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Copyright © 2001 by Butterworth–Heinemann A member of the Reed Elsevier group All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photo- copying, recording, or otherwise, without the prior written permission of the publisher. Every effort has been made to ensure that the drug dosage schedules within this text are accurate and conform to standards accepted at time of publica- tion. However, as treatment recommendations vary in the light of continuing research and clinical experience, the reader is advised to verify drug dosage schedules herein with information found on product information sheets. This is especially true in cases of new or infrequently used drugs. Recognizing the importance of preserving what has been written, Butter- worth–Heinemann prints its books on acid-free paper whenever possible. Library of Congress Cataloging-in-Publication Data ISBN 0-7506-7240-4 British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library. The publisher offers special discounts on bulk orders of this book. For information, please contact: Manager of Special Sales Butterworth–Heinemann 225 Wildwood Avenue Woburn, MA 01801-2041 Tel: 781-904-2500 Fax: 781-904-2620 For information on all Butterworth–Heinemann publications available, con- tact our World Wide Web home page at: http://www.bh.com 10 9 8 7 6 5 4 3 2 1 Printed in the United States of America Series Preface The Practical Veterinarian was developed to help veterinary students, veterinarians, and veterinary technicians quickly find answers to com- mon questions. Unlike larger textbooks, which are filled with detailed information and meant to serve as reference books, all the books in The Practical Veterinarian series are designed to cut to the heart of the subject matter. Not meant to replace the reference texts, the guides in the series complement the larger books by serving as an introduction to each topic for those learning the subject for the first time or as a quick review for those who already have mastered the basics. The titles are selected to provide information about the most com- mon subjects encountered in veterinary school and veterinary practice. The authors are experienced and established clinicians who can pre- sent the subject matter in an easy-to-understand format. This helps both the first-time student of the subject and the seasoned practitioner to assess information often difficult to comprehend. The editor and authors hope that the books in The Practical Vet- erinarian series will meet the needs of readers and serve as a constant source of practical and important information. We welcome comments and suggestions that will help improve future editions of the books in this series. Shawn P. Messonnier, D.V.M. vii Preface This book was written to provide the busy practitioner and the veteri- nary student a source of information concerning the more common intoxications in the United States. Veterinary toxicology is a very broad- based discipline with literally thousands of possible toxicants. The list was reduced using a core knowledge guidance paper written by the diplomates of the American Board of Veterinary Toxicology. Chapter 1 presents an initial discussion of the absorption, distri- bution, metabolism, and elimination of veterinary toxins and provides the reader with a framework for a rational therapeutic approach. It also provides the reader with information concerning calculations involved in veterinary toxicology. This begins the process of understanding the estimation of dose that is critical to differentiating between exposure and intoxication. Chapter 2 provides the reader with some “reminders” of possible toxins based upon the patient’s clinical signs. Chapter 3 discusses the pathophysiology of selected intoxications and gives the reader some deeper insight into the processes by which these poisons produce their clinical effects. It also provides a rational approach to symptomatic or antidotal therapy. Chapter 4 represents the bulk of this book, which is dedicated to individual monographs of specific toxins that are arranged alphabeti- cally. This chapter should provide the reader with the requisite infor- mation to diagnose and treat a veterinary toxicosis. Chapter 5 concerns antidotal therapy and provides a quick access to the relatively limited number of antidotes that are available to the veterinarian. Chapter 6 discusses some of the basics of diagnostic toxicology as well as other sources of information that may be beneficial to the reader. It is my hope that this text provides the reader with a greater understanding of veterinary toxicology and most importantly the infor- mation necessary to diagnose and treat our veterinary patients. I would like to take this opportunity to thank some individuals who made this whole process possible. I first would like to thank my col- leagues who are diplomates of the American Board of Veterinary Toxi- cology. I am greatly indebted to their original and clinical research (performed and published) that serve as the backbone of this text. I would also like to thank Leslie Kramer from Butterworth–Heinemann ix who patiently guided me through the process of putting these pages together. I am thankful that my sons, Adam, Alex, and Andrew, will soon see the fruits of this labor. Most especially, I am forever indebted to my loving wife, Karen, who supports me always in all things. J. D. R. x Preface 1 Overview of Veterinary Toxicology Introduction The art and science of toxicology are only slightly younger than humankind. Early in the development of hunting and warfare, there is evidence of the use of poisoned arrows to gain tactical advantage. The principles of toxicology predate poison arrows—they are as old as bac- teria and rooted in plants. The vascular plants developed many suc- cessful chemical strategies to discourage or prevent predation by herbivorous insects and animals. Today tens of thousands of potential toxins can affect our veterinary patients, and there are fewer than two dozen specific antidotes. Imagine treating the entire spectrum of infec- tious diseases with only 24 antibiotics. In human medicine, the diagnosis and management of intoxica- tion are simplified by the following: • Toxidromes: clinical syndromes strongly associated with certain toxins • Greater access to diagnostic tools • Fewer financial restraints In veterinary medicine, the diagnosis and management of intoxi- cation pose the following challenges: 1 • Numerous species with differing presentations • Malicious poisoning • Treatment of herds of animals • Maintaining the safety of the food supply It is paramount for veterinarians to understand the more com- monly encountered toxins and to treat patients accordingly. The rewards are to return patients to their normal states and to prevent future cases of poisoning. Always remember—Treat the patient, not the poison. Toxicology • Toxicology is the study of poisons and their effects on normal phys- iologic mechanisms. • Information and concepts come from the following disciplines: • pharmacology • mathematics • chemistry • ecology • zoology • botany Definitions • LD50: lethal dose 50 • the dose of a toxin that causes the death of half of a group of ani- mals • generally only useful for an idea of the relative danger posed by an agent • many LD50 data are obtained from observations of rats • LC50: lethal concentration 50 • the concentration of a toxin that causes the death of half of a group of animals • generally used for toxins in air or water 2 Overview of Veterinary Toxicology • Toxicity • the quality of being poisonous • the dose (e.g., mg/kg) of a poison that elicits a response • often inappropriately used to equate toxicosis • Toxicosis • a clinical syndrome associated with exposure to a poison (e.g., acetaminophen toxicosis) • the physiologic response to a toxin • not the same as toxicity Scope of Veterinary Toxicology The toxins that affect the more common domestic species are extremely diverse. The types of toxins often encountered include: • Metals • Mycotoxins • Feed-related intoxicants • Pharmaceutical agents • Pesticides • insecticides • herbicides • Biotoxins • plants • poisonous animals* (insects) • venomous animals* (snakes, insects) • bacterial toxins *A poisonous animal contains a toxin within its body and must be ingested to elicit toxicosis. A com- mon veterinary example includes blister beetles (cantharidin toxicosis), which is discussed in Chapter 4. A venomous animal produces a toxin and has a delivery mechanism (e.g., fangs or stinger) to inject the toxin into the prey. Common examples would include bees, wasps, and rattlesnakes. Overview of Veterinary Toxicology 3 The Metabolic Fate of Toxins The Dose Makes the Poison • This fundamental precept of toxicology has been attributed to Paracelsus. • A dose-response relationship must exist (Figure 1–1). • The greater the dose, the more likely that toxicosis will occur. • Some toxins exhibit a steep dose-response relationship and are considered highly toxic. Exposure Is Not Equal to Intoxication • To cause intoxication, a substance must be absorbed and delivered to the site of action at a concentration high enough to elicit a phys- iologic response. For example, the presence of poisonous plants in a pasture is not enough; there must be evidence of consumption of these plants. 4 Overview of Veterinary Toxicology Figure 1–1 Example of dose-response relationship for three hypothetical toxins. The squares represent a toxin with a steep dose-response curve. If the response in this chart were mortality, the squares would present the greatest risk and the cir- cles the least risk. • Different animals in a herd may consume different plants or forage. • There are individual and species variations in susceptibility to toxins. • The clinical signs observed must correlate with the suspect plant. Toxicokinetics • Study of the metabolic processes that occur after exposure to a toxin (absorption, distribution, biotransformation, and elimination) • Mathematical description of the movement of a toxin into the body (absorption), to the target organ (distribution), and out of the body (elimination) • Concentration of a toxin at the site of action depends on • dose • physicochemical properties of the toxin or drug • absorption • distribution • specific tissue affinity • rate of metabolism • rate of elimination • The fate after exposure to toxins is influenced by • toxin or drug factors • host factors or physiologic factors Animal Factors • Age • Organ perfusion • Organ function (hepatic and renal) • Membrane permeability • pH of tissue or compartment • Species • Gastrointestinal anatomy and physiology Overview of Veterinary Toxicology 5 • Examination of the cumulative effects of metabolic processes allows classification by means of two different kinetic processes: zero-order and first-order elimination kinetics (Figures 1–2 and 1–3). 6 Overview of Veterinary Toxicology Figure 1–2 Comparison of zero-order and first-order elimination kinetics. Y-axis is linear serum concentration. Zero-order kinetics show a straight line in this graph, representing a direct relationship between time and decreased serum concentra- tion of the hypothetical toxin. Figure 1–3 Comparison of zero-order and first-order elimination kinetics. Y-axis is a logarithmic increase in serum concentration. First-order kinetics show a straight line in this graph, representing a direct relationship between time and the decrease in serum concentration of the hypothetical toxin. [...]... pKa) 1 + antilog(pHy − pKa) 1+ antilog(6.8 − 2. 7) milk plasma = 1+ antilog(7.4 − 2. 7) 1+ antilog(4.1) milk plasma = 1+ antilog(4.7) 1+ 125 89 milk plasma = 1+ 50118 125 90 milk plasma = 50119 milk plasma ≅ 0 .25 R x /y = R R R R R Figure 1–7 Example of equilibrium across the mammary gland Predict the concentration ratio (milk : plasma) for benzyl penicillin G (pKa 2. 7) given that plasma pH is 7.4 and milk... cottonseed meal contains 0 .25 % gossypol The recommended feeding concentration is ppm What is the ppm concentration of gossypol for this sample? Overview of Veterinary Toxicology 25 • Answer: 25 00 ppm gossypol • Use the guidelines to convert from percentage to ppm Move the decimal point four places to the right 0 .25 % = 25 00 ppm • Question: A sample of cottonseed meal contains 0 .25 % gossypol Determine the... available as a 10% or 20 % solution How many milligrams per milliliter are in each formulation? 10% solution = 10 g/100 mL 10% solution = 0.1 g/mL 10% solution = 100 mg/mL • 10% solution of N-acetylcysteine contains 100 mg/mL • 20 % solution contains 20 0 mg/mL • Milligram percentage (mg%) • Milligrams of substance in 100 mL of solution • A 12- mg% solution contains 12 mg/100 mL 2 Clinical Presentation... 0 .25 % gossypol Determine the concentration of gossypol in milligrams per pound • Answer: 5510 mg/lb • Convert percentage to ppm 25 00 ppm • Convert ppm to mg/kg 1 ppm = 1 mg/kg 25 00 mg/kg of cottonseed meal • Convert kilograms to pounds To convert kilograms to pounds multiply by 2. 204 5510 mg gossypol/lb cottonseed meal PERCENTAGE RELATIONSHIPS • Percentage (weight/weight) or %(w/w) • Grams of substance... the Mechanism of Action section for each toxin monograph later in the text Common Veterinary Neurotoxins Central Nervous System Toxicants TOXINS ASSOCIATED WITH SEIZURES • Bromethalin • Chocolate (methylxanthines) 27 28 • • • • • • • • Clinical Presentation and Diagnosis of Common Veterinary Toxicants Lead Metaldehyde Organochlorine insecticides Pyrethrins and pyrethoids Strychnine Urea Water deprivation/sodium... concentration of a feedstuff in a final ration (Figures 1–8 and 1–9) • Some guidelines: • Target concentration (e.g., toxin, crude protein, vitamin) must be intermediate to the concentration of each feedstuff 22 Overview of Veterinary Toxicology Figure 1–8 The Pearson square is a method for determining the composition of feedstuffs with different concentrations of a nutrient or toxin The composition of each... cattle He plans to mix this hay with another source of hay (tested 500 ppm nitrate) to produce feed with a target concentration of 20 00 ppm What quantity of each source would be needed to make 1 ton of feed with the target concentration? Overview of Veterinary Toxicology 23 • Composition (dry matter or as fed) of feedstuffs must be the same • The differences between numbers must be used (negative numbers... quantity of toxin or drug is eliminated per unit time (e.g., 25 ␮g eliminated per hour) FIRST-ORDER KINETICS • Occur with most drugs • Quantity eliminated proportional to concentration of toxin present within the body at any point in time • rate decreases as concentration of the toxin decreases • constant percentage eliminated per unit time (e.g., 7 .25 % of the toxin is eliminated every 4 hours) • Half-life... Toxicants 29 • Organophosphorus insecticides • Plants with insoluble oxalate crystals • family Araceae • family Euphorbiaceae • Pyrethroids • Slaframine • Bufo toads • Corrosives Toxins Associated with Gastritis or Gastroenteritis • • • • • • Aspirin Arsenic Lead Ibuprofen Naproxen Oak (Quercus spp.) or acorn toxicosis Pathophysiology of Emesis • Caused by a number of chemicals and toxins (Figure 2 1) •... Toxins or Drugs Capable of Producing Methemoglobin in Veterinary Medicine • • • • • • • • • • Acetaminophen Benzocaine Chlorates Lidocaine Methylene blue Nitrates Nitrites Onions (N-propyl disulfide) Red maple (Acer rubrum) Zinc CLINICAL SIGNS • Cyanosis • Dyspnea • Dark brown or chocolate-colored blood 33 . please contact: Manager of Special Sales Butterworth–Heinemann 22 5 Wildwood Avenue Woburn, MA 01801 -20 41 Tel: 781-904 -25 00 Fax: 781-904 -26 20 For information on all Butterworth–Heinemann publications. processes: zero-order and first-order elimination kinetics (Figures 1 2 and 1–3). 6 Overview of Veterinary Toxicology Figure 1 2 Comparison of zero-order and first-order elimination kinetics. Y-axis is. and respiratory deposition • >5 microns impaction on the mucosa of the nasopharynx • 2 5 microns 12 Overview of Veterinary Toxicology deposited in the tracheobronchial tree • <1 micron flow