A p p ro p r i a t e P re s c r i b i n g and Important Drug Interactions in Older A dults Jeffrey Wallace,



*, Douglas S. Paauw,



KEYWORDS  Elderly  Polypharmacy  Drug interactions  Adverse drug events  Potentially inappropriate medications  Adherence KEY POINTS  Polypharmacy, the use of 5 or more medications, is common in older adults.  Polypharmacy is associated with increased rates of adverse drug events, use of potentially inappropriate medications, and increased drug interactions.  Clinicians need to be aware of drug-drug and drug-disease interactions that are common and important.  Tools and approaches to reducing polypharmacy can enhance the care and health outcomes of older adults.


Adults 65 years of age and older represent 14% of the US population, but take 30% of prescription medications and 50% of over-the-counter medications.1 Most adverse drug events occur in older adults, a fact that is attributable to their greater use of medications, increased vulnerability from underlying medical conditions, and age-related physiologic changes (Box 1).2 The elderly also often suffer from suboptimal medication prescribing that ranges from underuse to overuse to misuse of medications. This article provides clinicians with approaches to optimize medication management in older adults with a focus on reducing polypharmacy and complications related to polypharmacy, medication adherence, use of potentially inappropriate medications, adverse drug reactions, and clinically important drug interactions in older adults.

a Division of Geriatric Medicine, Department of Internal Medicine, University of Colorado School of Medicine, 12631 East 17th Avenue, B-179, Aurora, CO 80045, USA; b Division of General Internal Medicine, Department of Medicine, University of Washington, 4245 Roosevelt way NE, #MC354760, Seattle, WA 98105, USA * Corresponding author. E-mail address: [email protected]

Med Clin N Am 99 (2015) 295–310 http://dx.doi.org/10.1016/j.mcna.2014.11.005 medical.theclinics.com 0025-7125/15/$ – see front matter Ó 2015 Elsevier Inc. All rights reserved.


Wallace & Paauw

Box 1 Age-related changes that increase susceptibility to adverse drug effects Pharmacodynamic changes: altered sensitivity to medications (very few) Increased sensitivity  Warfarin, opiates Decreased sensitivity  b-agonists Pharmacokinetic changes: alterations in factors that affect drug concentration Absorption: minimal clinical relevance (ie, if med is swallowed it generally will be absorbed) Distribution: significant clinical relevance but not readily predictable  Increased fat mass increases volume distribution and half-life of lipophilic medications  Decreased total body water results in decreased volume of distribution and increased concentration of water-soluble drugs  Decreased fat-free mass/plasma protein leads to higher percentage of unbound (active) drug Hepatic metabolism: some clinical relevance but not consistently predictable  Decreased first-pass metabolism leads to increased concentration of drugs that typically have high levels of first-pass metabolism (ie, hepatic clearance before reaching systemic circulation)  Diazepam, propranolol, lidocaine Renal clearance: significant impact and readily predictable  Increased concentration of renally cleared drugs  Serum creatinine alone does not provide adequate information to guide dosing  Use Cockcroft-Gault (CG)a to estimate glomerular filtration rate (eGFR)  More conservative that other calculations (eg, modification of diet in renal disease [MDRD]), less likely to overestimate eGFR, especially in frail older adults  Drug company renal dose recommendations are based on CG a

CG 5 [(140

age)  wt (kg)]  0.85 if female/(72  serum creatinine).


Polypharmacy, defined as taking 5 or more medications a day, is common in older adults.3,4 One national survey found that more than 50% of female Medicare beneficiaries took 5 or more medications daily, with 12% taking 10 or more medications a day.5 Although use of 5 or more medications often appears to be mandated by evidence-based care guidelines, evidence is generally lacking for applying such guidelines to older patients with multiple medical conditions. Conversely, evidence indicates that the use of more medications is associated with increased medication side effects and adverse health events, and these risks increase in a nonlinear fashion as number of drugs increases to 5 or more (Fig. 1). One study found that when compared with persons taking 4 or fewer medications, the risk of an adverse drug reaction nearly doubled (odds ratio [OR] 1.9, 95% confidence interval [CI] 1.35–2.68) for persons taking 5 to 7 medications, and quadrupled (OR 4.07, 95% CI 2.93–5.65) for those taking 8 or more medications.4 Although not always inappropriate, the use of 5 or more medications is associated with higher rates of unwanted health outcomes (Box 2).4,6 These and other issues related to polypharmacy are outlined in this section.

Optimizing Prescribing for Older Adults

Fig. 1. Association between polypharmacy and adverse drug reactions (ADR). (Data from Onder G, Petrovic M, Tangiisuran B, et al. Development and validation of a score to assess risk of adverse drug reactions among in-hospital patients 65 years or older: the GerontoNet ADR risk score. Arch Intern Med 2010;170(13):1142.)


Twenty percent of Medicare beneficiaries have 5 or more chronic conditions. Higher levels of multimorbidity (presence of multiple chronic diseases) are associated with an increased prevalence of polypharmacy, owing in part to guidelines that call for pharmacologic management of each of the multiple medical conditions that an older adult may have.7 However, the coexistence of multiple medical conditions and polypharmacy increases the potential for older adults to have more medication-related complications, ranging from difficulties managing their medications to increased rates of adverse medication effects.8,9 Few studies have enrolled significant numbers of this vulnerable population, older adults with multimorbidity and polypharmacy, to help discern if potential benefits of increased medication use outweighs potential risks.10 Clinicians are thus faced with an evidence/data gap in addressing medication use in older frail patients. Although this may feel disconcerting in this era of evidencebased care, it increases opportunities and impetus for clinicians to carefully evaluate the risk-benefit of each medication and work collaboratively with patients to ensure that medication regimens fit patient preferences and goals of care. USE OF HIGH-RISK AND POTENTIALLY INAPPROPRIATE MEDICATIONS

It is estimated that 20% to 65 % of older adults take potentially inappropriate medications.11 Clinicians should be familiar with well-known comprehensive reviews that Box 2 Problems associated with polypharmacy Adverse drug reactions Drug-drug interactions Drug-disease interactions Higher risk for use of potentially inappropriate medications Decreased adherence Increased risk for medication errors Increased cost Increased morbidity and mortality



Wallace & Paauw

provide lists of medications that should be used cautiously or not at all in older adults, such as the Beers Criteria12 and the annually updated list of high-risk medications in older adults published by The Healthcare Effectiveness Data and Information Set.13 However, two-thirds of adverse drug effects that result in emergency room visits and hospitalizations in older adults are not due to potentially inappropriate medications, but rather to the following 4 medications: warfarin and antiplatelet agents (due to bleeding), and insulin and sulfonylurea agents (due to hypoglycemia).14 When prescribing these 4 agents with high potential for serious adverse events, clinicians should intermittently assess if their continued use is providing health benefits that outweigh potential risks. It is also important to recognize that when aspirin is being used for cardioprotection in patients with stable coronary artery disease, it may be safely discontinued when such patients develop an indication for ongoing anticoagulation with warfarin. For example, if a patient with previous myocardial infarction taking daily aspirin develops atrial fibrillation or has a new thromboembolic event that leads to initiation of warfarin, aspirin should be discontinued because warfarin is cardioprotective. Continuing both warfarin and aspirin doubles the risk of bleeding without conferring additional cardioprotection relative to warfarin alone.15,16 A selected list of frequently problematic medications that should be used with caution or not at all in older adults is presented in Table 1. MEDICATION ADHERENCE AND ERRORS

Adherence to medication regimens is often problematic in patients of all ages.17 Nonadherence rates often approach 50% after 1 year, even for such seemingly important medications as aspirin, statins, and b-blockers following a myocardial infarction.18 Although there are many potential reasons for poor compliance with medications that should be explored with patients (Table 2), several studies indicate that Table 1 Selected medications that should be avoided in older adults Medication

Potential Harm/Concern

Muscle relaxants (eg, cyclobenzaprine, methocarbamol)

Sedating, anticholinergic, increased fall and fracture risk, uncertain efficacy.

Megestrol acetate

Not well proven and minimal effect on weight gain in older adults, lag time of several weeks to months for possible beneficial effect, increased risk of thrombotic events, increased mortality risk.

Iron more than once daily

Increased gastrointestinal side effects (eg, nausea, constipation) usually outweigh small marginal gains in iron absorbed when daily dose increased to twice a day (and even smaller marginal gains when increase twice-daily dose to 3 times a day).

Chronic daily nonsteroidal anti-inflammatory drug use

Gastrointestinal bleed, renal insufficiency, fluid retention, blood pressure elevation. Short-term use for acute injury/ acute pain may be appropriate.

Chronic benzodiazepine use

Fall risk, confusion, dependency/withdrawal. Better/safer agents available for sleep and anxiety, including nonpharmacological.

First-generation antihistamines (eg, diphenhydramine)

Sedating, anticholinergic effects: confusion, dry mouth, dry eyes, constipation, urinary retention.

Optimizing Prescribing for Older Adults

Table 2 Potential reasons for poor compliance with medications Issue

Approaches to Improve Adherence

High number of drugs and regimen complexity

Limit number of medications, ideally to

Appropriate prescribing and important drug interactions in older adults.

Polypharmacy, specifically the overuse and misuse of medications, is associated with adverse health events, increased disability, hospitalizations, an...
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