{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T10:46:00Z","timestamp":1782816360562,"version":"3.54.5"},"reference-count":31,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T00:00:00Z","timestamp":1782691200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJERPH"],"abstract":"<jats:p>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\u2014from 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 \u2018adverse drug reactions\u2019, \u2018polypharmacy\u2019, \u2018multimorbidity\u2019, \u2018frailty\u2019, \u2018deprescribing\u2019, and \u2018pharmacokinetics\u2019 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\u2014the augmented Type A to withdrawal Type E and failure-of-therapy Type F taxonomy (Types A\u2013F), the Dose-Time-Susceptibility (DoTS) classification, and the EIDOS mechanistic scheme\u2014which 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\u2013brain 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.<\/jats:p>","DOI":"10.3390\/ijerph23070849","type":"journal-article","created":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T10:01:17Z","timestamp":1782813677000},"page":"849","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Adverse Drug Reaction Trajectories in Older Adults: From Pharmacological Vulnerability to Clinical Complexity"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5287-9972","authenticated-orcid":false,"given":"Fulvio","family":"Lauretani","sequence":"first","affiliation":[{"name":"Geriatric Clinic Unit, University-Hospital of Parma, 43124 Parma, Italy"},{"name":"Department of Medicine and Surgery, University of Parma, 43124 Parma, Italy"},{"name":"Interdepartmental Centre for Sleep Medicine, University of Parma, 43124 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Crescenzo","family":"Testa","sequence":"additional","affiliation":[{"name":"Geriatric Clinic Unit, University-Hospital of Parma, 43124 Parma, Italy"},{"name":"Department of Medicine and Surgery, University of Parma, 43124 Parma, Italy"},{"name":"Interdepartmental Centre for Sleep Medicine, University of Parma, 43124 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6798-2948","authenticated-orcid":false,"given":"Marco","family":"Salvi","sequence":"additional","affiliation":[{"name":"Geriatric Clinic Unit, University-Hospital of Parma, 43124 Parma, Italy"},{"name":"Department of Medicine and Surgery, University of Parma, 43124 Parma, Italy"},{"name":"Interdepartmental Centre for Sleep Medicine, University of Parma, 43124 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7048-080X","authenticated-orcid":false,"given":"Irene","family":"Zucchini","sequence":"additional","affiliation":[{"name":"Geriatric Clinic Unit, University-Hospital of Parma, 43124 Parma, Italy"},{"name":"Department of Medicine and Surgery, University of Parma, 43124 Parma, Italy"},{"name":"Interdepartmental Centre for Sleep Medicine, University of Parma, 43124 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-3584-4754","authenticated-orcid":false,"given":"Aurora","family":"Merolla","sequence":"additional","affiliation":[{"name":"Vita-Salute San Raffaele University, 20100 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrizia","family":"Rovere-Querini","sequence":"additional","affiliation":[{"name":"Vita-Salute San Raffaele University, 20100 Milan, Italy"},{"name":"Department of Medicine, IRCCS San Raffaele Hospital, 20100 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcello","family":"Maggio","sequence":"additional","affiliation":[{"name":"Geriatric Clinic Unit, University-Hospital of Parma, 43124 Parma, Italy"},{"name":"Department of Medicine and Surgery, University of Parma, 43124 Parma, Italy"},{"name":"Interdepartmental Centre for Sleep Medicine, University of Parma, 43124 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"GBD 2019 Ageing Collaborators (2022). Global, regional, and national burden of diseases and injuries for adults 70 years and older: Systematic analysis for the Global Burden of Disease 2019 Study. BMJ, 376, e068208.","DOI":"10.1136\/bmj-2021-068208"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e161","DOI":"10.1016\/S2666-7568(24)00007-2","article-title":"Prevalence of multimorbidity and polypharmacy among adults and older adults: A systematic review","volume":"5","author":"Nicholson","year":"2024","journal-title":"Lancet Healthy Longev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1007\/s40266-025-01208-2","article-title":"Drugs and Healthy Aging","volume":"42","author":"Hilmer","year":"2025","journal-title":"Drugs Aging."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1007\/s41999-021-00481-9","article-title":"Adverse drug reactions in older adults: A narrative review of the literature","volume":"12","author":"Zazzara","year":"2021","journal-title":"Eur. Geriatr. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2002","DOI":"10.1056\/NEJMsa1103053","article-title":"Emergency hospitalizations for adverse drug events in older Americans","volume":"365","author":"Budnitz","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"B\u0142eszy\u0144ska, E., Wierucki, \u0141., Zdrojewski, T., and Renke, M. (2020). Pharmacological Interactions in the Elderly. Medicina, 56.","DOI":"10.3390\/medicina56070320"},{"key":"ref_7","unstructured":"Davies, D.M. (1977). Pathogenesis of adverse drug reactions. Textbook of Adverse Drug Reactions, Oxford University Press."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1222","DOI":"10.1136\/bmj.327.7425.1222","article-title":"Joining the DoTS: New approach to classifying adverse drug reactions","volume":"327","author":"Aronson","year":"2003","journal-title":"BMJ"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1111\/bcp.12596","article-title":"Adverse drug reactions in special populations\u2014The elderly","volume":"80","author":"Davies","year":"2015","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1","DOI":"10.12968\/hmed.2024.0388","article-title":"Polypharmacy in Older Patients","volume":"85","author":"Woodford","year":"2024","journal-title":"Br. J. Hosp. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1778","DOI":"10.1016\/S0140-6736(17)31188-1","article-title":"The prescribing cascade revisited","volume":"389","author":"Rochon","year":"2017","journal-title":"Lancet"},{"key":"ref_12","first-page":"CD015405","article-title":"Anticholinergic deprescribing interventions for reducing risk of cognitive decline or dementia in older adults with and without prior cognitive impairment","volume":"12","author":"Alharthi","year":"2023","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1585","DOI":"10.1017\/S1041610217000916","article-title":"Detecting delirium superimposed on dementia: Diagnostic accuracy of a simple combined arousal and attention testing procedure","volume":"29","author":"Richardson","year":"2017","journal-title":"Int. Psychogeriatr."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1017\/S1041610219001595","article-title":"A short delirium caregiver questionnaire for triage of elderly outpatients with cognitive impairment: A development and test accuracy study","volume":"33","author":"Luijendijk","year":"2021","journal-title":"Int. Psychogeriatr."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1001\/archinte.167.8.781","article-title":"A drug burden index to define the functional burden of medications in older people","volume":"167","author":"Hilmer","year":"2007","journal-title":"Arch. Intern. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3627","DOI":"10.1093\/eurheartj\/ehad195","article-title":"2023 Focused Update of the 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure","volume":"44","author":"McDonagh","year":"2023","journal-title":"Eur. Heart J."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e364","DOI":"10.1161\/STR.0000000000000375","article-title":"2021 Guideline for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack: A Guideline From the American Heart Association\/American Stroke Association","volume":"52","author":"Kleindorfer","year":"2021","journal-title":"Stroke"},{"key":"ref_18","unstructured":"Global Initiative for Chronic Obstructive Lung Disease (GOLD) (2024, March 22). Global Strategy for the Prevention, Diagnosis, Management and Prevention of COPD: 2024 Report. Available online: https:\/\/goldcopd.org."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"(2023). By the 2023 American Geriatrics Society Beers Criteria Update Expert Panel. American Geriatrics Society 2023 updated AGS Beers Criteria for potentially inappropriate medication use in older adults. J. Am. Geriatr. Soc., 71, 2052\u20132081.","DOI":"10.1111\/jgs.18372"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"(2024). Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int., 105, S117\u2013S314.","DOI":"10.1016\/j.kint.2023.10.018"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e45","DOI":"10.1164\/rccm.201908-1581ST","article-title":"Diagnosis and Treatment of Adults with Community-acquired Pneumonia. An Official Clinical Practice Guideline of the American Thoracic Society and Infectious Diseases Society of America","volume":"200","author":"Metlay","year":"2019","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3912","DOI":"10.1093\/eurheartj\/ehae178","article-title":"2024 ESC Guidelines for the management of elevated blood pressure and hypertension","volume":"45","author":"McEvoy","year":"2024","journal-title":"Eur. Heart J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"iv192","DOI":"10.1093\/annonc\/mdy275","article-title":"Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up","volume":"29","author":"Planchard","year":"2018","journal-title":"Ann. Oncol."},{"key":"ref_24","unstructured":"American Diabetes Association Professional Practice Committee (2024). Standards of Care in Diabetes\u20142024. Diabetes Care, 47, S1\u2013S321."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"European Association for the Study of the Liver (2018). EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J. Hepatol., 69, 406\u2013460.","DOI":"10.1016\/j.jhep.2018.08.009"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1007\/s41999-023-00777-y","article-title":"STOPP\/START criteria for potentially inappropriate prescribing in older people: Version 3","volume":"14","author":"Cherubini","year":"2023","journal-title":"Eur. Geriatr. Med."},{"key":"ref_27","first-page":"CD008165","article-title":"Interventions to improve the appropriate use of polypharmacy for older people","volume":"10","author":"Rankin","year":"2023","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1136\/bmj.38338.674583.AE","article-title":"Does home based medication review keep older people out of hospital? The HOMER randomised controlled trial","volume":"330","author":"Holland","year":"2005","journal-title":"BMJ"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1001\/jamainternmed.2015.0324","article-title":"Reducing inappropriate polypharmacy: The process of deprescribing","volume":"175","author":"Scott","year":"2015","journal-title":"JAMA Intern. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1016\/j.amjmed.2003.10.031","article-title":"Effects of geriatric evaluation and management on adverse drug reactions and suboptimal prescribing in the frail elderly","volume":"116","author":"Schmader","year":"2004","journal-title":"Am. J. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e47346","DOI":"10.2196\/47346","article-title":"Use of Artificial Intelligence in the Identification and Diagnosis of Frailty Syndrome in Older Adults: Scoping Review","volume":"25","author":"Arco","year":"2023","journal-title":"J. Med. 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