Small Animal Clinical Pharmacology 2nd Edition

594 Pages·2008·6.07 MB·English

by  Jill E. Maddison BVSc DipVetClinStud PhD FACVSc MRCVS

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© Elsevier Limited 2008. All rights reserved.
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First published 2002
Second edition 2008
ISBN: 978 0 7020 2858 8
British Library Cataloguing in Publication Data
A catalogue record for this book is available from the British Library
Library of Congress Cataloging in Publication Data
A catalog record for this book is available from the Library of Congress
Notice
Knowledge and best practice in this fi eld are constantly changing. As new research and experience
broaden our knowledge, changes in practice, treatment and drug therapy may become necessary
or appropriate. Readers are advised to check the most current information provided (i) on
procedures featured or (ii) by the manufacturer of each product to be administered, to verify the
recommended dose or formula, the method and duration of administration, and contraindications.
It is the responsibility of the practitioner, relying on their own experience and knowledge of the
patient, to make diagnoses, to determine dosages and the best treatment for each individual
patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the
Publisher nor the Authors assume any liability for any injury and/or damage to persons or
property arising out of or related to any use of the material contained in this book.
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FM-S2858.indd iv 11/19/2007 2:15:55 PM
Contributors
Macdonald Christie Sonya G Gordon
Royal North Shore Hospital Department of Small Animal Clinical Science
The University of Sydney College of Veterinary Medicine and Biomedical
Sydney, NSW, Australia Science
Texas A&M University
David B Church College Station, Texas, USA
Department of Veterinary Clinical Sciences
Amy M Grooters
The Royal Veterinary College
Department of Veterinary Clinical Sciences
North Mymms, Hertfordshire, UK
School of Veterinary Medicine
Louisiana State University
Michael J Day
Baton Rouge, Louisiana, USA
School of Clinical Veterinary Science
University of Bristol Grant Guilford
Langford, Bristol, UK Institute of Veterinary, Animal and Biomedical
Sciences
Jane M Dobson Massey University
Department of Veterinary Medicine Palmerston North, New Zealand
University of Cambridge
Cambridge, UK Richard Hammond
Associate Professor of Pharmacology and Anaesthesia
Head of the Division of Surgery
Timothy M Dyke
School of Veterinary Medicine and Science
Australian Pesticides and Veterinary Medicines
University of Nottingham, Sutton Bonington,
Authority
Leicestershire, UK
Kingston, ACT, Australia
Peter D Hanson
Jonathan Elliott Merial Limited
The Royal Veterinary College Duluth, Georgia, USA
London, UK
Ann E Hohenhaus
Alain Fontbonne The Animal Medical Center
Ecole Nationale Vétérinaire d’Alfort New York, USA
Maisons-Alfort, Paris, France
Boyd Jones
Veterinary Sciences Centre
Sandra Forsyth
School of Agriculture, Food Science and Veterinary
Institute of Veterinary, Animal and Biomedical
Medicine
Sciences
University College Dublin
Massey University
Belfi eld, Dublin, Ireland
Palmerston North, New Zealand
Mark D Kittleson
Alexander J German Department of Medicine and Epidemiology
Department of Veterinary Clinical Sciences School of Veterinary Medicine
University of Liverpool Small Animal Hospital University of California, Davis
Liverpool, UK Davis, California, USA
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CONTRIBUTORS
Matthias J Kleinz Anne E Peaston
Department of Veterinary Basic Sciences The Jackson Laboratory
The Royal Veterinary College Bar Harbor, Maine, USA
London, UK
Kersti Seksel
Richard A LeCouteur Seaforth Veterinary Hospital
Department of Surgical and Radiological Sciences Seaforth, NSW, Australia
School of Veterinary Medicine
University of California, Davis Ian Spence
Davis, California, USA Discipline of Pharmacology
School of Medical Sciences
Jill E Maddison The University of Sydney
Department of Veterinary Clinical Sciences Sydney, NSW, Australia
The Royal Veterinary College
North Mymms, Hertfordshire, UK Robin G Stanley
Animal Eye Care
Carmel T Mooney Malvern East, Victoria, Australia
University Veterinary Hospital
School of Agriculture, Food Science and Veterinary Joseph Taboada
Medicine Department of Veterinary Clinical Sciences
University College Dublin School of Veterinary Medicine
Belfi eld, Dublin, Ireland Louisiana State University
Baton Rouge, Louisiana, USA
Ralf S Mueller
Medizinische Kleintierklinik Philip G A Thomas
Ludwig-Maximilians-University Queensland Veterinary Specialists
Munich, Germany Stafford Heights, Queensland, Australia
Anthony Nicholson Karen M Vernau
The Jackson Laboratory Department of Surgical and Radiological Sciences
Bar Harbor, Maine, USA School of Veterinary Medicine
University of California, Davis
Philip Padrid Davis, California, USA
Chicago, Illinois, USA
A David J Watson
Stephen W Page Glebe, NSW, Australia
Advanced Veterinary Therapeutics
Berry, NSW, Australia
Patricia Pawson
Veterinary Clinical Services Unit
Faculty of Veterinary Medicine
University of Glasgow
Glasgow, Scotland, UK
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Preface
The philosophy and rationale behind the fi rst edition of prescriptive. It is not intended to be a therapeutics or
Small Animal Clinical Pharmacology developed out of “how to treat” textbook – the drugs, not diseases, are
my experience, as a small animal internal medicine clini- the “stars”. Nor is it intended to be a complete phar-
cian, of teaching pharmacology to undergraduates and macological reference book. The authors of the chapters
subsequently to practitioners. It became clear as I strove are all recognized specialists in their fi eld. They have an
to develop a course that would encourage understand- intimate understanding of how and why drugs are used
ing, facilitate deep learning and above all foster student in their area of clinical specialty and the clinical phar-
interest and enthusiasm, that pharmacology cannot be macological features of the drugs that are relevant to
taught in isolation from physiology, pathology or clini- the practicing clinician.
cal medicine otherwise it becomes just a bewildering I am indebted to my co-editors, Stephen Page and
blur of drug names and doses. The same philosophy and David Church, who have brought skills to the editing
rationale has informed the second edition. process that have immeasurably enhanced the depth,
A fundamental understanding of clinical pharmacol- breadth and quality of Small Animal Clinical Pharma-
ogy is essential for good clinicians. Certainly our clinical cology. They both have expertise that far exceeds my
mentors impressed upon us the importance of under- own in many areas of basic and clinical pharmacology
standing the clinical application, mechanism of action even if their interpretation of the meaning of the word
and potential side effects of any drug we prescribed. “deadline” is somewhat looser than mine and our
Similarly, knowledge of the pharmacological action of publishers.
drugs is meaningless unless one also has a basic under- The support and patience of the staff at Elsevier, in
standing of the relevant physiology and pathophysiol- particular Joyce Rodenhuis, Rita Demetriou-Swanwick,
ogy of the system or tissue adversely affecting the health and Kerrie-Anne Jarvis, have been superb and we extend
or welfare of the patient. Hence our undergraduate and to them our deepest thanks and appreciation.
continuing education courses in clinical pharmacology I hope that practitioners and veterinary students fi nd
evolved over many years to meet these needs culminat- the second edition of Small Animal Clinical Pharmacol-
ing in the particular and perhaps unique approach and ogy an invaluable addition to the resources they access
format of Small Animal Clinical Pharmacology. to increase and deepen their knowledge and understand-
The aim of the 2nd edition expands that of the 1st – to ing of drugs used in veterinary practice.
provide up to date drug information that is practical
and relevant to students and practitioners, and suffi - Jill Maddison
ciently comprehensive to increase the reader’s under- Senior Editor
standing of clinical pharmacology without being London, 2007
viii
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Dedication
To Tom, Rosalind and Jimmy, who are working on the music for the feature fi lm.
ix
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1
Principles of clinical pharmacology
Stephen W Page and Jill E Maddison
INTRODUCTION nosis, lack of effective intervention for a life-threatening
though curable disease, induction of toxicity, prolonga-
Clinical pharmacology in the veterinary setting is the tion of disease, development of a disorder that would
clinical discipline devoted to the optimal use of drugs in otherwise not be present, selection for antibiotic resis-
veterinary patients, maximizing their prophylactic or tance, false rejection of a drug wrongfully used and
therapeutic benefi ts while ensuring that the adverse con- increased cost.
sequences of drug use are minimized. The fi rst principle The response of each patient to treatment is an indi-
of clinical pharmacology was recognized and enunci- vidual event, with the possibility of a high degree of
ated by the famous Greek physician Hippocrates (460– interpatient variability. In determining the correct
377 bc), traditionally regarded as the father of medicine: dosage regimen for an individual patient, it may often
primum non nocere, ‘above all, do no harm’. Later, be appropriate to use a fi xed and predetermined dosage
Aureolus Paracelsus (1493–1541), a German-Swiss phy- schedule. However, in other cases, particularly in the
sician and the grandfather of modern pharmacology, presence of serious disease, the dosage regimen may
stated that ‘all things are poisons, for there is nothing need to be individualized to provide an improved
without poisonous qualities. It is only the dose that balance of benefi ts and risks. The process of defi ning
makes a thing a poison.’ These seminal observations the nature of the appropriate individualization is an
have been reinforced by the accumulation of centuries important function of clinical pharmacology and relies
of experience, remaining as pertinent and germane on a thorough knowledge of those characteristics of the
today. At the extremes the use of medicines can be either patient, the disease and the drug and its dosage form
life saving or lethal. Patient outcome can be biased that may lead to variation in clinical response. This
towards benefi t by the appropriate application of the chapter introduces key concepts and defi nitions that
principles of clinical pharmacology. It is salutary to underpin the discipline of clinical pharmacology, high-
recall the words of Arthur Bloomfi eld, an eminent lighting major sources of clinical variability and sum-
physician at Stanford University during the fi rst half of marizing the principal responsibilities of veterinarians
the 20th century, that ‘there are some patients whom in prescribing and dispensing drugs.
we cannot help; there are none whom we cannot
harm.’
Clinical pharmacology, then, is concerned with ensur- DEFINITIONS
ing that patients receive the right drug at the appropri-
ate dose for the correct duration, with appropriate ● Pharmacology is the study of the properties of drugs
supervision and surveillance of the response, guiding and all aspects of their interaction with living organ-
modifi cation and refi nement of the dose regimen as isms. Drugs include any chemical agent (other than
indicated. Figure 1.1 illustrates these important deci- food) used in the treatment, cure, prevention or
sions. Both Hippocrates and Paracelsus recognized that diagnosis of disease or the control of physiological
the body has an extraordinary ability to heal itself, if processes. The science of pharmacology draws on
given the opportunity. Thus, while drugs can be power- the knowledge and methods of many allied clinical
ful and effective tools, underlying every decision to treat and nonclinical disciplines, including chemistry,
must be a thorough and accurate diagnosis and the biochemistry, biology, physiology, pathology and
development of a therapeutic plan. The decision to medicine.
avoid interventions with drug treatment may frequently ● Clinical pharmacology is a subset of the broad study
be as valid and scientifi cally and clinically sound as the of pharmacology and is devoted to the study of the
decision to administer drugs. The judgment remains clinical effects of drugs on patients with a goal of
with the clinician in consultation with the client. optimizing therapeutic dosage regimens. Knowledge
The outcome of successful drug treatment may be of the pharmacokinetic and pharmacodynamic pro-
alleviation of signs or cure of disease. By contrast, the perties of drugs and their toxic effects is inherent in
inappropriate use of a drug may result in delay in diag- this discipline.
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CHAPTER 1 PRINCIPLES OF CLINICAL PHARMACOLOGY
Take history, examine patient
and gather other data as
appropriate.
Make diagnosis.
Define therapeutic objective(s)
Non-drug measures:
and develop therapeutic plan
supportive, management,
(drug and/or non-drug
nutrition, environment
measures)
Modify therapeutic Select drug and dosage
objective/plan regimen.
Monitor and evaluate response Change drug or
Modify diagnosis
to treatment modify regimen
Continue treatment Stop treatment
Fig. 1.1 Steps in the initiation, management and reassessment of drug therapy.
● Pharmacokinetics is the study of the characteristics while macrolides are concentrated in cells and
of the time course and extent of drug exposure in have a high V.
individuals and populations and deals with the – Clearance (Cl) describes the effi ciency of irrever-
absorption, distribution, metabolism and excretion sible elimination of a drug from the body (princi-
(ADME) of drugs. Pharmacokinetics has been pally by the major organs of biotransformation
described as ‘what the body does to the drug’. Impor- and elimination, the liver and kidney) and is
tant pharmacokinetic terms are briefl y described defi ned as the volume of blood cleared of drug
below and are discussed more comprehensively in per unit time. Clearance determines the mainte-
Chapter 2. nance dose rate required to achieve a target
– Volume of distribution (V) is the constant that plasma concentration at steady state, as at steady
relates the amount of drug in the body (A) to the state there is an equilibrium whereby the rate of
plasma drug concentration (C) (i.e. V = A/C), but drug elimination is matched by the rate and extent
does not necessarily correspond to any actual of drug absorption.
anatomic volume or compartment. V is a charac- – First-pass effect is a type of drug clearance and
teristic of a drug rather than of the biological defi ned as the extent to which an enterally admin-
system, although it may change in the presence of istered drug is removed prior to reaching the
disease, pregnancy, obesity and other states. By systemic circulation by prehepatic and hepatic
knowing the value of V, it is possible to calculate metabolism. First-pass effects are important as a
the dose necessary to obtain a target plasma con- possible source of variability in clinical response
centration (i.e. A = V · C), which corresponds to to a drug and in explaining a component of the
the loading dose. The greater the volume of dis- difference in response between parenteral and
tribution of a drug, the higher the dose necessary enteral administration of the same drug.
to achieve a desired concentration. Amongst the – Half-life (t ): is the time taken for the amount of
1/2
antibibacterial drugs, β-lactams are ionized at drug in the body (or the plasma concentration) to
physiological pH and generally have a low V, fall by half. In most cases it is the elimination
2
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HOW DRUGS WORK
half-life that is referred to, to distinguish it from ● Pharmacodynamics is the study of the biochemical
the absorption half-life, a parameter that describes and physiological effects of drugs, their modes of
the rate of drug absorption and increase in plasma action and the relationship between drug concentra-
concentration. Half-life is a function of V and Cl tion and effect. Pharmacodynamics has been described
(t = 0.693 V/Cl) and frequently determines the as ‘what the drug does to the body’. An understand-
1/2
duration of action after a single dose of a drug, ing of pharmacodynamics forms the foundation of
the time taken to reach steady state with repeated rational therapeutic drug use and provides insights
dosing (generally 3–5 half-lives) and the dosing into improved dosage regimens and possible drug
frequency required to avoid large fl uctuations in interactions as well as the design of new drugs.
peak and trough plasma concentration during the
dosing interval (dosing at intervals of one half-life
will lead to plasma concentrations covering a HOW DRUGS WORK
twofold range).
– T represents the time after dosing at which the
max Drug action = initial consequence of drug–receptor
maximum plasma concentration is observed and
combination
indicates the time at which the rate of absorption Drug effect = biochemical and physiological changes that
equals the rate of dissipation (distribution and occur as a consequence of drug action
elimination).
– Cmax represents the maximum concentration of Structure-dependent drug action
the drug observed (or calculated) in plasma after
administration and occurs at T . The actions of the majority of drugs are intimately
max
– Area under the curve (AUC) is the area integrated related to their three-dimensional chemical structure.
below the plasma concentration versus time curve Seemingly minor alterations to a drug molecule can
and is a measure of the extent of drug absorption. result in major changes in pharmacological properties.
– Bioavailability (F) is defi ned as the rate and extent This can be exploited to develop drugs with a more
to which the active constituent or active moiety favorable therapeutic index, fewer side effects or a
of a drug is absorbed from a drug product and shorter or longer duration of action. As an example,
reaches the circulation. For systemically active chemical modifi cation of the penicillins and cefalospo-
drugs, absolute (100%) bioavailability is assigned rins has led to the availability of many new groups or
to intravenously administered drug (unless the generations of antibacterial agents with differing phar-
drug is likely to precipitate in blood). The bio- macokinetic (orally active, broader distribution, longer
availability of alternative formulations of the acting) and microbiological (broader spectrum, β-
same drug administered by other routes is com- lactamase resistant) characteristics, overcoming many of
pared to that of the IV route. In this case relative the limitations of the originally isolated substances.
bioavailability is assessed by determining the The actions of drugs on receptors that lead to
AUC and comparing it to the AUC following IV responses are governed by the same factors that infl u-
administration. For nonsystemically active drugs, ence the rate and direction of chemical or biochemical
bioavailability is frequently determined by non- reactions, i.e.:
pharmacokinetic means, often by comparing the ● temperature (although this is usually kept within
time course and degree of clinical response or tight limits in homeotherms but may be modifi ed
effect of a test drug with a standard (or reference) during episodes of fever or hypothermia)
drug preparation. ● the concentration of each reactant (including
– Bioequivalence is a clinical term referring to for- cofactors)
mulations of a drug with rates and extents of ● catalysts (enzymes that activate drug precursors).
absorption that are suffi ciently similar that there
In addition, there are biological processes that tend to
are not likely to be any clinically important dif-
reduce the concentration of a drug at the site of action,
ferences with respect to either effi cacy or safety.
including concentration gradients affected by local
In order to demonstrate bioequivalence for sys-
blood fl ow, degradative enzymes, cell uptake mecha-
temically active drugs, a comparative pharmaco-
nisms and changes in the characteristics of the receptors
kinetic study is generally undertaken and the
(allosteric changes, for example).
similarity (defi ned by statistical and biological
criteria) of C and AUC of the formulations is
max Structural nonspecifi city
assessed. For drugs not acting systemically, com-
parisons of clinical or other pharmacological end- A few drugs share the ability to accumulate in certain
points may be necessary. cells because of a shared physicochemical property
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CHAPTER 1 PRINCIPLES OF CLINICAL PHARMACOLOGY
rather than a specifi c chemical structure. For example, – neurotransmitters increase or decrease sodium
one of the theories of the mode of action of volatile ion permeability of excitable membranes.
anesthetics relates to the oil–water partition coeffi cients: ● Enzyme inhibition. Certain drugs exert their effects
the more lipid soluble a gas, the more potent. Also, by inhibiting the activity of specifi c enzyme systems,
anesthetic compounds have diverse structures, suggest- either in the host animal or in invading pathogens.
ing that biophysical rather than specifi c receptor- This inhibition may be competitive or noncompeti-
mediated mechanisms of action may be important. tive, reversible or irreversible.
Other examples of physicochemical actions include: ● Receptor-mediated effects. Many drugs interact with
● adsorbents bind toxins or poisons nonspecifi cally in specifi c cellular proteins known as receptors. As a
gut, rendering them biologically unavailable, e.g. result of this interaction, activation or inhibition of
activated charcoal a sequence of biochemical events is usually initiated.
● oily laxatives work partly because of their lubricant Receptors may be located on the cell membrane,
properties in the cytosol or in the nucleus. There is usually a
● osmotic diuretics, e.g. mannitol. close correlation between drug structure and drug
activity (see Table 1.1).
Noncellular mechanisms of drug action
Drug reactions may occur extracellularly and involve
DRUG RECEPTORS
noncellular constituents.
● Physical effects, e.g. protective, adsorbent and lubri-
Drug–receptor interactions are similar in concept to
cant properties of agents applied to the skin.
enzyme reactions. The simplest concept is the analogy
● Chemical reactions, e.g. neutralization of gastric HCl
of a lock and key (receptor and drug), although receptor
by antacids.
and drug structure are not necessarily rigid and may be
● Physicochemical mechanisms may alter the biophysi-
relatively plastic. The most potent drug at a receptor
cal properties of specifi c fl uids, e.g. surfactants,
will ‘fi t perfectly’ and other drugs with similar but non-
detergents, antifoaming agents.
identical structure may fi t less effectively and therefore
● Modifi cation of the composition of body fl uids. Sub-
be less potent and have no effect, a partial effect or
stances may exert osmotic infl uence across cellular
indeed inhibit (antagonize) the interaction of the refer-
membranes, e.g. mannitol, poultices, electrolyte solu-
ence drug.
tions, acidifying and alkalinizing salts to alter urine
Within a class of drugs one or more parts of the
pH.
molecule will be the key in the receptor interaction.
Paul Ehrlich, a pioneer of pharmacology, described the
Cellular mechanisms of drug action
essential molecular characteristics responsible for drug–
Most responses elicited by drugs occur at the cellular receptor interaction as the pharmacophore. To convey
level and involve either functional constituents of some specifi city, receptor pharmacophores generally
the cell or, more commonly, specifi c biochemical have multiple spatial and chemical requirements for full
reactions. effect. Different drugs in that class will have the same
● Physicochemical and biophysical mechanisms. Some key structure but the rest of the structure will be differ-
drugs can alter the physicochemical or biophysical ent. This often results in different pharmacological
characteristics of specifi c components of the cell, properties such as potency, duration of action, absorp-
e.g. inhalant anesthetics may affect the lipid matrix tion, protein binding, metabolism and adverse effects.
of the cell membrane and polymyxins are cationic Drug response may be graded (continuous) or quantal
surface active agents that disrupt membrane (present or absent). Examples of quantal drug responses
phospholipids. include prevention of seizures, prevention of death,
● Modifi cation of cell membrane structure and induction of parturition. They require a group of animals
function. Various drugs may infl uence the structure for study. Graded responses, e.g. changes in blood
or function of specifi c functional components of pressure, changes in hormone concentrations after
the cell membrane. Their action may also involve therapy, can be studied in an individual though to detect
enzyme systems or receptor-mediated reactions. For interindividual differences, groups of patients will
example: need investigation.
– local anesthetics bind to sodium channels in excit-
able membranes and prevent depolarization
Drug–receptor binding
– calcium channel blockers inhibit entry of calcium
into cells Drug–receptor interactions involve all known types of
– insulin facilitates transportation of glucose into cells bond: ionic, hydrogen, van der Waals, covalent. Drugs
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DRUG RECEPTORS
with short duration of action generally have weaker
bonds; long-duration or irreversible drug–receptor
Drug A Drug B Drug C
interactions may have stronger bonds such as covalent.
The drug–receptor interaction can be described as ct
e
follows. eff
%
Drug (D) + receptor (R) k ↔ k DR → effect
1 2
k = rate of association
1
k = rate of dissociation
2
(maximal effect×[D]) Log dose
Effect=
(K +[D])
d Fig. 1.3 Log dose–response curve. Drug A is more
Kd = dissociation constant potent than drug B or drug C. The curves for drugs A
= affi nity of the drug for the receptor and B have the same shape, indicating that they
= k2/k1 probably interact with the same receptor to achieve the
Effect is half maximal when [D] = K. drug effect. Drug A and drug C have different-shaped
d
curves indicating that, although the drugs cause the
Describing the drug–receptor interaction same effect, they most probably do so through
interacting with different receptors.
A measurable drug response can be illustrated in a
number of ways.
● Dose–response curve (Fig. 1.2)
● Log dose–response curve (Fig. 1.3)
● Lineweaver–Burk plot (linear), which is described
by the equation (Fig. 1.4):
1/effect = Kd/max effect [D] + 1/max effect ect Slope = kd/max. effect
eff
Several terms are useful when evaluating a drug dose– I/
response curve.
I/max. effect
● Potency is a measure of the drug concentration
required to elicit a particular effect and is related to
the distance between the response (y) axis and the
ED . Therefore, a shift to the right means a decrease I/dose
50
in potency, a shift to the left an increase in potency
Fig. 1.4 Lineweaver–Burk plot.
(Fig. 1.5).
● The slope of the linear part of the dose–response
curve indicates the degree to which a change in dose
results in a change in effect. The steeper the slope,
A
the greater the change in effect with small increments
C
B
of dose.
● Maximum effect is where the dose–response curve
reaches a plateau. ect
Eff
Log dose
ct
e
eff Fig. 1.5 Log dose–response curves. (A) Log dose–
%
response curve of an agonist (drug X). (B) Log dose–
response curve of the agonist, drug X, in the presence
of a noncompetitive antagonist or log dose–response
curve of a partial agonist (drug Y). (C) Log dose–
Drug dose response curve of the agonist, drug X, in the presence
of a competitive antagonist or log dose–response curve
Fig. 1.2 Dose–response curve. of a less potent agonist (drug Z).
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