Vol. 7, Issue 2, Part E (2025)

Polypharmacy—commonly defined as the concurrent use of five or more medications—has become widespread among older adults due to increasing multimorbidity, advances in disease-specific therapies, and fragmented care delivery. Recent global meta-analyses estimate that roughly one in three to two in five older adults meet commonly used thresholds for polypharmacy, with hyperpolypharmacy (≥10 medications) present in a substantial minority of patients; prevalence varies by region, setting (community, outpatient, inpatient), and study definition. Polypharmacy increases the risk of clinically significant drug–drug interactions (DDIs), adverse drug events (ADEs), hospitalizations, cognitive impairment, falls, and mortality. Mechanistically, age-related pharmacokinetic and pharmacodynamic changes (reduced renal and hepatic clearance, altered body composition, increased sensitivity of target organs) compound risks from complex drug regimens. Observational and pharmacoepidemiologic studies report DDI prevalence estimates among older adults that range widely but consistently identify potentially clinically significant interactions in a notable proportion (often ~10–30% depending on the population and detection method). Key contributors include cardiovascular polytherapy (antiplatelets, anticoagulants, statins, antihypertensives), psychotropics (antidepressants, benzodiazepines, antipsychotics), analgesics (opioids, NSAIDs), and combinations involving enzyme inhibitors/inducers and narrow therapeutic index drugs. Tools such as the AGS Beers Criteria, STOPP/START, and electronic DDI-checkers help identify risky combinations; deprescribing interventions and pharmacist-led medication reconciliation reduce medication burden and some ADEs. However, evidence of sustained clinical benefit at scale remains mixed, and implementation barriers persist. This review synthesizes contemporary prevalence data, underlying mechanisms, clinical consequences, common problematic drug pairs, preventive strategies, and research gaps, and offers recommendations for clinicians and health systems to mitigate DDI risk in older adults.