Polypharmacy: What is the most common cause of adverse drug reactions in older adults?

October 11, 2025 •

4 min read

Hospitalization rates due to adverse drug effects are 4 to 7 times higher in older patients than in younger patients. A primary contributor is polypharmacy, making it the most common cause of adverse drug reactions in older adults. This issue arises not only from the sheer volume of drugs but also from complex age-related changes in the body that alter how medications are processed and their effects are felt.

Quick Summary

Polypharmacy, the concurrent use of multiple medications, is the leading cause of adverse drug reactions (ADRs) in older adults. This risk is amplified by age-related physiological changes, cognitive decline, medication errors, and prescribing cascades.

Key Points

Polypharmacy is the leading cause: The use of multiple medications is the most significant risk factor for adverse drug reactions in older adults due to increased potential for drug-drug interactions.
Age-related changes compound risk: Normal aging leads to a decline in kidney and liver function, altered body composition (more fat, less water), and increased sensitivity to certain drugs, all of which alter how the body processes medications.
Prescribing cascades are a key problem: This occurs when a new medication is prescribed to treat an adverse effect of another drug, mistaking the side effect for a new medical condition and increasing polypharmacy.
Cognitive and physical barriers affect adherence: Complex medication schedules, memory issues, physical limitations, and financial constraints all contribute to medication errors and non-adherence, increasing the risk of adverse events.
Proactive management is essential: Strategies to minimize risk include regular medication reviews, deprescribing unnecessary drugs, using screening tools (e.g., Beers criteria), and following the 'start low, go slow' principle for new medications.
Patient and caregiver education is vital: Clear communication and education about medications, potential side effects, and adherence are crucial for improving medication safety in older adults.

The Pervasive Role of Polypharmacy

Polypharmacy, typically defined as the regular use of five or more medications, is the most consistently identified risk factor for adverse drug reactions (ADRs) in older adults. Its prevalence is high, with a significant proportion of adults aged 65 and over regularly taking five or more prescription medications due to multimorbidity—the presence of multiple chronic health conditions. Each additional medication significantly increases the potential for drug-drug and drug-disease interactions, which can produce unexpected side effects or diminish therapeutic efficacy. Managing complex drug regimens also places a tremendous burden on older patients and their caregivers, raising the likelihood of medication errors and non-adherence.

Age-Related Physiological Changes: The Pharmacokinetic Shift

As the body ages, its ability to handle medications changes in predictable, though variable, ways. These alterations affect pharmacokinetics—the study of how drugs are absorbed, distributed, metabolized, and excreted (ADME)—and significantly increase susceptibility to ADRs.

Declining Renal Function

One of the most clinically significant changes is the progressive decline in renal function with age, impacting the kidneys' ability to clear drugs and their active metabolites. This can lead to drug accumulation and toxicity, especially for water-soluble medications. Assessing renal function in older adults can be challenging as serum creatinine alone may not be a reliable indicator due to reduced muscle mass.

Altered Hepatic Metabolism

Liver mass and blood flow decrease with age, reducing the efficiency of drug metabolism, particularly through the cytochrome P450 (CYP) system. This can result in higher concentrations of some drugs entering the bloodstream. Phase II metabolic pathways are generally less affected.

Changes in Body Composition

Aging alters body composition, increasing body fat and decreasing total body water and lean mass. This changes how drugs are distributed. Lipid-soluble drugs may accumulate in fat, extending their effects, while water-soluble drugs become more concentrated in the blood, increasing toxicity risk.

Increased Pharmacodynamic Sensitivity

Older adults may exhibit increased sensitivity to certain drugs, particularly those affecting the central nervous system like sedatives and opioids. This can lead to exaggerated effects such as sedation, confusion, and increased fall risk.

The Problem of Prescribing Cascades

A prescribing cascade occurs when an adverse drug reaction is misinterpreted as a new medical condition and treated with another drug, thus increasing polypharmacy and associated risks.

Examples of Prescribing Cascades

Calcium Channel Blockers and Diuretics: Peripheral edema from a calcium channel blocker is treated with a diuretic.
Antipsychotics and Antiparkinsonian Drugs: Drug-induced tremors from an antipsychotic are treated with an antiparkinsonian drug, misdiagnosing it as Parkinson's disease.

Medication Errors and Non-Adherence

Medication errors and non-adherence are significant contributors to ADRs in older adults. Complex regimens are often linked to self-administration errors.

Barriers to Adherence

Cognitive Decline: Memory issues can lead to missed doses or incorrect administration.
Complex Regimens: Managing multiple medications with varying instructions is challenging.
Physical Limitations: Difficulties with vision or dexterity can hinder proper medication use.
Side Effects: Unpleasant side effects may cause patients to intentionally stop or alter their medication.
Financial Constraints: The cost of medications can lead to rationing or not filling prescriptions.
Lack of Support: Insufficient caregiver or social support can impact consistent medication adherence.

Prevention Strategies for Adverse Drug Reactions

Preventing ADRs requires a collaborative effort among healthcare providers, patients, and caregivers.

Comparison Table: Age-Related Pharmacokinetic Changes and Clinical Effects


Factor	Change with Aging	Clinical Consequence
Hepatic Metabolism	Decreased liver blood flow and enzyme activity (Phase I)	Slower clearance of certain drugs, leading to potential accumulation and toxicity.
Renal Excretion	Decreased Glomerular Filtration Rate (GFR)	Slower drug and metabolite clearance, increasing risk of accumulation and toxicity, especially for renally excreted drugs.
Body Fat	Increased proportion of body fat	Increased volume of distribution for lipid-soluble drugs, leading to longer half-lives and extended effects.
Total Body Water	Decreased total body water	Higher concentration of water-soluble drugs in the bloodstream, increasing risk of toxicity.
Serum Albumin	Decreased levels, especially with illness or malnutrition	Higher free drug concentration for highly protein-bound drugs (e.g., warfarin), increasing potency and risk of toxicity.

Key Prevention Strategies

Medication Reconciliation: Maintain accurate medication lists.
Regular Medication Reviews: Periodically review all medications, including OTCs and supplements.
Deprescribing: Reduce or discontinue unnecessary medications.
Using Screening Tools: Utilize tools like the Beers List, STOPP, and START.
"Start Low, Go Slow": Begin new medications at the lowest effective dose and increase gradually.
Enhanced Education: Provide clear instructions to patients and caregivers.
Anticipate Prescribing Cascades: Identify new symptoms that may be drug-induced.
Consider Alternatives: Explore non-pharmacologic options when suitable.

Conclusion

Polypharmacy is the most common cause of adverse drug reactions in older adults, exacerbated by age-related physiological changes that impact drug processing. Declining kidney and liver function, altered body composition, and increased drug sensitivity make this population vulnerable. Practical issues like complex regimens, cognitive challenges, and prescribing cascades further increase ADR risk. Implementing proactive strategies such as collaborative medication management, deprescribing, and patient education is vital for safer medication use in older adults. A thoughtful, holistic approach to prescribing can significantly mitigate these risks. Resources like those from the American Geriatrics Society offer valuable guidance on prescribing for older adults.

Frequently Asked Questions

Polypharmacy is the regular use of five or more medications and is dangerous for older adults because it significantly increases the risk of drug-drug interactions, drug-disease interactions, and adverse drug reactions (ADRs). The more medications a person takes, the higher the chance of harmful side effects.

With age, the body experiences changes in pharmacokinetics (how drugs are absorbed, distributed, metabolized, and excreted) and pharmacodynamics (how drugs affect the body). Declining kidney and liver function can slow down drug clearance, leading to accumulation and toxicity. Changes in body fat and water content can also alter drug distribution and concentration.

A prescribing cascade occurs when an adverse drug reaction is misdiagnosed as a new medical condition, resulting in an additional medication being prescribed to treat the side effect. This adds to the number of drugs taken (polypharmacy), increases the risk of further ADRs, and complicates the patient's regimen.

Medication errors, often caused by complex regimens, cognitive impairment, or physical limitations, are a major contributing factor. Errors can include incorrect dosing, mixing up medications, or forgetting to take doses. These mistakes increase the likelihood of experiencing an ADR.

Key strategies include regular medication reviews by a healthcare professional, deprescribing unnecessary medications, following the 'start low, go slow' approach for new drugs, and using validated screening tools like the Beers criteria to identify potentially inappropriate medications.

Caregivers can assist by maintaining a comprehensive, up-to-date medication list (including OTCs and supplements), ensuring clear communication with healthcare providers, organizing medication using pillboxes, and helping with administration. They can also watch for signs of potential ADRs and advocate for medication reviews.

No, an altered mental status, such as confusion or sedation, should not be automatically attributed to dementia or normal aging. It can often be a symptom of an adverse drug reaction, especially with medications affecting the central nervous system like sedatives or antipsychotics. It's crucial to investigate if a new or changed medication is the cause.