Polypharmacy in the Elderly: Clinical Challenges in Emergency Practice
Part I: Overview, Etiology, and Drug Interactions
Authors: Katherine M. Prybys, DO, ACTM, Assistant Professor of Emergency Medicine, University of Maryland Medical System, Baltimore; Kraig A. Melville, MD, FACEP, FAAEM, Chief, Emergency Medical Services, Calvert Memorial Hospital, Prince Frederick, MD; Jeahan R. Hanna, MD, Chief Resident, Emergency Medicine, University of Maryland Medical System, Baltimore.
Peer Reviewers: Andrew Gee, MD, Fellow, Division of Toxicology, Department of Emergency Medicine and Traumatology, Hartford Hospital, Hartford, CT; Peter A. Chyka, PharmD, Professor, Pharmacy Practice and Pharmacoeconomics, Executive Director, Southern Poison Center, University of Tennessee, Memphis.
Never before has the topic of medical errors been so focused in the public eye as since the release of the National Institute of Medicine’s Report, To Err Is Human.1 Documenting the consequences of drug-related adverse patient events, this report estimates that 44,00098,000 hospitalized patients die each year in the United States from medical "mistakes"—i.e., medication errors and inappropriate and/or suboptimal drug prescribing. In fact, medical errors are the eighth leading cause of death in the United States, with more people dying from these events than from highway accidents, breast cancer, or AIDS.1 Although the true incidence of medical errors has become a subject of heated debate for the medical community, no one can argue with the fact that the problem exists and that it represents a serious and growing public health concern.2-6
What makes this problem particularly frustrating is that most drug-related problems are preventable. Elderly patients are most at risk for drug-related problems since they account for the highest incidence of adverse drug events (ADEs) and deaths. 2,7,8 The emergency department (ED) is hardly immune. Studies suggest that practice in this clinical environment is a significant risk for adverse drug-related events, with preventable medical errors ranging from 52-70%.8,9 In the emergency setting, rapid clinical decisions must be made in the treatment of elderly patients who often have multiple illnesses and take many medications. With these clinical issues in focus, this article will discuss the scope and causes of polypharmacy in the United States, why the elderly are at high risk, specific drug interactions, and some potential solutions to the problem. Part II of this article will cover high risk drugs, diagnosis of adverse drug effects, legal considerations, and the role of the emergency physician in preventing adverse drug effects.—The Editor
Introduction
The acutely ill elderly patient provides one of the most challenging patient encounters in the emergency setting. Multiple health-related variables must be considered when providing their medical care.10 The elderly constitute a heterogeneous group of patients. They possess varying degrees of physiological decline and disease process, which are not always parallel with their age. With aging, the prevalence of chronic diseases, including arthritis, high blood pressure, depression, heart disease, and diabetes, increases. Frequently, two or more diseases will coexist, necessitating the use of multiple medications. Normal physiologic changes of advancing age, such as decline in organ function and alteration in receptor response, often cause the elderly to manifest disease atypically and to have increased sensitivity to drug effects. In addition, these physiologic changes impact the patient’s ability physically to handle drugs, which may lead to toxic accumulations for some drugs despite utilization of therapeutic dosages. Psychosocial factors such as physical disabilities, nutritional status, and financial well-being all must be considered prior to therapeutic recommendations. These and other factors contribute to the clinical difficulty in managing the older patient in the emergency setting.
Polypharmacy is a particularly vexing problem for the emergency clinician. All too often, the elderly patient presents to the ED and hands the clinician a bag filled with multiple medications. This has become so common a phenomenon that it has been termed the "brown bag syndrome."11 The practitioner must sort through and decipher this bag of often unlabeled and intermingled medications. The emergency physician must determine whether any of these drugs are causing effects that are contributing to the acute presenting problem. Before prescribing any new medications, the clinician must consider each of the patient’s current medications to minimize potential drug and food interactions.
Scope of the Problem
Emergency physicians are caring for increasing numbers of older patients every day. There are currently more than 34 million Americans age 65 and older in the United States, accounting for 12.5% of the U.S. population. More than 4 million Americans are older than age 85.12 The elderly constitute the fastest growing segment of our society. It is projected that by the year 2010, 20% of the U.S. population will be age 65 or older.13 Between 1992 and 1999, the number of ED visits for the elderly substantially increased. The overall population-based visit rates increased by 18% for people ages 45-64, and by 17% for those ages 65 and older.14
Modern medical advances have played a paramount role in ensuring increased life expectancies and better quality of life despite age-related decline in physiologic function or chronic illness. New pharmaceutical products account for a majority of these medical advances in the treatment of the elderly. During the past decade, explosive growth in drug development and expeditious Food and Drug Administration (FDA) approval have led to the introduction of an enormous number of prescription drugs in the United States. An average of 340 new products are approved and added to the formulary each year. Emergency physicians are seeing increasing numbers of elderly patients with multiple diseases and complex pharmaceutical regimens.
Polypharmacy is predominantly a problem of the elderly. In 1998, nearly 2.5 billion prescription medications were dispensed by U.S. pharmacies at a cost of $92 billion.1 A large proportion of these prescription medications was dispensed to individuals ages 65 and older. In addition, adults older than age 65 buy 30% of all prescription drugs and 40% of all over-the-counter drugs. The elderly also have experienced a 116% increase in their prescription drug spending from 1992 to 2000. For the year 2000 alone, it is estimated that elderly individuals spent an average of $1205 on prescription medications.15 Further, 90% of people older than age 65 take one or more prescription medications on a daily basis, with most taking two or more medications per day.16 In one study, nursing home residents were shown to use an average of six different medications daily, with more than 20% using 10 or more different drugs per day.17
The annual national cost for medical care resulting from drug-related morbidity and mortality has been estimated as high as $76.6 billion.18 Studies reveal that 328% of hospital admissions are due to ADEs, and 34% of all hospitalized patients experience injuries from adverse events that lead to prolonged hospitalization or disability.1,9,19 The elderly are at highest risk for experiencing an adverse event.9,19,20 In a landmark study of more than 30,000 hospitalized patients, patients older than age 64 experienced adverse events at a rate that was more than double the rate for patients age 45 and younger.8,19 Drug complications were found to be the most common single type of adverse event and often were judged to be preventable.7,8,17,21,22 The elderly are at the highest risk for suffering a fatal adverse drug reaction. Mortality data for the year 1995 from the National Center for Health Statistics and the FDA surveillance system reveal that patients older than age 60 accounted for the majority of deaths attributable to adverse drug reactions.2
The true overall incidence of ADEs occurring in the United States is unknown. Currently, there is no national mandatory reporting system in existence, and voluntary reporting systems are notoriously poor.20,23,24 Hospitalized patients, for whom the most epidemiology is available, only represent a fraction of the entire patient population at risk for experiencing drug-related problems. Few studies of drug-related complications are available for the ambulatory care setting, and even fewer data exist for the emergency care setting.25-27 With more than 100 million ED visits per year in the United States, it would be expected that a significant number of patients present for care for drug-related problems or experience ADEs resulting from their emergency care. The incidence of clinically relevant drug interactions from ED-initiated medications was found to range from 3.1% to 10%.28,29
Etiology of Polypharmacy
There are several factors that account for the high prevalence of drug use in the elderly. Elderly individuals tend to suffer from both chronic medical illnesses and age-related decline in organ function. Often, multi-drug therapy is required for elderly individuals to maintain their health. Elderly patients frequently have several health care providers, each of whom prescribes different medicines, leading to large, complex medication regimens.
Self-medication is a significant contributor to polypharmacy. There is a plethora of over-the-counter products available, many containing ingredients capable of producing adverse reactions and dangerous drug interactions.30-32 In recent years, several formulations of prescription drugs have become over-the-counter medications. Some of these medications, such as cimetidine, non-steroidal anti-inflammatory drugs (NSAIDs), and antihistamines, are known to cause serious side effects and drug interactions. Alternative medical therapies have become increasingly popular, as well.33 In the past five years, herbal medicinal sales have skyrocketed.34 However, numerous herbal medicinal and homeopathic preparations have the potential to cause toxicity and serious drug interactions.35 Herbal products are not tested rigorously due to their classification as food supplements, and lack of standardized dosages and the potential for adulteration are of concern when using these products. The elderly frequently self-medicate with both over-the-counter medications and herbal preparations.36 They often do not consider these products to be "medications," nor do they consider the potential for adverse effects. Clinicians should ask all patients about their use of these products, because the majority of patients omit over-the-counter medications and herbal preparations from their medication histories.33,36
Physicians contribute to the problem of polypharmacy by over-prescribing to patients. Drug manufacturers spend billions of dollars on drug promotion efforts that target both physicians and elderly patients alike. In recent years, an increasing trend has been ob-served of drug companies advertising directly to consumers through television commercials and other popular media. This practice may result in patients placing pressure on practitioners to prescribe specific drug products. Nowhere is this problem of over-prescribing more apparent than in the emergency setting. A significant number of visits to the ED result in the addition of a new medication. Studies have found that a visit to the ED resulted in a new drug prescription for 47-61% of patients.13,28 Emergency providers often feel compelled to prescribe a new medication to meet a perceived patient expectation, or to provide symptomatic relief for ailments that have no cure. Unfortunately, given the fast pace of the ED, it often is more expeditious to pull out a prescription pad than to spend time educating a patient.
Vulnerability of the Elderly
Polypharmacy is an important risk factor for ADEs. (See Table 1 for factors that contribute to ADEs.) The number of medications a patient takes is directly related to his risk of experiencing ADEs.7,20,28,29,37 Patients taking two medications are at 13% risk for a drug interaction. A dramatic increase in risk is seen when more than three medications are used simultaneously. The risk increases to 58% for five medications and 82% for seven or more medications.37
| Table 1. Factors that Contribute to Adverse Drug Effects in the Elderly | |
| • | Polypharmacy |
| • | Multiple physicians and treatment locales |
| • | Use of over-the-counter medications and herbal products |
| • | Physiologic changes of aging |
| • | Chronic medical illness |
| • | Physical limitations (dementia/hearing impairment/ poor vision) |
| • | Look-alike medications |
| • | Sound-alike medication names |
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|
|
Multiple drug regimens are challenging to manage for any patient. Mistakes such as forgetting to take a medication dose, taking an extra medication dose, or mistaking the identity of a medication are common. Elderly patients frequently have physical limitations, such as poor eyesight, loss of hearing, or memory loss, that may contribute to medication dosing errors. Errors frequently occur in filling weekly drug chambers, particularly when the patient takes pills that are similar in appearance or name. Storing medications outside their original prescription bottles is a common and dangerous practice. Often the patient forgets the identity of the individual pills, greatly complicating the efforts of caregivers and health care providers. Drug manufacturers contribute to the problem of medication errors by marketing drugs with similar trade names or appearances.38 (See Tables 2 and 3 for important examples of drugs with similar names and appearances.) This became very evident with the three drugs Celebrex (celecoxib), Celexa (citalopram hydrochloride), and Cerebyx (fosphenytoin). By 1999, the FDA reported more than 50 mix-ups involving these drugs.39 With the recent passage of the "Fast Track" law that allows for rapid approval of a new drug if the manufacturer asserts a "desperate need," there is reduced time allotted to scrutinize clinical trials and to review drug naming, packaging, and labeling.40,41 Examples of "Fast Track" drugs that subsequently have been sanctioned are Lotronex, Posicor, Propulcid, and Raplon.
| Table 2. Examples of Drugs with Similar Names | ||||
| Adderall | — | Inderal | ||
| Accutane | — | Accupril | — | Aciphex |
| Albuterol | — | Atenolol | ||
| Celexa | — | Celebrex | — | Cerebyx |
| Clinoril | — | Clozaril | ||
| Dilaudid | — | Dolobid | ||
| Flomax | — | Fosamax | ||
| Klonopin | — | Clonidine | ||
| Stadol | — | Haldol | ||
| Zantac | — | Xanax | ||
| Zyprexa | — | Zyrtec | ||
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| Table 3. Examples of Drugs with Similar Appearance | ||||||
| Cordarone | — | Bethanechol 10 mg | ||||
| Dalmane | — | Prozac | ||||
| Famvir | — | Augmentin 500 mg | ||||
| Norpace 100 mg | — | Dyazide | ||||
| Prevacid | — | Sporanox | ||||
| Tylox | — | Feldene 20 mg | — | Rifamate | — | Mycobutin |
| Valium | — | Haldol | ||||
| Zileuton | — | Ibuprofen | ||||
| Diuril | — | Cortone | ||||
| Rhythmol | — | Toprol XL 100 | — | Vicoprofen | ||
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Elderly patients often have multiple chronic illnesses that predispose them to drug-related complications. Patients age 65 and older have an average of five coexisting medical conditions.42 Exacerbation of a preexisting medical illness or development of a new illness can affect dramatically the way a drug is handled in the body. For instance, a patient who suffers from mild renal insufficiency and develops gastroenteritis and dehydration may become suddenly lithium-toxic from his usual dose of this medication. Lithium, a cationic substance, is eliminated almost entirely by the kidneys, where it is handled like sodium. Any state that causes dehydration or excessive sodium reabsorption will cause lithium retention and possibly intoxication.
Physiology
With advancing age, everyone experiences some degree of physiologic decline that is characterized by a progressive decline in organ function and loss of the ability to preserve homeostasis. The degree and speed of decline varies from person to person and from organ system to organ system.43 Both pharmacokinetics and pharmacodynamics are affected by these physiologic changes. Pharmacokinetics describes the processes of drug absorption, distribution, metabolism, and clearance. Pharmacodynamics refers to how the body responds to medications. It is important for the clinician to recognize that significant declines in organ function occur even in elderly individuals who appear healthy, predisposing them to potential drug toxicity. This subclinical decline in organ function may become apparent only during times of physiologic challenge, such as that imposed by acute illness or new drug therapy. For example, a patient with marginal but compensated cardiac function may develop congestive heart failure shortly after beginning a newly prescribed nonselective beta-blocker agent.
Body Composition. Drug distribution is altered greatly in the elderly patient due to changes in body composition. With advancing age there is a significant loss of lean body mass in proportion to the gain of adipose tissue.43 There is also an age-related loss in total body water of up to 10-15%.44,45 Highly lipid-soluble drugs, such as diazepam, lidocaine, and phenytoin, tend to have a larger volume of distribution in older persons. This can result in a prolonged elimination half-life and increased risk for toxicity for these drugs. Conversely, water-soluble drugs, such as digoxin, theophylline, and various antibiotics, will have a reduced volume of distribution, resulting in peak effects that develop more rapidly and are more pronounced than would be anticipated. These medications should be reduced to the lowest recommended doses to avoid potential toxicity.
Age-related decreases in serum protein greatly affect drugs that are highly protein-bound, such as sulfonyureas and phenytoin. A decline in protein synthesis due to malnutrition or aging will result in fewer protein carriers and a larger fraction of unbound drug. The unbound portion of drug is the active fraction because an unbound drug can distribute freely across membranes and cause therapeutic effects. Caution must be exercised when interpreting serum drug levels, which typically reflect the total amount of free and unbound drug in the bloodstream. With diminished protein stores, the proportion of free drug can increase substantially and toxicity can occur at even therapeutic drug levels.46
Cardiovascular Function. Cardiac output decreases at a rate of 1% per year after age 30. As ventricular contractility declines, the heart increasingly depends on endogenous catecholamines for ionotropic support of the heart. With advanced age, the de-cline in cardiac output becomes clinically significant and results in decreased perfusion to vital organs. Sinus node dysfunction and conduction abnormalities also are more common in the elderly. Care must be taken in the administration of beta-blockers or calcium channel blockers because they may precipitate congestive heart failure and/or varying degrees of heart block in susceptible individuals.44
Maintenance of blood pressure with positional changes depends on the coordinated events of the autonomic nervous system. Upon standing, reflex sympathetic discharge and parasympathetic inhibition increase peripheral vascular tone, heart rate, and contractility to maintain blood pressure. Elderly patients have a decreased responsiveness to the autonomic nervous system, which predisposes them to develop orthostatic hypotension. This can be exacerbated by use of antihypertensives, tricyclic antidepressants, and phenothiazines.46
Renal Function. The most consistent pharmacokinetic change that occurs with aging is a decrease in renal function. With aging, a significant loss of renal mass occurs, resulting in a decreased number and size of glomeruli. Renal blood flow is reduced significantly and the glomerular filtration rate (GFR) decreases by 50% between the ages of 30 and 80.46 The decline in cardiac output that also occurs with advancing age contributes to decreased perfusion to the kidneys. Renal perfusion increasingly becomes more dependent on elevated renin-angiotensin levels. For this reason, care must be taken when prescribing angiotensin converting enzyme (ACE) inhibitors to the elderly, as they have been known to precipitate renal insufficiency.47 Patients with hypertensive renovascular disease especially are prone to acute deterioration in renal function from ACE inhibitors and nonsteroidal analgesic agents, due to their dependence on renal afferent arteriolar vasodilatation to maintain glomerular blood flow.48 Unfortunately, serum creatinine is not a reliable indicator of renal decline. Serum creatinine may be normal even in the face of a significant renal impairment. Several age-adjusted formulas and nomograms exist to aid clinicians in estimating creatinine clearance. However, as age-related declines in GFR are not universal, the clinician must be careful when using these formulas, which can overestimate creatinine clearance by as much as 20%.46 Use caution when prescribing drugs with narrow therapeutic ranges such as digoxin, aminoglycoside, lithium, and procainamide. This would be particularly true for the chronically ill patient, who can be assumed to have a decline in renal function. Precautionary measures, such as starting the patient on the lowest therapeutic dose and frequent initial monitoring of their serum drug levels and renal function, should be performed when prescribing these medications.
Gastrointestinal Function. The effects of aging on the gastrointestinal system include decreases in gastric acid production, motility, and active membrane transport. Despite these changes, the bioavailability of most drugs is not reduced significantly. Certain drugs, such as ketoconazole, digoxin, quinolones, tetracycline, phenytoin, and cimetidine, depend on an acid environment for absorption and may have a decreased bioavailability secondary to the age-related increase in gastric pH.48 The co-administration of antacids, proton pump inhibitors, and H2-blockers should be avoided with these drugs.
With aging there is a decline in mucosal function that normally protects the stomach from drugs associated with ulcer formation. This involves a decrease in production of mucosal prostaglandins as well as a decline in mucosal blood flow, gastric mucous, and bicarbonate secretion. These factors, in combination with delayed gastric emptying, increase the risk of gastrointestinal bleeding from NSAIDs and aspirin.48 Short-term use of NSAIDs at the lowest recommended dose should help avoid these complications. Some studies have shown that concomitant use of a proton pump inhibitor appears to be effective in preventing gastroduodenal ulcers in patients with previous history of ulcer. Proton pump inhibitors were found to be superior to H2-receptor blockers.49 The cyclooxygenase-2 inhibitors have been shown to have a reduced capacity to cause gastroduodenal injury.49-51
Hepatic Function. The general purpose of metabolism is to produce a water-soluble metabolite that can be excreted easily into the bile or urine. In contrast to renal metabolism, hepatic drug metabolism varies widely among patients, and there are no predictable age-related alterations. The efficiency of hepatic metabolism is influenced by blood flow, functional hepatocyte number, and activity of the cytochrome P450 mixed-function oxidase system.44 Hepatic mass, the number of functional hepatocytes, and the activity of the cytochrome P450 system decline with age. Hepatic blood flow declines by 40-50% with advancing age.43 Drugs that undergo rapid first-pass hepatic metabolism, including lidocaine, verapamil, propranolol, and nitrates, are most affected by age-related declines in hepatic blood flow.46
The metabolism of most drugs relies more upon enzyme activity than hepatic blood flow. There is a significant decrease in hepatic oxidative enzyme activity with advancing age. This results in a prolonged half-life and greater drug accumulation for many pharmaceuticals. This is seen particularly with some benzodiazepines such as diazepam and flurazepam.46 These two drugs have a prolonged duration of action and cause excess central nervous system (CNS) depression in the elderly. This is secondary to their large volume of distribution, decreased hepatic clearance rate, and the ongoing pharmacological effects of their active metabolites. The use of long-acting benzodiazepines in the elderly can produce devastating clinical consequences. Their use has been associated with excess sedation and an increased incidence of falls and hip fractures.52-55 When benzodiazepines are indicated for an elderly patient, safer choices include midazolam, oxazepam, lorazepam, and triazolam.
Pharmacodynamics
Elderly individuals commonly have a varied response to drugs. With aging, alterations in end-organ responsiveness occur that cause exaggerated or diminished therapeutic effects. Pharmacodynamic changes most likely occur at the receptor level and consist of changes in receptor number, binding kinetics, or biochemical reactions. The central nervous and cardiovascular systems are particularly vulnerable to changes in pharmacodynamics. Alterations in drug responsiveness in these systems are of the utmost clinical importance in the elderly. Slowing in cognition and memory function and diminished CNS dopaminergic activity are seen consistently with aging.52 Increased sensitivity occurs for many CNS depressant drugs, especially narcotic analgesics. For example, it has been shown that elderly individuals undergoing anesthesia require half the dose of fentanyl to induce the same degree of drug effect as seen in younger patients.52 Physiologic changes of aging that occur in the cardiovascular system include decreases in heart rate, cardiac output, coronary blood flow, and blood vessel elasticity. The clinical consequences of these changes are significant, such as decreased chronotropic response to beta-blockers and increased antihypertensive affect to calcium channel blockers, which can lead to dangerous, precipitous drops in blood pressure, such as seen with sublingual nifedipine.56
Drug Interactions
Many serious ADEs are due to drug interactions.57-59 Prescribing new medications in the emergency setting is particularly perilous. Patient encounters are brief and frequently result in pharmacologic interventions despite incomplete medication and illness histories. The risk of drug interaction has been shown to increase dramatically when three or more medications are administered simultaneously.37 In addition, up to 30% of patients presenting to the ED are already at risk for a potential drug interactions from their current medications.29
Drug interactions can occur through several different mechanisms. Pharmacokinetic interactions occur when one drug alters a second drug’s absorption, distribution, metabolism, or excretion. Alterations in drug metabolism most likely account for the majority of clinically significant and life-threatening drug interactions. Pharmacodynamic interactions occur when one drug potentiates or inhibits the effect of a second drug. Pharmacodynamic interactions are mediated through either direct or indirect receptor effects. For example, a patient taking a beta-2-adrenergic agent for asthma may experience reduced bronchodilation effects when also given a nonselective beta-blocker drug. Another example is the synergism that occurs between drugs with anticholinergic properties. Common drugs that possess anticholinergic activity include tricyclic antidepressants, antipsychotics, antihistamines (i.e., diphenhydramine), muscle relaxants, and scopolamine. Combining these medications can lead to anticholinergic toxicity (i.e., dry mouth; flushed, hot skin; confusion; dilated pupils; and urinary retention).
The bulk of drug metabolism occurs in the liver through the cytochrome P450 (CYP) microsomal enzyme system. The CYP3A4 enzyme is responsible for the majority of drug metabolism. A newly added drug that causes inhibition of the P450 enzyme system may cause decreased hepatic clearance of preexisting drugs that also are dependent on the P450 enzyme system for their metabolism. As result, these drugs will have increased plasma concentrations and prolonged half-lives that may lead to toxic effects. Clinicians should pay special attention to drugs that have a narrow range of therapeutic index. Serious drug interactions can occur, leading to life-threatening drug toxicity. A good example is theophylline, which has therapeutic effect at serum concentrations of 10-20 mcg/mL but typically causes toxic effects once drug levels rise above 20 mcg/mL. When erythromycin is taken concurrently with theophylline, serum theophylline levels rise an average of 30-35%.60 Drugs that cause induction of the P450 enzyme system may cause increased hepatic clearance and subtherapeutic concentrations of preexisting drugs. Dosage adjustments must be made to ensure therapeutic effect. (See Table 4 for common drugs that are P450 enzyme inducers or inhibitors.)
| Table 4. Common Drugs that Are Inhibitors and Inducers of the P450 Enzymes | ||
| P450 Enzyme Inhibitors | ||
| Allopurinol | Fluoxetine | |
| Amiodarone | Itraconazole | |
| Cimetidine | Ketoconazole | |
| Ciprofloxacin | Metronidazole | |
| Clarithromycin | Omeprazole | |
| Diltiazem | Paroxetine | |
| Disulfiram | Propoxyphene | |
| Erythromycin | Quinidine | |
| Fluconazole | Sulfonamides | |
| Indinavir | Verapamil | |
| Isoniazid | ||
| P450 Enzyme Inducers | ||
| Barbiturates | Griseofulvin | |
| Carbamazepine | Phenytoin | |
| Chronic ethanol use | Rifampin | |
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—Special thanks to Vincent Jackson, PharmD, for advisory assistance on certain parts of this paper.
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