A complicated medication regimen reduces adherence,98 increases errors,and increases the risk of clinically important xenobiotic interactions. Geriatric patients take more prescription and nonprescription xenobiotics than any other patient group.74 The likelihood of experiencing an ADE increases with the increasing number of xenobiotics taken.65 The problem can be amplified by the common practice of pharmacies to fill an ongoing prescription of a particular medication with different brands over time; this diversity is expected but often problematic, and it is not necessarily accompanied by an adequate discussion with the patient or caregiver, or in the case of a mail order pharmacy, without highlighting the change. The new drug will differ in size, shape, or color from the medication previously dispensed, sometimes also appearing similar or identical to a different medication on the regimen, and medication errors can occur. The same problem can occur when a generic version of the prescribed medication replaces the drug with the “brand” name.
Concurrent disease in target or nontarget organs may alter the patient’s sensitivity to a xenobiotic, resulting in a serious ADE even when the patient is given a standard or previously used dose. Coexistent disease is often subclinical, and the patient’s enhanced sensitivity may not be anticipated. For example, a patient with subclinical Alzheimer disease whose cognitive function is overtly normal may acutely develop delirium or symptoms of dementia when given standard doses of drugs such as sedative–hypnotics or TCAs. Delirium is a medical emergency and an important cause of ED visits by the elderly.67
Another factor contributing to ADEs is physician’s lack of knowledge with regard to the principles of geriatric prescribing.41,60,105 In addition to prescribing inappropriate doses or increasing the dose too rapidly, clinicians may prescribe drugs considered potentially inappropriate for the elderly at any dose, such as TCAs, anticholinergics, and long-acting benzodiazepines.4 At a minimum, and particularly in the case of potentially inappropriate medications, it is reasonable to attend to specific risk factors outlined here and elsewhere in an effort to prevent ADEs.
Another problem is that clinicians may be unduly ready to prescribe drugs recently on the market, despite availability of acceptable and often less expensive alternatives. Recently approved medications are sometimes promoted as being safer than older ones, but problems often become apparent only after marketing and use by large numbers of patients. For example, the hypnotic agent zolpidem was marketed as a safe alternative to benzodiazepines for the elderly. However, like benzodiazepines, zolpidem may cause confusion, global amnesia, memory loss, and falls.140,142 Low-molecular-weight heparins (LMWHs), such as enoxaparin and dalteparin, are other examples. LMWHs have more predictable pharmacokinetics than unfractionated heparin and are associated with a lower rate of overall bleeding. However, because therapeutic monitoring requires measurement of antifactor Xa activity, which is not as readily available as standard tests such as activated partial thromboplastin time (aPTT), monitoring is usually not performed.64 LMWHs such as enoxaparin and dalteparin are eliminated by the kidneys, and repeated doses lead to progressive increases in antifactor Xa activity when GFR is 30 mL/min or below,27,90 a degree of CKD that is common in frail elderly patients. Less severe levels of CKD may also result in reduced enoxaparin clearance that might be avoided with lowered doses.66 Most reported cases of serious, unexpected enoxaparin-induced bleeding occur in elderly patients who are receiving “standard,” not age-appropriate, dosing.96,135,137 Similar problems should be anticipated with other new anticoagulants. For example, the release of dabigatran, a renally eliminated direct thrombin inhibitor approved in 2010 for management of atrial fibrillation, was soon followed by many reports of severe GI bleeding and hemorrhagic stroke in the United States44 and internationally.63 The latter source specifically noted the preponderance of elderly patients in the reports. This finding is consistent with its use in atrial fibrillation, which is most prevalent among the elderly. Whether the risk of dabigatran is greater than that of warfarin is not known, because direct reports to the Food and Drug Administration (FDA) and others in the postmarketing period are not subject to comparison with other xenobiotics.123 Likewise, it is premature to conclude that lack of monitoring or failure to adjust for occult CKD is a cause; however, the clinical trial supporting approval of dabigatran, which randomized subjects with mean age of 71 years, specifically excluded those with estimated GFR ≤ 30 mL/min.32 Importantly, anticoagulants in general remain among the most important causes of ADEs, therapeutic errors, and hospitalizations.14,62 For elderly patients in particular, it is essential for clinicians to be mindful of the possible presence of occult CKD and lesions with the potential to bleed in order to reduce untoward bleeding in this high-risk group of patients.
It is not surprising that ADEs are first noted following drug approval in the postmarketing period when actual patients (as opposed to carefully selected research subjects) are exposed to the drug, because drugs and their effects are often inadequately studied in the elderly (Chap. 139).17,86 Reactions occurring in a small percentage of patients in a special subgroup can easily be missed during the initial drug evaluations. Even when a substantial number of subjects older than age 60 years are studied, a much smaller proportion of patients older than age 70 years may be included in clinical trials.86 Thus, the adults at highest risk for many forms of toxicity are in a population that is often the least studied. Xenobiotic testing is typically carried out in subjects who are young adults and disease free, so pharmacokinetic profiles do not reflect patterns of xenobiotic disposition characteristic of geriatric patients. Pharmacokinetic testing may be limited to a one-time dose, and frequently the evaluation takes place over a short period of time. On average, approximately five half-lives of a xenobiotic are necessary to achieve steady-state xenobiotic concentrations (Chap. 9). Thus, a xenobiotic with a half-life of 24 hours might not reach a steady state for 5 days, and in the presence of prolonged elimination associated with age-related factors, a steady state might not be reached for substantially longer. As a result, even if elderly subjects are included in a drug trial, the ultimate effect might not be appreciated during testing intervals designed for younger patients.
Another factor is the nature of pharmaceutical research itself. Morbidity and mortality in elderly patients as a result of specific drugs might be avoided if the responsible drugs were studied under the predictably high-risk conditions typically present in the elderly. For example, xenobiotics eliminated by the kidney need to be evaluated after repeated dosing in elderly subjects. Gatifloxacin was removed from the market only after several years of use when it was finally linked to both hypoglycemia and hyperglycemia in large numbers of elderly subjects.55,106 Adverse events from xenobiotics that are studied in the elderly or others with chronic illness may be less obvious in the presence of comorbidity in the population at risk. The cyclooxygenase-2 (COX-2) inhibitor rofecoxib (Vioxx) was withdrawn from the market in 2004 after it was shown to increase the risk of myocardial infarction and stroke, especially in older adults.39 Based on the complex actions of COX-1 and COX-2 in many tissues, the possibility existed that COX-2 inhibition might increase cardiovascular morbidity, for example, by leaving COX-1–mediated platelet aggregation unopposed while inhibiting prostacyclin-induced vasodilation or by leading to fluid retention and increased blood pressure via renal mechanisms.61,109 Because the elderly typically have one or more chronic illnesses28 as well as occult disease, extra vigilance is required when new xenobiotics are given, and clinicians and clinical investigators must be very mindful of the theoretical possibilities of adverse outcomes. In view of the vulnerability of older patients to many medications, the FDA now requires that sponsors of new drug applications present effectiveness and safety data for important demographic subgroups, including the elderly, in their FDA submission data.24 However, exceptions to the rule are allowed. For example, when studies have included insufficient numbers of subjects older than age 65 years to determine whether the elderly respond differently to the drug, the labeling must state this, but the statement is a poor substitute for providing actual efficacy and safety data.30 Unfortunately, geriatric recommendations in the package insert may thus be insufficiently specific to provide guidance for drugs commonly used in this population.126
Drugs, such as digoxin, warfarin, and diuretics, commonly prescribed in the elderly, are frequently involved in serious drug interactions. This situation is complicated by the frequency with which elderly patients, who often have multisystem disease, visit multiple physicians, who prescribe medications without specific knowledge of, or attention to, the remainder of the patient’s drug regimen, thereby increasing the risk of inappropriate combinations.52,132 Problems can also arise when patients obtain prescriptions from more than one pharmacy or mail order service. Warfarin is a particular problem, owing to its narrow therapeutic index and numerous pharmacokinetic as well as pharmacodynamic interactions, the potential for which (eg, with certain antibiotics) may often be ignored at the point of care.50
Herbal preparations used by the elderly also may interact with prescription medications.70 The use of herbal preparations has increased substantially in recent years, particularly in patients with illnesses such as cancer, dementia, and depression, which commonly affect the elderly. Very few patients voluntarily report use of these or other nonprescribed therapies to their physicians, and too often the physician fails to inquire specifically about such “alternative” or “complementary” therapies. Poisonings, herb–drug interactions, and other problems related to herbal preparations are discussed further in Chap. 45.
The use of nonprescription pharmaceuticals may also cause serious adverse effects. For example, excessive use of magnesium-containing preparations frequently causes severe toxicity in older individuals. Impaired GFR, decreased GI motility, and other medical comorbidities are just three risk factors that potentiate magnesium toxicity in the elderly. The source of magnesium in these cases may include the cathartics that contain magnesium hydroxide (Milk of Magnesia) and magnesium citrate, antacid preparations, and magnesium sulfate (Epsom salts).49 Magnesium-containing laxatives are still sometimes used in hospital settings with serious outcomes.104 Likewise, sodium phosphate formulations may harm kidney function in certain elderly patients despite normal baseline creatinine.76 Virtually all of the most popular nonprescription medications74 are more likely to produce problems in the elderly than in younger patients, including GI bleeding (aspirin and other NSAIDs), enhanced warfarin sensitivity (cimetidine), confusion and urinary retention (anticholinergic antihistamines), and cardiovascular symptoms (pseudoephedrine).
Outdated and discontinued xenobiotics are an additional problem for the elderly, who often retain unused or partially used products in their homes for decades or may continue to request prescription renewals when safer or more effective alternatives are available. Patients may be unwilling to change or physicians may continue to renew the prescription without sufficiently reevaluating the patient. Potential examples include digoxin and theophylline, which have been responsible for large numbers of adverse events diagnosed in EDs,14,15 as well as sedating antihistamines, other anticholinergics, and diazepam.
Other age-related factors may increase the risk of unintentional poisonings in geriatric patients; impaired vision, hearing, and memory may lead to misunderstanding or an inability to follow directions concerning the use of prescription and nonprescription drugs. Dementia is another important risk factor in unintentional poisonings. In addition to cognitive impairment, patients with dementia sometimes exhibit abnormal feeding behaviors, which may lead to ingestion of toxic xenobiotics.143