Chapter 32. Geriatric Principles

In developed countries, the population is aging steadily. In the United States, those older than 65 years of age comprise not only an increasing proportion of the population at large (12%) but also an increasing proportion of patients seen in medical practices. Compared with all other age groups, patients older than 65 years of age account for one-third of emergency department (ED) ambulance arrivals and the highest proportion of patients in EDs triaged as emergent.80

Although the elderly account for only a small minority of toxicologic exposures, after they have been exposed, they have a high mortality rate. Among exposures reported to the American Association of Poison Control Centers (AAPCC) in 2006, the fatality ratio (ie, number of cases divided by number of deaths) increased with age in a bimodal pattern, with peaks in the middle and latest decades of life (see Chap. 135). Previous AAPCC surveys had shown a steady increase in fatality ratio. In addition to possible methodologic changes and smaller numbers of exposures in the latest decades of life, potential explanations for the current change to a bimodal pattern may include an increase in intentional exposures in midlife and physiologic vulnerability in the later decades. However, this only accounts for part of the difference because suicide fatality ratios increase steadily with age (see Suicide and Intentional Poisonings below). In a separate study, seven specific pharmaceuticals were selected from the AAPCC database for analysis based on their prevalent use and potential toxicity from 1995 through 2002. These pharmaceuticals were theophylline, digoxin, benzodiazepines, tricyclic antidepressants (TCAs), calcium channel blockers, acetaminophen, and salicylate.97 The death rate from intentional or unintentional exposure to these pharmaceuticals was found to increase by 35% for each decade of life after age 19 years.97

Toxic exposures reported to the AAPCC may underestimate the serious consequences for elderly people exposed to toxic substances. Data from the National Electronic Injury Surveillance System—Cooperative Adverse Drug Event Surveillance Project (NEISS-CADES) indicate that patients aged 65 years and older accounted for 25% of estimated visits related to adverse drug events (ADEs) and almost 50% of such visits requiring hospitalization or prolonged monitoring in the ED.10 The problem may be even greater because the NEISS-CADES study did not capture recognized or unrecognized ADEs in patients treated or dying outside of EDs.

Underrecognition of toxic exposures in the elderly may occur for several reasons. First, because of pharmacokinetic and pharmacodynamic changes that occur as one ages,31 a "standard" therapeutic dose may produce an unexpected serious effect. Second, the presentation of disease, including drug toxicity, is often atypical in the elderly.59 For example, falls in the elderly may be a presenting sign of xenobiotic toxicity and are commonly due to prescribed xenobiotics, with sedative–hypnotics, antipsychotics, antidepressants, and class Ia antidysrhythmics (quinidine and procainamide) most often associated with an increased risk of falling.108 If the patient is cognitively impaired and the fall is unwitnessed, the immediate consequences of the fall may be adequately addressed, but the xenobiotic causing it may not.67 Likewise, the toxicologic etiology of neurologic deficits may not be recognized. For example, severe hypoglycemia can produce signs of classic stroke,116 which could be attributed to other etiologies, particularly in someone who is elderly and otherwise predisposed (see Chap. 48). Another important syndrome in older patients is delirium, which may be caused by many factors but is a common presentation of xenobiotic toxicity87 (see Chap. 18).87 A large variety of xenobiotics may cause mental status changes, which may mistakenly be attributed to for nonxenobiotic-related causes in the elderly.104 Conversely, altered mental status may be unrecognized75 and, even when obvious, misdiagnosed—for example, as Alzheimer's disease.

A striking case of drug-induced mental status changes is represented by a previously normal 66-year-old man who developed psychosis and attempted suicide after taking increasing doses of dextromethorphan-containing cough syrup for a respiratory infection. The patient was treated with psychiatric medications, and several months elapsed before providers realized that his behavior had been xenobiotic induced rather than due to a primary psychiatric condition.79

Finally, the presentation of drug toxicity may be delayed in elderly individuals. Drugs with long half-lives may not reach a steady state and hence not achieve peak action until days after the drug therapy is initiated. In some older patients, the active metabolite of flurazepam, desalkylflurazepam, has a half-life of up to 100 hours or longer, which requires days to achieve a steady state.47 When peak effects are delayed in this way, drug toxicities may easily be mistaken for nondrug-related illnesses.

Table 32–1 lists xenobiotics commonly responsible for toxicity in the elderly.

The risk of suicide by all methods increases steadily with age, particularly among men. Although data for individual ethnic groups are limited, white men have a substantially higher risk of suicide than age-matched cohorts among the African American population.20 Another high-risk group appears to be Native American and Alaskan Native men,61 although the number of deaths from all causes among elderly men in those groups is too low to make meaningful comparisons.20 Although less likely than men to complete suicide, women are more likely to attempt it.20 The male-to-female ratio of suicide attempts narrows with increasing age, and in the oldest age groups, men attempt suicide slightly more often than women, when all methods of attempted suicide are considered (Chap. 17).20,102

Data published in 2000 from eight states reveal that for all attempted and successful suicides combined, the case fatality rate increases with age and is highest for those aged 65 years and older compared with all other age groups (30.7% compared with 14.8% in the next highest group, which is those between 45 and 64 years old).102 Although the elderly are more likely to select a highly lethal method, the fatality rate is highest among the elderly regardless of method used. In the United States, firearms are the most frequent means of death by suicide. Among men older than age 65 years, xenobiotic overdose accounts for only 3% of completed suicides, and firearms account for 73%. In contrast, xenobiotic overdose and firearms each account for approximately 25% of successful suicides in women. When death by toxic inhalation is included, poison exposure may surpass gunshot wounds as a cause of death among elderly women.82 Xenobiotic overdose is an important factor in suicide attempts by the elderly of both genders.41

Geographic and cultural factors also determine the method of suicide. In countries other than the United States, firearms are only rarely used to commit suicide at any age; suicide by oral overdose and toxic inhalation consequently comprise a much greater proportion.106 A study of medical examiner–certified suicides in New York City between 1990 and 1998 revealed that falls from a height was the most common method used by people 65 years of age and older and accounted for 33.6% of suicides by people 85 years and older.2 These data likely represent a local phenomenon because they are inconsistent with national statistics.20 Falls from a substantial height in Manhattan, with its skyscrapers, landmarks, and bridges, accounts for 34% of suicides among residents and 43% of suicides among visitors.61

Among the elderly, the pattern of medications responsible for suicidal deaths may be changing because selective serotonin reuptake inhibitors (SSRIs) are increasingly prescribed for depression instead of TCAs.15 In the United States, higher suicide rates have been associated with greater use of TCAs than non-TCA antidepressants,45 which could be related to greater lethality of TCAs in overdose or poorer tolerability of TCAs, leading to nonadherence and enhanced suicide risk. In a Swedish study examining autopsy-confirmed suicides that included analysis of legal xenobiotics, the incidence of suicidal fatalities attributed to benzodiazepines was reported to be increasing despite a marked decrease in benzodiazepine prescriptions.15 Overdose of benzodiazepines is rarely fatal unless it is accompanied by alcohol or another toxic ingestion or occurs in the presence of serious medical conditions.35 However, the likelihood of fatality from an overdose of benzodiazepine taken alone increases markedly with each decade of life,97 perhaps because benzodiazepines in frail elderly people commonly lead to secondary morbidity and mortality from aspiration pneumonia, falls including hip fracture, and other medical complications that may be only the proximate cause of death in the case of overdose.

Notably, flunitrazepam and nitrazepam, the two most frequently implicated in single benzodiazepine suicides in Sweden,16 are not available in the United States. However, single-drug suicides have been reported with other benzodiazepines that are available, such as flurazepam, triazolam, diazepam, and oxazepam.16,28,81

Although poisoning exposures are much less frequent in the elderly than in other age groups, the incidence of ADEs among adults increases steadily with age and increases steeply from age 65 years through the tenth decade of life (Fig. 32–1).10 An ADE is defined as "one that occurs with normal, prescribed, labeled or recommended use of the [drug]."9 ADEs are more likely to be serious in the elderly than in younger adults. Serious ADEs are those resulting in death, hospitalization, life-threatening outcome, disability, or other serious outcome18 and are most prevalent among people 85 years of age and older.13

It may be challenging for a clinician to distinguish an intentional or unintentional overdose from an ADE in an elderly patient. The history, if available, must be explored carefully to identify and prevent recurrent problems. However, exposures in persons older than age 60 years are more likely the result of therapeutic errors and "misuse" than in younger adults.24,29 A therapeutic error is defined as "an unintentional deviation from a proper therapeutic regimen that results in the wrong dose, incorrect route of administration, administration to the wrong person, or administration of the wrong substance" and includes "unintentional administration of xenobiotics or foods which are known to interact." 9 These age-related differences may be because of physiologic changes that affect xenobiotic disposition or effect, patient errors caused by cognitive or visual impairment, or lack of provider proficiency in geriatric prescribing principles.

In contrast to serious consequences of therapeutic errors, reactions such as the serotonin syndrome and neuroleptic malignant syndrome (NMS), which are potentially life threatening, may occur with correctly prescribed therapeutic doses or drug interactions.5 Although abnormalities in thermoregulation are more common in late life,8 the risk of developing NMS has not been linked to advanced age per se.17 However, these syndromes can be overlooked in a patient with comorbidities that could obscure a precise diagnosis. For example, NMS must be distinguished from such geriatric syndromes as cerebrovascular events, heat stroke, or neuroleptic sensitivity syndrome seen in Lewy body dementia.17

Both serotonin syndrome and NMS, which are relatively unpredictable, and can occur at any age, are relatively rare. Among elderly patients, serious or life-threatening ADEs are more typically caused by commonly prescribed drugs, such as anticoagulants; insulin and oral hypoglycemics; and drugs that cause delirium, such as sedative–hypnotics, opioids, and anticholinergic agents (see Table 32–1).

As many as 42% of serious ADEs reported in elderly patients are potentially preventable.4,51 National data from the NEISS-CADES study revealed that drugs requiring careful outpatient monitoring were disproportionately represented among ED visits attributed to unintentional drug overdose. Data gathered as recently as 2004 and 2005 show that hypoglycemics, warfarin, certain anticonvulsants, lithium, digitalis glycosides, and perhaps surprisingly, theophylline account for more than 50% of unintentional overdoses among all age groups and 42% of all estimated hospitalizations.10 These xenobiotics pose a particular problem for patients 65 years of age and older, being implicated in 85% of visits attributed to unintentional overdose, 87% of overdoses requiring hospitalizations, and 54% of hospitalizations overall.10 Insulin, warfarin, and digoxin were the most common specific xenobiotics implicated in such events.

The above-mentioned xenobiotics are generally monitored with routine blood testing. Other drugs that commonly cause ADEs in the elderly must be monitored clinically, and these ADEs are often best prevented by not prescribing these xenobiotics to vulnerable patients or by cautioning against their use when they are available without prescription. Criteria have been developed to guide clinicians regarding "inappropriate" medications in elderly patients.38 Xenobiotics deemed inappropriate in the elderly cause numerically fewer ADEs than more frequently prescribed xenobiotics.11 However, there is consensus as well as evidence that these xenobiotics pose great risk to older adults, especially those who are frail.42,72 For example, the elderly are at enhanced risk of severe upper gastrointestinal (GI) bleeding from nonsteroidal antiinflammatory drugs (NSAIDS).119 Although this could be partly explained by increased exposure to and regular use of these drugs, for chronic conditions, older adults are more vulnerable to their effects because of underlying atrophic gastritis. There is controversy as to cause of age-related gastric mucosal changes, but they may partly be caused by underlying Helicobacter pylori infection, which appears to increase with age.3,33 The elderly are also at greater risk of prolonged hypoglycemia from certain sulfonylureas, particularly glyburide.100 Age-related mechanisms to explain this vulnerability to glyburide may include a decreased counterregulatory hormonal response to xenobiotic-induced hypoglycemia,84 inappropriate stimulation of insulin in response to hypoglycemia,105 or reduced excretion of a renally eliminated active metabolite of glyburide.60 Other age-related factors involved in enhanced susceptibility to ADEs are given in Tables 32–2 and 32–3.

Substance abuse declines with age39 but is important to consider in older adults under relevant clinical circumstances. Alcohol is the most common substance of abuse in people older than age 65 years. Abuse of alcohol or other xenobiotics may be a continuation of long-term habits, but some individuals may first begin to use and abuse xenobiotics late in life.63

Substance abuse in late life is probably underrecognized and underreported.96 In one Illinois study of patients presenting to a trauma facility, only 5% of those aged 65 years and older were tested for alcohol or other substances, but among those younger than age 65 years, 22% were tested for alcohol and 29% for other xenobiotics.122 However, almost half of the elderly patients tested for alcohol were positive and 72% of those had a blood alcohol level of 80 mg/dL (the legal limit in Illinois) or above, results that were comparable to those of younger patients who were studied, 75% of whom tested positive. For a comparable amount of alcohol ingested, the blood alcohol concentration of an elderly person will be higher than that of a younger adult because changes in body composition reduce the volume of distribution (Vd) of ethanol.109,113 Moreover, because of an age-associated diminished tolerance to alcohol, the impact on cognitive or motor function tends to be greater.

In the Illinois study noted above, 11% of elderly patients who were tested had positive urine toxicology screening results compared with 43% of tested younger adults.122 The most common xenobiotics detected in the elderly were benzodiazepines, opioids, and barbiturates, which, like alcohol, are more likely to impair older than younger adults. The failure to consider use of these xenobiotics, whether illicit or by prescription, may have serious consequences. When admitted to hospitals, if a careful history is not elicited, withdrawal from these xenobiotics may be missed, be misdiagnosed, and as a result be inappropriately managed.

Age-related pharmacokinetic changes have important clinical implications for elderly patients. The most consistent pharmacokinetic change that occurs with aging is a decrease in renal function. Glomerular filtration rate (GFR) declines, on the average, by 50% between the ages of 30 and 80 years32,98 and cannot be accurately predicted by serum creatinine, which does not increase significantly with age,98 because muscle mass, the source of serum creatinine, declines with age.68,89

Because it is impractical and often difficult to measure 24-hour creatinine clearance before instituting therapy with a renally excreted xenobiotic, clinicians commonly estimate creatinine clearance using age-adjusted formulas or nomograms. Frequently applied formulas are fairly predictive of renal function when renal function is stable.88 However, age-related declines in GFR are not universal, and limited data from longitudinal studies suggest that as many as 33% of elderly individuals do not experience this age-related decline.77 Conversely, predictive formulas could significantly overestimate actual creatinine clearance in chronically ill, debilitated elderly people, especially those with renal insufficiency.71 Modifications to the Cockcroft-Gault equation to correct for body surface area58,99 have been proposed to better reflect renal function (see Table 27–5 for details). However, anthropomorphic measurements are unreliable in the elderly,66,101 and physiologic variability is great. Alternative measurements, such as the Modification of Diet in Renal Disease(MDRD) Study Group equation, serum cystatin C, and others have also been proposed, but no current method of estimating renal function in the elderly appears to be superior for use in the clinical setting.111 For all of these reasons, it is difficult to accurately predict the renal elimination of xenobiotics or their metabolites in the elderly. A practical solution is to assume that renal function has declined significantly and to exercise caution when prescribing maintenance doses of drugs with a narrow therapeutic-to-toxic ratio (Table 32–4). Failure to do so is an important cause of toxicity.74

The nature and degree of impact of age-related hepatic changes on drug elimination is controversial. Liver mass decreases with an associated decrease in hepatic blood flow,120 which results in decreased efficiency of hepatic extraction. Enzymatic processes are often unpredictable,65 and although hepatic oxidation appears to decline with age,31 this change is difficult to demonstrate. There is substantial genetic variability among cytochrome P450 isoenzymes, making it difficult to interpret studies of age-related alterations in oxidative metabolism. Some studies that consider cofactors that could affect hepatic enzymes, such as concurrent medications or cigarette smoking, or that determine isoenzyme genotype may demonstrate that there is no age-related change in hepatic oxidative enzyme function.7

Hepatic conjugation does not decline significantly with age, so xenobiotics such as temazepam and oxazepam that are metabolized by these processes do not have prolonged elimination half-lives. In contrast, xenobiotics such as diazepam and flurazepam, which are metabolized by hepatic oxidative enzymes, are eliminated more slowly with age.47 Similar to many oxidized xenobiotics, metabolites of diazepam and flurazepam are active, undergo further metabolism, and remain in circulation after the parent xenobiotic has been metabolized. The active metabolites of some drugs, such as opioids, are renally eliminated, and excretion may be prolonged because of an age-related decline in renal function (see Table 32–4).

Other changes in enzyme systems may occur late in life. For example, a decline in gastric alcohol dehydrogenase level increases the bioavailability of ingested ethanol in the elderly.93 The decline in this enzyme is attributed to the increased incidence of gastric atrophy with age (see below). Whether age-related changes occur in metabolic enzymes that are present in the intestines, brain, kidneys, and other organ systems and what impact such changes have on drug disposition and drug interactions are likely to become active areas of research. Studies to date have not demonstrated a substantial effect of age on P-glycoprotein, a transmembrane transport protein involved in xenobiotic interactions in the kidneys, intestines, and other organs.7

Age-related alterations in body composition may affect xenobiotic disposition in later life (see Table 32–2). For example, lean muscle mass and total body water decline, and the fat-to-lean ratio increases with advancing age.68,89 Thus, highly lipid-soluble xenobiotics tend to have an increased volume of distribution. As a result, there may be a delay before steady state is reached, and peak effect and toxicity may occur later than expected. This mechanism may be an additional reason xenobiotics such as diazepam and flurazepam have prolonged half-lives in otherwise healthy elderly patients. In contrast, xenobiotics that distribute in water, such as ethanol, have a smaller Vd, leading to higher peak concentrations, accounting at least in part for the more pronounced peak effect of ethanol in the elderly. This may also account for the increased blood alcohol concentration attained in an older adult drinking an equivalent amount of alcohol as a younger person, as noted above.109,113

Protein reserve diminishes with age as a consequence of decreased muscle mass and decreased protein synthesis.95 Although serum albumin concentration remains in the normal range in healthy elderly individuals,14 people in this age group are more likely to experience a rapid decrease in albumin concentrations when experiencing acute or chronic illness or when their protein intake diminishes.27,121 A decline in serum protein level increases the free or active fraction of xenobiotics that are otherwise highly protein bound. Free xenobiotic is able to travel more readily to the liver and kidney for metabolism or excretion, so a gradual change in the serum protein concentration is unlikely to lead to a change in the patient's response to the xenobiotic. However, these changes may be clinically important for interpreting serum concentrations of highly protein bound xenobiotics. Clinical laboratories typically measure total xenobiotic concentrations, which include both free and bound xenobiotic. Because most xenobiotic is bound, the reported value reflects mostly bound xenobiotic; therefore, the total xenobiotic concentration may be in the therapeutic range even though the active unbound fraction is actually elevated. Phenytoin, which is highly bound to albumin, serves as an illustrative example. If the serum concentration of phenytoin is reported as subtherapeutic, the physician might order a dose increase even though the free fraction of phenytoin actually is in the therapeutic range. With a dose increase, the free or active fraction may increase to toxic concentrations. Basic xenobiotics are not bound to albumin but to α-1-acid glycoprotein (AAG), an acute-phase reactant that tends to increase, rather than decrease, with age.1 However, the increase attributed to age is most likely related to underlying disease. These unpredictable changes would be expected to have the reverse effect on the ratio of bound to unbound xenobiotic in any laboratory report. However, the correlation between clinical effect and free xenobiotic concentrations requires further study because there may be complex factors involved, for example, alterations in Vd, tissue-specific xenobiotic concentrations, and the contribution of other serum proteins to xenobiotic binding.

The precise contributions of gastric and intestinal tract mechanisms to toxicity have not been adequately determined. Changes in gastric absorption with age are not substantial enough to have an important clinical impact, and if anything, there is a modest decline, partly because of delayed gastric emptying, which could cause a delay in absorption of certain xenobiotics. However, age-associated changes in the gastric mucosa may account for enzymatic changes, as demonstrated in the case of alcohol dehydrogenase, noted above.

Pharmacodynamic factors may also affect a patient's response to a particular xenobiotic. In general, age-related physiologic changes in target or nontarget organs lead to increased sensitivity to most xenobiotics, although sensitivity to some xenobiotics may also be decreased. For example, there is evidence that β-adrenergic receptor sensitivity declines with aging, leading to a diminished response to both β-adrenergic agonists and antagonists, although this is not necessarily demonstrated clinically.26,40,114

The observation of enhanced sensitivity to xenobiotics is probably due to altered pharmacokinetics in many, if not most, cases.50 Proving that enhanced sensitivity is related to altered pharmacodynamics would require demonstrating that the concentration of drug at the tissue site was not increased as the result of diminished elimination. Regardless of the mechanism, it is important to recognize that the response to a given xenobiotic might be altered in specific ways among the elderly. These altered responses are probably caused less by chronologic aging and more by an increased prevalence of disease.23,50 Table 32–3 provides examples of pathologic or physiologic changes that frequently occur in the elderly and disorders that are worsened or unmasked by xenobiotics.

A complicated xenobiotic regimen reduces adherence,86 increases medication errors, and increases the risk of clinically important drug interactions. The likelihood of experiencing an ADE increases with the increasing number of xenobiotics taken.55 Geriatric patients take more prescription and nonprescription xenobiotics than any other patient group.62 ADEs may occur as a consequence of xenobiotic–xenobiotic interactions, but the exact relationship between the two phenomena is sometimes difficult to quantitate.55

Concurrent disease in target or nontarget organs may also alter the patient's sensitivity to a xenobiotic,87 resulting in a serious ADE even when the patient is given a standard or previously used xenobiotic dose. Coexistent disease is often subclinical, and the patient's enhanced sensitivity may not be anticipated. A patient with subclinical Alzheimer's 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 and CAs. Delirium is a medical emergency and an important cause of ED visits by the elderly.57

Another contributing factor to an ADE is physician lack of knowledge with regard to the principles of geriatric prescribing.37,52,91 New xenobiotics are sometimes promoted as being safer than older ones, but problems often become apparent 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, similar to benzodiazepines, zolpidem may also cause confusion, global amnesia, memory loss, and falls.115,117 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), they have not been recommended for routine use.54 LMWHs such as enoxaparin and dalteparin are eliminated by the kidneys, and repeated doses lead to progressive increases in antifactor Xa activity when creatinine clearance is 30 mL/min or below,21,76 a degree of renal insufficiency that is common in frail elderly patients. Less severe levels of renal impairment may also result in reduced enoxaparin clearance that might be avoided with lowered doses.56 Most reported cases of serious, unexpected enoxaparin-induced bleeding, occur in elderly patients who are receiving "standard," not age-appropriate, dosing.83,110,112

In addition to dosing incautiously, clinicians often prescribe drugs considered inappropriate for the elderly at any dose,30 drugs such as CAs, long-acting benzodiazepines, and anticholinergics.22 In all of these cases, attention to geriatric risk factors might prevent ADEs.

Compounding the problem of lack of knowledge is the common practice of not adequately studying the effects of new xenobiotics in the elderly (see Chap. 138 for further details).12,73 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.73 Thus, the adults at highest risk for many forms of xenobiotic 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 5 half-lives of a xenobiotic are necessary to achieve steady-state xenobiotic concentrations. 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 xenobiotic trial, the ultimate effect of that xenobiotic might not be appreciated during testing intervals designed for younger patients.

Morbidity and mortality in elderly patients as a result of specific xenobiotics might be avoided if the responsible xenobiotics 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.49,92 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.34 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.53,94 Because elderly individuals typically have one or more chronic illnesses23 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 Food and Drug Administration (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.19 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.25 Also, unfortunately, geriatric recommendations in the package insert may thus be insufficiently specific to provide guidance for drugs commonly used in this population.103

Xenobiotics, such as digoxin, warfarin, and diuretics, commonly prescribed in the elderly population 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 xenobiotic regimen, thereby increasing the risk of inappropriate xenobiotic combinations.46,107 Problems can also arise when patients obtain prescriptions from more than one pharmacy or mail order service.

Herbal preparations used by the elderly also may interact with prescription medications.43,85 The use of herbal preparations has increased substantially in recent years, particularly among patients with illnesses such as cancer, dementia, and depression that 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. 43.

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 renal clearance, 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).44 Magnesium-containing laxatives are still sometimes used in hospital settings with serious outcomes.90 Likewise, oral sodium phosphate formulations, frequently used to cleanse the large intestine before endoscopy, may harm renal function in certain elderly patients despite normal baseline creatinine.64 Virtually all of the most popular nonprescription medications 62 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 are still responsible for large numbers of adverse events diagnosed in EDs,10 as well as diazepam, propoxyphene, and sedating antihistamines and other anticholinergics.

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 substances.118

Management decisions must be made with the foregoing principles in mind. GI decontamination should proceed as in younger patients. Because constipation is a more frequent problem in the elderly, when multiple-dose activated charcoal is used, particular attention must be paid to GI function and motility. The specific precautions and contraindications in the basic management and GI decontamination detailed in Chapter 7 are particularly pertinent for the geriatric population.

The presence of clinical or subclinical heart failure or renal failure may increase the risk of fluid overload when sodium bicarbonate is used. In the elderly, hemodialysis or hemoperfusion may be indicated earlier in cases of aspirin, lithium, or theophylline poisoning, in which elimination may be hampered by a decreased creatinine clearance or reduced endogenous clearance.

A problem that may go unrecognized in geriatric patients is the development of alcohol or xenobiotic withdrawal symptoms. Because elderly patients are typically not perceived as xenobiotic users, a physician evaluating an unfamiliar patient may not be aware of the patient's chronic use of prescribed benzodiazepines or opioids and consequently might fail to consider the possibility of substance withdrawal when unanticipated complications occur during hospitalization.

Strategies to limit unintentional toxic exposures in elderly patients with cognitive or sensory impairment should be similar to those used in young children, who are also at high risk of ingesting toxic substances or pharmaceuticals prescribed for others in the household. The strategies should include the removal of potentially dangerous substances and unnecessary xenobiotics from the patient's environment. The physician should request that the patient or caregiver bring all medications to the office in the original bottles and then make an effort to limit the number of medications prescribed or to seek alternative medications with a safer therapeutic index or appropriate geriatric safety profile. Administration and control of the medications by directly observed therapy may, of necessity, become the responsibility of the caregiver rather than the patient.

When geriatric patients are evaluated in the ED for poisonings or serious ADEs, the need for hospital admission should be guided by concerns about the patient's frailty weighed carefully against the known hazards of hospitalization for the elderly.28 The physician should be particularly alert to certain situations that might mandate admission, including elder abuse or neglect, unexplained mental status changes, inadequate home care manifested by unexplained falls, and overdose of xenobiotics with prolonged durations of action.

When there is concern that the established caregivers at home may be abusing or neglecting the patient, the patient requires further observation, removal from the environment, and possibly hospitalization. Signs of actual physical abuse may be more obvious than signs of neglect.69 Vulnerable elderly who are physically disabled or cognitively impaired may be brought to the hospital because of presumed illness, but the source of the problem may actually be the caregiver. The caregiver, frequently a family member, may be depleting the patient's funds for personal use. Patients may become ill because funds were diverted from the purchase of food or because the patient's prescription drugs were sold on the street. More direct abuse may take the form of intentional poisoning of the patient by overdose of the patient's own prescription drugs. Provision for follow-up care, such as an alternative place to live and guardian appointment, is essential because abuse and neglect are associated with serious outcomes.70

Unresolved mental status changes may require close observation and hospitalization. Elderly patients who are confused or unable to walk are sometimes mistakenly assumed to be chronically impaired. However, incomplete explanation of an altered mental status or physical impairment should prompt careful inquiry into the patient's baseline functional status. Functional deterioration should never be assumed to be age related. Many very elderly patients are cognitively normal, physically robust, and independent in all activities of daily living.

Patients with overdoses with long-acting medications require careful monitoring. Because the durations of action of certain xenobiotics may be markedly prolonged among geriatric patients, a higher degree of vigilance is required. A classic example is associated with the use of the long-acting benzodiazepine flurazepam, mentioned above. Although this drug has been less often used in the United States in recent years, other long-acting benzodiazepines, such as flunitrazepam and nitrazepam, are still widely used in other countries.36 The ultra-long-acting sulfonylurea chlorpropamide is rarely used today, but glyburide may cause relatively prolonged hypoglycemia compared with other hypoglycemics, as noted above.

Older patients may account for only a small fraction of total poisoning victims, but when poisoned, they have a high mortality rate. More importantly, the elderly are much more likely to experience serious ADEs as a consequence of both appropriate and inappropriate use of medications. Attention to risk factors is essential in this vulnerable population. Important risk factors include pharmacokinetic and pharmacodynamic changes; the presence of overt or subclinical disease, including dementia; patient and provider error; suicide risk; complex therapeutic drug regimens; and a general lack of knowledge about the principles of prescribing for the geriatric population.