Goodman
`cmd Gilmcmi’s
`* 7796
`,
`Pharmacological
`Basis of*
`Themgeutz'cs
`
`Palmer Taylor IVY/((14 HUN l’li’lffi'fij
`
`Theodore W. Rall
`
`Alan S. Nies
`
`1510/! TH [31)] 'l’l()_\'
`
`EDITORS
`
`Alfred Goodman Giiman
`
`Page 1
`
`ARGENTUM EX1023
`
`

`

`GOODMAN and GILMAN's · " __ :
`
`__ The· ·__ -------'---(cid:173)
`~· .·
`
`Basis of
`TherapeUtics·.·
`
`~~
`
`...
`
`..·-
`
`~--
`
`.·_
`
`_:
`
`-
`
`.
`
`-~.
`
`·..
`
`.-·-
`
`--~..;
`
`Page 2
`
`

`

`EDITORS
`
`Alfred Goodman Gilman
`
`M.D., Ph.D.
`Raymond and Ellen Willie Professor of Molecular Neuropharmacology
`Chairman, Department of Pharmacology
`University of Texas Southwestern Medical Center
`Dallas, Texas
`
`Theodore W Rail
`
`Ph.D., D.Med. (Hon.)
`Professor of Pharmacology
`University ofVirginia School of Medicine
`Charlottesville, Virginia
`
`AlanS. Nies
`
`M.D.
`Professor of Medicine and Pharmacology
`Head, Division of Clinical Pharmacology
`University of Colorado School of Medicine
`Denver, Colorado
`
`Palmer Taylor
`
`Ph.D.
`Professor and Chairman, Department of Pharmacology
`University of California, San Diego
`La Jolla, California
`
`Page 3
`
`

`

`GOODMAN and GILMAN's
`
`___ The __ _
`Pharmacological
`Basis of
`Therapeutics
`
`EIGHTH EDITION
`
`PERGAMON PRESS
`Member of Maxwell Macmillan Pergamon Publishing Corporation
`New York • Oxford • Beijing • Frankfurt • Sao Paulo • Sydney • Tokyo • Toronto
`
`Page 4
`
`

`

`Pergamon Press Offices:
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`Copyright ©. 1990 Pergamon Press, Inc.
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`All rights reserved. No part of this publication may be reproduced,
`stored in a retrieval system or transmitted in any form or by any
`means: electronic, electrostatic, magnetic tape, mechanical,
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`from the publishers.
`
`Earlier editi_ons entitled· The Pharmacoiogical Basis of Therapeutics
`copyright 1941 and 1955, © copyright 1965, copyright © 1970, and
`copyright © 1975 by Macmillan Publishing Company. Earlier editions
`entitled Goodman and Gilman's The Pharmacological Basis of
`Therapeutics copyright © 1980 and copyright © 1985 by Macmillan
`Publishing Company.
`
`Library of Congress Cataloging-in-Publication Data
`
`Goodman and Gilman's the pharmacological basis of
`therapeutics.
`
`Includes bibliographical references.
`Includes index.
`I. Goodman,
`2. Chemotherapy.
`1. Pharmacology.
`II. Gilman, Alfred, 1908-
`Louis Sanford, 1906-
`111. Gilman, Alfred Goodman, 1941-
`IV. Title: Pharmacological basis of therapeutics.
`[DNLM: 1. Drug Therapy. 2. Pharmacology. QV 4 G6532]
`RM300.G644 1991
`615'.7
`90-7660
`ISBN 0-08-Q40296-8 (hardcover)
`
`Printing: 1 2 3 4 5 6 7 8 9 10 Year: 0 1 2 3 4 5 6 7 8 9
`Printed in the United States of America
`
`In this textbook, reference to proprietary names of drugs is ordinarily
`made only in chapter sections dealing with preparations. Such
`names are given in SMALL-CAP TYPE, usually immediately following
`the official or nonproprietary titles. Proprietary names of drugs also
`appear in the Index.
`
`The paper used in this publication meets the minimum requirements
`of American National. Standard for ·Information Sciences(cid:173)
`Permanence of Paper for Printed Library Materials, ANSI
`Z39.48-1984
`
`Page 5
`
`

`

`CHAPTER
`PRINCIPLES OF THERAPEUTICS
`
`4
`
`Alan S. Nies
`
`THERAPY AS A SCIENCE
`
`·Over a century ago Claude Bernard for(cid:173)
`malized criteria for gathering valid informa(cid:173)
`tion in experimental medicine. However,
`application of these criteria to therapeutics
`and ·to the process of making decisions
`about therapeutics has, until recently, been
`slow and inconsistent. At a time when the
`diagnostic aspects of medicine had become
`scientifically sophisticated, therapeutic de(cid:173)
`cisions were often made on the basis of
`impressions and traditions. Historically,
`the absence of accurate data on the effects
`of drugs in man was due in large part tq
`ethical standards of human experimenta(cid:173)
`tion. '"Experimentation" in human beings
`was precluded, and it was not generally
`conceded that every treatment by any phy(cid:173)
`sician should be designed and in some
`sense recorded as an experiment.
`Although there must always be ethical
`concern about experimentation in man,
`principles have been defined, and there are
`no longer ethical restraints on the gathering
`of either experimental or observational data
`on the efficacy and toxicity of drugs in
`adults. Furthermore, it should now be con(cid:173)
`sidered absolutely unethical to use the art
`as opposed to the science of therapeutics
`on any patient who directly (the adult or
`child) or indirectly (the fetus) receives
`drugs for therapeutic purposes. Observa(cid:173)
`tional (nonexperimental) techniques that
`can greatly add to our knowledge of the ef(cid:173)
`fects of drugs can be applied to all popula(cid:173)
`tions (Sheiner and Benet, 1985; Whiting
`et al., 1986). The fact that such observa(cid:173)
`tional techniques have largely been applied
`in a nonsystematic fashion has led us to rely
`on a relative paucity of information about
`many drugs. Therapeutics must now be
`dominated by objective evaluation of an
`adequate base of factual knowledge.
`
`Conceptual Barriers to Therapeutics as a
`Science. The most important barrier that
`inhibited the development of therapeutics
`as a science seems to have been the belief
`that multiple variables in diseases and in
`the effects of drugs are uncontrollable. If
`this were true, the scientific method would
`not be applicable to the study of pharmaco(cid:173)
`therapy. In fact, therapeutics is the aspect
`of patient care that is most amenable to the
`acquisition of useful data, since it involves
`an intervention and provides an opportu(cid:173)
`nity to observe a response. It is now appre(cid:173)
`ciated that clinical phenomena can be de(cid:173)
`fined, described, and quantified with some
`precision. The approach to complex clinical
`data has been artfully discussed by
`Feinstein (1983).
`Another barrier to the realization of ther(cid:173)
`apeutics· as a science was ·overreliance on
`traditional diagnostic labels for disease.
`This encouraged the physician to think of a
`disease as static rather than dynamic, to
`view patients with the same ··label'' as a
`homogeneous rather than a heterogeneous
`population, and to consider a disease as an
`entity even when information about patho(cid:173)
`genesis was not available. If diseases are
`not considered to be dynamic, ··standard''
`therapies in ··standard'' doses will be the
`order of the day; decisions will be reflexive.
`Needed instead is an attitude that makes
`the physician responsible for recognition of
`and compensation for changes that occur in
`pathophysiology as the underlying process
`evolves. For example, the term myocardial
`infarction refers to localized destruction of
`myocardial cells caused by interruption of
`the blood supply; however, decisions about
`therapy must take into account a variety of
`autonomic, hemodynamic, and electrophys(cid:173)
`iological variables that change as a func(cid:173)
`tion of time, size, and location of the infarc(cid:173)
`tion. Failure to take all such variables into
`
`62
`
`Page 6
`
`

`

`THERAPY As A SciENCE
`
`63
`
`account while planning a therapeutic ma(cid:173)
`neuver may result in ineffective therapy in
`some patients while exposing others to
`avoidable toxicity. If groups of patients are
`in reality heterogeneous and receive alter(cid:173)
`native treatments, true differences in effi(cid:173)
`.cacY or toxicity between therapies may go
`unrecognized. A diagnosis or label of a dis(cid:173)
`ease or syndrome usually indicates a spec(cid:173)
`trum of possible causes and outcomes.
`Therapeutic experiments that fail to match
`groups for the known variables that affect
`prognosis yield uninterpretable data. ·
`A third conceptual barrier was the incor(cid:173)
`rect notion that data derived empirically are
`useless because they are not generated by
`application of the scientific method. Empir(cid:173)
`icism is often defined as the practice of
`medicine founded on mere experience,
`without the aid of science or a knowledge of
`principles. The connotations of this defini(cid:173)
`tion are misleading; empirical observations
`need not be scientifically unsound. In fact,
`concepts of therapeutics have been greatly
`advanced by the clinical observer who
`,makes careful and controlled observations
`on the outcome of a therapeutic interven(cid:173)
`tion. The results, even when the mecha(cid:173)
`nisms of disease and their interactions with
`the effects of drugs are not understood, are
`nevertheless often crucial to appropriate
`therapeutic decisions. Frequently, the ini(cid:173)
`tial suggestion that a drug may be effica(cid:173)
`cious in one condition arises from careful,
`empirical observations that are made while
`the drug is being used for another purpose.
`Examples of valid empirical observations
`that have resulted in new uses of drugs in(cid:173)
`clude the use of penicillamine· to treat ar(cid:173)
`thritis, lidocaine to treat cardiac arrhyth(cid:173)
`mias, and propranolol and clonidine to treat
`hypertension. Conversely,
`emptnctsm,
`when not coupled with appropriate obser(cid:173)
`vational methods and statistical techniques,
`often results in findings that are inadequate
`or invalid.
`
`Clinical Trials. Application of the scien(cid:173)
`tific method to experimental therapeutics is
`exemplified by a well-designed and well(cid:173)
`executed clinical trial. Clinical trials form
`the basis for therapeutic decisions by all
`physicians, and it is therefore essential that
`they be able to evaluate the results and con-
`
`elusions of such trials critically. To maxi(cid:173)
`mize the likelihood that useful infonnation
`Will result from the experiment, the objec(cid:173)
`tives of the study must be defined, homoge(cid:173)
`neous populations of patients must be. se(cid:173)
`lected, appropriate control groups must be
`found, meaningful arid sensitive indices of
`drug effects m·ust be chosen for observa(cid:173)
`tion, and the observations. must be con(cid:173)
`verted into data and then into valid conclu(cid:173)
`sions (Feinstein, 1977). The sine qua non of
`any clinical trial is its controls. Many differ(cid:173)
`ent types of controls may be used, and the
`term controlled study is not synonymous
`with randomized double-blind technique.
`Selection of a proper control group is as
`critical to the eventual utility of an experi(cid:173)
`ment as the selection of the experimental
`group. Although the randomized, double(cid:173)
`blind controlled trial is the most effective
`design for distributing bias and unknown
`variables between the ''treatment'' and the
`''control'' groups, it is not necessarily the
`optimal design for all studies. It may be
`impossible to use this design to· study dis(cid:173)
`orders that occur rarely, disorders in pa(cid:173)
`tients who cannot, by regulation or ethics
`or both, be studied (e.g ..• children, women
`of childbearing age, fetuses, or some pa(cid:173)
`tients with psychiatric diseases), or dis(cid:173)
`orders with a uniformly fatal outcome (e.g.,
`rabies, where historical controls can be
`used).
`There are several requirements in the design of
`clinical trials to test the relative effects of alterna(cid:173)
`tive therapies. (l) Specific outcomes of therapy
`that are clinically relevant and quantifiable must be
`measured. (2) The accuracy of diagnosis and the
`severity of the disease must be comparable in the
`groups being contrasted; otherwise, false-positive
`and false-negative errors may occur. (3) The dos(cid:173)
`ages of the drugs must be chosen and individual(cid:173)
`ized in a manner that allows relative efficacy to be
`compared at equivalent toxicities or allows relative
`toxicities to be compared at equivalent efficacies.
`(4) Placebo effects, which occur in a large percent(cid:173)
`age of patients, can confound many studies(cid:173)
`particularly
`those that
`involve subjective re(cid:173)
`sponses; controls must take this into account.
`However, subjective assessments are important in
`determining whether a therapy improves the pa(cid:173)
`tient's well-being. In fact, quality of life can be ·as(cid:173)
`sessed by the experimental subject and can be ob(cid:173)
`jectively
`tabulated
`c;tnd
`incorporated
`into
`evaluation of a therapy (Williams, 1987). (5) Com(cid:173)
`pliance with the experimental regimens should be
`assessed before subjects are assigned to experi(cid:173)
`mental or control groups. The drug-taking behavior
`
`Page 7
`
`

`

`64
`
`PRINCIPLES OF THERAPEUTICS
`
`[Chap. 4]
`
`of the subjects should be reassessed during the
`course of the trial. Noncompliance, even if ran(cid:173)
`domly distributed between both groups, may cause
`falsely low estimates of the true potential benefits
`or toxicity of a particular treatment. (6) Sample size
`should be estimated prior to beginning a clinical
`trial and must be taken into account in interpreting
`the results of the trial. Depending upon such fac(cid:173)
`tors as the overall p:rognosis of the disease and the
`anticipated improvement in outcome or toxicity
`from the new treatment, very large numbers of sub(cid:173)
`jects may be needed; otherwise, the possibility of a
`false-negative result is high (i.e., no statistically
`significant differences between the two treatments
`will be found, even though differences actually
`exist) (Young et al., 1983; Simon, 1986). (7) Ethical
`considerations may be major determinants of the
`types of controls that can be used and must be eval(cid:173)
`uated explicitly (Rosner, 1987; Rothman, 1987).
`For example, in therapeutic trials that involve life(cid:173)
`threatening diseases for which there is already an
`effective therapy, the use of a placebo is unethical,
`and new treatments must be compared with ··stan(cid:173)
`dard'' therapies.
`
`The results of clinical trials of new thera(cid:173)
`peutic agents or of old agents for new indi(cid:173)
`cations may have severe limitations in
`terms of what can be expected of drugs
`when they are used in an office practice.
`The selection of the patients for experimen(cid:173)
`tal trials usually eliminates those with coex(cid:173)
`isting diseases, and such trials usually as(cid:173)
`sess the effect of only one or two drugs, not
`the many that might be given to or taken by
`the same patient under the care of a physi(cid:173)
`cian. Clinical trials are usually performed
`with relatively small numbers of patients
`for periods of time that may be shorter than
`are necessary in practice, and compliance
`may be better controlled than it can be in
`practice. These factors lead to several ines(cid:173)
`capable conclusions:
`1) Even if the result of a valid clinical trial
`of a drug is thoroughly understood, the
`physician can only develop a hypothesis
`about what the drug might do to a particular
`patient, and there can be no assurance that
`what occurred in other patients will be
`seen. In effect, the physician uses the re(cid:173)
`sults of a clinical trial to establish an experi(cid:173)
`ment in each patient. The detection of an(cid:173)
`ticipated and unanticipated effects and the
`determination of whether or not they are
`due to the drug(s) being used are important
`responsibilities of the physician during the
`supervision of a therapeutic regimen. If an
`effect of a drug is not seen in a clinical trial,
`
`it may still be revealed in the setting of clin(cid:173)
`ical practice. About one half or more of
`both useful and adverse effects of drugs
`that were not recognized in the initial for(cid:173)
`mal trials were subsequently discovered
`and reported by practicing physicians.
`2) If an anticipated effect of a drug has
`not occurred in a patient, this does not
`mean that the effect cannot occur in that
`patient or in others. Many factors in the
`individual patient may contribute to lack of
`efficacy of a drug. They include, for exam(cid:173)
`ple, misdiagnosis, poor compliance by the
`patient to the regimen, poor choice of dos(cid:173)
`age or dosage intervals, coincidental devel(cid:173)
`opment of an undiagnosed separate illness
`that influences the outcome, the use of
`other agents that interact with primary
`drugs to nullify or alter their effects, unde(cid:173)
`tected genetic or environmental variables
`that modify the disease or the pharmacolog(cid:173)
`ical actions of the drug, or unknown ther(cid:173)
`apy by another physician who is caring for
`the same patient. Of equal importance,
`even when a regimen appears to be effica(cid:173)
`cious and innocuous, a physician should
`not attribute all improvement to the thera(cid:173)
`peutic regimen chosen, nor should a physi(cid:173)
`cian assume that a deteriorating condition
`reflects only the natural course of the dis(cid:173)
`ease. Similarly, if an anticipated untoward
`or toxic effect is not seen in a particular pa(cid:173)
`tient, it can still occur in others. Physicians
`who use only their own experience with a
`drug to make decisions about its use unduly
`expose their patients to unjustifiable risk or
`unrealized efficacy. For example, simply
`because a doctor has not seen a case of
`chloramphenicol-induced aplastic anemia
`in his own practice does not mean that such
`a disaster may not occur; the drug should
`still be used for the proper indications.
`3) Rational therapy is therapy based on
`the use of observations that have been eval(cid:173)
`uated critically. It is no less crucial to have
`a scientific approach to the treatment of an
`individual patient than to use this approach
`when investigating drugs in a research set(cid:173)
`ting. In both instances, it is the patient who
`benefits. Such an approach can be formal(cid:173)
`ized in the practice setting by performing
`randomized, controlled trials in individual
`patients who have stable clinical symptom(cid:173)
`atology. With this strategy a specific ther-
`
`Page 8
`
`

`

`INDIVIDUALIZATION OF DRUG THERAPY
`
`65
`
`apy of uncertain efficacy can be compared
`with a placebo or alternative therapy in a
`double-blind design with well-defined end
`points that are tailored to the individual pa(cid:173)
`tient. The outcome of such a trial is imme(cid:173)
`diately relevant to the particular patient,
`although it may not apply to all other pa(cid:173)
`tients (Guyatt et al., 1986).
`
`INDIVIDUALIZATION OF DRUG
`THERAPY
`
`As has been implied above, therapy as a
`science does not apply simply to the evalu(cid:173)
`ation and testing of new, investigational
`drugs in animals and man. It applies with
`equal importance to the treatment of each
`patient as an individual. Therapists of every
`type have long recognized and acknowl(cid:173)
`edged that individual patients show wide
`variability in response to the same drug or
`treatment method. Progress has been made
`in identifying the sources of variability
`(Vesell, 1986). Important factors are pre(cid:173)
`sented in Figure 4-1; the basic principles
`that underlie these sources of variability
`have been presented in Chapters 1 and 2.
`
`PRESCRIBED
`
`DOSE j
`
`ADMINISTERED
`DOSE
`
`CONCENTRATION
`AT LOCUS
`OF ACTION
`
`• patient compliance
`• medication errors
`
`• rote and extent of absorption
`• body size and composition
`• distribution in body fluids
`• binding in plasma and tissues
`•rote of elimination
`
`\
`
`•physiolo<;lical variables
`•pathological factors
`•genetic factors
`
`•development of tolerance
`
`( • interaction with other drugs
`
`•drug-receptor interaction
`• functional state
`• placebo effects
`
`INTENSITY
`OF EFFECT
`
`Figure 4-1. Factors that determine the rela(cid:173)
`tionship between prescribed drug dosage and
`(Modified from Koch-Weser,
`drug effect.
`1972.)
`
`The following discussion relates to the
`strategies that have been developed to deal
`with variability in the clinical setting. (See
`also Appendix II.)
`
`PHARMACOKINETIC CONSIDERATIONS
`Interpatient and intrapatient variation in
`disposition of a drug must be taken into
`account in choosing a drug regimen. For a
`given drug, there may be wide variation in
`its pharmacokinetic properties among indi(cid:173)
`viduals. For some drugs, this variability
`may account for one half or more of the
`total variation in eventual response. The
`relative importance of the many factors that
`contribute to these differences depends in
`part on the drug itself and on its usual route
`of elimination. Drugs that are excreted pri(cid:173)
`marily unchanged by the kidney tend to
`have smaller differences
`in disposition
`among patients with similar renal function
`than do drugs that are inactivated by me(cid:173)
`tabolism. Of drugs that are extensively me(cid:173)
`tabolized, those with high metabolic clear(cid:173)
`ance and large first-pass elimination have
`marked differences
`in bioavailability,
`whereas those with slower biotransforma(cid:173)
`tion tend to have the largest variation in
`elimination
`rates between
`individuals.
`Studies in identical and nonidentical twins
`have revealed that genotype is a very im(cid:173)
`portant determinant of differences in the
`rates of metabolism (Penno and Vesell,
`1983). For many drugs, physiological and
`pathological variations in organ function
`are major determinants of their rate of dis(cid:173)
`position. For example, the clearance of di(cid:173)
`goxin and gentamicin is related to the rate
`of glomerular filtration, whereas that of lid(cid:173)
`ocaine and propranolol is primarily depen(cid:173)
`dent on the rate of hepatic blood flow. The
`effect of aging and diseases that involve the
`kidneys or liver is to impair elimination and
`to increase the variability in the disposition
`of drugs. In such settings, measurements of
`concentrations of drugs in biological fluids
`can be used to assist in the individualization
`of drug therapy (Spector et al., 1988). Since
`old age and renal or hepatic diseases may
`also affect the responsiveness of target tis(cid:173)
`sues (e.g., the brain), the physician should
`be alert to the possibility of a shift in the
`range of therapeutic concentrations.
`
`Page 9
`
`

`

`66
`
`PRINCIPLES OF THERAPEUTICS
`
`[Chap. 4]
`
`A test should not be performed simply
`because an assay is available. More assays
`of drugs are available than are generally
`useful. Determinations of concentrations of
`drug in blood, serum, or plasma are particu(cid:173)
`larly useful when well-defined criteria are
`fulfilled. (1) There must be a demonstrated
`relationship between the concentration of
`the drug in plasma and the eventual thera(cid:173)
`peutic effect that is desired and/or the toxic
`effect that must be avoided. (2) There
`should be substantial interpatient variabil(cid:173)
`ity in- disposition of the drug (and small in(cid:173)
`trapatient variation). Otherwise, concentra(cid:173)
`tions of drug in plasma could be predicted
`adequately from dose alone. (3)It should be
`difficult to monitor intended or unintended
`effects of the drug. Whenever clinical ef(cid:173)
`fects or minor toxicity are easily measured
`(e.g., the effect of a drug on blood pres(cid:173)
`sure). such assessments should be pre(cid:173)
`ferred in the decision to make any neces(cid:173)
`sary adjustment of dosage of the drug.
`However, the effects of some drugs in cer(cid:173)
`tain settings are not easily monitored. For
`example, the effect of Li+ on manic(cid:173)
`depressive psychosis may be delayed and
`difficult to quantify. For ·some drugs, the
`initial manifestation of toxicity may be seri(cid:173)
`ous (e.g., digitalis-induced arrhythmias or
`theophylline-induced seizures). The same
`concepts apply to a number of agents used
`for cancer chemotherapy. Other drugs
`(e.g., antiarrhythmic agents) produce toxic
`effects that mimic symptoms or signs of the
`disease being treated. Many drugs are used
`for prophylaxis of an intermittent, potenti(cid:173)
`ally dangerous event; examples include an(cid:173)
`ticonvulsants and antiarrhythmic agents. In
`each of these situations, titration of drug
`dosage may be aided by measurements of
`concentrations of the drug in blood. (4) The
`concentration of drug required . to produce
`therapeutic effects should be close to the
`value that causes substantial toxicity (see
`below). If this circumstance does not apply,
`patients could simply be given the largest
`dose known to be necessary to treat a dis(cid:173)
`order, as is commonly done with penicillin.
`However, if there is an overlap in the con(cid:173)
`centration-response relationship for desir(cid:173)
`able and undesirable effects of the drug, as
`is true for theophylline, determinations of
`concentration of drug in plasma may allow
`
`the dose to be optimized. All four of the
`above-described ,-criteria should be met if
`the measurement of drug concentrations is
`to be of significant value in the adjustment
`of dosage. Knowledge of concentrations of
`drugs in plasma or urine is also particularly
`useful for- detection of therapeutic failures
`that are due to lack of patient compliance
`with a medical regimen or for identification
`of patients with unexpected extremes "in the
`rate of drug disposition.
`Assay of drugs to assist the physician in
`achieving a desired concentration of drug in
`_
`blood or plasma (i.e., "targeting" the dose)
`is an example of the use of an· inter_mediate __ __
`end point of therapy. An intermediate end
`point is defined as a specific goal of treat(cid:173)
`ment that is used in place of the ultimate
`clinical goal, which may be difficult to as(cid:173)
`sess. The concept of intermediate end
`points, including concentrations of drugs,
`as a. guide to indivi<;Iualization of therapy
`can also be applied in other ways; one is to
`provide an indication for a change in the
`choice of drug therapy. Measurements of
`concentrations of drugs in plasma and/or
`measurements of one or more pharmaco(cid:173)
`logical effects of the drug can provide an
`indication of probable lack of efficacy.
`Other issues of importance with regard to
`the measurement and interpretation of drug
`concentrations are discussed in Chapter 1
`and Appendix II.
`
`PHARMACODYNAMIC. CON SID ERA TIONS
`Considerable interindividual variation in
`the response to drugs remains after the con(cid:173)
`centration of the drug in plasma has been
`adjusted to a target value; for some drugs
`this pharmacodynamic variability accounts
`for much of the total variation in respon(cid:173)
`siveness between· patients. As discussed in
`Chapter 2, the relationship between the
`concentration of a drug and the magnitude
`of the observed response may be complex,
`even when responses are measured in sim(cid:173)
`plified systems in vitro, although typical
`sigmoidal concentration-effect curves are
`usually seen (Figure 2-6). When- drugs are
`administered to patients, however, there is
`no single characteristic relationship be(cid:173)
`tween the drug concentration in plasma and
`the measured effect; the concentration-
`
`Page 10
`
`

`

`INDIVIDUALIZATION OF DRUG THERAPY
`
`67
`
`effect curve may be concave upward, con(cid:173)
`cave downward, linear, or sigmoid. More(cid:173)
`over, the concentration-effect relationship
`maY be distorted if the response being mea(cid:173)
`sured is a composite of several effects, such
`as the change in blood pressure produced
`by a combination of cardiac, vascular, and
`reflex effects. However, such a composite
`concentration-effect ·curve can often be
`resolved into simpler curves for- each of its
`components. These simplified concentra(cid:173)
`tion-effect relationships, regardless of their
`exact shape, can be viewed as having four
`characteristic variables: potency, slope,
`maximal efficacy, and individual variation.
`These are illustrated in Figure 4-2 for the
`common sigmoid log dose-effect curve.
`
`Potency. The location of the concentra(cid:173)
`tion-effect curve ·along the ·concentration
`axis is an expression of the potency of q.
`drug. Although often related to the dose of
`a drug required to produce an effect, PO-:(cid:173)
`tency is more properly related to the con(cid:173)
`centration of the drug in plasma in order to
`approximate more closely the situation in
`isolated systems in vitro and to avoid the
`complicating factors of pharmacokinetic
`variables. Although potency obviously af(cid:173)
`fects drug dosage, potency per se is rela(cid:173)
`tively unimportant in the clinical use of
`drugs as long as the required dose can be
`given conveniently. There is no justifica(cid:173)
`tion for the view that more potent drugs are
`supenor therapeutic agents. However, if
`
`lL.
`
`1-(cid:173)u w
`fu
`lL.
`0
`.>-
`1-(cid:173)
`Ci5
`z
`w
`~
`
`VARIABILITY
`
`POTENCY
`
`CONCENTRATION
`
`Figure· 4-2. The log dose-effect relationship.
`
`Representative log dose-effect curve, illus(cid:173)
`trating its four characterizing variables (see
`text for explanation).
`
`the drug is to be administered by transder(cid:173)
`mal ·a-bso.I:J2.!ion, a highly potent drug is re(cid:173)
`quired, sincethe capacity of the skin to ab(cid:173)
`sorb drugs is limited.
`
`Maximal Efficahy. The maximal effect
`that can be produced by a drug is its maxi-·
`mal efficacy ·or, simply, efficacy. As dis(cid:173)
`cussed in Chapter 2, maximal efficacy is
`determined by the properties of the drug
`and its receptor-effector system and is re(cid:173)
`flected in the plateau of the concentration(cid:173)
`effect curve. In clinical use, however, a
`drug's dosage may be limited by undesired
`effects, and the true maximal efficacy of the
`drug may not be achievabie. Efficacy of a
`drug is clearly a major characteristic-of
`much more clinical importance than is po(cid:173)
`tency; furthermore, the two properties are
`not related and should not be confused. For
`instance, although some thiazide diuretics
`have similar or greater potency than the
`loop diuretic furosemide, the maximal effi(cid:173)
`cacy of furosemide is ·considerably greater.
`
`Slope. The slope of the concentration~
`effect curve reflects the mechanism of
`action of a drug, including the shape of the
`curve that describes drug binding to its re(cid:173)
`ceptor (see Chapter 2). The steepness of the
`curve dictates the range of doses that are
`useful for achieving a clinical effect. Aside
`from this fact, the slope of the concentra(cid:173)
`tion-effect curve has more theoretical than
`practical usefulness.
`
`Biological Variability. Different individ(cid:173)
`uals vary in the magnitude of their response
`to the same concentration of a single drug
`or to similar drugs when the appropriate
`correction has been made for differences in
`potency, maximal- efficacy, and slope. In
`fact, a single individual may not always· re(cid:173)
`spond in the same way to the same concen(cid:173)
`tration of drug. A concentration-effect
`curve applies only to a single individual at
`one time or to an average individual. The
`intersecting brackets in Figure 4__,2 indicate
`that an effect of varying intensity will occur
`in different individuals at a specified con(cid:173)
`centration of a drug or that a range of con(cid:173)
`~entrations ··is required to produce an effect
`of specified intensity in all of the patients.
`
`Page 11
`
`

`

`68
`
`PRINCIPLES OF THERAPEUTICS
`
`[Chap. 4]
`
`Specific terms are used to refer to indi(cid:173)
`viduals who are unusually sensitive or re(cid:173)
`sistant to a drug and to describe those in
`whom the drug produces a qualitatively dif(cid:173)
`ferent effect. The mechanisms of these unu(cid:173)
`sual effects are described in general in this
`chapter and are discussed for individual
`drugs throughout this textbook. If a drug
`produces an effect at a very low dosage, the
`individual is said to be hyperreactive. (Hy(cid:173)
`persensitivity usually refers to effects asso(cid:173)
`ciated with drug allergy, and supersensitiv(cid:173)
`is used
`to describe the
`increased
`ity
`sensitivity that results from denervation or
`long-term treatment with a receptor antago(cid:173)
`nist.) Individuals who are resistant to drug
`effect are said to be hyporeactive. Toler(cid:173)
`ance connotes hyporeactivity acquired as a
`result of exposure to the drug, a