Geriatric Pharmacology

Pharmacokinetic Changes

Absorption is the parameter least altered by aging itself; gastric emptying and intestinal surface area change only modestly. Real-world absorption problems in older adults usually stem from comorbidity and drug interactions instead — reduced stomach acid from acid-suppressing therapy, altered motility from anticholinergic or opioid use, and feeding interactions layered on chronic conditions.

Distribution changes are more consistent and important: total body water declines and body fat rises with age, shifting volume of distribution in opposite directions across drug classes. Lipophilic drugs, such as many benzodiazepines and sedatives, find a larger fat compartment, extending half-life and sedation well beyond a younger adult's response to the same dose, while hydrophilic drugs face a smaller water compartment, yielding a higher initial concentration. Serum albumin also tends to fall with age, especially with frailty; for highly protein-bound drugs, this raises the free, active fraction, increasing toxicity risk even when total measured concentration looks unchanged.

Hepatic metabolism slows as liver mass and blood flow decline, reducing first-pass metabolism and overall clearance. The two phases are affected unequally: Phase I oxidation (largely cytochrome P450-mediated) is more vulnerable, while Phase II conjugation is relatively preserved. This is why certain benzodiazepines are comparatively safer in older adults — cleared by direct conjugation, they bypass the age-vulnerable oxidative pathway, so clearance stays predictable and metabolites do not accumulate as with oxidatively metabolized, long-acting agents.

Renal elimination shows the widest gap between appearance and reality. Glomerular filtration typically declines with age, reducing clearance of renally eliminated drugs. But serum creatinine, the routine marker of kidney function, comes from muscle metabolism, and older adults typically have less muscle mass — so they produce less of it even when true clearance is significantly reduced. A normal-looking creatinine can thus coexist with impaired elimination, so relying on it alone, instead of an estimate accounting for age, sex, and body composition, risks overestimating clearance.

Pharmacodynamic Changes

Aging also changes how sensitive receptors and regulatory systems are to a given drug concentration. The central nervous system becomes more sensitive to sedatives, opioids, and anticholinergics, so a dose a younger adult tolerates comfortably can cause confusion, sedation, or falls at an equivalent measured level. Anticholinergic effects deserve special attention because many drug classes carry some such activity and effects accumulate across a regimen, while older adults have less reserve to buffer the resulting confusion, constipation, retention, and dry mouth.

Cardiovascular reflexes are blunted too: the baroreceptor reflex, which normally corrects blood pressure on standing, responds more sluggishly with age, increasing orthostatic hypotension from antihypertensives, diuretics, and other vasoactive drugs — a major contributor to falls, which carry disproportionate fracture and independence-loss risk. Thermoregulation is similarly impaired, limiting compensation for drug effects on body temperature or heat and cold stress.

The Practical Framework

The Beers criteria, maintained by a geriatrics professional society, catalog medications potentially inappropriate for older adults because risks generally outweigh benefits in this population. Flagged categories commonly include first-generation antihistamines, long-acting benzodiazepines and other sedative-hypnotics, certain antipsychotics for dementia-related behavioral symptoms, muscle relaxants, and drugs with high anticholinergic burden. The criteria support clinical judgment rather than replace it.

A recurring hazard is the prescribing cascade: a side effect from an existing drug is misread as a new condition, prompting another prescription instead of reconsidering the original one. This compounds quickly in a patient already on multiple medications, adding risk without benefit and obscuring the real cause.

"Start low, go slow" reflects the realities above: lower starting doses and slower titration reduce accumulation and exaggerated effect. But excessive caution can itself undertreat serious problems such as pain, depression, and conditions needing anticoagulation, leaving patients to suffer preventable harm from the untreated disease. Good prescribing balances both risks rather than defaulting to withholding treatment.

Deprescribing — the deliberate, systematic review and discontinuation of medications that no longer offer net benefit — is an active clinical skill, not passive neglect, requiring an ongoing weigh-up of each drug's benefit against its accumulating risk, particularly for indications that may have resolved.

Adherence faces concrete barriers beyond willingness: cost, impaired vision that makes labels or similar pills hard to distinguish, reduced dexterity for handling tablets or bottles, cognitive changes affecting schedule tracking, and sheer regimen complexity. Improving adherence means addressing these obstacles directly.

Finally, medication review at every care transition — admission, discharge, a new facility, or a new prescriber — is among the highest-yield safety interventions, since transitions are exactly when drugs get added, duplicated, or lost without full reconciliation.