Pharmacokinetics

The time course by which the body absorbs, distributes, metabolizes, and excretes drugs.

Absorption: Despite an age-related decrease in small-bowel surface area and an increase in gastric pH, changes in drug absorption tend to be trivial and clinically inconsequential.

Distribution: Total body water decreases by 10 to 15% between ages 20 and 80 years. In contrast, the percentage of body weight that is body fat increases from 18 to 36% in men and from 33 to 45% in women. The relative decrease in total body water and thus in sodium space leads to higher blood (and often tissue) concentrations of some water-soluble drugs. Increased body fat increases the volume of distribution for lipophilic drugs and may result in increased elimination half-lives.

With age, serum albumin levels decrease slightly and ₁-acid glycoprotein levels increase, but the clinical effect of these changes on serum drug binding is unclear. In a patient with acute disease or malnutrition, rapid decreases in the serum albumin level may enhance drug effects because serum concentrations of unbound drug are increased until metabolic excretory compensation occurs.

Hepatic metabolism: With age, hepatic mass and hepatic blood flow decrease. Decreased hepatic blood flow significantly affects hepatic elimination of drugs in rare situations--eg, when a drug with high clearance, such as lidocaine, is given IV.

Although expression of drug-metabolizing enzymes in the cytochrome P-450 system does not appear to decrease with age, overall hepatic metabolism of many drugs by these enzymes is reduced. For drugs with reduced hepatic metabolism (see Table 6-2), clearance typically decreases 30 to 40%. Theoretically, maintenance drug doses should be reduced by the same percentage; however, the rate of hepatic metabolism of drugs can vary greatly from person to person, and individual titration is required.

In the elderly, presystemic (first-pass) metabolism of some oral drugs (eg, labetalol, propranolol, verapamil) is reduced, increasing their serum concentration and bioavailability. Consequently, initial doses of these drugs should be reduced by about 30%. However, presystemic metabolism of other metabolized drugs (eg, imipramine, amitriptyline, morphine, meperidine) is not reduced.

Hepatic clearance of drugs metabolized by the cytochrome P-450 system (phase I reactions)--eg, diazepam, amitriptyline, chlordiazepoxide--is often reduced in the elderly. Age less often has been shown to affect the clearance of drugs that are metabolized by glucuronate or sulfate conjugation (synthetic or phase II reaction), such as lorazepam, desipramine, and oxazepam.

Many drugs produce active metabolites in clinically relevant concentrations. Examples are some benzodiazepines (eg, diazepam, chlordiazepoxide), tertiary amine antidepressants (eg, amitriptyline, imipramine), antipsychotics (eg, chlorpromazine, thioridazine, risperidone), and opioid analgesics (eg, morphine, meperidine, propoxyphene). Accumulation of active metabolites (eg, N-acetylprocainamide, morphine-6-glucuronide) increases the risk of toxicity in the elderly due to age-related decreases in renal clearance, particularly in patients with renal disease, unless the maintenance doses are reduced.

Renal elimination: With age, renal mass and renal blood flow (mainly in the renal cortex) decrease significantly. After age 30, creatinine clearance decreases an average of 8 mL/min/1.73 m²/decade in about two thirds of persons but remains the same in the rest. However, serum creatinine levels may remain within normal limits because the elderly have less lean body mass and produce less creatinine. Decreases in tubular function parallel those in glomerular function.

These physiologic changes decrease renal elimination of drugs (see Table 6-2). Clinical implications depend on the contribution of renal elimination to total systemic elimination and on the drug's therapeutic index (ratio of the maximum tolerated dose to the minimum effective dose). Creatinine clearance (measured or estimated using computer programs or the Cockcroft-Gault formula) is used to guide drug dose. The Cockcroft-Gault formula uses the serum creatinine concentration to calculate creatinine clearance (Cl_creat):

For women, the calculated values are multiplied by 0.85.

Because renal function is dynamic, maintenance doses of drugs should be adjusted if a patient becomes acutely ill or dehydrated or has recently recovered from dehydration. Also, because renal function may continue to decline with age, the dose of drugs given long-term should be reviewed periodically.