Variation in Drug Responsiveness
Individuals
may vary considerably in their response to a drug; indeed, a single individual
may respond differently to the same drug at different times during the course
of treatment. Occasionally, individuals exhibit an unusual or idiosyncratic drug response, one that
is infrequently observed in most patients. The idiosyn-cratic responses are
usually caused by genetic differences in metabolism of the drug or by
immunologic mechanisms, includ-ing allergic reactions.
Quantitative
variations in drug response are in general more common and more clinically
important. An individual patient is hyporeactive
or hyperreactive to a drug in
that the intensity ofeffect of a given dose of drug is diminished or increased
compared with the effect seen in most individuals. (Note: The term hypersen-sitivity
usually refers to allergic or other immunologic responses todrugs.) With
some drugs, the intensity of response to a given dose may change during the
course of therapy; in these cases, responsive-ness usually decreases as a
consequence of continued drug adminis-tration, producing a state of relative tolerance to the drug’s effects. When
responsiveness diminishes rapidly after administration of a drug, the response
is said to be subject to tachyphylaxis.
Even
before administering the first dose of a drug, the pre-scriber should consider
factors that may help in predicting the direction and extent of possible
variations in responsiveness. These include the propensity of a particular drug
to produce tolerance or tachyphylaxis as well as the effects of age, sex, body
size, disease state, genetic factors, and simultaneous administration of other
drugs.
Four
general mechanisms may contribute to variation in drug responsiveness among
patients or within an individual patient at different times.
Patients
may differ in the rate of absorption of a drug, in distribut-ing it through
body compartments, or in clearing the drug from the blood . By altering the
concentration of drug that reaches relevant receptors, such pharmacokinetic
differences may alter the clinical response. Some differences can be predicted
on the basis of age, weight, sex, disease state, and liver and kidney function,
and by testing specifically for genetic differences that may result from
inheritance of a functionally distinctive comple-ment of drug-metabolizing
enzymes. Another important mechanism influencing drug availability is active
transport of drug from the cytoplasm, mediated by a family of membrane
transporters encoded by the so-called multidrug resistance (MDR) genes. For example, up-regulation
of MDR gene-encoded transporter
expression is a major mechanism by which tumor cells develop resistance to
anticancer drugs.
This
mechanism contributes greatly to variability in responses to pharmacologic
antagonists. Thus, propranolol, a β-adrenoceptor antagonist, markedly slows the
heart rate of a patient whose endogenous catecholamines are elevated (as in
pheochromocy-toma) but does not affect the resting heart rate of a well-trained
marathon runner. A partial agonist may exhibit even more dra-matically
different responses: Saralasin, a weak partial agonist at angiotensin II
receptors, lowers blood pressure in patients with hypertension caused by
increased angiotensin II production and raises blood pressure in patients who
produce normal amounts of angiotensin.
Experimental
studies have documented changes in drug response caused by increases or
decreases in the number of receptor sites or by alterations in the efficiency
of coupling of receptors to distal effector mechanisms. In some cases, the
change in receptor num-ber is caused by other hormones; for example, thyroid
hormones increase both the number of β receptors in rat heart muscle and cardiac
sensitivity to catecholamines. Similar changes probably contribute to the
tachycardia of thyrotoxicosis in patients and may account for the usefulness of
propranolol, a β-adrenoceptor
antagonist, in ameliorating symptoms of this disease.
In
other cases, the agonist ligand itself induces a decrease in the number (eg,
down-regulation) or coupling efficiency (eg, desensiti-zation) of its
receptors. These mechanisms (discussed previously under Signaling Mechanisms
& Drug Actions) may contribute to two clinically important phenomena:
first, tachyphylaxis or toler-ance to the effects of some drugs (eg, biogenic
amines and their congeners), and second, the “overshoot” phenomena that follow
withdrawal of certain drugs. These phenomena can occur with either agonists or
antagonists. An antagonist may increase the number of receptors in a critical
cell or tissue by preventing down-regulation caused by an endogenous agonist.
When the antagonist is withdrawn, the elevated number of receptors can produce
an exaggerated response to physiologic concentrations of agonist. Potentially
disastrous withdrawal symptoms can result for the oppo-site reason when
administration of an agonist drug is discontinued. In this situation, the number
of receptors, which has been decreased by drug-induced down-regulation, is too
low for endogenous ago-nist to produce effective stimulation. For example, the
withdrawal of clonidine (a drug whose α2-adrenoceptor agonist activity reduces blood
pressure) can produce hypertensive crisis, probably because the drug
down-regulates α2 adrenoceptors .
Genetic
factors also can play an important role in altering the number or function of
specific receptors. For example, a specific genetic variant of the α2C adrenoceptor—when
inherited together with a specific variant of the α1 adrenoceptor—confers increased risk for
developing heart failure, which may be reduced by early intervention using
antagonist drugs. The identification of such genetic factors, part of the rapidly
developing field of pharmaco-genetics, holds promise for clinical diagnosis and
in the future may help physicians design the most appropriate pharmacologic
therapy for individual patients.
Another
interesting example of genetic determination of effects on drug response is
seen in the treatment of cancers involving excessive growth factor signaling.
Somatic mutations affecting the tyrosine kinase domain of the epidermal growth
factor receptor confer enhanced sensitivity to kinase inhibitors such as gefitinib
in certain lung cancers. This effect enhances the antineoplastic effect of the
drug and, because the somatic mutation is specific to the tumor and not present
in the host, the therapeutic index of these drugs can be significantly enhanced
in patients whose tumors harbor such mutations.
Although
a drug initiates its actions by binding to receptors, the response observed in
a patient depends on the functional integrity of biochemical processes in the
responding cell and physiologic regulation by interacting organ systems.
Clinically, changes in these postreceptor processes represent the largest and
most impor-tant class of mechanisms that cause variation in responsiveness to
drug therapy.
Before
initiating therapy with a drug, the prescriber should be aware of patient
characteristics that may limit the clinical response. These characteristics
include the age and general health of the patient and—most importantly—the
severity and pathophysio-logic mechanism of the disease. The most important
potential cause of failure to achieve a satisfactory response is that the
diag-nosis is wrong or physiologically incomplete. Drug therapy is always most
successful when it is accurately directed at the pathophysiologic mechanism
responsible for the disease.
When
the diagnosis is correct and the drug is appropriate, an unsatisfactory
therapeutic response can often be traced to com-pensatory mechanisms in the
patient that respond to and oppose the beneficial effects of the drug.
Compensatory increases in sym-pathetic nervous tone and fluid retention by the
kidney, for example, can contribute to tolerance to antihypertensive effects of
a vasodilator drug. In such cases, additional drugs may be required to achieve
a useful therapeutic result.
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