Adverse Drug Reaction Trajectories in Older Adults: From Pharmacological Vulnerability to Clinical Complexity

Background: Adverse drug reactions (ADRs) represent a major and often underestimated source of morbidity, hospitalization, and functional decline in older adults. The convergence of age-related pharmacokinetic and pharmacodynamic changes, multimorbidity, polypharmacy, and frailty creates a clinical environment in which ADR risk is not static but evolves along progressive trajectories—from mild, early manifestations toward severe, potentially irreversible outcomes. Understanding these trajectories is essential for rational geriatric prescribing. Methods: This narrative review synthesizes evidence from epidemiological studies, systematic reviews, Cochrane analyses, and clinical trials published between 2000 and 2025, focusing on adults aged 65 years and older with two or more chronic conditions. Sources were identified through a structured, non-systematic literature search of PubMed, EMBASE, Cochrane Library, Web of Science, and Scopus using the terms ‘adverse drug reactions’, ‘polypharmacy’, ‘multimorbidity’, ‘frailty’, ‘deprescribing’, and ‘pharmacokinetics’ in older adults, alone and in combination. Evidence quality was assessed narratively, distinguishing trial evidence from observational and expert consensus data. Results: ADRs in older adults are best classified using complementary frameworks—the augmented Type A to withdrawal Type E and failure-of-therapy Type F taxonomy (Types A–F), the Dose-Time-Susceptibility (DoTS) classification, and the EIDOS mechanistic scheme—which together capture the heterogeneity of drug-related harm in this population. Age-related pharmacokinetic changes (altered absorption, increased volume of distribution of lipophilic drugs, reduced hepatic and renal clearance) and pharmacodynamic shifts (heightened receptor sensitivity, baroreflex impairment, increased blood–brain barrier permeability) interact with polypharmacy and frailty to amplify ADR trajectories from mild to severe. Anticholinergic burden, prescribing cascades, and inappropriate polypharmacy function as structural accelerators of these trajectories. Medication review and deprescribing improve prescribing quality but evidence for hard outcome benefits remains of low to very low certainty. Emerging AI-enabled digital tools show promising accuracy for identifying frailty and pharmacological vulnerability, but this performance relates to frailty classification and has not yet been shown to prevent ADR trajectories; they require validation for routine clinical use. Conclusions: Recognizing ADRs in older adults as dynamic trajectories rather than isolated events repositions prescribing review and deprescribing from optional to essential clinical acts. An integrated approach combining pharmacological vigilance, comprehensive geriatric assessment, structured deprescribing, and emerging digital decision-support tools offers the most realistic pathway to reduce the trajectory-related burden of drug-related harm in complex older patients.