Pharmacokinetics in Older Adults

Overall hepatic metabolism of many drugs through the cytochrome P-450 enzyme system decreases with age. For drugs with decreased hepatic metabolism (see table Effect of Aging on Metabolism and Elimination of Some Drugs), clearance typically decreases 30 to 40%. Theoretically, maintenance drug doses should be decreased by this percentage; however, rate of drug metabolism varies greatly from person to person, and dose adjustments should be individualized.

Hepatic clearance of drugs metabolized by phase I reactions (oxidation, reduction, hydrolysis—see table Common Substances That Interact With Cytochrome P-450 Enzymes) is more likely to be prolonged in older adults. Usually, age does not greatly affect clearance of drugs that are metabolized by conjugation and glucuronidation (phase II reactions).

Other factors can also influence hepatic metabolism of drugs being taken, including smoking, decreased hepatic blood flow in patients with heart failure, and taking drugs that induce or inhibit cytochrome P-450 metabolic enzymes.

One of the most important pharmacokinetic changes associated with aging is decreased renal elimination of drugs. After age 40, glomerular filtration rate (GFR) decreases an average of 8 mL/min/1.73 m²/decade (0.1 mL/sec/m²/decade); however, the age-related decrease varies substantially from person to person. Serum creatinine levels often remain within normal limits despite a decrease in glomerular filtration rate (GFR) because older adults generally have less muscle mass and are generally less physically active than younger adults and thus produce less creatinine. Maintenance of normal serum creatinine levels can mislead clinicians to assume those levels reflect normal kidney function. Decreases in tubular function with age parallel those in glomerular function.

These changes decrease renal elimination of many drugs (see table Effect of Aging on Metabolism and Elimination of Some Drugs). Clinical implications depend on the extent that renal elimination contributes to total systemic elimination and on the drug’s therapeutic index (ratio of maximum tolerated dose to minimum effective dose). Creatinine clearance (measured or estimated using computer programs or a formula, such as Cockcroft-Gault—see Evaluation of the Renal Patient: Creatinine clearance) is used to guide dosing for most drugs eliminated by the kidneys. The daily dose of drugs that rely heavily on renal elimination should be lower and/or the frequency of dosing should be decreased. Because renal function is dynamic, maintenance doses of drugs may need adjustment when patients become ill or dehydrated or have recently recovered from dehydration.