over several decades. Nevertheless, a balanced look at the role medications play in the health of the elderly requires consideration of such events, even though they may be identifiable only by the traces they leave in morbidity and mortality rates, rather than as observable entities in their own right.

There are important physiologic reasons why the role of medication increases (as does its potential for good or ill effect) throughout the second 50 years of life. First, in this part of the life cycle, illness occurs with increasing frequency, and such illness is often amenable to drug therapy. Less well understood are the ways in which the effects of medications are magnified by the physiology of even normal aging. There is a well-documented decrease in renal function with advancing age, which increases the effect of medications (e.g., digoxin, cimetidine, aminoglycosides) that are excreted primarily through the kidney.39 Although there is a clear age-related decline on average as people age, more recent research has made it clear that there is great interindividual variability in the pace with which such declines occur.28 This finding has important implications for the effect of medications on individual elderly patients: the older the patient, the less able the physician will be to predict the optimal dose of a medication on the basis of clinical judgment and routine laboratory tests alone. An even greater controversy surrounds the role of aging in the impairment of hepatic function, the other major route of elimination of drugs. Certain hepatic metabolic functions appear to diminish with age; they certainly do so in the face of illnesses that are more common in the elderly than in younger patients (e.g., congestive heart failure), thus decreasing the margin of safety for many medications.48

Other changes that occur in the second half of life also have profound implications for drug effects in the elderly. There is an age-related increase in the proportion of body weight that is fat as opposed to muscle, which tends to increase the half-life and steady-state concentration of lipophilic medications (such as the benzodiazepines) but has the reverse effect on polar drugs (such as lithium). There is also an inverse relationship between age and weight in the current American population. However, data indicate that physicians do not correct for such changes in determining the dose of several commonly used medications in the elderly, which results in the prescription of more milligrams per kilogram in elderly patients than in younger ones.15

Furthermore, research on changes in receptor physiology with age suggests that receptors for many commonly used medications may actually become more sensitive with advancing age, thus intensifying

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