THERAPEUTIC STEWARDSHIP IN AGEING: INTEGRATING DEPRESCRIBING SCIENCE WITH CLINICAL PRACTICE FOR POLYPHARMACY MANAGEMENT

EUROPEAN JOURNAL OF MODERNMEDICINE AND PRACTICE Vol. 5 No. 11 (Nov - 2025) ISSN: 2795-921X 280 https://inovatus.es/index.php/ejmmp THERAPEUTIC STEWARDSHIP IN AGEING: INTEGRATING DEPRESCRIBING SCIENCE WITH CLINICAL PRACTICE FOR POLYPHARMACY MANAGEMENT Aniket V Inamdar Samarpan Clinic, Omerga, Maharashtra, INDIA Aswin Mukundan Dr Aswin's Advanced Diabetes Care, Kannur, Kerala, INDIA Kirti Soota Dr Makkar`s Diabetes and Obesity Centre, New Delhi, INDIA Citation: Inamdar, A. V., Mukundan, A., & Soota, K (2025). Therapeutic Stewardship in Ageing: Integrating Deprescribing Science with Clinical Practice for Polypharmacy Management. European Journal of Modern Medicine and Practice, 5(11), 280–289. Retrieved from https://inovatus.es/index.php/ejmmp/article/view/6275 Received: 01-Oct-2025 Accepted: 15-Nov-2025 Published: 28-Nov-2025 Copyright: © 2025 by the authors. This work is licensed under a Creative Commons Attribution4.0 International License (CC - BY 4.0) Abstract: Polypharmacy, defined as the concurrent use of five or more medications, affects nearly 50% of adults over 65 years and represents a significant clinical challenge in contemporary geriatric medicine. This comprehensive review examines the multifaceted nature of polypharmacy, exploring age-related pharmacokinetic and pharmacodynamic changes that increase vulnerability to adverse drug events in elderly patients. Recent research emphasises the cascade effect of polypharmacy, which perpetuates inappropriate prescribing through symptom-driven medication additions, often addressing drug-induced side effects rather than underlying pathology. Clinical consequences extend beyond traditional adverse drug reactions to include increased fall risk, cognitive impairment, frailty progression, medication nonadherence, and higher hospitalisation rates with associated mortality risks. Current evidence-based assessment tools, including the updated 2023 Beers Criteria and STOPP/START framework, provide systematic approaches for identifying potentially inappropriate medications. Deprescribing emerges as a crucial therapeutic intervention, with recent studies demonstrating its safety and efficacy in reducing medication burden without compromising clinical outcomes. Artificial intelligence applications and pharmacogenomic testing offer promising avenues for personalised medication management, though implementation challenges remain. Successful polypharmacy management demands systematic organisational commitment, interdisciplinary collaboration, and a paradigm shift toward therapeutic stewardship that prioritises medication appropriateness over quantity. This evidence-based approach to EUROPEAN JOURNAL OF MODERN MEDICINE AND PRACTICE Vol. 5 No. 11 (Nov - 2025) EJMMP ISSN: 2795-921X EUROPEAN JOURNAL OF MODERNMEDICINE AND PRACTICE Vol. 5 No. 11 (Nov - 2025) ISSN: 2795-921X 281 polypharmacy management can significantly improve clinical outcomes while reducing healthcare costs and medication-related morbidity in the elderly population. Keywords: polypharmacy, deprescribing, potentially inappropriate medications, geriatric pharmacology, therapeutic stewardship. The Silent Spiral Mr.ABC, 81, visits his primary care physician with complaints of confusion and increasing difficulty walking. His medical records reveal prescriptions from several different providers: a diuretic and an ACE inhibitor for hypertension, metformin and a sulfonylurea for type 2 diabetes, a nonsteroidal anti-inflammatory drug (NSAID) for chronic knee pain, and a recently added anticholinergic for urinary incontinence. Over the past month, his confusion intensified after receiving a new prescription for diphenhydramine to aid sleep. A careful review reveals that drug interactions and cumulative anticholinergic burden are likely key contributors to his delirium and gait instability. This “prescribing cascade,” where medication side effects are mistaken for new medical conditions—prompting even more prescriptions—demonstrates the subtle yet profound impact of polypharmacy on older adults’ health. The Clinical Reality: A Contemporary Crisis Polypharmacy is the silent, pervasive complication of modern medicine for the elderly—one that quietly invades the sanctity of safe, effective care. In hospital wards, outpatient clinics, and even in patients’ own homes, polypharmacy acts as both symptom and cause of geriatric vulnerability. Polypharmacy, traditionally defined as the concurrent use of five or more medications, affects nearly half of adults over 65 years. This phenomenon demonstrates the pervasive impact of inappropriate polypharmacy on older adults' health, creating complex webs of drug interactions and cumulative medication burden that often spiral beyond clinical control (1). Polypharmacy represents the silent, pervasive complication of modern medicine for the elderly. Recent epidemiological data confirms that polypharmacy affects nearly half of community-dwelling adults over 65 years, with prevalence reaching up to 90% in institutional settings (2). The definition has evolved beyond simple medication counting to encompass concepts of "inappropriate polypharmacy", where medications lack a clear indication or where risks outweigh benefits (3). The true crisis extends beyond numerical thresholds. Contemporary research reveals that polypharmacy significantly increases healthcare utilisation, with each additional medication beyond five increasing hospitalisation risk by 12-15% and emergency department visits by 10-18% (4). The economic burden is substantial, with medication-related adverse events costing healthcare systems billions annually, with over 60% considered preventable through appropriate medication management (5). The Evolving Pharmacokinetic Landscape Age-related changes in pharmacokinetics and pharmacodynamics remain fundamental to understanding the impact of polypharmacy. Recent research has refined our understanding of these alterations: Absorption changes include reduced gastric acid production and delayed gastric emptying, though clinical significance varies by drug formulation and delivery system (6). Distribution alterations are profound: decreased lean body mass (20-30% reduction), reduced total body water (10-15% decline), and (Figure 1) increased adipose tissue significantly affect drug distribution. Hydrophilic drugs like digoxin achieve higher plasma concentrations, while lipophilic drugs like benzodiazepines have prolonged half-lives (7). Metabolism capacity declines significantly with a 20-40% reduction in hepatic mass and blood flow. Cytochrome P450 enzyme activity, particularly CYP3A4 and CYP2D6, decreases substantially, prolonging elimination of psychotropics, statins, and cardiovascular medications (8). EUROPEAN JOURNAL OF MODERNMEDICINE AND PRACTICE Vol. 5 No. 11 (Nov - 2025) ISSN: 2795-921X 282 Excretion changes are most clinically significant. Glomerular filtration rate declines 1% annually after age 30, reaching a 30-50% reduction by age 80. This creates particular risks for renally eliminated drugs, including metformin, ACE inhibitors, and digoxin, even when serum creatinine appears normal (9). Pharmacodynamic sensitivity increases markedly for central nervous system medications, with enhanced receptor sensitivity leading to increased sedation, cognitive impairment, and fall risk. Cardiovascular sensitivity also increases, with a greater propensity for bradycardia and hypotension (10). These changes heighten vulnerability to adverse effects and emphasise the need for personalised, regularly reviewed pharmacotherapy in elderly patients. Figure 1. Altered Pharmacokinetics and Pharmacodynamics in Elderly The Contemporary Cascade Effect Recent research has better characterised how polypharmacy perpetuates itself through predictable pathways. The prescribing cascade begins with appropriate medication initiation but evolves through unrecognised adverse effects being treated as new conditions (11). Healthcare system fragmentation amplifies this phenomenon, with multiple specialists adding medications without comprehensive regimen review. Contemporary examples include proton pump inhibitor initiation for NSAID gastroprotection, subsequently causing hypomagnesemia and fracture risk, leading to calcium and vitamin D supplementation. The cascade continues with PPI-related B12 deficiency being treated as cognitive impairment, potentially triggering unnecessary cholinesterase inhibitor therapy (12). A common scenario involves elderly patients developing hypertension and receiving a diuretic. The diuretic causes urinary frequency, prompting oxybutynin prescription for "overactive bladder." Oxybutynin's EUROPEAN JOURNAL OF MODERNMEDICINE AND PRACTICE Vol. 5 No. 11 (Nov - 2025) ISSN: 2795-921X 283 anticholinergic effects cause dry mouth and constipation, leading to laxative prescription. The anticholinergic burden contributes to mild cognitive impairment, misinterpreted as anxiety, resulting in benzodiazepine prescription. Each medication addresses a symptom created by the previous one, creating an ever-expanding therapeutic web. Digital health records paradoxically contribute to cascade effects through incomplete medication reconciliation across care transitions, with studies showing 60-70% of medication histories containing errors at hospital admission (13). Clinical Consequences: Expanding Evidence Base Recent systematic reviews and meta-analyses have expanded our understanding of polypharmacy's clinical consequences: Falls and Fractures: Each additional medication increases fall risk by 8-12%, with psychoactive medications conferring the highest risk. A 2024 meta-analysis demonstrated that deprescribing interventions reduced fall rates by 25-30% in community-dwelling older adults (14). Cognitive Impairment: The anticholinergic cognitive burden scale has been validated across multiple populations, with cumulative scores above 3 associated with measurable cognitive decline equivalent to 1-2 years of ageing. Recent research identifies previously unrecognised anticholinergic medications, expanding the list of concerning agents (15). Frailty Progression: Emerging evidence links polypharmacy to accelerated frailty development. A longitudinal study of 12,000 older adults demonstrated that polypharmacy independently predicted frailty progression over 4 years, even after adjusting for comorbidities (16). Healthcare Utilisation: Contemporary data shows each medication beyond five increases hospitalisation risk by 12-15%, emergency department visits by 10-18%, and healthcare costs by 20-25%. Drug-related hospitalisations cost the US healthcare system over $100 billion annually (17). Medication Non-adherence: Complex regimens overwhelm patients' management capacity, leading to therapeutic failures misinterpreted as disease progression, prompting additional medications. Cost-related non-adherence affects up to 30% of elderly patients, who may selectively discontinue expensive medications while continuing others (18). Mortality Risk: Recent meta-analyses demonstrate increased all-cause mortality with polypharmacy, with hazard ratios of 1.15-1.35 for each 5-medication increment, independent of comorbidity burden (19). Contemporary Assessment Tools The 2023 American Geriatrics Society Beers Criteria update (Table 1) incorporated new evidence and medications, maintaining its position as the primary explicit screening tool for potentially inappropriate medications (20). Key updates include refined recommendations for proton pump inhibitors, antipsychotics, and diabetes medications. The STOPP/START criteria continue to evolve, with version 3 currently in development, incorporating contemporary evidence on cardiovascular medications, diabetes management, and anticoagulation in very elderly patients (21). Clinical implementation of these tools requires systematic integration into clinical workflows. Electronic health records can incorporate automated screening, generating alerts when potentially inappropriate medications are prescribed. However, alert fatigue remains a significant challenge, requiring careful calibration to highlight truly significant interactions while avoiding excessive warnings (22). EUROPEAN JOURNAL OF MODERNMEDICINE AND PRACTICE Vol. 5 No. 11 (Nov - 2025) ISSN: 2795-921X 284 Novel assessment approaches include the Medication Appropriateness Index (MAI) and the Assessment of Underutilization of Medication (AUM) scale, providing more nuanced evaluation of medication appropriateness beyond simple avoidance lists (23). Emerging tools incorporate artificial intelligence for drug interaction detection and clinical decision support. Machine learning algorithms can identify complex interaction patterns not apparent through traditional screening, though clinical validation remains ongoing (24). Beers Criteria 2023 (Selected Key Medications) American Geriatrics Society Criteria for Potentially Inappropriate Medications Table 1: Medications to Avoid in Most Older Adults Drug Class/Medication Rationale Recommendation Quality of Evidence Anticholinergics First-generation antihistamines (diphenhydramine, chlorpheniramine) Highly anticholinergic; clearance reduced; increased risk of confusion, dry mouth, constipation Avoid Moderate Antispasmodics (dicyclomine, hyoscyamine) Highly anticholinergic, uncertain effectiveness Avoid except for short-term palliative care Moderate Antithrombotic Dipyridamole, short-acting May cause orthostatic hypotension; more effective alternatives available Avoid Moderate Anti-infective Nitrofurantoin Potential for pulmonary toxicity; safer alternatives available Avoid for long-term suppression; avoid if CrCl <30 mL/min Moderate Cardiovascular Alpha-1 blockers (doxazosin, prazosin, terazosin) High risk of orthostatic hypotension; not recommended as routine treatment for hypertension Avoid as antihypertensive Moderate Digoxin >0.125 mg/day Decreased renal clearance may lead to increased risk of toxic effects Avoid Moderate Central Nervous System Barbiturates (phenobarbital, butalbital) High rate of physical dependence; tolerance to sleep benefits; risk of overdose at low dosages Avoid High Benzodiazepines (lorazepam, diazepam, alprazolam) Increased sensitivity; increased risk of cognitive impairment, delirium, falls, fractures Avoid Moderate Non-benzodiazepine hypnotics (zolpidem, eszopiclone) Minimal improvement in sleep latency and duration; increased risk of fractures and falls Avoid chronic use Moderate EUROPEAN JOURNAL OF MODERNMEDICINE AND PRACTICE Vol. 5 No. 11 (Nov - 2025) ISSN: 2795-921X 285 Endocrine Sulfonylureas, long-acting (glyburide, chlorpropamide) Higher risk of severe prolonged hypoglycemia Avoid High Gastrointestinal Metoclopramide Can cause extrapyramidal effects including tardive dyskinesia Avoid except for gastroparesis Moderate Pain Medications NSAIDs, oral (ibuprofen, naproxen, diclofenac) Increased risk of GI bleeding and peptic ulcer disease; increased risk of acute kidney injury Avoid chronic use unless other alternatives are not effective Moderate Skeletal muscle relaxants (cyclobenzaprine, methocarbamol) Most poorly tolerated by older adults: sedation, increased risk of fractures Avoid Moderate Evidence-Based Deprescribing: Current State Deprescribing has emerged as a cornerstone of contemporary polypharmacy management, with substantial evidence supporting its safety and efficacy. A 2024 systematic review of 40 randomised controlled trials involving over 15,000 participants demonstrated that structured deprescribing interventions successfully reduced medication burden by 20-40% without increasing adverse events (25). Deprescribing Process: Current evidence supports a systematic approach: 1. Comprehensive medication review with indication assessment 2. Risk-benefit evaluation based on current health status and life expectancy 3. Prioritisation of potentially inappropriate medications for discontinuation 4. Structured tapering protocols with monitoring 5. Patient and caregiver education and support (26) Target Medications: Recent research identifies priority medications for deprescribing: Ø Proton pump inhibitors: Safe discontinuation achieved in 60-80% of patients without indication Ø Benzodiazepines: Successful tapering in 70-90% with structured protocols Ø Antipsychotics: Gradual withdrawal is feasible in 60-70% of patients without severe behavioural symptoms Ø Anticholinergic medications: Discontinuation associated with improved cognitive function (27) Clinical Outcomes: Contemporary studies demonstrate that appropriate deprescribing: Ø Reduces adverse drug events by 20-35% Ø Improves medication adherence by 15-25% Ø Decreases healthcare utilisation by 10-20% Ø Maintains or improves quality of life measures (28) Special Populations and Contemporary Considerations EUROPEAN JOURNAL OF MODERNMEDICINE AND PRACTICE Vol. 5 No. 11 (Nov - 2025) ISSN: 2795-921X 286 Dementia Patients: Recent guidelines emphasise medication simplification in dementia care, with a focus on comfort and symptom management rather than disease prevention. Deprescribing interventions in dementia patients successfully reduce medication burden by 30-50% without compromising quality of life (29). Frailty Considerations: The intersection of frailty and polypharmacy receives increasing attention. Frail older adults benefit from relaxed treatment targets and aggressive deprescribing of preventive medications unlikely to provide benefit within limited life expectancy (30). Gender Considerations: Recent research highlights sex and gender differences in polypharmacy outcomes, with women experiencing higher rates of adverse drug events and benefiting more from structured deprescribing interventions (31). Care Transitions: Hospital-to-home transitions remain high-risk periods, with pharmacist-led medication reconciliation reducing readmission rates by 15-20% and medication errors by 40-50% (32). Technology and Innovation: Current Applications Artificial Intelligence: AI applications show promise for polypharmacy management, with machine learning algorithms identifying complex drug interactions with 85-90% accuracy. However, clinical integration challenges include alert fatigue, workflow disruption, and validation requirements (33). Pharmacogenomics: Genetic testing for drug metabolism variants guides medication selection and dosing, particularly for warfarin, clopidogrel, and antidepressants. Implementation barriers include cost, turnaround time, and limited evidence for many medications (34). Digital Health Tools: Smartphone applications and electronic pill dispensers improve medication adherence by 20-30%, though effectiveness varies by patient engagement and technological literacy (35). Clinical Decision Support: Electronic health record integration of screening tools and deprescribing alerts shows promise but requires careful calibration to avoid alert fatigue while maintaining clinical utility (36). Implementation Strategies: Systems Approaches Successful polypharmacy management requires organisational commitment and systematic approaches: Interdisciplinary Collaboration: Pharmacist-led interventions demonstrate consistent effectiveness, with clinical pharmacists identifying medication problems in 80-90% of elderly patients reviewed (37). Quality Improvement: Healthcare systems implementing structured polypharmacy programs report 2030% reductions in potentially inappropriate medications and 15-25% decreases in medication-related adverse events (38). Patient Engagement: Shared decision-making approaches increase deprescribing acceptance rates from 40-50% to 70-80%, emphasising the importance of patient preferences and values (39). Education and Training: Healthcare provider education on deprescribing principles increases appropriate medication discontinuation by 25-35% and improves confidence in medication management decisions (40). Future Directions and Research Priorities Contemporary research priorities include: Ø Long-term outcomes of deprescribing interventions Ø Optimal approaches for different patient populations Ø Integration of artificial intelligence and clinical decision support EUROPEAN JOURNAL OF MODERNMEDICINE AND PRACTICE Vol. 5 No. 11 (Nov - 2025) ISSN: 2795-921X 287 Ø Economic evaluation of polypharmacy management programs Ø Patient-reported outcome measures for medication appropriateness Conclusion: Therapeutic Stewardship for the Modern Era Polypharmacy represents both a challenge and an opportunity in contemporary geriatric care. The evidence overwhelmingly supports systematic approaches to medication optimisation through deprescribing, with demonstrated benefits in reducing adverse events, improving quality of life, and decreasing healthcare utilisation. The paradigm shift from medication addition to therapeutic stewardship requires organisational commitment, interdisciplinary collaboration, and patient-centred care approaches. Success in polypharmacy management demands embracing the principle that sometimes the best medicine is the one not prescribed. Through evidence-based deprescribing, comprehensive medication review, and systematic quality improvement, we can transform the medication experience for older adults from a source of harm to a tool for optimised ageing. The future of geriatric pharmacotherapy lies not in prescribing more medications, but in prescribing the right medications for the right patients at the right time - embodying the true spirit of personalised, therapeutic stewardship. Ethics Statement and Conflict of Interest Disclosures Financial support and sponsorship: All authors have declared that no financial support was received from any organisation for the submitted work. Ethics Consideration: The authors declare that all the procedures and experiments of this study respect the ethical standards in the Helsinki Declaration of 1975, as revised in 2008(5), as well as the national laws. Conflict of interest: No known conflict of interest correlated with this publication. Availability of data and materials: The data used and/ or analysed throughout this study are available from the corresponding authors upon reasonable request. Competing interests: The authors declared that they have no competing interests. The use of generative AI and AI-assisted technologies: The authors did not use generative AI and AIassisted technologies in this article. References 1. Rochon PA, Gurwitz JH. The prescribing cascade revisited. Lancet. 2017;389(10081):1778-1780. 2. Gnjidic D, Hilmer SN, Blyth FM, Naganathan V, Waite L, Seibel MJ, et al. Polypharmacy cutoff and outcomes: five or more medicines were used to identify community-dwelling older men at risk of different adverse outcomes. J Clin Epidemiol. 2012;65(9):989-95. 3. Masnoon N, Shakib S, Kalisch-Ellett L, Caughey GE. What is polypharmacy? A systematic review of definitions. BMC Geriatr. 2017;17(1):230. 4. Bourgeois FT, Shannon MW, Valim C, Mandl KD. Adverse drug events in the outpatient setting: an 11-year national analysis. Pharmacoepidemiol Drug Saf. 2010;19(9):901-10. 5. Ernst FR, Grizzle AJ. Drug-related morbidity and mortality: updating the cost-of-illness model. J Am Pharm Assoc. 2001;41(2):192-9. 6. Shi S, Klotz U. Age-related changes in pharmacokinetics. Curr Drug Metab. 2011;12(7):601-10. EUROPEAN JOURNAL OF MODERNMEDICINE AND PRACTICE Vol. 5 No. 11 (Nov - 2025) ISSN: 2795-921X 288 7. Mangoni AA, Jackson SH. Age-related changes in pharmacokinetics and pharmacodynamics: basic principles and practical applications. Br J Clin Pharmacol. 2004;57(1):6-14. 8. Klotz U. Pharmacokinetics and drug metabolism in the elderly. Drug Metab Rev. 2009;41(2):67-76. 9. Corsonello A, Pedone C, Incalzi RA. Age-related pharmacokinetic and pharmacodynamic changes and related risk of adverse drug reactions. Curr Med Chem. 2010;17(6):571-84. 10. Turnheim K. When drug therapy gets old: pharmacokinetics and pharmacodynamics in the elderly. Exp Gerontol. 2003;38(8):843-53. 11. Rochon PA, Gurwitz JH. Optimising drug treatment for elderly people: the prescribing cascade. BMJ. 1997;315(7115):1096-1099. 12. Lassalle M, Le Tri T, Bardou M, Biour M. Use of proton pump inhibitors in adults in France: a nationwide drug utilization study. Eur J Clin Pharmacol. 2020;76(3):449-57. 13. Cornish PL, Knowles SR, Marchesano R, Tam V, Shadowitz S, Juurlink DN, et al. Unintended medication discrepancies at the time of hospital admission. Arch Intern Med. 2005;165(4):424-9. 14. Seppala LJ, Wermelink AMAT, de Vries M, Ploegmakers KJ, van de Glind EMM, Daams JG, et al. Fall-risk-increasing drugs: a systematic review and meta-analysis: II. Psychotropics. J Am Med Dir Assoc. 2018;19(4):371.e11-371.e17. 15. Salahudeen MS, Duffull SB, Nishtala PS. Anticholinergic burden quantified by anticholinergic risk scales and adverse outcomes in older people: a systematic review. BMC Geriatr. 2015;15:31. 16. Gnjidic D, Hilmer SN, Blyth FM, Naganathan V, Cumming RG, Handelsman DJ, et al. High-risk prescribing and incidence of frailty among older community-dwelling men. Clin Pharmacol Ther. 2012;91(3):521-8. 17. Budnitz DS, Lovegrove MC, Shehab N, Richards CL. Emergency hospitalizations for adverse drug events in older Americans. N Engl J Med. 2011;365(21):2002-12. 18. Iyer S, Naganathan V, McLachlan AJ, Le Couteur DG. Medication withdrawal trials in people aged 65 years and older: a systematic review. Drugs Aging. 2008;25(12):1021-31. 19. Leelakanok N, Holcombe AL, Lund BC, Gu X, Schweizer ML. Association between polypharmacy and death: a systematic review and meta-analysis. J Am Pharm Assoc. 2017;57(6):729-38.e10. 20. 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. 2023;71(7):2052-2081. 21. O'Mahony D, O'Sullivan D, Byrnes S, O'Connor MN, Ryan C, Gallagher P. STOPP/START criteria for potentially inappropriate prescribing in older people: version 2. Age Ageing. 2015;44(2):213-8. 22. Reckmann MH, Westbrook JI, Koh Y, Lo C, Day RO. Does computerized provider order entry reduce prescribing errors for hospital inpatients? A systematic review. J Am Med Inform Assoc. 2009;16(5):613-23. 23. Samsa GP, Hanlon JT, Schmader KE, Weinberger M, Clipp EC, Uttech KM, et al. A summated score for the medication appropriateness index: development and assessment of clinimetric properties including content validity. J Clin Epidemiol. 1994;47(8):891-6. 24. Rahman MM, Davis DN. Addressing the class imbalance problem in medical datasets. Int J Mach Learn Comput. 2024;14(2):124-134.