Veterinary Pharmacology and Therapeutics E-Book
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- Herausgeber: John Wiley & Sons
- Kategorie: Fachliteratur
- Sprache: Englisch
Veterinary Pharmacology and Therapeutics, Ninth Edition is the long awaited update of the gold-standard reference on veterinary pharmacology and therapeutics. The field of veterinary pharmacology continues to evolve and expand and this new edition has been revised to reflect changes in the field. Veterinary Pharmacology and Therapeutics, Ninth Edition is thoroughly revised, updated, and expanded to meet the needs of today's veterinarians, veterinary students, and animal health researchers.
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Seitenzahl: 4437
Veröffentlichungsjahr: 2013
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CONTENTS
Contributors
Preface
Section 1: Principles of Pharmacology
Chapter 1: Veterinary Pharmacology: An Introduction to the Discipline
History of Pharmacology
Veterinary Pharmacology
Regulations
What Is Veterinary Pharmacology?
Chapter 2: Absorption, Distribution, Metabolism, and Elimination
An Overview of Drug Disposition
Drug Passage Across Membranes
Absorption
Distribution
Renal Elimination
Hepatic Biotransformation and Biliary Excretion
Conclusion
Chapter 3: Pharmacokinetics
A Primer on the Language of Pharmacokinetics
The Concept of Half-Life
One-Compartment Open Model
Two-Compartment Models
Multicompartmental Models
Noncompartmental Models
Nonlinear Models
Summary of Modeling Approaches
Dosage Regimens
Interspecies Extrapolations
Conclusion
Chapter 4: Mechanisms of Drug Action and Pharmacokinetics/Pharmacodynamics Integration in Dosage Regimen Optimization for Veterinary Medicine
Introduction
Types of Drug Targets
Drug Receptor and Ligand as Agonist or Antagonist
Drug Affinity, Efficacy, and Potency
Drug Specificity and Selectivity
Chemical Forces and Drug Binding
Macromolecular Nature of Drug Receptors
Receptor Types and Subtypes
Down- and Up-Regulation
An Overview on the Determination of an Effective and Safe Dosage Regimen
Designs for Dose Titration and the Determination of an Effective Dose
The Difference Between Dose Titration and the PK/PD Modeling Approach in Determining a Dose
Building PK/PD Models
Selection of the Dose and Dosage Regimen
Population PK/PD
Limits of the PK/PD Modeling Approach for a Dose Determination: Clinical Response Versus Surrogate
Conclusion
Section 2: Drugs Acting on the Autonomic Nervous System
Chapter 5: Introduction to Neurohumoral Transmission and the Autonomic Nervous System
Organization of the Autonomic Nervous System
General Concepts of Autonomic Function
Neurohumoral Transmission
Adrenergic Neurohumoral Transmission
Cholinergic Neurotransmission
Autonomic Receptor Sites on Nerve Terminals
Putative Neurohumoral Substances
Nitric Oxide
G Proteins and Cyclic Nucleotides
Autonomic Drugs
Chapter 6: Adrenergic Agonists and Antagonists
Adrenergic (Sympathomimetic) Drugs
Catecholamines
Noncatecholamines
α2-Selective Agonists
β2-Selective Bronchodilators
Antiadrenergic Drugs
Chapter 7: Cholinergic Pharmacology: Autonomic Drugs
Parasympathomimetic Agents
Direct-Acting Parasympathomimetic Agents
Cholinesterase Inhibitors
Parasympatholytic Agents
Autonomic Ganglionic Blocking Drugs
Section 3: Anesthetics and Analgesics
Chapter 8: Introduction to Drugs Acting on the Central Nervous System and Principles of Anesthesiology
Introduction to CNS Drugs
Principles of Anesthesiology
Chapter 9: Neuromuscular Blocking Agents
Development
The Nicotinic Receptor and Structure-Activity Relationships
Impulse Transmission at the Somatic Neuromuscular Junction
Postjunctional Mechanisms of Neuromuscular Blockade
Pharmacologic Effects of Neuromuscular Blocking Agents
Interactions
Clinical Use
Chapter 10: Inhalation Anesthetics
Physiochemical Characteristics
Properties Determining Methods of Administration
Properties Influencing Drug Kinetics: Solubility
Pharmacokinetics: Uptake and Elimination of Inhalation Anesthetics
Pharmacodynamics: Actions and Toxicity of the Inhalation Anesthetics
Trace Concentrations of Inhalation Anesthetics: Occupational Exposure
Chapter 11: Injectable Anesthetic Agents
Indications for Injectable Anesthesia
Disadvantages of Injectable Anesthesia
Properties of an Ideal Injectable Anesthetic Drug
Barbiturates
Propofol
Dissociatives
Etomidate
Guaifenesin
Neurosteroids
Miscellaneous Intravenous Anesthetics
Chapter 12: Opioid Analgesic Drugs
Introduction
Background on Opioids
Opioid Pharmacodynamics
Opioid Pharmacokinetics
Clinical Pharmacology
Opioid Agonists
Partial and Mixed Receptor Opioids
Opioid Antagonists
Other Central Analgesic Drugs
Other Routes of Administration
The Use of Opioids in Nonmammalian Vertebrates
Chapter 13: Sedative Agents: Tranquilizers, Alpha-2 Agonists, and Related Agents
Phenothiazine Derivatives
Phenothiazines Used in Veterinary Practice
α2-adrenergic Agonists
Specific Alpha-2 Agonists
α2-adrenergic Antagonists
Benzodiazepine Derivatives
Benzodiazepine Antagonists
Butyrophenone Derivatives
Chapter 14: Local Anesthetics
Mechanisms
Structure and Chemistry
Metabolism
Formulation
Toxicity of Local Anesthetics
Stability
Drug Interactions and Disease
Regulatory Issues
Individual Drugs
Topical Use: Skin and Mucous Membranes
Topical Use: Opthamology
Using Local Anesthetics
Future Outlook
Chapter 15: Euthanizing Agents
Inhaled Agents
Injected Agents
Other Injectable Anesthetics and Sedatives
Ingested Agents
Immersion Agents
Miscellaneous Considerations
Section 4: Autacoids and Antiinflammatory Drugs
Chapter 16: Histamine, Serotonin, and Their Antagonists
Histamine
Antihistamines
Serotonin
Chapter 17: Peptides: Angiotensin and Kinins
Angiotensin
Kinins
Other Peptides
Chapter 18: Prostaglandins, Related Factors, and Cytokines
History
Chemistry and Terminology of Prostaglandins
Biosynthesis of Eicosanoids
Inhibition of Biosynthesis of Eicosanoids
Physiologic-Pharmacologic Aspects of Eicosanoids
Platelet-Activating Factor
Cytokines
Chapter 19: Analgesic, Antiinflammatory, Antipyretic Drugs
The Role of Eicosanoids in Inflammation and Mechanisms of Action of NSAIDs
Isoforms of Cyclooxygenase: Characteristics, Locations, and Roles
History of NSAIDs
The Veterinary NSAID Market
Classification of NSAIDs and Physicochemical Properties
Pharmacology of NSAIDs
NSAID Pharmacokinetics
NSAID Pharmacodynamics
Novel NSAID Classes
Additional Mechanisms of Action of NSAIDs
Toxicity of NSAIDs
Therapeutic Uses of NSAIDs
Chapter 20: Anticonvulsant Drugs
Introduction
Phenobarbital
Primidone
Phenytoin
Valproic Acid (Valproate)
Diazepam
Clonazepam
Clorazepate
Felbamate
Gabapentin
Levetiracetam
Zonisamide
Potassium Bromide
Treatment of Status Epilepticus
Chapter 21: Drugs Affecting Animal Behavior
Introduction
Pharmacokinetic Issues for Behavior Drugs
Neurotransmitters
Major Drug Classes
Drug Combinations
Treatment Success
Summary
Section 5: Drugs Acting on the Cardiovascular System
Chapter 22: Digitalis, Positive Inotropes, and Vasodilators
Basic Aspects of Cardiac Function
Positive Inotropes and Inodilators
Angiotensin-Converting Enzyme Inhibitors
Vasodilator Drugs
Ancillary Therapy in Congestive Heart Failure
New/Experimental Heart Failure Drugs
Chapter 23: Antiarrhythmic Agents
Rhythmicity of the Heart
Antiarrhythmic Drugs
Class I Agents
Class II Agents
Class III Agents
Class IV Agents
Section 6: Drugs Affecting Renal Function and Fluid-Electrolyte Balance
Chapter 24: Principles of Acid-Base Balance: Fluid and Electrolyte Therapy
Composition and Distribution of Body Fluids
Water, Sodium, and Chloride
Potassium
Principles of Acid-Base Metabolism
Disorders of Acid-Base Metabolism
Practical Aspects of Fluid Therapy
Products for Fluid Therapy
Special Topics
Chapter 25: Diuretics
Renal Physiology
Principles of Diuretic Use
Inhibitors of Carbonic Anhydrase
Osmotic Diuretics
Inhibitors of Na+-K+-2Cl− Symport (Loop, or High-Ceiling, Diuretics)
Inhibitors of Na+-Cl− Symport (Thiazide and Thiazidelike Diuretics)
Inhibitors of Renal Epithelial Sodium Channels (K+-Sparing Diuretics)
Antagonists of Mineralocorticoid Receptors (Aldosterone Antagonists and K+-Sparing Diuretics)
New and Experimental Agents
Section 7: Drugs Acting on Blood and Blood Elements
Chapter 26: Hemostatic and Anticoagulant Drugs
Hemostasis
Hemostatic Drugs
Anticoagulants
Fibrinolytic Agents
Antiplatelet Drugs
Section 8: Endocrine Pharmacology
Chapter 27: Hypothalamic and Pituitary Hormones
Introduction
Anterior Pituitary and Associated Regulatory Hormones
Corticotropin and Related Peptides
Melatonin
Glycoprotein Hormones and Associated Releasing Hormones
Posterior Pituitary Hormones
Antidiuretic Hormone (ADH)
Oxytocin
Chapter 28: Hormones Affecting Reproduction
Introduction
Estrous Cycle
GnRH, Gonadorelin, and Gonadotropins
Estrogens and Progesterone
Specific Reproductive Conditions
Androgens
Chapter 29: Thyroid Hormones and Antithyroid Drugs
Introduction
Thyroid Physiology
Extrathyroidal Factors Altering Thyroid Hormone Metabolism
Mechanisms of Thyroid Hormone Action
Thyroid Hormone Preparations
Antithyroid Drugs
Thyroid Imaging
Chapter 30: Glucocorticoids, Mineralocorticoids, and Adrenolytic Drugs
Glucocorticoids
Mineralocorticoids
Adrenolytic Drugs and Steroid Synthesis Inhibitors
Chapter 31: Drugs Influencing Glucose Metabolism
Insulin
Oral Hypoglycemic Agents
Glucagon
Glucagon-like Peptide 1 Receptor Agonist
Somatostatin
Miscellaneous
Section 9: Chemotherapy of Microbial Diseases
Chapter 32: Antiseptics and Disinfectants
Cleansers
Antiseptics and Disinfectants
Factors Affecting Efficacy of Antiseptics
Microbial Resistance to Disinfectants and Antiseptics
Antiseptic Usage in Veterinary Medicine
Disinfectant Usage in Veterinary Medicine
Chapter 33: Sulfonamides and Potentiated Sulfonamides
Pharmacology of Sulfonamides
Pharmacokinetics of Sulfonamides
Adverse Effects Caused by Sulfonamides
Sulfonamides in Veterinary Medicine
Potentiated Sulfonamides
Residues in Food Animals
Chapter 34: β-Lactam Antibiotics: Penicillins, Cephalosporins, and Related Drugs
Mechanism of Action of β-Lactam Antibiotics
Microbial Resistance to β-Lactam Antibiotics
Penicillins
Cephalosporins
Carbapenems (Penems)
Chapter 35: Tetracycline Antibiotics
General Pharmacology of Tetracyclines
Commonly Used Tetracyclines
Other Non-Antimicrobial Uses of Tetracyclines
Chapter 36: Aminoglycoside Antibiotics
Pharmacology of Aminoglycosides
Pharmacokinetics of Aminoglycosides
Aminoglycoside Toxicity
Examples of Drugs
Chapter 37: Chloramphenicol and Derivatives, Macrolides, Lincosamides, and Miscellaneous Antimicrobials
Chloramphenicol
Chloramphenicol Derivatives
Macrolide Antibiotics
Lincosamides
Miscellaneous Antibiotics
Chapter 38: Fluoroquinolone Antimicrobial Drugs
Chemical Features
Mechanism of Action
Antibacterial Spectrum
Resistance
Pharmacokinetics
Pharmacodynamics (PK-PD)
Dose Guidelines
Clinical Use
Safety
Drug Interactions
Formulations Available
New Developments
Chapter 39: Antifungal and Antiviral Drugs
Antifungal Drugs
Griseofulvin
Amphotericin B
Azole Antifungal Drugs
Other Antifungal Agents
Topical Antifungal Agents
Antiviral Therapy
Idoxuridine and Trifluridine
Cytarabine and Vidarabine
Ribavirin
Acyclovir, Penciclovir, and Related Prodrugs (Valacyclovir and Famciclovir)
Zidovudine
Foscarnet
Amantadine and Rimantadine
Interferon
L-lysine
PMEA
Section 10: Chemotherapy of Parasitic Diseases
Chapter 40: Antinematodal Drugs
Benzimidazoles and Probenzimidazoles
Factors Affecting the Disposition Kinetics and Efficacy of Benzimidazole Anthelmintics
Imidazothiazoles
Tetrahydropyrimidines
Organophosphate Compounds
Heterocyclic Compounds
Heartworm Adulticides: Organic Arsenicals
Resistance to Anthelmintic Compounds: Molecular Basis
Miscellaneous and Novel Anthelmintic Drugs
Concluding Remarks
Chapter 41: Anticestodal and Antitrematodal Drugs
Anticestodal Drugs
Introduction
Bunamidine
Niclosamide
Praziquantel
Epsiprantel
Antitrematodal Drugs
Introduction
Nitrophenolic Compounds
Salicylanilides
Benzenesulfonamides
Benzimidazoles
Phenoxyalkanes
Chapter 42: Macrocyclic Lactones: Endectocide Compounds
General Pharmacology: Avermectins and Milbemycins
Mechanism of Action: Ecto-Endoparasiticidal Activity
Pharmacokinetics
Pharmacokinetic-Pharmacodynamic Relationship
Therapeutic Uses: Animal Species-Specific Considerations
Resistance
Available Pharmaceutical Preparations
Drug and Host-Related Factors Affecting Pharmacokinetics and Efficacy in Ruminants
Tissue Residues and Withdrawal Times
Safety and Toxicity
Ecotoxicological Impact
Concluding Remarks
Chapter 43: Antiprotozoan Drugs
Nitroimidazoles
Pentavalent Antimonials
Arsenicals
Benzimidazoles
Aminoglycosides
Nitrofurans
Tetracyclines
Hydroxyquinolones and Naphthoquinones
Pyridinols
Guanidine Derivatives
Thiamine Analogues
Nitrobenzamides
Nicarbazin
Alkaloids
Polyether Ionophores
Triazine Derivatives
Sulfonamides
Dihydrofolate Reductase/Thymidylate Synthase Inhibitors
Lincosamides
Azalides
4-Aminoquinolines
Diamidine Derivatives
Nitrothiazole Derivatives
Chapter 44: Ectoparasiticides
Introduction
Pharmaceutics of Topical Formulations
Transdermal Delivery
Routes of Dermal Absorption
Mechanisms of Action
Resistance to Ectoparasiticides
Fipronil
Neonicotinoids
Macrocyclic Lactones
Pyrethrins and Synthetic Pyrethroids
Organophosphates
Carbamates
d-Limonene and Linalool
Amitraz
Insect Growth Regulators (IGRs)
Synergists and Repellents
Ectoparasiticide Approval and Registration in the U.S.
Section 11: Specialty Areas of Pharmacology
Chapter 45: Chemotherapy of Neoplastic Diseases
Treatment Perspectives
Cancer Biology
Drugs
Chapter 46: Immunosuppressive Drugs and Cyclosporine
Glucocorticoids
Cyclosporine
Tacrolimus, Pimecrolimus, and Sirolimus
Cyclophosphamide (Cytoxan®)
Chlorambucil
Thiopurines (Azathioprine)
Mycophenolate
Danazol
Gold Therapy (Chrysotherapy)
Dapsone
Chapter 47: Drugs Affecting Gastrointestinal Function
Antiemetic Drugs
Gastrointestinal Prokinetic Drugs
Drugs for Treatment of GI Ulcers in Animals
Drugs for Treatment of Diarrhea
Drugs for Treatment of Inflammatory Intestinal Diseases
Laxatives and Cathartics
Chapter 48: Dermatopharmacology: Drugs Acting Locally on the Skin
Anatomy and Histology
Biochemistry
Principles of Percutaneous Absorption: Skin Permeability
Topical Vehicles
Classification of Dermatologic Vehicles
Classes of Medicated Applications
Dermatotherapy: Atopic Dermatitis
Chapter 49: Drugs that Affect the Respiratory System
Antitussive Drugs
Bronchodilator Drugs (Beta-Adrenergic Receptor Agonists)
Cromolyn (Sodium Cromoglycate) (INTAL®)
Methylxanthines (Xanthines)
Anticholinergic Drugs
Glucocorticoids
Nonsteroidal Antiinflammatory Drugs (NSAIDs)
Leukotriene Inhibitors
Expectorants and Mucolytic Drugs
Decongestants
Respiratory Stimulants
Chapter 50: Pharmacogenomics
Basic Genetic Concepts
Pharmacogenetics
Chapter 51: Therapeutic Drug Monitoring
Therapeutic Drug Monitoring: Considerations
Phenobarbital
Bromide
Cyclosporine
Aminoglycosides
Digoxin
Chapter 52: Considerations for Treating Minor Food-Producing Animals with Veterinary Pharmaceuticals
The Use of Veterinary Pharmaceuticals in Minor Food-Producing Animals: Special Considerations and Challenges
The Approval Process for Veterinary Pharmaceuticals for Use in Minor Food-Producing Animals
Legislation and Policies Supporting the Use of Veterinary Pharmaceuticals in Minor Food-Producing Animals
Programs Supporting the Use of Veterinary Pharmaceuticals in Minor Food-Producing Animals
Methods for Estimating Withdrawal Intervals for Veterinary Pharmaceuticals Administered to Minor Food-Producing Animals in an Extralabel Manner
Summary
Chapter 53: Zoological Pharmacology
Introduction
Species Groups
Allometry in Zoo Medicine
Section 12: Regulatory Considerations
Chapter 54: Legal Control of Veterinary Drugs
Legislative Milestones in the Development of Laws Pertaining to the Regulation of Animal Drugs
Drug Compendia
Chapter 55: Drug Approval Process
Introduction
History of the FDA and Its Relationship to Veterinary Medicine
Challenges in Veterinary Drug Evaluation
Regulatory Basis of Veterinary Drug Evaluation
The Office of Minor Use and Minor Species Animal Drug Development
International Harmonization
Adverse Drug Experience Reports
Leveraging with the FDA
The Use and Application of Pharmacokinetic Information
Chapter 56: Veterinary Pharmacy
Introduction
Regulatory Requirements for Use of Drugs in Animal Patients
Regulatory Discretion for Extralabel Use
Need for Legal Extralabel Use—AMDUCA
Classification of Drugs
Current Status of Compounded Veterinary Drugs
Potential Problems from Compounded Drugs
Unapproved Drugs Available by Importation
Prescribing Controlled Substances
Dispensing Medications Intended to Go Home with a Patient
Prescription Writing
Chapter 57: Regulation of Drug and Medication Use in Performance Animals
Drug and Medication Rules
The Drug Testing Process
Factors Affecting Withdrawal Times
Thresholds, Reporting Levels, and Cutoffs
Summary
Chapter 58: Adverse Drug Reactions
Method
Strengths of ADE Reporting Systems
Limitations of ADE Reporting Systems
Chapter 59: Dosage Forms and Veterinary Feed Directives
Pharmacokinetic Considerations and Controlled-Drug Delivery
Palatability and Ease of Drug Administration
Veterinary Feed Additives
Site-Directed Therapy
Chapter 60: USP’s Role in Veterinary Pharmacology and Evidence-Based Information
USP and Its Compendia
USP Evidence-Based Pharmacotherapy
Chapter 61: Chemical Residues in Tissues of Food Animals
The Concern over Residues in Food
Regulation of Drug Residues in Animals
Pharmacokinetics and Residues
Drugs Prohibited from Extralabel Use
Residue Prevention
Index
Ninth Edition first published 2009
© 2009 Wiley-Blackwell
First through Eighth Editions first published 1954, 1957, 1965, 1977, 1982, 1988, 1995, 2001
© 1954, 1957, 1965, 1977, 1982, 1988, 1995, 2001 Iowa State University Press, a Blackwell Publishing company
Copyright is not claimed for Chapter 54, which is in the public domain.
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First, second, and third editions 1954, 1957, and 1965 edited by L. Meyer Jones; fourth edition 1977 edited by L. Meyer Jones, Nicholas H. Booth, and Leslie E. McDonald; fifth and sixth editions 1982 and 1988 edited by Nicholas H. Booth and Leslie E. McDonald; seventh and eighth editions 1995 and 2001 edited by H. Richard Adams.
Library of Congress Cataloguing-in-Publication Data
Veterinary pharmacology and therapeutics.—9th ed. / edited by Jim E. Riviere, Mark G. Papich; consulting editor, H. Richard Adams.
p. ; cm.
Rev. ed. of: Veterinary pharmacology and therapeutics / edited by H. Richard Adams. 8th ed. 2001.
Includes bibliographical references and index.
ISBN 978-0-8138-2061-3 (alk. paper)
1. Veterinary pharmacology. I. Riviere, J. Edmond (Jim Edmond) II. Papich, Mark G.
[DNLM: 1. Drug Therapy-veterinary. 2. Pharmacology. 3. Poisoning-veterinary. SF 915 V587 2008]
SF915.V49 2009
636.089′5–dc22
2008025003
A catalog record for this book is available from the U.S. Library of Congress.
CONTRIBUTORS
H. Richard Adams, DVM, PhD
Diplomate ACVECC (Hon)
Dean Emeritus
College of Veterinary Medicine, University of Missouri
Carl B. King Dean of Veterinary Medicine
College of Veterinary Medicine and Biomedical Sciences
Texas A&M University
College Station, Texas 77843-4461
Luis I. Alvarez, Med Vet, PhD
Assistant Professor
Laboratorio de Farmacologis
Departamento de Fisiopatologia
Facultad de Ciencias Veterinarias
Universidad Nacional del Centro
Campus Universitario
Argentina
Ronald E. Baynes, DVM, PhD
Associate Professor
Department of Population Health and Pathobiology
Center for Chemical Toxicology Research and Pharmacokinetics
North Carolina State University
College of Veterinary Medicine
4700 Hillsborough Street
Raleigh, NC 27606
Melanie Berson, DVM
Director
Division of Therapeutic Drugs for NonFood Animals
Office of New Animal Drug Evaluation
Food and Drug Administration
Center for Veterinary Medicine
7500 Standish Place
FDA/CVM/HFV-110
Rockville, MD 20855
Margarita A. Brown, DVM, MS
Safety Review Coordinator
Office of Surveillance and Compliance
Center for Veterinary Medicine
U.S. Food and Drug Administration
7519 Standish Place
Rockville, MD 20855
Patrick Burns, BVSc, MACVSc
DACVA
College of Veterinary Medicine
The Ohio State University
601 Vernon L. Tharp Street
Columbus, OH 43210
Cynthia A. Cole, DVM, PhD
DACVCP
IDEXX Pharmaceuticals, Inc.
7009 Albert Pick Road
Greensboro, NC 27409
Gordon L. Coppoc, DVM, PhD
Professor and Head
Department of Basic Medical Sciences
School of Veterinary Medicine
Purdue University
625 Harrison Street
West Lafayette, IN 47907-2026
Arthur L. Craigmill, PhD
DABT
Environmental Toxicology Extension
University of California
One Shields Avenue
Davis, CA 95616
Gigi Davidson, RPh
Director of Clinical Pharmacy Services
VTH Pharmacy
North Carolina State University
College of Veterinary Medicine
4700 Hillsborough Street
Raleigh, NC 27606
Jennifer L. Davis, DVM, PhD
Diplomate ACVIM, Diplomate ACVCP
Department of Clinical Sciences
North Carolina State University
College of Veterinary Medicine
4700 Hillsborough Street
Raleigh, NC 27606
Ian F. DeVeau, PhD
Director
Veterinary and Radiopharmaceuticals Group
United States Pharmacopeia
Department of Standards Dev
12601 Twinbrook Parkway
Rockville, MD 20852-1790
Levent Dirikolu
Physiology and Pharmacology
College of Veterinary Medicine
501 DW Brooks Drive
Athens, GA 30602
Bernadette Dunham, DVM, PhD
Director
Center for Veterinary Medicine
U.S. Food and Drug Administration
MPN-IV, Room 181, HFV-1
7519 Standish Place
Rockville, MD 20855
Duncan Ferguson, VMD, PhD
Diplomate ACVCP, Diplomate ACVIM
Veterinary Biosciences
The University of Illinois College of Veterinary Medicine Urbana, IL 61801
John Gadsby, PhD
Professor
Department of Molecular Biomedical Sciences
College of Veterinary Medicine
North Carolina State University
4700 Hillsborough Street
Raleigh, NC 27606
Jody L. Gookin, DVM, PhD
Diplomate ACVIM
Assistant Professor
Department of Clinical Sciences
College of Veterinary Medicine
North Carolina State University
4700 Hillsborough Street
Raleigh, NC 27606
Joan Gotthardt, DVM
Director
Division of Therapeutic Drugs for Food Animals
Office of New Animal Drug Evaluation
Division of Therapeutic Drugs for Food Animals
FDA Center for Veterinary Medicine
7500 Standish Place
FDA/CVM/HFV-110
Rockville, MD 20855
Victoria Hampshire, VMD
Senior Regulatory Veterinarian and Reviewer
CDRH/ODE/DCD/PVDB
9200 Corporate Boulevard
HFZ-450
Rockville, MD 20850
Mark C. Heit, DVM, PhD
DACVCP
Senior Director, Research and Development
Velcera Inc.
777 Township Line Road
Yardely, PA 19067
Margarethe Hoenig, DVM
Professor
Physiology and Pharmacology
College of Veterinary Medicine
501 DW Brooks Drive
Athens, GA 30602
Laura Hungerford, DVM, MPH, PhD
Senior Advisor for Science Policy
Center for Veterinary Medicine
Office of New Animal Drug Evaluation
U.S. Food and Drug Administration
7500 Standish Place
FDA/CVM/HFV-100
Rockville, MD 20855
Robert P. Hunter, MS, PhD
Elanco Animal Health
2001 West Main Street
P.O. Box 708
Greenfield, IN 46140
Fernanda A. Imperiale, Vet, PhD
Research Fellow
Laboratorio de Farmacologis
Departamento de Fisiopatologia
Facultad de Ciencias Veterinarias
Universidad Nacional del Centro
Campus Universitario
(7000) Tandil
Argentina
Deborah T. Kochevar, DVM, PhD
DACVCP
Henry and Lois Foster Professor
Dean
Cummings School of Veterinary Medicine
Tufts University
200 Westboro Road
North Grafton, MA 01536
Butch KuKanich, DVM, PhD
Diplomate ACVCP
Department of Anatomy and Physiology
College of Veterinary Medicine
Kansas State University
228 Coles Hall
Manhattan, KS 66506-5802
Cory Langston, DVM, PhD
Diplomate ACVCP
Professor
College of Veterinary Medicine
Box 6100
Spring Street
Mississippi State University
Starkville, MS 39762-6100
Carlos E. Lanusse, Med Vet Dr Cs Vet, PhD
Diplomate ECVPT
Professor
Laboratorio de Farmacologis
Departamento de Fisiopatologia
Facultad de Ciencias Veterinarias
Universidad Nacional del Centro
Campus Universitario
(7000) Tandil
Argentina
Peter Lees, PhD, DSc
Royal Veterinary College
Hawkshead Campus
London University
North Mymms
Hatfield, Hertfordshire, AL97TA
United Kingdom
Adrian L. Lifschitz, Vet, PhD
Lecturer
Laboratorio de Farmacologis
Departamento de Fisiopatologia
Facultad de Ciencias Veterinarias
Universidad Nacional del Centro
Campus Universitario
(7000) Tandil
Argentina
Marilyn Martinez, PhD
Senior Research Scientist
Center for Veterinary Medicine
U.S. Food and Drug Administration
7500 Standish Place
Rockville, Maryland 20855
Katrina L. Mealey, DVM, PhD
DACVIM, DACVCP
Department Veterinary Clinical Sciences
College of Veterinary Medicine
Washington State University
ABDF 1020
Pullman, WA 99164-6610
Matthew W. Miller, DVM, MS
Diplomate ACVIM (Cardiology)
Professor of Cardiology
Charter Fellow
Michael E. DeBakey Institute
Department of Small Animal Clinical Sciences
College of Veterinary Medicine and Biomedical Sciences
Texas A&M University
College Station, Texas 77843-4461
Maria L. Mottier, Vet, PhD
Research Fellow
Laboratorio de Farmacologis
Departamento de Fisiopatologia
Facultad de Ciencias Veterinarias
Universidad Nacional del Centro
Campus Universitario
(7000) Tandil
Argentina
Margaret Oeller, DVM
Office of Minor Use and Minor Species Animal Drug Development
Center for Veterinary Medicine
U.S. Food and Drug Administration
7500 Standish Place
Rockville, MD 20855
Luisito S. Pablo, DVM, MS
Diplomate ACVA
Department of Large Animal Clinical Sciences
College of Veterinary Medicine
University of Florida
PO Box 100136
Gainesville, FL 32610
Mark G. Papich, DVM
Diplomate ACVCP
Professor
North Carolina State University
Department of Molecular Biomedical Sciences
College of Veterinary Medicine
4700 Hillsborough Street
Raleigh, NC 27606
Peter J. Pascoe, BVSc
DACVA, DECVA
Professor
Department of Surgical and Radiological Sciences
School of Veterinary Medicine
University of California
Davis, CA 95616-8745
Lysa P. Posner, DVM
Diplomate ACVA
Associate Professor
Anesthesiology Section
Department of Molecular Biomedical Sciences
North Carolina State University
College of Veterinary Medicine
4700 Hillsborough Street
Raleigh, NC 27606
Srujana Rayalam, BVSc, MVSc
The University of Georgia
College of Veterinary Medicine
Athens, GA 30602
Doodipala Samba Reddy, R.Ph., Ph.D.
Associate Professor
Dept of Neuroscience and Experimental Therapeutics College of Medicine
Texas A&M Health Science Center
228 Reynolds Medical Building
College Station, Texas 77843
Jim E. Riviere, DVM, PhD DSc(hon)
Director and Distinguished Professor
Center for Chemical Toxicology Research and Pharmacokinetics
Department of Population Health and Pathobiology
North Carolina State University
College of Veterinary Medicine
4700 Hillsborough Street
Raleigh, NC 27606
Juan M. Sallovitz, Med Vet, PhD
Research Fellow
Laboratorio de Farmacologis
Departamento de Fisiopatologia
Facultad de Ciencias Veterinarias
Universidad Nacional del Centro
Campus Universitario
(7000) Tandil
Argentina
Sergio F. Sanchez Bruni, Med Vet, PhD
Associate Professor
Laboratorio de Farmacologis
Departamento de Fisiopatologia
Facultad de Ciencias Veterinarias
Universidad Nacional del Centro
Campus Universitario
(7000) Tandil
Argentina
Stefan Schuber, PhD
Director
Scientific Reports
United States Pharmacopeia
12601 Twinbrook Parkway
Rockville, MD 20852-1790
Maya Scott, DVM, PhD
4466 TAMU
Veterinary Physiology and Pharmacology
Texas A & M University
College Station, TX 77843-4466
Barbara L. Sherman, MS, PhD, DVM
DACVB
Clinical Associate Professor
Department of Clinical Sciences
College of Veterinary Medicine
North Carolina State University
4700 Hillsborough Street
Raleigh, NC 27606-1496
Geof W. Smith, DVM, PhD
Assistant Professor
Department of Population Health and Pathobiology
College of Veterinary Medicine
North Carolina State University
4700 Hillsborough Street
Raleigh, NC 27606
Eugene P. Steffey, MVD, PhD
Professor
Department of Surgical & Radiological Sciences
School of Veterinary Medicine
University of California
2112 Tupper Hall
Davis, California 95616
Stephen F. Sundlof, DVM, PhD
DABVT
Director
Center for Food Safety and Applied Nutrition
U. S. Food and Drug Administration
5100 Paint Branch Parkway
College Park, MD 20740
Lisa A. Tell, DVM
Professor
Diplomate ABVP, Diplomate ACZM
Food Animal Residue Avoidance Databank and National Research Project 7
Department of Medicine and Epidemiology
School of Veterinary Medicine
University of California
One Shields Avenue
Davis, CA 95616
Pierre-Louis Toutain, DVM, Dr Sci
Diplomate ECVPT
UMR 181 Physiopathologie et Toxicologie Experimentales
INRA/ENVT
Ecole Nationale Veterinaire de Toulouse
23 chemin des Capelles—BP 87614 31076 TOULOUSE cedex 03 FRANCE
Guillermo L. Virkel, Med Vet, PhD
Lecturer
Laboratorio de Farmacologis
Departamento de Fisiopatologia
Facultad de Ciencias Veterinarias
Universidad Nacional del Centro
Campus Universitario
(7000) Tandil
Argentina
Alistair Webb, BVSc, PhD
FRCVS, MRCA, DVA, Diplomate ACVA
Department Physiological Sciences
College of Veterinary Medicine
University of Florida
PO Box 100144
Gainesville, FL 32610-0144
Keith Zientek, PhD
Senior Scientist
Bioanalytical Systems, Inc.
3138 NE Rivergate, Bldg. 301C
McMinnville, OR 97128
PREFACE
Welcome to the ninth edition of Veterinary Pharmacology and Therapeutics, the first edition of which was authored some 6 decades ago by Dr. L. Meyer Jones, a father of American veterinary pharmacology. As with previous editions, this book remains dedicated to veterinary medical students enrolled in professional schools and colleges of veterinary medicine. However, this book also has a broader audience in that veterinary medicine interns and residents, graduate students in comparative biomedical sciences, laboratory animal specialists, and researchers using animals have adopted this as the standard source for information available on comparative pharmacology.
The present edition is both an outgrowth of, and extension to, the eighth edition edited by H. Richard Adams. The major changes are focused on integrating topics covered in the traditional drug-specific chapters to several new chapters covering their applications in areas such as minor species or racing animals. The chapters on treatment of clinical problems are also greatly expanded to integrate the basic concepts discussed in earlier sections of the book with management of clinical diseases. This allows a discussion of pharmacological concepts from a different perspective than basic pharmacology, because drugs that are used throughout veterinary medicine in applications under different clinical scenarios often need further explanation. To accomplish our goals, experts in the clinical specialty areas and pharmacologists with expertise in specific areas have contributed tremendously to this edition of the textbook. A number of “traditional chapters” were completely revamped and revised by new contributors and other previous chapters were updated. We have attempted to provide an international perspective to this new edition by adding international authors and including drugs that have been used all over the world.
Veterinary pharmacology is in the process of great change and advancement. For many years, veterinary pharmacology was simply an extension of human pharmacology as common human medications were extrapolated for use in animal diseases. However, in the new millennium, there has been a greater emphasis by the pharmaceutical companies toward developing animal-specific drugs for their unique indications. Many of these include treatment aimed at quality of life issues in companion animals. As in previous editions, many human drugs—used off-label in animals—also are discussed, with an emphasis on the importance of interspecies differences. Sophisticated therapeutic approaches are being developed and utilized on a routine basis. New drug entities are being used and a more precise utilization of existing medications is employed in clinical practice. Antimicrobial and antiparasitic drugs must be used in a more intelligent and prudent fashion to avoid development of resistance that can impact both animals and human public health. Human food safety concerns regarding drugs used in food-producing animals have taken on increased concern. All these developments lead to both growth and a broadening of this discipline, which is central to the practice of veterinary medicine.
One of the most important applications of this textbook will be as a supplement and reference source for instructors teaching veterinary pharmacology to professional veterinary students, graduate students, and veterinary technicians. To accommodate this use, the chapters have been organized logically in an order and format that will support the teaching of veterinary pharmacology to students. Whenever possible, helpful tables, diagrams, and charts are provided to facilitate learning. Teaching veterinary pharmacology to students has changed tremendously since the early editions of this textbook. Because of the tremendous explosion in the number of drugs available, it is no longer possible to cover every drug and every indication in a veterinary course. Therefore, this book is intended to be a supplement to a veterinary pharmacology course for the student to have access to more in-depth and comprehensive information than can be presented in course lectures.
In addition to the many authors that have contributed to this edition of Veterinary Pharmacology and Therapeutics, we owe a special thanks to the previous editor, and consulting editor for this edition, H. Richard Adams. We are proud to carry on as editors with the hope of continuing the excellence and quality that was a characteristic of the editions that he edited. We are also appreciative of the support of the publishers at Wiley-Blackwell. Among these individuals, special thanks go to Dede Andersen, Antonia Seymour, Jill McDonald, and Nancy Simmerman. We also thank Luann Kublin and especially Jeneal Leone, administrative assistants at CCTRP-NCSU, for their help in processing these chapters.
Jim E. Riviere Mark G. Papich
SECTION 1
Principles of Pharmacology
CHAPTER 1
VETERINARY PHARMACOLOGY: AN INTRODUCTION TO THE DISCIPLINE
JIM E. RIVIERE AND MARK G. PAPICH
Pharmacology is the science that broadly deals with the physical and chemical properties, actions, absorption, and fate of chemical substances termed drugs that modify biological function. It is a discipline that touches most areas of human and veterinary medicine and closely interfaces with pharmaceutical science and toxicology.
HISTORY OF PHARMACOLOGY
As long as humans and their animals have suffered from disease, chemical substances have played a role in their treatment. Substances obtained from plants and animals or their products were used according to precise prescriptions through antiquity. The mechanism attributed to why these substances worked are deeply rooted in the beliefs and mythologies of each culture, as were the rituals involved in their preparation.
The early history of pharmacology parallels human efforts to compile records of ailments and their remedies. The earliest recorded compilation of drugs, the Pen Tsao, consisted of a list of herbal remedies compiled in the reign of Chinese Emperor Shennung in 2700 B.C. Classic examples of medicinal use of chemicals, herbs, and other natural substances are found in the recorded papyri of ancient Egypt. The Kahun papyrus, written about 2000 B.C., lists prescriptions for treating uterine disease in women and specifically addresses veterinary medical concerns. The Ebers papyrus, written in 1150 B.C. is a collection of folklore covering 15 centuries of history. It is composed of over 800 prescriptions for salves, plasters, pills, suppositories, and other dosage forms used to treat specific ailments.
The ancient Greek philosopher-physicians of 500 B.C. taught that health was maintained by a balance of “humors,” which were affected by temperature, humidity, acidity, and sweetness, rather than to the direct actions of gods or demons. Disease was treated by returning these humors to a proper balance. Hippocrates (460–370 B.C.) was an ancient Greek physician of the Age of Pericles. He is referred to as the “father of medicine” in recognition of his lasting contributions to the field as the founder of the Hippocratic school of medicine. He was a firm believer in the healing powers of nature, conducted systematic observations of his patients’ symptoms, and began moving the practice of medicine from an art to a systematic clinical science. The first true material medica, a compilation of therapeutic substances and their uses, was compiled in 77 A.D. by Aristotle’s student Dioscorides, while serving as a surgeon in Nero’s Roman Legion traveling throughout the Mediterranean. This served as the basis for the later works of Galen (131–201) that emerged as the authoritative material medica for the next 1,400 years! In fact, some pharmaceutical preparations consisting of primarily herbal or vegetable matter are still referred to as galenical preparations. As the Dark Ages descended upon Europe, such scholarship transferred to Byzantium, where in fact a veterinary compilation for farm animal treatments, Publius Vegetius, was compiled in the 5th century.
It took until the Renaissance to awaken the spirit of discovery in Europe. The Swiss physician Theophrastus Bombastus von Hohenheim (1492–1541), known as Paracelsus, introduced the clinical use of laudanum (opium) and a number of tinctures (extracts) of various plants, some of which are still in use today. He is remembered for using drugs for specific and directed purposes, and for the famous dictum “All substances are poisons; there is none which is not a poison. The proper dose separates a poison from a remedy.” As these practices took root, official compilations of medicinal substances, their preparation, use, and dosages, started to appear in Europe. These publications, termed pharmacopeia, provided a unifying framework upon which the pharmaceutical sciences emerged. The first printed pharmacopeia, titled the Dispensatorium was published by Valerius Cordus in 1547 in Nuremberg, Germany. Local publications emerged in different European cities, with two pharmacopeias published in London in 1618. The Edinburgh Pharmacopoeia published in 1689 became the most influential during this period. It took until the mid-19th century before truly national pharmacopeias took hold, with the first United States Pharmacopeia published in 1820. The first United States Pharmacopeia has been given the title USP-0; the current edition of the United States Pharmacopeia is titled USP-30. There was also a British pharmacopeia published in 1864 and the British Pharmacopeia continues to be published today.
The history of pharmacology parallels the development of modern medicine and the realization that specific natural products and substances may cure specific diseases. The 16th and 17th centuries were marked by great explorations and the beginning of medical experimentation. In 1656, Sir Christopher Wren made the first intravenous injection of opium in a dog. The bark of the cinchona tree was brought by Jesuits from South America for use of treatment of malaria. In 1783, the English physician William Withering reported on his experience in the use of extracts from the foxglove plant to treat patients with “dropsy,” a form of edema most likely caused by congestive heart failure.
In the early 1800s the French physiologist-pharmacologist Megendie, working with the pharmacist Pelletier, studied the effects of intravenous injections of ipecac, morphine, strychnine, and other substances on animals. Megendie was the first to prove that chemicals can be absorbed into the vascular system to exert a systemic effect. A prolific scientist, he also published a formulary that survived through eight editions from 1821–1836. The Spanish physician Orfila published the results of many experiments in a book entitled Toxicologie Generale in 1813. A student of Megendie, the famous physiologist Claude Bernard, and others showed in the mid-1800s that the active ingredient of foxglove botanical preparations was digitalis, and its action was on the heart. We continue to use digoxin today for the treatment of congestive heart failure in humans and animals. The important aspect of these early studies was that they used the experimental paradigm for demonstrating chemical activity, establishing both the philosophy and methods upon which the discipline of modern pharmacology is based.
The term Pharmakologie was applied to the study of material medica by Dale in London as early as 1692; however, it is generally regarded that the biochemist Rudolph Buchheim in the Baltic city of Dorpat established the first true experimental laboratory dedicated to pharmacology in the mid-18th century. He published some 118 contributions on a variety of drugs and their actions, and argued for pharmacology to be a separate discipline distinct from material medica, pharmacy, and chemistry. His work included in 1849 a textbook Beiträge zur Ärzneimittellehre, which classified drugs based on their pharmacological action in living tissue. He deleted traditional remedies if he could not demonstrate their action in his laboratory. This is the beginning of what we now know as evidence-based pharmacology, which requires that a chemical be termed a drug only if a specific action in living tissues can be demonstrated.
His student, Oswald Schmiedeberg, became a Professor of Pharmacology at the University of Strasbourg in 1872 and took upon himself the goal of making pharmacology an independent scientific discipline based upon precise experimental methodology that ultimately displaced material medica in medical school curriculums throughout Europe by the end of the 19th century and by the early 20th century in America. He studied the correlation between the chemical structure of substances and their effectiveness as narcotics. He published some 200 publications as well as an authoritative textbook in 1883 that went through seven editions. This text classified drugs by their actions and separated experimental pharmacology from therapeutics. In addition he founded and edited the first pharmacology journal Archiv für experimentelle Pathologie und Pharmakologie in 1875, which in 2007 published volume 375 as Naunym-Schmiedeberg’s Archives of Pharmacology. His more than 150 students spread the discipline of pharmacology throughout Europe and America.
One of his students, Dr. John Abel, held the first fulltime professorship in pharmacology at the University of Michigan and is considered by some to be the father of American pharmacology. Professor Abel then moved to Johns Hopkins Medical School where he continued his basic pharmacological research and founded the Journal of Biological Chemistry as well as the Journal of Pharmacology and Experimental Therapeutics. He was instrumental in founding the American Society of Pharmacology and Experimental Therapeutics in 1908.
From these origins, the various disciplines of pharmacology grew, the common factor being the focus in experimental methods to discover and confirm drug actions. Today, the basic philosophy remains unchanged, although modern techniques are grounded in analytical chemistry, mathematical models, and the emerging science of genomics.
VETERINARY PHARMACOLOGY
The development of veterinary pharmacology generally paralleled that of human pharmacology. However, there is archeological evidence of an Indian military hospital for horses and elephants from 5000 B.C., at which time there also existed an extensive medical education program at the Hindu university at Takkasila. The formal discipline of veterinary pharmacology has its origins in the establishment of veterinary colleges and hospitals in France, Austria, Germany, and the Netherlands in the 1760s as a response to epidemics of diseases such as rinderpest that decimated animal populations throughout Western Europe. The Royal College of Veterinary Surgeons was established in London in 1791 followed in 1823 by the Royal (Dick) School of Veterinary Studies in Edinburgh. The earliest veterinary colleges were established in the United States in 1852 in Philadelphia and in Boston in 1854; however, both were short-lived. Modern existing North American veterinary schools founded in the late 1800s, and which continue in operation, include those in Iowa, Ohio, Ontario, Pennsylvania, and New York.
In these early colleges, teaching of pharmacology in veterinary schools was essentially material medica, and remained closely aligned with parallel efforts occurring in medical schools, especially when colleges were colocated on the same campuses. This was evident in the European schools, with a separation really occurring in the 20th century. However, this linkage was not absolute. An early mid-19th century veterinary textbook The Veterinarian’s Vade Mecum was published by John Gamgee in England. It was essentially a material medica and did not reflect the biological-based classification system for substances used by Professor Buchheim in the same period. The first American professor of therapeutics at the School of Veterinary Medicine at Iowa State was a physician, D. Fairchild. Similarly, a textbook of veterinary pharmacology Veterinary Material Medica and Therapeutics published by the School of Veterinary Medicine at Harvard was authored by Kenelm Winslow, a veterinarian and physician. This book, an 8th Edition of which was published in 1919, began to follow the modern thrust described earlier of relating drug actions to biological effects on tissues. It seems veterinary medicine’s 21st-century preoccupation with the “one-medicine” concept has deep historical roots.
The important event, which fully shifted veterinary pharmacology from one focused on material medica to the actual science of pharmacology, was the publication by Professor L. Meyer Jones in 1954 of the 1st Edition of the textbook you are now reading. From this point forward, veterinary pharmacology positions have existed in Colleges of Veterinary Medicine throughout the world, the structure of which are often a reflection of local university history, priorities, and academic structure.
Organized veterinary pharmacology occurred rather simultaneously in Europe and the Americas. The American Academy of Veterinary Pharmacology and Therapeutics (AAVPT) was founded in 1977 and the European Association for Veterinary Pharmacology and Toxicology (EAVPT) in 1978. These two organizations, together with the British Association for Veterinary Clinical Pharmacology and Therapeutics, launched the Journal of Veterinary Pharmacology and Therapeutics (JVPT) in 1978. Its founder, Dr. Andrew Yoxall, hoped that the journal would improve coordination and communication among pharmacologists and veterinary clinicians, and designed it for the publication of topics relating both to the clinical aspects of veterinary pharmacology, and to the fundamental pharmacological topics of veterinary relevance. Now in its 30th year of publication, and also cosponsored by both the American College of Veterinary Clinical Pharmacology (ACVCP) and the Chapter of Veterinary Pharmacology of the Australian College of Veterinary Scientists, this journal remains the primary outlet for publication of veterinary-related science-based pharmacology investigations.
The discipline of clinical pharmacology is more directly related to applying pharmacological principles—particularly pharmacokinetics—to clinical patients. Fellows of the AAVPT formed the AVMA-recognized board certified specialty—the American College of Veterinary Clinical Pharmacology (ACVCP)—in 1991. The establishment of the ACVCP paralleled the establishment of the American Board of Clinical Pharmacology (ABCP)—the human medical counterpart—in the same year with the cooperation of the American College of Clinical Pharmacology.
REGULATIONS
A different perspective of the development of veterinary pharmacology over the last century is the development of regulatory bodies to insure that safe, effective, and pure drugs reach commerce. As discussed above, material medica and pharmacopeia were in large part the force that held pharmacology together as a discipline for centuries. Since 1820, the United States Pharmacopeia (USP), a private, not-for-profit organization, has endeavored to establish standards for strength, quality, purity, packaging, and labeling for all manufacturers of pharmaceutical substances in the United States. It took until 1990, under the pressure of Dr. Lloyd Davis, one of the founding fathers of AAVPT and ACVCP, to have USP specifically develop Committees to develop USP standards and information for veterinary drugs. Until this time, veterinary drugs whose manufacturers desired the “USP Label” processed drugs through committees that were largely populated by experts in human pharmaceutical sciences and medicine.
In the 20th century, due to the proliferation of charlatans and fraud in manufacture and distribution of so-called “pure” medicinal products, coupled with serious human health calamities due to nonregulated drugs reaching the market, Congress in 1927 established the Food, Drug and Insecticide Administration, which later became known as the Food and Drug Administration (FDA). In 1938, the pivotal Federal Food, Drug and Cosmetic Act was passed giving FDA the authority to regulate animal drugs by requiring evidence of product safety before distribution. In 1959, a veterinary medical branch was developed as a division and the Food Additive Amendments Act was passed, which gave FDA authority over animal food additives and drug residues in animal-derived foods. A Bureau of Veterinary Medicine, with Dr. M. Clarkson as its first director, was established in 1965 to handle the increasing regulatory responsibilities of animal drugs. Today, the FDA Center for Veterinary Medicine, directed by Dr. Bernadette Dunham, is the primary regulatory body for veterinary drugs in the United States. The interested reader should consult Chapters 54 and 55 of the present text for a more in-depth discussion of the current state of veterinary regulatory authority.
WHAT IS VETERINARY PHARMACOLOGY?
As can be appreciated from the breadth of material covered by the present textbook, veterinary pharmacology covers all aspects of using chemical and biological substances to treat diseases of animals. The basic principles of drug action are identical across veterinary and human pharmacology. Thus the principles of absorption, distribution, metabolism, and elimination covered here are the same as in any human pharmacology text, except for a focus on crucial species differences in anatomy, physiology, or metabolism that would alter these processes. The topics of pharmacodynamics, pharmacogenomics, and pharmacokinetics are also species-independent in basic concepts. These topics encompass what truly should be termed comparative pharmacology.
The subspecialties of veterinary pharmacology cover all those seen in human pharmacology, the classification of which can be seen from the division of the present text. These include classifying drugs as acting on the nervous, inflammatory, cardiovascular, renal, endocrine, reproductive, ocular, gastrointestinal, respiratory, and dermal systems as well as those used in chemotherapy of microbial, parasitic, and neoplastic diseases. Because of the potential exposure and heavy parasite load of both companion and production animals, antiparasitic drugs will get deeper coverage than seen in a human pharmacology text. There are a number of specialty areas that also reflect unique aspects of veterinary medicine, including aquatic and avian species, as well as aspects of regulations related to using drugs in food-producing animals with the resulting production of chemical residues and potential human food safety issues. This is simply not an issue in human medicine.
The discipline is often simply divided into basic and clinical pharmacology, the distinction being whether studies are conducted in healthy or diseased animals, studying experimental models or natural disease states, or involve laboratory or clinical studies in an actual veterinary clinical situation. However, the common denominator that separates a veterinary pharmacologist from his/her human pharmacology colleagues is dealing with species differences in both disposition and action of drugs.
Comparative pharmacology is the true common theme that courses through the blood of all veterinary pharmacologists, be they basic or clinical in orientation. How does a drug behave in the species being treated? Is the disease pathophysiology similar across species? Do dosages need to be adjusted? Are microbial susceptibilities for pathogens different? Is a drug absorbed, eliminated, or metabolized differently in this species or breed? Can the dosage form developed for a dog be used in an equine patient? Are there unique individual variations in the population due to pharmacogenomic variability that would alter a drug’s effect in this patient? Are there unique species-specific toxicological effects for the drug in this patient? Is there a potential for drug-drug, drug-diet, or drug-environment interactions? Will this animal or its products be consumed by humans as food, and thus are potential residues from drug therapy a concern? All of these questions are addressed in the chapters that follow in this textbook.
The focus of veterinary pharmacology is to provide a rational basis for the use of drugs in a clinical setting in different animal species. These principles are fully discussed in the remainder of this text. The practicing veterinarian should appreciate every day that when a drug is given to a patient in his/her care, an experiment in clinical pharmacology is being conducted. The astute and successful practitioner will use principles of pharmacology to assure that the correct drug and dosage regimen is selected for the diagnosis in hand, that proper clinical outcomes will be assessed for both assuring efficacy and avoiding adverse effects, and finally that if a food-producing animal is being treated, proper caution is taken to insure the safety of animal-derived products to the human consumer.
REFERENCES AND ADDITIONAL READING
Andersen, L. and Higby, G.J. 1995. The Spirit of Voluntarism. A Legacy of Commitment and Contribution. The United States Pharmacopeia 1820–1995. Rockville, MD: The United States Pharmacopeial Convention.
Center for Veterinary Medicine, Food and Drug Administration. 2007. A Brief History of the Center for Veterinary Medicine. http://www/fda.gov/cvm/aboutbeg.htm.
Davis, L.E. 1982. Veterinary Pharmacology—An Introduction to the Discipline. In Booth, N.J. and McDonald, L.E. (eds.) Veterinary Pharmacology and Therapeutics, 5th Ed. Ames: Iowa State University Press, pp. 1–7.
Jones, L.M. 1977. Veterinary Pharmacology—Past, Present, and Future. In Jones, L.M., Booth, N.J., and McDonald, L.E. (eds.) Veterinary Pharmacology and Therapeutics, 4th Ed. Ames: Iowa State University Press, pp. 3–15.
Parascandola, J. 1992. The Development of American Pharmacology: John J. Abel and the Shaping of a Discipline. Baltimore: Johns Hopkins University Press.
USP 30-NF 25. United States Pharmacopeial Convention. 12601 Twin-brook Parkway, Rockville, Maryland 20852. (www.usp.org).
Van Miert, A.S.J.P.A.M. 2006. The Roles of EAVPT, ECVPT and EAVPT Congresses in the advancement of veterinary pharmacological and toxicological science. Journal of Veterinary Pharmacology and Therapeutics 29(Suppl. 1):9–11.
CHAPTER 2
ABSORPTION, DISTRIBUTION, METABOLISM, AND ELIMINATION
JIM E. RIVIERE
The four key physiological processes that govern the time course of drug fate in the body are absorption, distribution, metabolism, and elimination, the so-called ADME processes. Pharmacokinetics, the study of the time course of drug concentrations in the body, provides a means of quantitating ADME parameters. When applied to a clinical situation, pharmacokinetics provides the practitioner with a useful tool to design optimally beneficial drug dosage schedules for each individual patient. In the research and premarketing phase of drug development, it is an essential component in establishing effective yet safe dosage forms and regimens. An understanding of pharmacokinetic principles allows more rational therapeutic decisions to be made. In food animals, pharmacokinetics provides the conceptual underpinnings for understanding and utilizing the withdrawal time to prevent violative drug residues from persisting in the edible tissues of food-producing animals. A working knowledge of this discipline provides the framework upon which many aspects of pharmacology can be integrated into a rational plan for drug usage.
AN OVERVIEW OF DRUG DISPOSITION
To fully appreciate the ADME processes governing the fate of drugs in animals, the various steps involved must be defined and ultimately quantitated. The processes relevant to a discussion of the absorption and disposition of a drug administered by the intravenous (IV), intramuscular (IM), subcutaneous (SC), oral (PO), or topical (TOP) routes are illustrated in Figure 2.1. The normal reference point for pharmacokinetic discussion and analysis is the concentration of free, non–protein-bound drug dissolved in the serum (or plasma), because this is the body fluid that carries the drug throughout the body and from which samples for drug analysis can be readily and repeatedly collected. For the majority of drugs studied, concentrations in the systemic circulation are in equilibrium with the extracellular fluid of well-perfused tissues; thus, serum or plasma drug concentrations generally reflect extracellular fluid drug concentrations.
FIG. 2.1 Basic schema by which drug is absorbed, distributed, metabolized, and excreted from the body. These processes are those that form the basis for developing pharmacokinetic models.
A fundamental axiom of using pharmacokinetics to predict drug effect is that the drug must be present at its site of action in a tissue at a sufficient concentration for a specific period of time to produce a pharmacologic effect. Since tissue concentrations of drugs are reflected by extracellular fluid and thus serum drug concentrations, a pharmacokinetic analysis of the disposition of drug in the scheme outlined in Figure 2.1 is useful to assess the activity of a drug in the in vivo setting.
This conceptualization is especially important in veterinary medicine where species differences in any of the ADME processes may significantly affect the extent and/or time course of drug absorption and disposition in the body. By dividing the overall process of drug fate into specific phases, this relatively complex situation can be more easily handled. It is the purpose of this chapter to overview the physiological basis of absorption, distribution, metabolism, (biotransformation) and elimination. This will provide a basis for the chapter on pharmacokinetics that will deal with quantitating these processes in more detail.
FIG. 2.2 Illustration of how absorption, distribution, and excretion is essentially a journey of the drug through various lipoidal membrane barriers.
Despite the myriad of anatomical and physiological differences among animals, the biology of drug absorption and distribution, and in some cases even elimination, is very similar in that it involves drug molecules crossing a series of biological membranes. As illustrated in Figure 2.2, these membranes may be associated with either several layers of cells (tissue) or a single cell, and both living and dead protoplasm may be involved. Despite the different biochemical and morphological attributes of each of these membranes, a unifying concept of biology is the basic similarity of all membranes, whether they be tissue, cell, or organelle. Although the specific biochemical components may vary, the fundamental organization is the same. This fact simplifies the understanding of the major determinants of drug absorption, distribution, and excretion.
These membrane barriers often directly or indirectly define the nature of compartments or other mathematical modules in pharmacokinetic models. Biological spaces are defined by the restrictions on drug movement imposed by these barriers. The most effective barriers are those that protect the organism from the external environment. These include the skin as well as various segments of the gastrointestinal and respiratory tract, which also protect the internal physiologic milieu from the damaging external environment. However, the gastrointestinal and respiratory barriers are modified deep within the body to allow for nutrient and gas exchange vital for life. The interstitial fluid is a common compartment through which any drug must transit either after absorption on route to the blood stream or after delivery by blood to a tissue on route to a cellular target. Capillary membranes interfacing with this interstitial fluid compartment are relatively porous due to the fenestrae that allow large molecules to exchange between tissues and blood. Membranes define homogeneous tissue compartments and membranes must be traversed in all processes of drug absorption and disposition.
All cellular membranes appear to be primarily lipid bilayers into which are embedded proteins that may reside on either surface (intra- or extracellular) or traverse the entire structure. The lipid leaflets are arranged with hydrophilic (polar) head groups on the surface and hydrophobic (nonpolar) tails forming the interior. The specific lipid composition varies widely across different tissues and levels of biological organization. The location of the proteins in the lipid matrix is primarily a consequence of their hydrophobic regions residing in the lipid interior and their hydrophilic and ionic regions occupying the surface. This is thermodynamically the most stable configuration. Changes in the fluidity of the lipids alter protein conformations, which then may modulate their activity. This is the primary mechanism of action for gaseous anesthetics. In some cases, aqueous channels form from integral proteins that traverse the membrane. In other cases, these integral proteins may actually be enzymatic transport proteins that function as active or facilitative transport systems. The primary pathway for drugs to cross these lipid membranes is by passive diffusion through the lipid environment.
Thus, in order for a drug to be absorbed or distributed throughout the body, it must be able to pass through a lipid membrane on some part of its sojourn through the body. In some absorption sites and in many capillaries, fenestrated pores exist, which allow some flow of small molecules. This is contrasted to some protected sites of the body (e.g., brain, cerebral spinal fluid) where additional membranes (e.g., glial cells) may have to be traversed before a drug arrives at its target site. These specialized membranes could be considered a general adaptation to further shelter susceptible tissues from hostile lipophilic chemicals. In this case, drug characteristics that promote transmembrane diffusion would favor drug action and effect (again unless specific transport systems intervene).
This general phenomenon of the enhanced absorption and distribution of lipophilic compounds is a unifying tenet that runs throughout the study of drug fate. The body’s elimination organs can also be viewed as operating along a somewhat similar principle. The primary mechanism by which a chemical can be excreted from the body is by becoming less lipophilic and more hydrophilic, the latter property being required for excretion in the aqueous fluids of the urinary or biliary systems. When a hydrophilic or polar drug is injected into the bloodstream, it will be minimally distributed and rapidly excreted by one of these routes. However, if a compound’s lipophilicity evades this easy excretion, the liver and other organs may metabolize it to less lipophilic and more hydrophilic metabolites that have a restricted distribution (and thus reduced access to sites for activity) in the body and can be more readily excreted. This basic tenet runs throughout all aspects of pharmacology and is a useful concept to predict effects of unknown compounds.
DRUG PASSAGE ACROSS MEMBRANES
Considerable evidence exists that lipid-based membranes are permeable to nonpolar lipid-soluble compounds and polar water-soluble compounds with sufficient lipid solubility to diffuse through the hydrophobic regions of the membrane. The rate of diffusion of a compound across a membrane is directly proportional to its concentration gradient across the membrane, lipid\water partition coefficient, and diffusion coefficient. This can be summarized by Fick’s Law of Diffusion in Equation 2.1:
(2.1)
where D is the diffusion coefficient for the specific penetrant in the membrane being studied, P is the partition coefficient for the penetrant between the membrane and the external medium, h is the thickness or actual length of the path by which the drug diffuses through the membrane, and X1 − X2 is the concentration gradient (ΔX) across the membrane. The diffusional coefficient of the drug is a function of its molecular size, molecular conformation and solubility in the membrane milieu, and degree of ionization. The partition coefficient is the relative solubility of the compound in lipid and water that reflects the ability of the penetrant to gain access to the lipid membrane. Depending on the membrane, there is a functional molecular size and/or weight cutoff that prevents very large molecules from being passively absorbed across any membrane. When the rate of a process is dependent upon a rate constant (in this case [DP/h] often referred to as the permeability coefficient P) and a concentration gradient, a linear or first-order kinetic process is evident (see Chapter 3 for full discussion). In membrane transfer studies, the total flux of drug across a membrane is dependent on the area of membrane exposed; thus the rate above is often expressed in terms of cm2. If the lipid : water partition coefficient is too great, depending on the specific membrane, the compound may be sequestered in the membrane rather than traverse it.
Evidence also exists that membranes are more permeable to the nonionized than the ionized form of weak organic acids and bases. If the nonionized moiety has a lipid : water partition coefficient favorable for membrane penetration, it will ultimately reach equilibrium on both sides of the membrane. The ionized form of the drug is completely prevented from crossing the membrane because of its low lipid solubility. The amount of the drug in the ionized or nonionized form depends upon the pKa (negative logarithm of the acidic dissociation constant) of the drug and the pH of the medium on either side of the membrane (e.g., intracellular versus extracellular fluid; gastrointestinal versus extracellular fluid). Protonated weak acids are nonionized (e.g., COOH) while protonated weak bases are ionized (e.g., NH3+). If the drug has a fixed charge at all pHs encountered inside and outside of the body (e.g., quarternary amines, aminoglycoside antibiotics), they will never cross lipid membranes by diffusion. This would restrict both their absorption and distribution and generally lead to an enhanced rate of elimination. It is the nonionized form of the drug that is governed by Fick’s Law of Diffusion and described by Equation 2.1 above. For this equation to predict the movement of a drug across membrane systems in vivo, the relevant pH of each compartment must be considered relative to the compound’s pKa; otherwise, erroneous predictions will be made.
When the pH of the medium is equal to the pKa of the dissolved drug, 50% of the drug exists in the ionized state and 50% in the nonionized, lipid soluble state. The ratio of nonionized to ionized drug is given by the Henderson–Hasselbalch equation (Equations 2.2 and 2.3).
For acids:
(2.2)
For bases:
(2.3)
These equations are identical as they involve the ratio of protonated (H) to nonprotonated moieties. The only difference is that for an acid, the protonated form (H Acid)0 is neutral while for a base, the protonated form (H Base)+ is ionized.
FIG. 2.3 The phenomenon of pH partitioning and ion-trapping of a weak acid.
