Review articlePotentially Harmful Drug–Drug Interactions in the Elderly: A Review
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.
Section snippets
Methods
The authors conducted a review of the literature focusing on human studies published in English in the PubMed and International Pharmaceutical Abstracts databases over the past 10 years (December 2000–December 2010). For a summary of studies published prior to this time frame, readers are referred to a relevant textbook and a previously published review.15, 16 Pertinent Medical Subject Headings (MeSH) terms were identified after a review of the literature and consultation with an academic
Results
The 17 studies (reported in 15 articles) that met the inclusion criteria are summarized in the Table.19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33 Sixteen studies reported an elevated risk for hospitalization due to adverse drug-drug interactions, including angiotensin-converting enzyme (ACE) inhibitors and potassium-sparing diuretics19; ACE inhibitors or angiotensin receptor blockers (ARBs) and sulfamethoxazole/trimethoprim (SMX/TMP)20; benzodiazepines (BZDs) or zolpidem and other
Discussion
In contrast to some reports of drug interactions (eg, premarketing studies in healthy subjects, case reports), population-based studies are useful in evaluating the consequences of drug interactions in clinical practice. This information is needed for clinicians to make reasonable estimates of risk in specific patients and to guide therapeutic decision making.
Many other potentially hazardous drug combinations exist beyond the interactions described in the present review. For example, other
Conclusions
The elderly population consumes a disproportionate share of prescription and over-the-counter drugs relative to younger persons. These factors, combined with age-related changes in pharmacokinetic and pharmacodynamic parameters, make the elderly population more susceptible to drug interactions. Therefore, when the elderly receive drug therapy, it should be absolutely necessary for the achievement of well-defined goals and given at the lowest effective doses. Adverse drug interactions may be
Acknowledgments
L.E.H. received an honorarium from The American Journal of Geriatric Pharmacotherapy for writing this manuscript. She has received research grant support from the Agency for Healthcare Research and Quality (1R18HS019220-01, U18HS017001-01), honoraria from professional organizations, and a consultancy from Ortho Clinical Diagnostics. J.E.M. has not received funding from any source other than the Agency for Healthcare Research and Quality and foundations for research, and professional
References (91)
- et al.
The challenge of managing drug interactions in elderly people
Lancet
(2007) Pharmacokinetics in older persons
Am J Geriatr Pharmacother
(2004)- et al.
Aging and the response to inhibition and induction of theophylline metabolism
Exp Gerontol
(1993) - et al.
Pharmacodynamics in older adults: a review
Am J Geriatr Pharmacother
(2007) Understanding and preventing drug interactions in elderly patients
Crit Rev Oncol Hematol
(2003)- et al.
Drug–drug interactions in older adults: which ones matter?
Am J Geriatr Pharmacother
(2005) - et al.
Hospital admissions for hyperkalemia with trimethoprim–sulfamethoxazole: a cohort study using health care database codes for 393,039 older women with urinary tract infections
Am J Kidney Dis
(2011) Interaction of grapefruit juice and calcium channel blockers
Am J Hypertens
(2006)- et al.
Influence of aging on serum phenytoin concentrations: a pharmacokinetic analysis based on therapeutic drug monitoring data
Epilepsy Res
(2004) - et al.
Characterization of human cytochromes P450 involved in theophylline 8–hydroxylation
Biochem Pharmacol
(1995)
Role of ciprofloxacin in fatal seizures
Chest
Theophylline toxicity: clinical features of 116 consecutive cases
Am J Med
Effect of disease states on theophylline serum concentrations: are we still vigilant?
Am J Med Sci
Human P450 metabolism of warfarin
Pharmacol Ther
A comparison of four methods to quantify the cumulative effect of taking multiple drugs with sedative properties
Am J Geriatr Pharmacother
Identification of serious drug–drug interactions: results of the partnership to prevent drug–drug interactions
J Am Pharm Assoc (2003)
The science of drug therapy
The role of P-glycoprotein and organic anion-transporting polypeptides in drug interactions
Drug Saf
Aging and drug interactions. II. Effect of phenytoin and smoking on the oxidation of theophylline and cortisol in healthy men
J Pharmacol Exp Ther
Aging and drug interactions. III. Individual and combined effects of cimetidine and cimetidine and ciprofloxacin on theophylline metabolism in healthy male and female nonsmokers
J Pharmacol Exp Ther
Aging and drug interactions. I. Effect of cimetidine and smoking on the oxidation of theophylline and cortisol in healthy men
J Pharmacol Exp Ther
Pharmacokinetics and drug metabolism in the elderly
Drug Metab Rev
Drug–drug interactions in the elderly
Ann Pharmacother
Quality of pharmacotherapy and outcomes for older veterans discharged from the emergency department
J Am Geriatr Soc
The relationship between number of drugs and potential drug–drug interactions in the elderly: a study of over 600,000 elderly patients from the Swedish Prescribed Drug Register
Drug Saf
Use of prescription and over-the-counter medications and dietary supplements among older adults in the United States
JAMA
Therapeutics in the Elderly
The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies
PLoS Med
Drug–drug interactions among elderly patients hospitalized for drug toxicity
JAMA
Trimethoprim–sulfamethoxazole–induced hyperkalemia in patients receiving inhibitors of the renin–angiotensin system: a population–based study
Arch Intern Med
Impact of drug interactions, dosage, and duration of therapy on the risk of hip fracture associated with benzodiazepine use in older adults
Pharmacoepidemiol Drug Saf
The risk of hypotension following co-prescription of macrolide antibiotics and calcium-channel blockers
CMAJ
Macrolide-induced digoxin toxicity: a population–based study
Clin Pharmacol Ther
Risk of digoxin intoxication caused by clarithromycin–digoxin interactions in heart failure patients: a population–based study
Eur J Clin Pharmacol
Drug–induced lithium toxicity in the elderly: a population–based study
J Am Geriatr Soc
Trimethoprim/sulfamethoxazole–induced phenytoin toxicity in the elderly: a population–based study
Br J Clin Pharmacol
Anti–infectives and the risk of severe hypoglycemia in users of glipizide or glyburide
Clin Pharmacol Ther
Selective serotonin reuptake inhibitors and breast cancer mortality in women receiving tamoxifen: a population based cohort study
BMJ
Ciprofloxacin–induced theophylline toxicity: a population–based study
Eur J Clin Pharmacol
Warfarin with fluoroquinolones, sulfonamides, or azole antifungals: interactions and the risk of hospitalization for gastrointestinal bleeding
Clin Pharmacol Ther
Hemorrhage during warfarin therapy associated with cotrimoxazole and other urinary tract anti–infective agents: a population–based study
Arch Intern Med
Risk of upper gastrointestinal hemorrhage in warfarin users treated with nonselective NSAIDs or COX–2 inhibitors
Arch Intern Med
Gastrointestinal safety of nonsteroidal antiinflammatory drugs and selective cyclooxygenase–2 inhibitors in patients on warfarin
Ann Pharmacother
Managing hyperkalemia caused by inhibitors of the renin–angiotensin–aldosterone system
N Engl J Med
Benzodiazepines and risk of hip fractures in older people: a review of the evidence
CNS Drugs
Cited by (223)
Design, development, implementation, and evaluation of a severe drug–drug interaction alert system in the ICU: An analysis of acceptance and override rates
2023, International Journal of Medical InformaticsAge-related considerations in the use of cannabinoids: Focus on drug interactions, physiology, and drug effects
2023, Cannabis Use, Neurobiology, Psychology, and TreatmentDrug interactions case studies
2023, Clinical Case Studies on Medication SafetyDrug–drug interactions and the risk of adverse drug reaction-related hospital admissions in the older population
2024, British Journal of Clinical PharmacologyHelicobacter pylori Eradication Treatment in Older Patients
2024, Drugs and AgingPotential drug–drug interactions in patients with non-small cell lung cancer at a university hospital in Turkey
2023, Journal of Cancer Research and Clinical Oncology