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Adverse Drug Reactions
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Epidemiology and Risk Factors
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Adverse drug reactions (ADRs) are substantially more common in older than in younger adults. Up to 35% of ambulatory older adults experience 1 or more ADRs annually, 5% to 10% of hospital admissions in older adults are ascribable to ADRs, and 5% or more of older hospitalized patients experience an ADR during their inpatient stay. Simply being old does not meaningfully increase ADR risk. Rather, it is the number of medications taken and the burden of disease (which often, but not always, increases as patients get older) that are the strongest risk factors for ADRs in the outpatient setting.
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Several observational studies have failed to find a globally increased risk of ADRs in older adults with impaired functional status and geriatric syndromes. However, the risk of ADRs may increase with specific drugs that can interact with specific impairments. For example, central nervous system-acting drugs may have a particularly high risk of causing ADRs in patients with underlying cognitive impairment.
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A note on terminology: “Adverse drug reactions” refers to the unwanted effects of drugs at normal dosage and use. “Adverse drug events” refers to a broader range of potential harms associated with the drug, including overdose, withdrawal reactions from abrupt discontinuation of a drug, and more.
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Causes of Adverse Drug Reactions
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ADRs are commonly classified into 2 predominant types. Type A ADRs result from expected yet unwanted or exaggerated physiologic effects of the drug. For example, β blockers may cause bradycardia that results in syncope. Type B ADRs, which are less common, result from idiosyncratic effects unrelated to the drug’s usual physiologic targets; for example, anaphylaxis to penicillin.
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In older adults, type A ADRs often arise from the interaction of a drug and underlying characteristics of the patient. Medications with a narrow therapeutic index and prolonged half-life cause the most trouble for the older patient. Patients with multiple medications, disease states, and/or subclinical physiologic changes associated with aging can be more susceptible to unwanted effects of a drug.
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Drug–drug interactions can lead to ADRs by pharmacokinetic and pharmacodynamic mechanisms. In the former, Drug A inhibits the activity of a cytochrome P450 isoenzyme, resulting in delayed clearance of Drug B which is metabolized by that isoenzyme. This results in excessive tissue levels of Drug B, and resultant adverse effects. Common culprits that inhibit P450 activity include antimicrobials such as ciprofloxacin, fluconazole, and clarithromycin; some selective serotonin reuptake inhibitors; amiodarone; and verapamil and diltiazem. For example, diltiazem inhibits cytochrome P450 isoenzyme 3A4 (CYP3A4). Atorvastatin and several other (but not all) statin medications are metabolized by CYP3A4. Thus, if a patient is taking both diltiazem and atorvastatin, atorvastatin will accumulate because the enzyme that metabolizes it has been rendered less active. Tissue levels of atorvastatin will rise, potentially to the level where they cause substantial toxicity (ie, increase the risk of rhabdomyolysis and liver injury).
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Cytochrome P450 isoenzymes can also be induced (“sped up”). This induction results in rapid clearance and thus decreased effectiveness of drugs metabolized by the affected isozyme. Medications that are potent inducers of P450 enzymes include rifampin, barbiturates, carbamazepine, and phenytoin. In general, cytochrome P450-mediated interactions are most important when induction or inhibition is potent (eg, greater than 5-fold change in enzyme activity) and the substrate drug has a narrow therapeutic index (eg, warfarin, sulfonylureas). In contrast, drug interactions that involve weak induction or inhibition and a substrate drug with a wide safety margin are less likely to be clinically relevant.
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Use of 2 or more drugs with mutually reinforcing physiologic effects can also result in harms. For example, third-degree heart block may occur in a patient prescribed digoxin and a β blocker, as both suppress conduction of atrial impulses through the atrioventricular node.
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Drug–disease interactions occur when an underlying disease state makes a patient more susceptible to the unwanted physiologic effects of a drug. Not every potential interaction results in harm. For example, many patients with mild or moderate chronic obstructive pulmonary disease can tolerate β blockers without adverse effects, although some will develop worse pulmonary symptoms in this setting.
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In addition to ADRs, an expanded range of adverse events can occur from misuse of drugs. This can include complications of excessive doses of a drug, failure to prevent or treat disease because of nonadherence to or insufficient dosing of a drug, or withdrawal reactions caused by abrupt discontinuation of a drug to which the body has physiologically adapted (ie, chronic opioids).
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Preventing Adverse Drug Reactions and the Role of Monitoring
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Fewer than one-quarter of ADRs in ambulatory older adults are a result of clinicians making clearly inappropriate prescribing decisions. In contrast, most ADRs result from drugs that were reasonable to prescribe, and represent the known but unwelcome potential adverse reactions of a given drug. Warfarin and insulin are the most common causes of ADRs severe enough to precipitate an emergency room visit. Nonetheless, these drugs have an important place in the therapeutic armamentarium for older adults. In fact, warfarin is often underprescribed, as for many patients the benefits of preventing a stroke or pulmonary embolism outweigh the risk of hemorrhage.
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True prevention is difficult in this setting, as it can be difficult to precisely predict which patients will be helped or harmed by a drug. Yet, many ADRs can be detected and managed early, sparing the patient prolonged symptoms or a cascade of ever-worsening adverse effects (such as untreated orthostasis resulting in a fall with fracture). Monitoring older adults for emerging ADRs thus plays a critical role in reducing the burden of ADRs, yet is often not done well. One important impediment to monitoring is that both patients and physicians may falsely attribute a new symptom to an underlying disease state or “getting old,” rather than recognizing it as an adverse drug reaction. This leads patients to underreport potential ADRs and to physicians not properly diagnosing a symptom as an ADR even when the patient reports it. The mantra “any symptom in an older adult is a medication side effect until proven otherwise” provides a useful reminder to always keep ADRs on the differential diagnosis when evaluating a new or worsened complaint.
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Any symptom in an older adult is a medication side effect until proven otherwise.
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Dedicated nurse-led and pharmacist-led programs are effective strategies for ADR monitoring, best exemplified by anticoagulation clinics. Although little data are available to support simple in-office or bedside tools for ADR monitoring, expert opinion suggests that several strategies may be helpful. These include: (a) at the time a drug is prescribed, warning the patient of which adverse reactions to watch for; (b) at the next patient encounter, use a combination of open-ended questions and specific prompts to query for adverse reactions (eg, “Are you having any side effects or problems from Drug X?” followed by specific questions about dangerous and common adverse reactions); and (c) using a similar strategy to query for adverse reactions during annual medication review.
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Multiple Medication Use
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Epidemiology and Potential Harms and Benefits of Using Multiple Medicines
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Nearly 20% of adults age 65 years and older use 10 or more medications. This use of multiple medications is commonly referred to as “polypharmacy.” This term carries a pejorative connotation, in part for good reason. Use of multiple medications substantially increases the risk of drug–drug interactions and of adverse drug events, can impose substantial cost burdens on patients, complicates adherence, and is associated with increased risk of using inappropriate medications. On the other hand, older patients often have multiple chronic conditions that can be substantially helped by medications. In many such patients, the use of multiple drugs is an appropriate therapeutic choice. Thus, while use of multiple medications is a risk factor for medication problems—and should prompt close attention to reducing unnecessary medications—the focus on reducing medications needs to be balanced with the harms to longevity and quality of life that arise from undertreated chronic conditions (see Chapter 53, “Addressing Polypharmacy & Improving Medication Adherence in Older Adults”).
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The Prescribing Cascade
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One important contributor to multiple medication use is “the prescribing cascade,” in which the adverse effects of one drug are treated with another drug, which itself causes adverse effects that are treated with a third drug, and so forth. This can result from misinterpreting a sign or symptom as the manifestation of an underlying disease process, rather than as an adverse drug effect. As noted above, remembering the mantra “any symptom in an older adult is a medication side effect until proven otherwise” can help guard against potential prescribing cascades. Except in unusual circumstances, it is typically better to withdraw or substitute the offending drug rather than treating its adverse effects with another drug.
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Overuse, Misuse, and Underuse of Medications
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For many older adults, the question is not whether a patient is taking too many or too few medications, but whether the patient is taking the right medications given the patient’s diseases, preferences, and ability to adhere. Deviations from an optimal regimen can be viewed as problems of overuse (use of a drug where no medication therapy is needed), misuse (use of a drug where a better alternative is available), and underuse (nonuse of a drug that would be beneficial).
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Overuse and misuse of drugs are common. Approximately 20% to 30% of older ambulatory adults use at least 1 drug that consensus criteria recommend avoiding in older patients. Expert review of medication regimens in outpatient, inpatient, and nursing home settings has also identified large proportions of patients taking drugs that are not indicated, ineffective for the condition being treated, or otherwise problematic. It is common for drugs to be continued long after they are no longer necessary. For example, roughly half of patients who are started on a proton pump inhibitor for stress ulcer prophylaxis during a hospital stay are continued on these medications after discharge, for no discernible reason.
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Several explicit criteria, commonly called “drugs-to-avoid lists,” have been developed to identify medications and therapeutic situations that are potentially inappropriate for older adults. These tools have proved useful for quality improvement, including flagging instances of such prescribing for special scrutiny and review. Nonetheless, clinical judgment needs to be applied for individual patients, as there are situations in which use of many of these drugs is reasonable.
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The Beers criteria of potentially inappropriate medications are shown in Table 9–1. The most frequently cited part of these criteria concern drugs that are potentially inappropriate in any setting. Commonly used medications on this “drugs-to-avoid” list include first-generation antihistamines (eg, diphenhydramine and hydroxyzine), tertiary-amine tricyclic antidepressants, use of benzodiazepines for insomnia, agitation, or delirium, long-acting sulfonylureas (eg, glyburide), and sliding-scale insulin.
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The STOPP (Screening Tool of Older Person’s Prescriptions) criteria define an extensive list of specific clinical situations in which drug use is potentially inappropriate (Table 9–2). Examples include use of loop diuretics for ankle edema in the absence of heart failure; selective serotonin reuptake inhibitors in patients with a history of hyponatremia; and use of NSAIDs in patients with heart failure or moderate-to-severe hypertension.
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The ACOVE (Assessing Care of Vulnerable Elders) criteria for vulnerable older adults cover a wide range of topics, including a number of criteria related to medication use. ACOVE criteria address not only potentially inappropriate medications but also recommended care practices, including patient education about medications and regular medication review.
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Although use of inappropriate drugs is commonly discussed in older adults, equally important is the undertreatment of conditions that could be helped by drug therapy. Older adults are less likely to receive indicated medications than their younger counterparts, even after accounting for contraindications to these therapies. Excessive fear of causing adverse events, distraction by other clinical issues, a sense of futility, and subtle ageism likely contribute to this pattern. In addition, treatable conditions are often underdiagnosed in older patients, and symptoms such as pain, fatigue, depressed mood, or orthostasis may be incorrectly attributed to “getting old.”
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The START (Screening Tool to Alert doctors to Right Treatment) criteria are consensus criteria that identify potential underuse of beneficial medications in older adults (Table 9–3). As with other explicit criteria, these are intended as a guide but not as a substitute for clinical judgment for individual patients. Examples of drugs which the START criteria recommend should routinely be used include warfarin for chronic atrial fibrillation (in the absence of contraindications); regular inhaled β-agonist or anticholinergic therapy for patients with mild to moderate asthma or chronic obstructive pulmonary disease (COPD); and bisphosphonates in patients on chronic corticosteroid therapy.
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The ACOVE criteria also identify instances of potential underuse for a variety of chronic illnesses. This includes not only omissions of specific medication but other recommended care processes, including annual medication review, educating patients about their medications, and monitoring for medication effectiveness and toxicity.
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High-Risk Medications
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The following medications are often associated with adverse reactions and merit special caution in prescribing.
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Warfarin and Other Anticoagulants
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The benefits of warfarin for stroke prevention in atrial fibrillation and for the treatment of venous thromboembolism (VTE) outweigh the risk of hemorrhage for most patients, even for patients older than age 80 years and patients with a history of falls. Yet, warfarin is the most common medication implicated in emergency room visits and hospitalizations for ADRs. Safe use requires close monitoring to keep patients in the target anticoagulation range and attention to the increased risk of hemorrhage when used with antiplatelet agents. Close to 700 known medications, supplements, and foods interact with warfarin, either by inhibiting cytochrome P450 enzyme activity, displacing plasma protein binding, affecting vitamin K metabolism, or potentiating bleeding risk through other antithrombotic mechanisms. Antibiotics, antiplatelet agents, and amiodarone are commonly implicated as the source of drug–drug interactions that result in bleeding. Patients receiving warfarin must be monitored closely to keep the international normalized ratio (INR) in target range, as well as for drug–drug interactions whenever a new medication is added.
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Despite the risks of warfarin, newer anticoagulant medications have not yet displaced its use. Dabigatran is an oral direct thrombin inhibitor that is approved for stroke prevention in nonvalvular atrial fibrillation and is used outside the United States for VTE prophylaxis after hip or knee replacement surgery. Dabigatran overdose cannot be reversed, and thus, the risk of severe, or even fatal, hemorrhage may make warfarin a more desirable choice. Reduced dosing is recommended in renal impairment. In Canada, doses are reduced for people age 80 years and older, although at this writing the labeling in the United States does not recommend any alteration in dose based on age.
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Older age is associated with increased risk of drug-induced hypoglycemia. Insulin is the second-most common cause of ADRs that lead to emergency room visits in older adults. Although insulin has a useful place in the treatment of diabetes, caution in prescribing is merited. Special attention should be paid to factors that may increase the risk and consequences of severe hypoglycemia. These risk factors include diminished renal function, use of medications that may interact with insulin’s effects, and impaired cognitive function (which may interfere both with proper use and with the patient’s ability to obtain help if hypoglycemia begins to occur). Long-acting basal insulins (eg, insulin glargine and insulin detemir) are less likely to cause hypoglycemia than neutral protamine Hagedorn (NPH) insulin. Sliding-scale insulin should be avoided, as it increases the risk of hypoglycemia without yielding improved glycemic control. (See also Chapter 42, “Diabetes.”)
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Long-acting Sulfonylureas
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All sulfonylureas have the potential to cause hypoglycemia. In older adults, the risk of adverse events is particularly high with the long-acting sulfonylureas, including glyburide (also known as glibenclamide) and chlorpropamide. This excess risk is partly a consequence of accumulation of these drugs in patients with diminished drug clearance. If a sulfonylurea is used, a shorter-acting version, such as glipizide, is preferred.
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Digoxin toxicity is common, often manifesting as neurologic abnormalities (including fatigue, confusion, or changes in color perception) and/or GI disturbances. Toxic effects including arrhythmias are accentuated in the presence of hypokalemia, which commonly occurs in patients who are also receiving loop diuretics. Impaired renal function and drug–drug interactions often result in elevated serum digoxin levels in older adults, although toxicity can occur even at serum digoxin levels within the normal range. Other agents are typically preferred for management of heart failure and atrial fibrillation with rapid ventricular response, although digoxin may be appropriate in select patients. If used, digoxin should be prescribed at doses ≤0.125 mg/day and patients carefully monitored for serum digoxin levels (aiming for the low-normal range), electrolytes (particularly hypokalemia), and for clinical signs of toxicity. New or worsening neurologic, GI, or cardiac signs or symptoms in a patient taking digoxin should be considered an adverse drug reaction until proven otherwise.
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NSAID-induced peptic ulcer disease and renal impairment occur more commonly in older adults than in younger adults. In addition, these drugs exacerbate hypertension, promote fluid retention in patients with heart failure, and antagonize the cardioprotective effects of aspirin through competitive inhibition of the cyclooxygenase (COX)-1 enzyme. The Beers criteria and pain guidelines from the American Geriatrics Society discourage regular, chronic use of systemic NSAIDs in older adults, preferring acetaminophen, and in many cases opioids, for pain control. NSAIDs are contraindicated in patients with heart failure, renal dysfunction, and those at high risk of peptic ulcer-induced GI bleeding. Risk of this latter complication increases substantially in patients also taking warfarin, selective serotonin reuptake inhibitors (SSRIs), or systemic corticosteroids. If NSAIDs are used for longer than brief episodic use, the following considerations are advised: (a) use at the lowest dose and for the shortest duration possible; (b) coadminister proton pump inhibitors or misoprostol for gastroprotection; (c) maximize the time between taking cardioprotective aspirin and taking an NSAID (ie, take aspirin upon awakening, delay taking NSAIDs until at least 2 hours later); and (d) consider followup in 2–4 weeks after starting an NSAID to evaluate for renal dysfunction, fluid retention, and blood pressure elevation. NSAIDs with a balanced inhibition of COX-1 and COX-2 are preferred in patients who are at risk of cardiovascular disease. Consistent with this, some data suggest that naproxen has among the most favorable cardiovascular risk profiles. Topical NSAIDs, such as topical diclofenac gel, have relatively minimal systemic absorption and thus substantially lower risk of causing systemic toxicity.
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Drugs that block the action of acetylcholine include sedatives, antihistamines, antidepressants, antipsychotics, bladder and GI antispasmodics, muscle relaxants, and antiemetics (see examples in Table 9–4). The cumulative burden of multiple anticholinergic drugs has been associated with an increased risk of falls, functional decline, and impaired cognition in older persons. If a medication with anticholinergic properties is considered necessary, substitution with a less anticholinergic medication in the same therapeutic category should be attempted when possible.
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Opioids are useful to treat moderate to severe pain in older persons, but opioids may be underused because of difficulty in diagnosing and assessing pain and concerns about safety and correct use of opioids. Safety concerns include an increased risk of delirium, GI side effects, and ventilatory depression. However, untreated pain can result in delirium, depression, decreased mobility, and impaired sleep. Changes in pharmacokinetics, as well as the increased pharmacodynamic effects of opioids, increase the risk of ADRs. Nonetheless, opioids can often be used safely when keeping these age-related changes in mind. In general, the dosing interval should be the same for an older person of any age, but it is typically appropriate to start with a low dose and titrate up the dose slowly, often termed ‘start low and go slow.’ Drug–drug interactions need to be kept in mind, as many opioids are substrates for P450 enzymes. Finally, tailoring treatment for renal or liver dysfunction may be necessary. For those with substantial renal impairment, morphine should be avoided, and hydromorphone, fentanyl, and methadone may be preferred alternatives. Methadone and codeine should not be used in severe liver impairment, and, in general, opioid dose should be reduced even further, with a longer dosing interval.
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Antipsychotics in Dementia
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The use of antipsychotics to treat behavioral and psychological symptoms of dementia is associated with increased likelihood of myocardial infarction, stroke, falls, fractures, VTE, and mortality. As a result, FDA warnings, practice guidelines, and initiatives from the Centers for Medicare and Medicaid Services have decreased their use. Older antipsychotics also have significant anticholinergic and extrapyramidal side effects. When possible, behavioral and psychological symptoms of dementia should be treated by nonpharmacologic means. When antipsychotics are deemed necessary for symptoms causing severe distress or harm, benefits and risks should be discussed with a patient’s family or caregiver, the discussion should be clearly documented, and the antipsychotics should be used for a minimum duration of therapy with attempts to taper and discontinue the medication when possible.