Pathophysiology
Clinical meaning
Aging produces predictable changes in drug disposition that increase adverse drug reaction risk. Absorption: generally preserved, though delayed gastric emptying and reduced splanchnic blood flow may slow onset. Distribution: decreased total body water (10-15% reduction) increases concentration of hydrophilic drugs (digoxin, lithium, aminoglycosides); increased body fat (20-40% increase) prolongs half-life of lipophilic drugs (diazepam half-life extends from 20 to 90 hours); decreased albumin (by 15-20%) increases free fraction of highly protein-bound drugs (warfarin, phenytoin). Metabolism: hepatic volume decreases 25-35%, hepatic blood flow decreases 40%, and Phase I metabolism (CYP-mediated oxidation, reduction) declines significantly while Phase II metabolism (conjugation) is relatively preserved. This disproportionately affects drugs with high hepatic extraction ratios (propranolol, morphine, verapamil) and CYP-dependent prodrug activation. Elimination: GFR declines approximately 1 mL/min/year after age 40, with average GFR of 60-70 mL/min by age 80. Serum creatinine may be falsely normal due to decreased muscle mass - always calculate eGFR using CKD-EPI equation. Drugs requiring renal dose adjustment: gabapentin, pregabalin, metformin, DOACs, digoxin, lithium, allopurinol, enoxaparin.