`
`4
`
`PRINCIPLES OF THERAPEUTICS
`
`Alan S. Nies
`
`THERAPY AS A SCIENCE
`
`Over a century ago Claude Bernard for-
`malized criteria for gathering valid informa-
`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-
`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 to
`ethical standards of human experimenta-
`tion. “Experimentation” in human beings
`was precluded, and it was not generally
`conceded that every treatment by any phy-
`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-
`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-
`tional
`(nonexperimental)
`techniques that
`can greatly add to our knowledge of the ef-
`fects of drugs can be applied to all popula-
`tions (Sheiner and Benet, 1985; Whiting
`et a1., 1986). The fact that such observa-
`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.
`
`62
`
`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-
`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-
`nity to observe a response. It is now appre-
`ciated that clinical phenomena can be de-
`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-
`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-
`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-
`iological variables that change as a func-
`tion of time, size. and location of the infarc-
`tion. Failure to take all such variables into
`
`account
`neuver r.
`some pz
`avoidabl
`in reality
`native ti
`cacy or
`unrecogi
`ease or :
`trum of
`Therape
`groups 1
`Drognos
`A thir
`rect noti
`useless
`applicat
`icism is
`medicin
`without
`principh
`tion are
`need no
`concept
`advance
`makes <
`on the -
`tion. Tl
`nisms o
`the effe
`neverth
`therape
`tial sug
`cious if
`empiric
`the dru.
`Examp‘
`that ha‘
`clude t’
`thritis,
`rnias, a‘
`hyperte
`when r.
`vationa
`often rt
`or inva
`
`- Clini
`tific me
`exempt
`-executi
`the bar
`physici
`they be
`
`
`
`WCK1032
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`Page 1
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`
`
`Therapeutics as a
`‘tant barrier that
`t of therapeutics
`e been the belief
`diseases and in
`uncontrollable. If
`'ic method would
`idy of pharmaco-
`tics is the aspect
`t amenable to the
`since it involves
`ides an opportu-
`. It is now appre-
`mena can be de-
`itified with some
`» complex clinical
`discussed by
`
`aalization of ther-
`l overreliance on
`uels
`for disease.
`cian to think of a
`han dynamic,
`to
`me “label” as a
`a heterogeneous
`:r a disease as an
`tion about patho-
`.. If diseases are
`LIIllC, “standard"
`loses will be the
`will be reflexive.
`itude that makes
`for recognition of
`iges that occur in
`iderlying process
`term myocardial
`ed destruction of
`iv interruption of
`‘, decisions about
`:ount a variety of
`and electrophys-
`iange as a func-
`tion of the infarc-
`lCll variables into
`
`
`
`-.-.-.-.-.--—..-,_.._.,,,\.,,«.-.»-.,.7.,$3.»?
`
`
`
`
`
`THERAPY AS A SCIENCE
`
`63
`
`account while planning a therapeutic ma-
`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-
`native treatments, true differences in effi-
`cacy or toxicity between therapies may go
`unrecognized. A diagnosis or label of a dis-
`ease or syndrome usually indicates a spec-
`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-
`rect notion that data derived empirically are
`useless because they are not generated by
`application of the scientific method. Empir-
`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-
`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-
`tion. The results, even when the mecha-
`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-
`tial suggestion that a drug may be effica-
`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-
`clude the use of penicillamine to treat ar-
`thritis, lidocaine to treat cardiac arrhyth-
`mias, and propranolol and clonidine to treat
`hypertension. Conversely,
`empiricism,
`when not coupled with appropriate obser-
`vational methods and statistical techniques,
`often results in findings that are inadequate
`or invalid.
`
`Clinical Trials. Application of the scien-
`tific method to experimental therapeutics is
`exemplified by a well-designed and well-
`cxecuted 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-
`
`clusions of such trials critically. To maxi-
`mize the likelihood that useful information
`will result from the experiment, the objec-
`tives of the study must be defined, homoge-
`neous populations of patients must be se-
`lected, appropriate control groups must be
`found. meaningful and sensitive indices of
`drug effects must be chosen for observa-
`tion, and the observations must be con-
`verted into data and then into valid conclu-
`sions (Feinstcin, 1977). The sine qua non of
`any clinical trial is its controls. Many differ-
`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-
`ment as the selcction of the experimental
`group. Although the randomized, double-
`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-
`orders that occur rarely, disorders in pa-
`tients who cannot, by regulation or ethics
`or both, be studied (e.g., children, women
`of childbearing age, fetuses, or some pa-
`tients with psychiatric diseases). or dis-
`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-
`tive therapies. (l) Specific outcomes of therapy
`that are clinically relevant and quantifiable must be
`measured. (2) The accuracy of diagnosis and the
`severity oft/ie disease must be comparable in the
`groups being contrasted; otherwise, false-positive
`and false-negative errors may occur. (3) The dos-
`ages of the drugs must be chosen and individual-
`ized in a manner that allows relative efficacy to be
`compared at equivalent toxicities or allows relative
`toxicitics to be compared at equivalent efficacies.
`(4) Placebo effects, which occur in a large percent-
`age of patients, can confound many studies—
`particularly those that
`involve subjective re-
`sponses; controls must
`take this into account.
`However, subjective assessments are important in
`determining whether a therapy improves the pa-
`ticnt's well-being. In fact, quality of life can be as-
`sessed by the expcrimental subject and can be ob-
`jectively
`tabulated
`and
`incorporated
`into
`evaluation of a therapy (Williams, 1987). (5) Com-
`pliance with the experimental regimens should be
`assessed before subjects are assigned to experi-
`mental or control groups. The drug-taking behavior
`
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`
`64
`
`of the subjects should be reassessed during the
`course of the trial. Noncompliance, even if ran-
`domly distributed between both groups, may cause
`falsely low estimates of the true potential benefits
`or toxicity of a particular treatment. (6) Sample xize
`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-
`tors as the overall prognosis of the disease and the
`anticipated improvement
`in outcome or toxicity
`from the new treatment, very large numbers of sub-
`jects may be needed; otherwise, the possibility of a
`fa1se~negative result
`is high (1'.c., 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-
`uated explicitly (Rosner, 1987: Rothman, 1987).
`For example, in therapeutic trials that involve life-
`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-
`dard" therapies.
`
`The results of clinical trials of new thera-
`peutic agents or of old agents for new indi-
`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-
`tal trials usually eliminates those with coex-
`isting diseases, and such trials usually as-
`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-
`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-
`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-
`sults of a clinical trial to establish an experi-
`ment in each patient. The detection of an-
`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,
`
`PRINCIPLES OF THERAPEUTICS
`it may still be revealed in the setting of clin-
`ical practice. About one half or more of
`both useful and adverse effects of drugs
`that were not recognized in the initial for-
`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-
`ple, misdiagnosis, poor compliance by the
`patient to the regimen, poor choice of dos-
`age or dosage intervals, coincidental devel-
`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-
`tected genetic or environmental variables
`that modify the disease or the pharmacolog-
`ical actions of the drug, or unknown ther-
`apy by another physician who is caring for
`the same patient. Of equal
`importance,
`even when a regimen appears to be effica-
`cious and innocuous, a physician should
`not attribute all improvement to the thera-
`peutic regimen chosen, nor should a physi-
`cian assume that a deteriorating condition
`reflects only the natural course of the dis-
`ease. Similarly, if an anticipated untoward
`or toxic effect is not seen in a particular pa-
`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-
`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-
`ting. In both instances, it is the patient who
`benefits. Such an approach can be formal-
`ized in the practice setting by performing
`randomized, controlled trials in individual
`patients who have stable clinical symptom-
`atology. With this strategy a specific ther-
`
`[Chap. 4]
`
`am’ of unce
`with a plac
`double—blini
`points that
`tient. The c
`diately rele
`although it
`tients (Guy
`
`INDIVIDU1
`THERAPY
`
`As has b»
`science doe
`ation and
`drugs in at
`equal impo
`patient as a
`type have
`edged that
`variability
`treatment I
`in identify
`(Vesell, 19
`sented in 1
`that under
`have been
`
`PRESCRIBED
`DOSE
`
`V
`ADMINISTERE
`DOSE
`
`
`
`Y
`CONCENTRATN
`AT LOCUS
`OF ACTION
`
`7
`INTENSITY
`OF EFFECT
`
`Figure 4—I
`tionship b
`drug effe
`v 1972.)
`
`
`
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`
`65
`INDIVIDUALIZATION or DRUG THERAPY
`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-
`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-
`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-
`tabolism. Of drugs that are extensively me-
`tabolized, those with high metabolic clear-
`ance and large first-pass elimination have
`marked
`differences
`in
`bioavailability,
`whereas those with slower biotransforma-
`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-
`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-
`position. For example, the clearance of di-
`goxin and gentamicin is related to the rate
`of glomerular filtration, whereas that of lid-
`ocaine and propranolol is primarily depen-
`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-
`sues (e.g., the brain), the physician should
`be alert to the possibility of a shift in the
`range of therapeutic concentrations.
`
`WCK1032
`Page 4
`
`[Chap. 4]
`
`is bf clin-
`more of
`of drugs
`nitial for-
`iscovered
`:ians.
`drug has
`does not
`ur in that
`us in the
`to lack of
`for exam-
`.ce by the
`cc of dos-
`1taldevel—
`ate illness
`me use of
`1 primary
`cts, unde-
`variables
`.rmacolog-
`IOWII ther-
`caring for
`iportance,
`be effica-
`an should
`the thera-
`ld a physi-
`: condition
`of the dis-
`. untoward
`rticular pa-
`Physicians
`nce with a
`use unduly
`ible risk or
`lle, simply
`a case of
`:ic anemia
`n that such
`rug should
`zations.
`v based on
`2 been eval-
`:ial to have
`ment of an
`s approach
`search set-
`iatient who
`be formal-
`performing
`. individual
`I symptom-
`iecific ther-
`
`
`
`4-y;zv,—~:z«-.e~j~,-«,w--J.av-_~,
`
`
`
`
`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-
`tient. The outcome of such a trial is imme-
`diately relevant to the particular patient,
`although it may not apply to all other pa-
`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-
`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-
`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-
`sented in Figure 4-1; the basic principles
`that underlie these sources of variability
`have been presented in Chapters 1 and 2.
`
`PRESCRlBED
`DOSE
`
`'
`ADMINISTERED
`DOSE
`
`«patient compliance
`0 medication errors
`
`-rota and extent of absorption
`-body size and composition
`-distribution in body fluids
`oblnding in plasma and tissues
`-rate of elimination
`
`'
`CONCENTRA1-‘ON
`AT Locus
`of: lichen
`
`-physiological variables
`-pathological factors
`-genetic factors
`- interaction with other drugs
`-development of tolerance
`
`-drug-receptor interaction
`-functional slate
`
`- placebo effects
`
`*
`INTENSITY
`OF EFFECT
`
`Figure 4-1. Factors that determine the rela-
`tionship between prescribed drug dosage and
`drug effect.
`(Modified from Koch-Weser,
`1972.)
`
`WCK1032
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`
`
`
`66
`
`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-
`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-
`peutic effect that is desired and/or the toxic
`effect
`that must be avoided.
`(2) There
`should be substantial interpatient variabil-
`ity in disposition of the drug (and small in-
`trapatient variation). Otherwise, concentra-
`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-
`fects or minor toxicity are easily measured
`(e.g.,
`the effect of a drug on blood pres-
`sure), such assessments should be pre-
`ferred in the decision to make any neces-
`sary adjustment of dosage of the dmg.
`However, the effects of some drugs in cer-
`tain settings are not easily monitored. For
`example,
`the effect of Li+ on manic-
`depressive psychosis may be delayed and
`difficult to quantify. For some drugs, the
`initial manifestation of toxicity may be seri-
`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-
`ally dangerous event; examples include an-
`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-
`order, as is commonly done with penicillin.
`However, if there is an overlap in the con-
`centration—response relationship for desir-
`able and undesirable effects of the drug, as
`is true for theophylline, determinations of
`concentration of drug in plasma may allow
`
`[Chap. 4]
`
`PRINCIPLES or THERAPEUTICS
`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 extremesin 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 intermediate
`end point of therapy. An intermediate end
`point is defined as a specific goal of treat-
`ment that is used in place of the ultimate
`clinical goal. which may be difficult to as-
`sess. The concept of intermediate end
`points, including concentrations of drugs,
`as a guide to individualization 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-
`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 CONSIDERATIONS
`Considerable interindividual variation in
`the response to drugs remains after the con-
`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-
`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-
`plified systems in vizro, 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-
`tween the drug concentration in plasma and
`the measured effect;
`the concentration—
`
`effect
`cave c
`over,
`may b
`sured
`as the
`by a c
`reflex
`conce
`resolv
`compi
`tion—E
`exact
`charai
`maxin
`These
`comm
`
`Pots
`tion—<
`axis i:
`drug.
`a driu
`tency
`centre
`appro
`isolatt
`comp)
`varial
`
`fects
`tively
`drugs
`given
`tion f(
`super
`
`
`
`INTENSRTYV_OFEFFECT
`
`
`
`
`
`text
`
`
`
`WCK1032
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`
`INDIVIDUALIZATION or DRUG THERAPY
`
`67
`
`effect curve may be concave upward, con-
`cave downward, linear, or sigmoid. More-
`over. the concentration—effect relationship
`may be distorted if the response being mea-
`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-
`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-
`tion—effect curve along the concentration
`axis is an expression of the potency of a
`drug. Although often related to the dose of
`a drug required to produce an effect. po-
`tency is more properly related to the con-
`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-
`fects drug dosage, potency per se is rela-
`tively unimportant
`in the clinical use of
`drugs as long as the required dose can be
`given conveniently. There is no justifica-
`tion for the view that more potent drugs are
`superior therapeutic agents. However,
`if
`
`INTENSITYOFEFFECT
`
`MAXIMAL
`EFFECT
`
`VARIABILITY
`
`
`
`
`CONCENTRATION
`
`Figure 4-2. The log d0se—effect relationship.
`
`Representative log dose—effect curve, illus-
`trating its four characterizing variables (see
`text for explanation).
`
`the drug is to be administered by transder—
`mal absorption, a highly potent drug is re-
`quired, since the capacity of the skin to ab-
`sorb drugs is limited.
`
`Maximal Efficacy. The maximal effect
`that can be produced by a drug is its maxi-
`mal efficacy or, simply, efficacy. As dis-
`cussed in Chapter 2, maximal efficacy is
`determined by the properties of the drug
`and its receptor—effector system and is re-
`flected in the plateau of the concentration—
`effect curve. In clinical use, however, a
`drugs dosage may be limited by undesired
`effects, and the true maximal efficacy of the
`drug may not be achievable. Efficacy of a
`drug is clearly a major characteristic—of
`much more clinical importance than is po-
`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-
`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-
`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-
`tion—effect curve has more theoretical than
`practical usefulness.
`
`Biological Variability. Different individ-
`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-
`spond in the same way to the same concen-
`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-
`centration of a drug or that a range of con-
`centrations is required to produce an effect
`of specified intensity in all of the patients.
`
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`68
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`[Chap. 4]
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`PRINCIPLES OF TI-IERAPEUTICS
`that is influenced by both endogenous and
`exogenous factors (see Chapters 2 and 5).
`Concentration-Percent Curve.
`The
`concentration of a drug that produces a
`specified effect in a single patient is termed
`the individual effective concentration. This
`is a quanta] response, since the defined ef-
`fect is either present or absent. Individual
`effective concentrations are usually log-
`normally distributed, which means that a
`normal variation curve is the result of plot-
`ting the logarithms of the concentration
`against the frequency of patients achieving
`the defined effect (Figure 4—3A). A cumula-
`tive frequency distribution of individuals
`achieving the defined effect as a function of
`drug concentration is the concentration-
`percent curve or the qaantal concentration-
`effect curve. This curve resembles the sig-
`moid shape of the graded concentration-
`effect curve discussed above (Figure 4-2),
`but the slope of the concentration—percent
`curve is an expression of the pharmacody—
`namic variability in the population rather
`than an expression of the concentration
`range from a threshold to a maximal effect
`in the individual patient.
`The dose of a drug required to produce a
`specified effect in 50% of the population is
`the median effective dose, abbreviated as
`the ED5o (Figure 4-38). In preclinical stud-
`ies of drugs, the median lethal dose, as de-
`termined in experimental animals, is abbre-
`viated as LD5g. The ratio of the LD50 to the
`ED50 is an indication of the therapeutic
`index, which is a statement of how selective
`the drug is in producing its desired effects.
`In clinical studies, the dose, or preferably
`the concentration, of a drug required to
`produce toxic effects can be compared to
`the concentration required for the thera-
`peutic effects in the population in order to
`evaluate the clinical
`therapeutic index.
`However, since pharmacodynamic varia-
`tion in the population may be marked, the
`concentration or dose of drug required to
`produce a therapeutic effect in most of the
`population will usually overlap the concen-
`tration required to produce toxicity in some
`of the population, even though the drug’s
`therapeutic index may be large. Also, the
`concentration—percent curves for efficacy
`and toxicity need not be parallel, adding yet
`
`Specific terms are used to refer to indi-
`viduals who are unusually sensitive or re-
`sistant to a drug and to describe those in
`whom the drug produces a qualitatively dif-
`ferent effect. The mechanisms of these unu-
`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-
`persensitivity usually refers to effects asso-
`ciated with drug allergy, and supersensitiv-
`ity is used to describe the increased
`sensitivity that results from denervation or
`long-term treatment with a receptor antago-
`nist.) Individuals who are resistant to drug
`effect are said to be hyporeactive. Toler-
`ance connotes hyporeactivity acquired as a
`result of exposure to the drug, and if toler-
`ance develops rapidly, it is called tachyphy-
`laxis. Idiosyncrasy is a term that describes
`an unusual effect of the drug, irrespective
`of intensity or dosage, that occurs in a small
`percentage of the population. However,
`because this term is often confused with
`drug allergy and because it conveys no use-
`ful information, it should probably be aban-
`doned in favor of simple descriptions of the
`effect and terms that refer to the underlying
`mechanisms, w