Medication Safety and Polypharmacy

Adil Abbasi, MD FACP FACN

Learning Objectives

By the end of this chapter, the learner should be able to:

• Define medication safety and polypharmacy.
• Differentiate appropriate from inappropriate polypharmacy.
• Understand the epidemiology and clinical significance of polypharmacy.
• Identify major risk factors for medication-related harm.
• Recognize common adverse outcomes associated with polypharmacy.
• Describe strategies for medication reconciliation and medication review.
• Apply deprescribing principles in clinical practice.
• Utilize validated tools such as Beers Criteria and STOPP/START criteria.
• Develop practical approaches to improving medication safety in ambulatory, acute care, and long-term care settings.
• Understand the role of interdisciplinary teams in reducing medication-related harm.

Introduction

Medication therapy has transformed modern medicine and significantly improved survival and quality of life for patients with acute and chronic diseases. However, increasing longevity and the growing prevalence of multiple chronic conditions have led to an unprecedented rise in medication use. Many patients, particularly older adults, receive multiple medications from several healthcare providers simultaneously, creating substantial risks for adverse outcomes.

Medication safety refers to the prevention of medication-related errors and adverse drug events throughout the prescribing, dispensing, administration, monitoring, and discontinuation processes. Medication safety is now recognized as a major component of patient safety worldwide.

Polypharmacy generally refers to the concurrent use of five or more medications. Although numerical definitions vary, the concept is clinically important because medication-related risks increase substantially as the number of medications rises. Polypharmacy is not inherently inappropriate; many patients require multiple medications to achieve evidence-based disease management. The primary concern is inappropriate polypharmacy, where medications provide limited benefit, duplicate therapeutic effects, interact adversely, or create risks that outweigh potential benefits.

Epidemiology

Polypharmacy has become increasingly common worldwide.

Recent studies indicate that more than 40% of adults aged 65 years and older regularly take five or more prescription medications. This prevalence has nearly doubled over the past two decades.

The prevalence is particularly high among:

• Older adults
• Nursing home residents
• Patients with multiple chronic diseases
• Individuals receiving care from multiple specialists
• Recently hospitalized patients

As populations continue to age, polypharmacy is expected to remain a major public health challenge.

Definitions

Polypharmacy

Traditionally defined as the routine use of five or more medications concurrently.

Hyperpolypharmacy

Often defined as the use of ten or more medications simultaneously.

Appropriate Polypharmacy

The use of multiple medications when each medication has a clear evidence-based indication and the expected benefits outweigh the risks.

Inappropriate Polypharmacy

The use of medications that:

• Lack a current indication
• Duplicate therapeutic effects
• Cause significant adverse effects
• Interact with other medications
• Fail to provide meaningful benefit

Pathophysiology of Medication-Related Harm

Medication-related harm results from multiple interacting mechanisms.

Pharmacokinetic Changes

Aging affects:

Absorption

Changes in gastric acidity, gastric emptying, and intestinal motility may alter drug absorption.

Distribution

Older adults experience:

• Increased body fat
• Reduced lean body mass
• Reduced total body water
• Lower serum albumin levels

These changes alter drug distribution and protein binding.

Metabolism

Reduced hepatic blood flow and liver mass decrease drug metabolism.

Elimination

Declining renal function significantly impairs drug clearance, increasing the risk of drug accumulation and toxicity.

Pharmacodynamic Changes

Older adults often become more sensitive to:

• Sedatives
• Antipsychotics
• Opioids
• Anticoagulants
• Antihypertensives

Even standard doses may produce exaggerated effects.

Risk Factors for Polypharmacy

Several factors increase the likelihood of medication-related harm:

Patient Factors

• Advanced age
• Frailty
• Cognitive impairment
• Multiple chronic illnesses
• Limited health literacy

System Factors

• Multiple prescribers
• Fragmented healthcare systems
• Poor communication during care transitions
• Incomplete medication reconciliation

Medication Factors

• Narrow therapeutic index drugs
• High-risk medications
• Complex dosing regimens
• Drug-drug interactions
• Drug-disease interactions

Clinical Consequences of Polypharmacy

The risk of adverse outcomes increases progressively as medication burden increases.

Adverse Drug Reactions

Adverse drug reactions are among the most common consequences of polypharmacy and account for a substantial proportion of emergency department visits and hospitalizations.

Drug-Drug Interactions

Potential interactions increase exponentially as the number of medications rises.

Examples include:

• Warfarin interactions
• DOAC interactions
• QT-prolonging combinations
• Serotonergic combinations
• Sedative combinations

Falls and Fractures

Particularly associated with:

• Benzodiazepines
• Sedative hypnotics
• Antidepressants
• Antipsychotics
• Antihypertensives

Falls are a major source of morbidity and mortality among older adults.

Cognitive Impairment

Medication-induced cognitive decline may mimic dementia.

Common contributors include:

• Anticholinergics
• Benzodiazepines
• Sedative hypnotics
• Opioids
• Certain antihistamines

Recent reports describe improvement in cognition following reduction of excessive medication burden.

Delirium

Polypharmacy is a major precipitating factor for hospital-acquired delirium.

Functional Decline

Patients may experience:

• Reduced mobility
• Weakness
• Fatigue
• Impaired balance
• Loss of independence

Hospitalization

Polypharmacy independently increases hospitalization risk.

Mortality

Numerous studies have demonstrated an association between excessive medication burden and increased mortality.

High-Risk Medication Classes

The following medication groups frequently contribute to medication-related harm:

Medication Reconciliation

Medication reconciliation is the formal process of obtaining and verifying an accurate medication list whenever patients transition between care settings.

This process includes:

1. Reviewing all prescription medications.
2. Reviewing over-the-counter medications.
3. Reviewing herbal products and supplements.
4. Confirming dosages and schedules.
5. Identifying discrepancies.
6. Communicating changes to all providers.

Medication reconciliation is particularly important during:

• Hospital admission
• Transfer between units
• Discharge
• Specialist referrals

Care transitions remain among the highest-risk periods for medication errors.

Medication Review

Medication review involves a systematic evaluation of all medications to determine:

• Current indication
• Effectiveness
• Safety
• Adherence
• Necessity

Questions that should be asked include:

1. Is the medication still indicated?
2. Is it effective?
3. Is it causing harm?
4. Is there duplication?
5. Can the dose be reduced?
6. Can the medication be discontinued?

Deprescribing

Definition

Deprescribing is the planned and supervised reduction or discontinuation of medications that may no longer be beneficial or may be causing harm.

Deprescribing has emerged as a cornerstone of medication safety initiatives worldwide.

Deprescribing Process

Step 1

Identify potentially inappropriate medications.

Step 2

Assess risk-benefit ratio.

Step 3

Prioritize medications for discontinuation.

Step 4

Develop tapering strategy when needed.

Step 5

Monitor for withdrawal symptoms or recurrence of disease.

Step 6

Reassess clinical outcomes.

Tools for Assessing Polypharmacy

AGS Beers Criteria

The 2023 AGS Beers Criteria provides a list of medications that should generally be avoided or used cautiously in older adults. It remains one of the most widely used tools for identifying potentially inappropriate medications.

Examples include:

• Diphenhydramine
• Benzodiazepines
• Certain antipsychotics
• Long-acting sulfonylureas
• Skeletal muscle relaxants

STOPP/START Criteria

STOPP:
Screening Tool of Older Persons' Prescriptions.

START:
Screening Tool to Alert to Right Treatment.

These tools help identify both:

• Medications that should be discontinued.
• Evidence-based therapies that have been omitted.

Medication Appropriateness Index (MAI)

Assesses medication appropriateness using multiple domains including indication, effectiveness, dosage, and interactions.

Strategies to Improve Medication Safety

Patient-Level Strategies

• Maintain an updated medication list.
• Use a single pharmacy when possible.
• Avoid self-medication without consultation.
• Understand medication indications.
• Improve adherence.

Provider-Level Strategies

• Perform regular medication reviews.
• Minimize prescribing cascades.
• Review renal and hepatic function.
• Avoid duplicate therapies.
• Utilize clinical decision support systems.

System-Level Strategies

• Electronic prescribing
• Drug interaction alerts
• Pharmacist involvement
• Structured medication reconciliation
• Multidisciplinary rounds

Pharmacist-led interventions have demonstrated reductions in medication-related harm and improved prescribing quality.

Polypharmacy in Special Populations

Older Adults

Represent the highest-risk group because of physiological changes, multimorbidity, and frailty.

Patients with Dementia

Particularly vulnerable to:

• Delirium
• Falls
• Cognitive worsening
• Functional decline

Nursing Home Residents

Frequently receive multiple psychotropic medications and require ongoing medication review.

Hospitalized Patients

Medication burden often increases during hospitalization and may persist after discharge unless deliberate deprescribing occurs.

Future Directions

Emerging approaches include:

• Artificial intelligence-assisted medication review
• Advanced clinical decision support systems
• Pharmacogenomics-guided prescribing
• Precision deprescribing
• Remote medication monitoring

These technologies may improve identification of drug interactions and reduce medication-related harm.

Summary

• Polypharmacy is commonly defined as the use of five or more medications.
• Appropriate polypharmacy may be necessary for optimal disease management.
• Inappropriate polypharmacy increases risks of adverse drug reactions, falls, cognitive impairment, hospitalization, and mortality.
• Older adults are particularly vulnerable because of age-related pharmacokinetic and pharmacodynamic changes.
• Medication reconciliation is essential during transitions of care.
• Regular medication review should be performed in all patients receiving multiple medications.
• Deprescribing is a patient-centered strategy for reducing medication-related harm.
• Beers Criteria and STOPP/START criteria are widely used tools for identifying potentially inappropriate medications.
• Interdisciplinary collaboration among physicians, pharmacists, nurses, patients, and caregivers is critical for medication safety.
• Medication safety should remain a central focus of modern healthcare systems.

References

American Geriatrics Society Beers Criteria® Update Expert Panel. (2023). American Geriatrics Society 2023 updated AGS Beers Criteria® for potentially inappropriate medication use in older adults. Journal of the American Geriatrics Society, 71(7), 2052–2081.

Boateng, I., et al. (2025). The impact of polypharmacy on health outcomes in the aged. Journal of Clinical Medicine, 14, 112-126.

Daunt, R., et al. (2024). Optimizing drug therapy for older adults: shifting away from problematic polypharmacy. Expert Opinion on Pharmacotherapy, 25, 1–14.

Jandu, J. S., & Khan, M. (2024). Strategies to reduce polypharmacy in older adults. StatPearls Publishing.

McGrory, F., et al. (2025). Pharmacist-led interventions for polypharmacy management in older adults. Healthcare, 13, 1127.

Ngcobo, N. N., et al. (2025). Polypharmacy and deprescribing among geriatric patients. Aging Medicine, 8, 145–159.

Pazan, F., & Wehling, M. (2021). Polypharmacy in older adults: a narrative review of definitions, epidemiology and consequences. European Geriatric Medicine, 12, 443–452.

Varghese, D., & Vakkalanka, P. (2024). Polypharmacy. StatPearls Publishing.

Yang, J., et al. (2026). Quality and recommendations of guidelines for multimorbidity and polypharmacy in older adults: A systematic review. International Journal of Clinical Practice, 80, e16234.