic acid

Thuja occidentalis, 180, 306, 359, 365, 369–371

Tick paralysis, 94

Tiger lily, see Lilium tigrinum

Tiger orchid, see Grammatophyllum speciosum

Tilia spp., 379

Tillandsia spp., 379

TNT explosive, see Explosives

Toads, 65, 79, 99, 207, 244–245, 337

Tobacco, see Nicotiana spp.

Tolazamide, 210

Tolerance, 6

Tolmiea menziesii, 371

Tomato, see Solanum lycopersicum

Townsendia exscapa, 379

Toxic, 37

Toxicant, 3

Toxicity, 3, 37, 235

Toxicokinetics, 3, 10–12

absorption, 10–11

bioactivation, 12

distribution, 11

elimination, 12

metabolism, 11–12

Phase I, 12

Phase II, 12

Toxicology, 3

Toxin, 3

Trachelospermum jasminoides, 379

Trachycarpus fortune, 379

Tradescantia spathacea, 359, 359, 371

Traveler’s joy, see Clematis spp.

Tramadol, 52, 69, 95, 201, 235, 236

Tranexamic acid, 346

Trazodone, 52, 95, 200, 201, 202

Tree gloxinia, see Kohleria amabilis

Tree tobacco, see Nicotiana spp.

Tremorgenic mycotoxins, see Mycotoxins, tremorgenic

Triage, telephone, 34, 35, 48

Trichlorfon, 140

Trichothecene mycotoxins, 121, 283, 283, 286–288

Trichocentrum lanceanum, 379

Tricholoma muscarium, 276

Tricyclic antidepressants, 52, 52, 63, 67, 70, 71, 95, 99, 99, 200, 201, 202, 339; see also Antidepressants

Trientine, 64, 346

Trifolium spp., 68

Triglochin spp., 68

Triterpenes, 162, 168, 271

Tropane alkaloids, 99

Trout lily, see Erythronium Americanum

Tsuga spp., 379

Tulipa spp., 119, 162, 163, 359, 367, 368, 371

Tulip tree, see Liriodendron tulipifera

Tung oil tree, see Vernicia fordii

Turpentine, 95, 312, 313, 314, 327

Umbrella plant, see Eriogonum spp.

Urginea maritima, 66

Urinary system, 113–115, 115

Ursodiol, 347

Urtica spp., 359, 364, 367, 368

US EPA, see Environmental Protection Agency

Valeriana spp., 94, 179–180

Valerian root, see Valeriana spp.

Vandal root, see Valeriana spp.

Vasodilators, 71, 99, 101, 102, 114, 198, 205, 207, 208, 219, 223, 291

Vasopressin, 93, 347

Venlafaxine, 52, 201, 203

Venom

Apid (bee), 240–242

elapid snakes, see Snakes, envenomation

fire ant, 242–244

Mojave A rattlesnake, see Snakes, envenomation

pit viper, see Snakes, envenomation

recluse spider, 248

scorpion, 250

Vespid (hornet, wasp), 240–242

widow spider, 64, 247

Venus fly trap, see Dionaea muscipula

Verapamil, 52, 63, 67, 100–101, 206–207

Veratrum spp., 359, 364, 367, 368, 372

Vernicia fordii, 359, 361, 365, 371

Viburnum spp., 359–360

Vilazodone, 201

Vinca spp., 71, 360, 367

Vining peperomia, see Peperomia spp.

Virgin’s bower, see Clematis spp.

Viscum spp., 360, 371

Vitamin, 42, 68, 69, 72, 135, 143, 172, 185, 186, 223–224, 267, 278, 286, 298, 327

unit conversion, 42

Vitamin D, see Cholecalciferol

Vitamin K1, 51, 72, 118, 121, 128–129, 182, 281, 282, 286, 325, 326, 347

Vitis spp., 260–262, 261

Vomitoxin, 282, 283, 286–287, 287, 288

Vortioxetine, 201

Vriesea spp., 379

Waffle plant, see Strobilanthes alternata

Warfarin, 11, 121, 127–129, 128

Wasp sting, see Hymenopteran insects; Venom, Vespid

Water hemlock, see Cicuta spp.

Water intoxication, 79

Watermelon peperomia, see Peperomia spp.

Water moccasin, see Snakes, pit viper

Watusi (dancing) firecracker, 322, 323

Wax plant, see Hoya spp.

Weasel’s snout, see Misopates orontium

Weeping bottlebrush, see Melaleuca spp.

Weeping fig, see Ficus benjamina

Western sword fern, see Polystichum spp.

White clintonia, see Clintonia spp.

White garland lily, see Hedychium spp.

White phosphorus, 108, 109

White snakeroot, see Ageratina altissiama

Widow spiders, see Latrodectus spp., see also Venom

Wild mustard, see Sinapis arvensis

Wild radish, see Raphanus rhaphinistrum

Wild sage, see Lantana spp.

Wild sarsaparilla, see Aralia nudicaulis

Willowherb, see Epilobium spp.

Windmill palm, see Trachycarpus fortunei

Wintergreen oil, 308

Wisconsin Alumni Research Foundation, 127

Wisteria spp., 360, 360

Withered snapdragon, see Sairocarpus multiflorus

Working dogs, and explosives, 323

Wormwood, see Artemisia absinthium

Wood alcohol, see Methanol

Wood fern, see Dryopteris spp.

Woodland phlox, see Phlox spp.

Wood sorrel, see Oxalis spp.

Xylazine, 57, 66, 69, 334, 347

Xylitol, 18–20, 51, 52, 58, 70, 79, 109, 233, 235, 267–268, 297, 331

Yellow jessamine, see Gelsemium sempervirens

Yellow oleander, see Cascabela thevetia

Yellow sage, see Lantana spp.

Yesterday‐and‐today plant, see Brunfelsia pauciflora

Yesterday‐today‐tomorrow plant, see Brunfelsia pauciflora

Yew, see Taxus spp.

Yohimbine, 69–70, 71, 138, 220, 267, 347

Zamia spp., 109, 167, 168, 360, 364–366, 370

Zantedeschia spp., 119, 162, 169, 360, 366, 368, 369, 371

Zearalenone, 283, 286, 288

Zebra cactus, see Haworthia spp.

Zephyranthes spp., 360, 364, 367

Zigadenus glaberrimus, 360, 364, 367

Zinc, 53, 62–64, 88, 114, 118, 119, 121, 192, 194–196, 335

Zinc oxide, 119, 121, 194

Zinc phosphide, 57, 79, 94, 105, 115, 134–135

Zoledronate (zoledronic acid), 72, 133, 347

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