Pharmacologic Changes Associated With Aging

PHARMACOLOGIC CHANGES ASSOCIATED WITH AGING

In the general population, measurements of functional capacity of most of the major organ systems show a decline beginning in young adulthood and continuing throughout life. As shown in Figure 60–1, there is no “middle-age plateau” but rather a linear decrease beginning no later than age 45. However, these data reflect the mean and do not apply to every person above a certain age; approximately one third of healthy subjects have no age-related decrease in, for example, creatinine clearance up to the age of 75. Thus, the elderly do not lose specific functions at an accelerated rate compared with young and middle-aged adults but rather accumulate more deficiencies with the passage of time. Some of these changes result in altered pharmacokinetics. For the pharmacologist and the clinician, the most important of these is the decrease in renal func-tion. Other changes and concurrent diseases may alter the pharma-codynamic characteristics of particular drugs in certain patients.

Pharmacokinetic Changes

A. Absorption

There is little evidence of any major alteration in drug absorption with age. However, conditions associated with age may alter the rate at which some drugs are absorbed. Such conditions include altered nutritional habits, greater consumption of nonprescription drugs (eg, antacids and laxatives), and changes in gastric emptying, which is often slower in older persons, especially in older diabetics.

B. Distribution

Compared with young adults, the elderly have reduced lean body mass, reduced body water, and increased fat as a percentage of body mass. Some of these changes are shown in Table 60–1. There is usually a decrease in serum albumin, which binds many drugs, especially weak acids. There may be a concurrent increase in serum orosomucoid (α-acid glycoprotein), a protein that binds many basic drugs. Thus, the ratio of bound to free drug may be signifi-cantly altered. As explained, these changes may alter the appropriate loading dose of a drug. However since both the clearance and the effects of drugs are related to the free concentra-tion, the steady-state effects of a maintenance dosage regimen should not be altered by these factors alone. For example, the loading dose of digoxin in an elderly patient with heart failure should be reduced (if used at all) because of the decreased apparent volume of distribution. The maintenance dose may have to be reduced because of reduced clearance of the drug.

C. Metabolism

The capacity of the liver to metabolize drugs does not appear to decline consistently with age for all drugs. Animal studies and some clinical studies have suggested that certain drugs are metabolized more slowly; some of these drugs are listed in Table 60–2. 

The great-est changes are in phase I reactions, ie, those carried out by microsomal P450 systems. There are much smaller changes in the ability of the liver to carry out conjugation (phase II) reactions . Some of these changes may be caused by decreased liver blood flow (Table 60–1), an important variable in the clearance of drugs that have a high hepatic extraction ratio. In addition, there is a decline with age of the liver’s ability to recover from injury, eg, that caused by alcohol or viral hepatitis. 

Therefore, a history of recent liver disease in an older person should lead to caution in dosing with drugs that are cleared primarily by the liver, even after apparently complete recovery from the hepatic insult. Finally, malnutrition and diseases that affect hepatic function—eg, heart failure—are more common in the elderly. Heart failure may dramatically alter the abil-ity of the liver to metabolize drugs by reducing hepatic blood flow. Similarly, severe nutritional deficiencies, which occur more often in old age, may impair hepatic function.

D. Elimination

Because the kidney is the major organ for clearance of drugs from the body, the age-related decline of renal functional capacity is very important. The decline in creatinine clearance occurs in about two thirds of the population. It is important to note that this decline is not reflected in an equivalent rise in serum creati-nine because the production of creatinine is also reduced as muscle mass declines with age; therefore, serum creatinine alone is not an adequate measure of renal function. The practical result of this change is marked prolongation of the half-life of many drugs, and the possibility of accumulation to toxic levels if dosage is not reduced in size or frequency. Dosing recommendations for the elderly often include an allowance for reduced renal clearance. If only the young adult dosage is known for a drug that requires renal clearance, a rough correction can be made by using the Cockcroft-Gault formula, which is applicable to patients fromages 40 through 80:

For women, the result should be multiplied by 0.85 (because of reduced muscle mass). It must be emphasized that this estimate is, at best, a population estimate and may not apply to a particular patient. If the patient has normal renal function (up to one third of elderly patients), a dose corrected on the basis of this estimate will be too low—but a low dose is initially desirable if one is uncertain of the renal function in any patient. If a precise measure is needed, a standard 12- or 24-hour creatinine clearance determi-nation should be obtained. As indicated above, nutritional changes alter pharmacokinetic parameters. A patient who is severely dehydrated (not uncommon in patients with stroke or other motor impairment) may have an additional marked reduc-tion in renal drug clearance that is completely reversible by rehydration.

The lungs are important for the excretion of volatile drugs. As a result of reduced respiratory capacity (Figure 60–1) and the increased incidence of active pulmonary disease in the elderly, the use of inhalation anesthesia is less common and parenteral agents more common in this age group.

Pharmacodynamic Changes

It was long believed that geriatric patients were much more “sensitive” to the action of many drugs, implying a change in the pharmacodynamic interaction of the drugs with their receptors. It is now recognized that many—perhaps most—of these appar-ent changes result from altered pharmacokinetics or diminished homeostatic responses. Clinical studies have supported the idea that the elderly are more sensitive to some sedative-hypnotics and analgesics. In addition, some data from animal studies suggest actual changes with age in the characteristics or numbers of a few receptors. The most extensive studies suggest a decrease in responsiveness to β-adrenoceptor agonists. Other examples are discussed below.

Certain homeostatic control mechanisms appear to be blunted in the elderly. Since homeostatic responses are often important components of the overall response to a drug, these physiologic alterations may change the pattern or intensity of drug response. In the cardiovascular system, the cardiac output increment required by mild or moderate exercise is successfully provided until at least age 75 (in individuals without obvious cardiac dis-ease), but the increase is the result primarily of increased stroke volume in the elderly and not tachycardia, as in young adults. Average blood pressure goes up with age (in most Western coun-tries), but the incidence of symptomatic orthostatic hypotension also increases markedly. It is thus particularly important to check for orthostatic hypotension on every visit. Similarly, the average 2-hour postprandial blood glucose level increases by about 1 mg/dL for each year of age above 50. Temperature regulation is also impaired, and hypothermia is poorly tolerated by the elderly.

Behavioral & Lifestyle Changes

Major changes in the conditions of daily life accompany the aging process and have an impact on health. Some of these (eg, forget-ting to take one’s pills) are the result of cognitive changes associ-ated with vascular or other pathology. Others relate to economic stresses associated with greatly reduced income and, possibly, increased expenses due to illness. One of the most important changes is the loss of a spouse.