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 significantly altered. As explained in Chapter 3, 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 concentration, 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 declines with age for some, but not all, drugs. Animal studies and some clinical studies have suggested that certain drugs are metabolized more slowly
TABLE 60–1 Some changes related to aging that affect pharmacokinetics of drugs.
TABLE 60–2 Effects of age on hepatic clearance of some drugs.
in the elderly; some of these drugs are listed in Table 60–2. The greatest 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 (see Chapter 4). 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 ability 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. A decline in creatinine clearance (Clcr)—the usual measure of estimated glomerular filtration rate (eGFR)—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 creatinine 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 to estimate the GFR and multiplying the recommended young adult dosage by eGFR/100. The Cockcroft-Gault formula is applicable to patients age 40 through 80: