Potentially Harmful Drug–Drug Interactions in the Elderly: A Review

Abstract

Background

Elderly patients are vulnerable to drug interactions because of age-related physiologic changes, an increased risk for disease associated with aging, and the consequent increase in medication use.

Objective

The purpose of this narrative review was to describe findings from rigorously designed observational cohort and case-control studies that have assessed specific drug interactions in elderly patients.

Methods

The PubMed and International Pharmaceutical Abstracts databases were searched for studies published in English over the past 10 years (December 2000–December 2010) using relevant Medical Subject Headings terms (aged; aged, 80 and over; and drug interactions) and search terms (drug interaction and elderly). Search strategies were saved and repeated through September 2011 to ensure that the most recent relevant published articles were identified. Additional articles were found using a search of review articles and reference lists of the identified studies. Studies were included if they were observational cohort or case-control studies that reported specific adverse drug interactions, included patients aged ≥65 years, and evaluated clinically meaningful end points. Studies were excluded if they used less rigorous observational designs, assessed pharmacokinetic/pharmacodynamic properties, evaluated drug-nutrient or drug-disease interactions or interactions of drug combinations used for therapeutic benefit (eg, dual antiplatelet therapy), or had inconclusive evidence.

Results

Seventeen studies met the inclusion criteria. Sixteen studies reported an elevated risk for hospitalization in older adults associated with adverse drug interactions. The drug interactions included: angiotensin-converting enzyme (ACE) inhibitors and potassium-sparing diuretics, ACE inhibitors or angiotensin receptor blockers and sulfamethoxazole/trimethoprim, benzodiazepines or zolpidem and interacting medications, calcium channel blockers and macrolide antibiotics, digoxin and macrolide antibiotics, lithium and loop diuretics or ACE inhibitors, phenytoin and sulfamethoxazole/trimethoprim, sulfonylureas and antimicrobial agents, theophylline and ciprofloxacin, and warfarin and antimicrobial agents or nonsteroidal anti-inflammatory drugs. One study reported the risk for breast cancer-related death as a function of paroxetine exposure among women treated with tamoxifen.

Conclusions

Several population-based studies have reported significant harm associated drug interactions in elderly patients. Increased awareness and interventions aimed at reducing exposure and minimizing the risks associated with potentially harmful drug combinations are needed.

Introduction

Drug interactions may have potentially life-threatening consequences in older adults, who may take several drugs at once for multiple conditions. Elderly patients are more susceptible to drug interactions than younger patients because of age-related physiologic changes, an increased risk for disease associated with aging, and the consequent increase in medication use.

For the purpose of this review, drug interaction was defined as a clinically meaningful alteration in the effect of one drug (object drug) as a result of coadministration of another (precipitant drug). Although some drug interactions may be used for therapeutic benefit, interactions may also increase the effects of a drug, leading to toxicity, or inhibit the effects of a drug, leading to a diminished therapeutic benefit. A potential drug interaction was defined as an occurrence in which 2 drugs known to interact were concurrently prescribed, regardless of whether adverse events occurred. Drug interactions may broadly be categorized as pharmacokinetic (delivery of the object drug to its site of action is altered by the precipitant) or pharmacodynamic (response of the object drug is modified by the precipitant without changes in the pharmacokinetics of the object drug).¹ Drugs that inhibit or induce the cytochrome P450 (CYP) isozymes are commonly associated with pharmacokinetic interactions.¹ The role of drug transporters is increasingly appreciated as an important pharmacokinetic drug-interaction mechanism.² Pharmacodynamic interactions may be predicted based on the pharmacologic effects of a drug, and the result may be additive or antagonistic.

The elderly are more susceptible to drug interactions due to gradual age-related physiologic changes that affect the pharmacokinetic and pharmacodynamic properties of a variety of medications. These changes may be influenced by genetics, lifelong living habits, and/or the environment, which may contribute to wide interpatient variability and the complexity of managing drug interactions in the elderly population.1, 3 The inhibition and induction of drug metabolism are generally not altered with aging.4, 5, 6, 7, 8 Even without the influence of drug interactions, pharmacokinetic alterations may result from changes in body composition and the function of drug-eliminating organs. For example, age-related changes in body composition (increased fat mass [at the expense of lean mass] and decreased total body water) may lead to an increased volume of distribution and a prolonged half-life with lipophilic drugs, whereas water-soluble drugs tend to have a decreased volume of distribution.⁹ The most prominent age-related change affecting drug excretion is a decrease in renal drug clearance corresponding with the decline in creatinine clearance.4, 9 It may be difficult to distinguish age-related physiologic changes from those resulting from comorbid diseases. For example, confounding factors, such as diabetes, hypertension, and coronary artery disease, may account for diminished kidney function in the elderly population.⁹ Hepatic blood flow and drug metabolism may be reduced in elderly patients, but these changes are highly variable.1, 4 Changes in pharmacodynamic responses also are important factors that contribute to drug interaction susceptibility.¹⁰ Even if a dosage is decreased appropriately to account for age-related pharmacokinetic changes, physiologic changes and decreased homeostasis may result in greater sensitivity to adverse drug reactions.¹

The prevalence of potential drug interactions in the elderly population is not known. Estimates vary considerably among published reports due to variability in patient populations and settings, drug interactions evaluated, and databases and information sources used.11, 12, 13, 14 Hastings et al¹² reported that 13% of elderly veterans were discharged from the emergency department with a drug that introduced a new drug interaction. In a study that used data from in-home interviews of a nationally representative sample of 3005 community-residing older adults, Qato et al¹⁴ reported that nearly 30% of individuals used at least 5 prescription medications concurrently and that 4% were at risk for a major drug interaction. Studies that have evaluated the prevalence rates of potential drug interactions may have overestimated the clinical significance of drug interactions because exposure to a drug interaction may not result in adverse reactions.³ Studies that have focused on drug interactions that led to adverse patient outcomes may provide more accurate estimates of the risks for adverse reactions. However, the prevalence of actual drug interactions is likely underestimated.

The purpose of this narrative review was to describe data from population-based studies that have reported adverse events associated with drug interactions in elderly patients.