Pharmacokinetics and Pharmacodynamics in Older Adults
Absorption and Distribution
Absorption changes are modest and rarely clinically decisive, though reduced gastric acidity, delayed gastric emptying, and first-pass variability matter for some agents. Distribution changes are more important: total body water falls, so hydrophilic drugs (gentamicin, lithium, alcohol) have smaller volumes of distribution and higher peak concentrations; body fat proportion rises, prolonging half-life of lipophilic drugs (diazepam, amiodarone, thiopental). Serum albumin often declines, increasing the free fraction of highly protein-bound acidic drugs such as warfarin and phenytoin - but measured total levels may understate free drug, so interpret unbound levels when available.
Metabolism and Elimination
Hepatic mass and blood flow decline, and phase I oxidative reactions (CYP450) slow more than phase II conjugation, though individual variability is large. The most reliable pharmacokinetic change is the age-related fall in glomerular filtration rate, roughly 1 mL/min/1.73 m2 per year after age 40, often with a normal-looking serum creatinine because muscle mass is reduced. Estimate creatinine clearance with Cockcroft-Gault for drug dosing; do not rely on serum creatinine alone.
Pharmacodynamics
Older adults show increased sensitivity to benzodiazepines, opioids, anticoagulants, and anticholinergics, and reduced beta-adrenergic responsiveness. Orthostasis, sedation, and bleeding risk rise disproportionately.
Traps
Stems often give a normal creatinine to lure you into standard dosing; another classic is attributing a fall or confusion to aging rather than to a lipophilic sedative accumulating. Remember that pharmacodynamic interactions can occur with normal kinetics.
Worked Example
A 78-year-old woman, weight 55 kg, serum creatinine 1.0 mg/dL. Cockcroft-Gault gives about (140−78)×55/(72×1.0) ≈ 47 mL/min, then ×0.85 for female sex ≈ 40 mL/min. Renally cleared drugs need dose adjustment despite the "normal" creatinine.