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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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