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Articles

Medications in Older Patients MANA HOBSON, MD, San Francisco, California

Adverse drug reactions are common in persons aged 65 and older and are associated with increased morbidity and mortality. A heightened susceptibility to adverse reactions is due to a number of factors, including an increased incidence of disease, multiple drug use, and altered pharmacokinetic and pharmacodynamic properties of many drugs. The risk of drug interactions increases with the number of medications taken. Adverse drug reactions can be prevented through prudent prescribing practices, patient education, and adequate monitoring of drug efficacy and side effects. Several types of medications are of particular concern, including many antihypertensive agents, drugs with anticholinergic effects, psychoactive medications, and nonsteroidal anti-inflammatory drugs. Some drugs, such as histamine H2-receptor antagonists, are relatively safe but are overprescribed. Data regarding the risks associated with these problem drugs are presented, with recommendations for safe and effective treatment alternatives. (Hobson M: Medications in older patients. West J Med 1992 Nov; 157:539-543)

he proper use of medications in older persons is an important topic for primary care physicians, medical specialists, and surgeons. In the United States, older patients are major consumers of pharmaceuticals, using 40% of all prescription medications. In this article I review factors that influence the efficacy and safety of medications in older persons, examine particular problem drugs, and suggest practical guidelines for drug prescribing. Although the appropriate use of medications can prevent, control, or cure disease, inappropriate use may have serious consequences. Because of changes in homeostatic mechanisms and supervening diseases, elderly persons are less tolerant of many drugs. About 10% to 30% of geriatric hospital admissions are due to medication toxicity,"'2 and 1 of 1,000 older patients admitted to a hospital dies of an adverse drug reaction.3 The risk of adverse drug reactions is probably related more to the degree of frailty and medical condition of the patient, however, than to age alone.4 Older patients are different from younger ones in several ways that may affect safe medication use. Older persons have an average of five coexisting medical conditions, and the treatment of one problem may adversely affect another. Also, they are especially prone to polypharmacy: the average older person takes 4.5 medications and fills 13 prescriptions yearly.5 Because of cognitive, functional, and social factors, some older persons differ from their younger counterparts in their ability to comply with medication regimens. T

There is a deficit of information about the efficacy and safety of drugs in elderly persons. Most drug trials exclude the old and infirm, and it is not until after Food and Drug Administration approval and widespread use that the actual incidence and severity of toxicity are known.

Pharmacokinetics Pharmacokinetics refers to the temporal absorption, distribution, metabolism, and excretion of a drug. Because of physiologic changes, disease states, and other medications, the pharmacokinetics of many drugs are altered in older persons (Table 1).6 Except in special cases, changes in the absorption of medications are of little clinical consequence. Decreased gastric acid production may decrease the absorption of cations such as iron and calcium, and medications that increase the gastric pH will accentuate this physiologic change. Decreased gastrointestinal motility and splanchnic blood flow may slow absorption and delay the onset of action of a drug but do not usually alter the total amount of drug absorbed. Well-documented changes in the body composition of most older persons affect the volume of distribution of a drug, depending on its fat or water solubility. Because of a relatively smaller lean body mass, most older persons require a smaller loading dose of water-soluble drugs like digoxin. Conversely, because of older persons' expanded fat stores, fat-soluble drugs such as benzodiazepines distribute

TABLE 1.-Physiologic Changes in Older Persons and the Effect on Selected Drugs Physiologic Alteretion

Decreased gastric acid ................ Decreased lean body mass ............. Increased fat stores .................. Diminished serum albumin level ......... Reduced hepatic oxidative metabolism ... Reduced hepatic blood flow ............ Decline in renal function ..............

Effect on Drugs

Reduced absorption of cations Increased levels of water-soluble drugs Increased half-life of fat-soluble drugs Increased activity of highly bound drugs Increased drug concentrations Decreased first-pass metabolism Reduced renal clearance

Examples

Iron, calcium Digoxin

Benzodiazepines Phenytoin Theophylline Lidocaine, isosorbide Aminoglycosides, digoxin, ciprofloxacin

Care, From the Department of Medicine, Division of General Internal Medicine, University of California, San Francisco, School of Medicine, and the Hospital Based Home Division of General Internal Medicine, Veterans Affairs Medical Center, San Francisco, California. Reprint requests to Mana Hobson, MD, Division of General Internal Medicine, VA Medical Center, 4150 Clement St, San Francisco, CA 94121.

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540 are more slowly cleared. In addition, because serum albumin levels tend to decrease with age, drugs that are substantially bound to albumin have a higher concentration of free, active drug at any given serum level. For example, target levels of phenytoin need to be adjusted downward in proportion to a decrease in albumin levels. Altered metabolism and excretion of drugs are, by far, the most clinically important changes that occur with aging. In the liver, a reduction in the activity of the cytochrome P450, or oxidative pathway, may reduce the clearance of drugs such as theophylline that are metabolized in this manner. Other processes such as glucuronidation are relatively unaffected. In addition, elderly persons tend to have a lower resting cardiac output, which reduces hepatic blood flow. Therefore, drugs such as isosorbide and lidocaine that are flow dependent in their hepatic metabolism should be started at lower doses and titrated according to clinical effect or blood level. Most older persons have a decreased ability to excrete medications in the urine. Cross-sectional studies have shown a linear decline of 50% in renal function by age 85. Longitudinal studies, however, reveal considerable individual variation.' Long-standing diabetes mellitus, hypertension, or other risk factors increase the likelihood of notable impairment. Unfortunately, the serum creatinine level may be an unreliable indicator of renal function. The Cockcroft-Gault equation* is a useful tool to estimate creatinine clearance from the serum creatinine level, taking into account the patient's age, weight, and sex.8 The value derived from this equation may be unreliable if renal function is changing rapidly. When using potentially toxic drugs with primarily renal excretion, such as digoxin, it is important to use measured drug levels, when available, to ensure safe dosing. Many other commonly prescribed drugs are cleared by the kidneys. These include the combination of sulfamethoxazole and trimethoprim, ciprofloxacin, and H2-receptor antagonists. Generally if the estimated creatinine clearance is less than 30 ml per minute, the dose of such drugs should be halved. Ifthe estimated creatinine clearance is less than 15 ml per minute, a timed urine collection and consultation with a clinical pharmacologist are recommended. Pharmacodynamics Pharmacodynamics can be defined as the body's sensitivity to medications. Many pharmacodynamic changes must be considered when prescribing medications in elderly persons.9 In general, older persons are more sensitive to the central nervous system (CNS) effects of most drugs, particularly if there is underlying cognitive impairment. It has been shown that many medications, including sedatives, antihypertensives, analgesics, and H2-receptor antagonists, are associated with cognitive impairment. 10 Benzodiazepines cause more psychomotor impairment in older than in younger persons, not accounted for by differences in blood levels."I In the elderly, narcotics not only have increased CNS effects, but these effects may be qualitatively differentdelirium instead of oversedation. 2 Increased CNS effects from anticholinergic agents are probably due to an agerelated decline in cholinergic activity in the brain. The anticoagulant effect of warfarin sodium may be enhanced in older persons; elderly patients generally require a

to a larger compartment, from which they

*Creatinine clearance (140-age) 72; multiply by 0.85 for women. =

x

x

weight (kg)/serum creatinine (mg per dl)

lower dose.13 In addition, they are more likely to bleed while anticoagulated because of a higher prevalence of predisposing conditions."4 There is also convincing evidence that older patients are less responsive to 3-blockers. This appears to be due to reduced receptor sensitivity, especially at the O31-receptor.11 Drug Interactions Patients who take several medications concurrently are at risk for substantial drug interactions"6; this risk increases with the number of medications. It is estimated that the rate of adverse effects is 4% for persons receiving 5 or fewer drugs, 10% for those receiving 6 to 10 drugs, and 28% for those receiving 11 to 15 drugs.17 Drugs may interact with each other when they have opposing effects (the renal effects of nonsteroidal anti-inflammatory agents and diuretics), when they have similar effects (sedation from anticholinergic agents and benzodiazepines), or when they alter each other's pharmacokinetics. Drugs also interact with diseases, causing adverse effects. Examples of this phenomenon are plentiful and include acute urinary retention in persons taking anticholinergic agents and worsened congestive heart failure due to (blockers. Drug-nutrient interactions are also common.18 The absorption of drugs such as levodopa, isoniazid, tetracycline, erythromycin, and oral (-lactamase antibiotics is notably inhibited by the presence of food in the stomach. The absorption of other drugs, including nitrofurantoin and propranolol hydrochloride, is increased by administering with food. There is convincing evidence that the bioavailability of phenytoin suspension is dramatically reduced in patients receiving continuous enteral feedings. 19 Drugs may also cause substantial nutrient depletion. Clinically important interactions of this type include isoniazid-induced vitamin B6 deficiency and diuretic-induced potassium and magnesium depletion. To screen for possible drug interactions, a complete list of all medications and medical problems should be kept for every patient. Note that there are several types of drugs that patients may fail to report. These include over-the-counter medications, ophthalmic preparations, topical medications, liquids, and vitamins. If there is any question, the patient should be instructed to bring in all medication bottles, or a home visit should be carried out. Also, patients should be asked about alcohol use; alcohol has the potential to interact with at least half of the most commonly prescribed drugs.20 Principles of Prescribing for Older Patients When prescribing a new medication in an old or frail person, the following principles should be considered: * Decide if the disease or symptom is worth treating. Some conditions may not require any intervention or may respond adequately to nonpharmacologic approaches. The treatment of many conditions, such as hyperlipidemia,21 is of unproven benefit in elderly patients. * Review the risks of treatment and of substantial drug interactions. In some patients an otherwise useful medication is contraindicated because of the risk of adverse effects. In particular, remember to consider the possible effects of a drug on a patient's function and quality of life. * Assess the patient's ability to comply with the treatment regimen. Common reasons for noncompliance include

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an inability to obtain medications-cannot get to the pharmacy or pay for the drug-trouble remembering to take medications, side effects, and difficulties opening a bottle or swallowing pills. Patients living alone may be particularly vulnerable to noncompliance. Intentional noncompliance is common.22 Patients may alter a dosing regimen to reduce side effects, to acquire greater self-control, or for convenience. For example, it is common for older persons with urinary incontinence to avoid diuretics on days they plan to go out of the home. Efforts to enhance compliance begin with assessing current medication use. Try to limit the total number of medications, and keep dosing regimens simple, using medications with once- or twice-a-day dosing requirements where possible. Patient and family education is important. Medication delivery aids such as seven-day pillboxes that are filled according to day and time (for example, Mediset boxes) are also helpful. * Start low and go slow. To avoid untoward effects, it is prudent to begin most medications at a low dose and to increase the dose slowly. This is especially important with antihypertensive and psychoactive drugs where patient sensitivity may be unpredictable and the consequences of overtreatment severe. * Monitor therapy for efficacy and side effects. When starting a drug regimen, determine how its effects will be monitored and plan an approximate duration of therapy. Medications should be reviewed at each office visit and at every hospital admission and discharge. Many medications may be started or continued unnecessarily and can be safely withdrawn.

Problem Drugs Problem drugs are those that have a high potential for toxicity and those that are relatively safe but are not efficacious or are overprescribed.

Antihypertensive Drugs Antihypertensive agents can cause orthostatic hypotension, sedation, depression, impotence, and constipation.23 In general, elderly persons are less tolerant of central adrenergic inhibitors like clonidine and peripheral a-adrenergic blockers such as prazosin hydrochloride. Low-dose thiazide diuretics are relatively safe for most patients and cause less metabolic aberrations and hypovolemia than higher doses. Calcium channel blockers are theoretically ideal, but nifedipine may cause orthostasis and edema, and diltiazem and verapamil hydrochloride are contraindicated in patients with ventricular systolic dysfunction. Verapamil causes considerable constipation, and the other calcium channel blocking agents do so to a lesser extent. Angiotensin-converting enzyme inhibitors can reduce renal function in predisposed patients or when combined with other drugs such as nonsteroidal anti-inflammatory agents. ,8-Blockers may have reduced efficacy, more CNS effects, and are contraindicated in many common conditions. Overall, the choice of antihypertensives will depend on a patient's susceptibility to certain side effects and on coexisting conditions. In patients with blood pressure measurements persistently higher than 160/ 95 mm of mercury and in whom a program of sodium restriction and exercise fails, initial treatment with 12.5 to 25 mg per day of hydrochlorothiazide (or an equivalent) is recommended. If this treatment fails and the patient has normal

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cardiac function, sustained-release diltiazem, 120 to 480 mg per day in two doses, can be added or substituted. For those with congestive heart failure, a judicious trial of an angiotensin-converting enzyme inhibitor such as lisinopril is indicated. If this is not tolerated due to renal dysfunction or cough, other medications with prominent arterial vasodilatory effects such as nifedipine or hydralazine hydrochloride may be useful. A difficult subset of patients to treat are those with hypertension and orthostatic hypotension.24 These patients typically have hypovolemia and become dangerously orthostatic when given diuretics. The using of pindolol, a fl-blocker with intrinsic sympathomimetic activity, may improve orthostasis. To reduce supine hypertension, the head of the patient's bed should be raised. In any case, close monitoring of orthostatic symptoms and close follow-up are recommended. Anticholinergic Drugs Drugs with anticholinergic effects include antidepressants, antipsychotics, antihistamines, and intestinal and bladder relaxants. Orthostatic hypotension is a common and potentially serious side effect of these agents and can contribute to immobility, falls, and fractures. In addition, anticholinergics may precipitate acute urinary retention in predisposed patients and cause sedation, confusion, and delirium. Less serious but troublesome side effects include dry mouth, blurred vision, and constipation. Psychoactive Drugs Though often useful, psychoactive medications must be administered with extreme caution and restraint in older persons. The initial treatment of insomnia, for example, should concentrate on nonpharmacologic approaches and the treatment of symptoms such as pain and nocturia that contribute to sleeplessness. In intermediate and long-term care facilities, attention has been focused on the use of psychoactive medications as "chemical restraints." About half of nursing home patients receive these medications (26% antipsychotics, 28% sedative-hypnotics).25 This apparent overuse has led to increasing requirements for documenting medical indications and for periodic reviews. For insomnia, long-acting benzodiazepines such as diazepam and flurazepam hydrochloride may have week-long half-lives in elderly patients, cause daytime sedation and mental slowing, and increase the risk of falls and fractures.26 Shorter acting agents are much safer, especially if low doses are used intermittently. Lorazepam, 0.5 to 1 mg, is ideal because of its rapid onset of action, and it can also be absorbed from the buccal mucosa for patients who cannot swal-

low pills. Triazolam is short-acting but can cause more severe rebound insomnia and paradoxic agitation.27 In addition, peak levels of triazolam are twofold higher in healthy older persons than in younger subjects, resulting in greater psychomotor impairment.28 Chloral hydrate is a good choice for insomnia because it has less potential for addiction and abuse. Diphenhydramine hydrochloride and amitriptyline hydrochloride should be avoided because of their anticholinergic side effects.

Antipsychotic Drugs Antipsychotic agents are frequently prescribed for agitation and behavioral problems in patients with dementia. Despite their popularity, there is little information confirming

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their efficacy. In a review of the few randomized, controlled clinical trials, improvement over placebo use was modest at best.29 In addition to questionable efficacy, antipsychotics have substantial side effects. Extrapyramidal movement disorders, including akathisia (motor restlessness), parkinsonism, and tardive dyskinesia, are common and uncomfortable side effects of these drugs. Antipsychotics also have anticholinergic side effects and are associated with a twofold increase in the risk of hip fracture.26 Improvement in nonpsychotic patients is likely due to sedation. Therefore, when nonpharmacologic approaches fail, it is preferable to achieve sedation with intermittent, shorter-acting benzodiazepines. Lorazepam, 0.5 to 1 mg, may be given three or four times a day when needed. This approach avoids anticholinergic and extrapyramidal side effects and may also palliate underlying anxiety symptoms. Increasing clinical experience suggests that buspirone, a serotonergic anxiolytic with no sedative properties, may also be useful. Neuroleptic agents should be reserved for patients who have prominent delusions, hallucinations, or both and may be tried in patients in whom other pharmacologic approaches have failed. Of the phenothiazines, haloperidol is recommended because it has fewer anticholinergic effects. Antidepressant Drugs Antidepressants can be helpful in episodes of major depression. When considering pharmacotherapy, it is important to distinguish major depression from medical disease such as hypothyroidism and less severe dysphoric syndromes. Amitriptyline and doxepin hydrochloride are extremely anticholinergic and sedating, and their use should be avoided. If a sedating agent is needed, trazodone hydrochloride is preferred because it has minimal anticholinergic side effects.30 For depression with psychomotor slowing, desipramine hydrochloride or nortriptyline hydrochloride are effective and are better tolerated than other tricyclic antidepressants. Fluoxetine may cause anorexia and weight loss, but it has virtually no anticholinergic or sedative effects. The role of psychostimulants such as dextroamphetamine or methylphenidate hydrochloride in geriatric depression is dubious: only one of ten controlled studies showed advantage over placebo.31 Hypoglycemic Drugs The use of hypoglycemic agents must be closely monitored in elderly patients. Hypoglycemic episodes may mani-

fest atypically as confusion or apathy and therefore go undetected. Chlorpropamide has a half-life of several days in patients with renal impairment and is also associated with hyponatremia due to inappropriate antidiuretic hormone excretion. Because of its short half-life, tolbutamide taken with meals is the safest alternative for patients who have an erratic caloric intake. Tolazamide, glyburide, and glipizide can be given once a day to enhance compliance and have similar efficacy and side effects.32 Tolazamide is available in generic form and is considerably less expensive. Digoxin The use of digoxin for congestive heart failure in patients with normal cardiac rhythm has been questioned.33 Although several studies have shown that digoxin can be safely withdrawn in 50% to 100% of such patients, a subset of patients with ventricular gallops (and presumably poor systolic function) do benefit from its use. Because symptoms of cardiac failure may also be caused by diastolic dysfunction, cardiac ischemia, or primary pulmonary disease, it is vital to verify the presence and degree of systolic dysfunction before prescribing this potentially toxic medication. Nonsteroidal Anti-inflammatory Drugs Nonsteroidal anti-inflammatory agents are commonly used by elderly persons and are available over the counter. Although these agents improve the quality of life for many patients with arthritis, they must be used with caution. In healthy elderly patients elevated serum creatinine levels rarely develop due to nonsteroidal drug therapy, but patients with renal disease, volume depletion, low cardiac output, or who are taking angiotensin-converting enzyme inhibitors are at higher risk.34 Dyspepsia develops in at least a third of older persons, gastric or duodenal erosions in 20%, and major complications such as bleeding and ulcer perforation in 1% to 2%.3 These side effects may be mitigated by the coadministration of antiulcer drugs or misoprostol. Central nervous system side effects of sedation and confusion also occur with nonsteroidal therapy. Acetaminophen, enteric-coated aspirin, and intermittent intra-articular administration of corticosteroids are useful alternatives for patients at risk for serious adverse reactions.36 H12-Receptor Antagonists Overall, H2-receptor antagonists are safe and effective therapy for peptic ulcer disease, but they are greatly overused

ts TABLE 2.-Recommended Drug Theatment Alternatives for Common Conditions in Elderly Pet;ien Recmmended Drug

Condition

Hypertension Without LV failure ........... Low-dose thiazide diuretic plus or minus slowrelease diltiazem HCI With LV failure ............. Lisinopril or enalapril maleate; if renal failure, hydralazine HCI With sgnificant orthostatic hypotension .......

.........

Diabetes mellitus ....

.........

Arthritis......................

Pindolol Tolazamide

Acetaminophen, enteric-coated aspirin, ibuprofen

(with monitoring) Insomnia ..................... Chloral hydrate, lorazepam* Agitation in dementia ........... Lorazepam* Depression ........T...........Trazodone HCI, desipramine HCI Ha - hydrochloride, LV= left ventricular

With intermittent or as-needed dosing

use

t Cution

Clonidine and other central adrenergic inhibitors; prazosin HCI

p3-Blockers, diltiazem HCI, verapamil HCI Diuretics, central adrenergic inhibitors, prazosin HaCI nifedipine Chlorpropamide Indomethacin, piroxicam

Diazepam, flurazepam, triazolam, diiphenhydramine HCI Phenothiazines

Amitriptyline HCI

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in patients with nonulcer dyspepsia, patients without recent disease, and as prophylaxis in patients admitted to hospitals. Any H2 blocker can cause CNS effects, especially at higher doses and in those with renal or hepatic impairment.37 Cimetidine also has many drug interactions: it substantially inhibits the hepatic metabolism of warfarin, phenytoin, lidocaine, quinidine, and nifedipine, among others, and decreases the renal excretion of procainamide hydrochloride. Recommendations for the drug treatment of common conditions in elderly persons are summarized in Table 2.

Conclusions Adverse drug reactions are common in elderly patients but often preventable. A knowledge of altered physiologic processes from normal aging and supervening diseases facilitates the selection of appropriate therapy and limits adverse reactions. Awareness of the dangers associated with multiple drug use and with specific medications is important, as is continuous monitoring of patients to determine whether the prescribed drug regimen is beneficial. Understanding a patient's treatment goals, social situation, and functional state, in combination with patient education, may improve medical compliance. Finally, it is paramount to consider the effects of medications on a patient's functional state and quality of life. Preserving functional independence and symptomatic relief are frequently more important than prolonging life in elderly persons, and this "geriatric imperative" should be reflected in medication prescribing, as in all other aspects of care in this

challenging population.

Acknowledgment Mark H. Beers, MD, contributed the concept of "Principles of Prescribing for Older Patients." REFERENCES

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Williamson J, Chopin JM: Adverse reactions to prescribed drugs in the elderly: A multicenter investigation. Age Ageing 1980; 9:73-80 2. Popplewell PY, Henschke PJ: Acute admissions to a geriatric assessment unit. Med J Aust 1982; 1:343-344 3. Porter I, Jick H: Drug-related deaths among medical inpatients. JAMA 1977; 237:879-881 4. Gurwitz JH, Avorn J: The ambiguous relation between aging and adverse drug reactions. Ann Intern Med 1991; 114:956-966 5. Beers MH, Ouslander JG: Risk factors in geriatric drug prescribing: A practical guide to avoiding problems. Drugs 1989; 37:105-112 6. Yuen GJ: Altered pharmacokinetics in the elderly. Clin Geriatr Med 1990; 6:257-267 7. Lindeman RD, Tobin J, Shock NW: Longitudinal studies on the rate of decline in renal function with age. J Am Geriatr Soc 1985; 33:278-285 8. Cockcroft DW, Gault MJ: Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16:31-41 9. Feely J, Coakley D: Altered pharmacodynamics in the elderly. Clin Geriatr Med 1990; 6:269-283 10. Larson EB, Kukull WA, Buchner D, Reifler BV: Adverse drug reactions associated with global cognitive impairment in elderly persons. Ann Intern Med 1987; 107:169-173

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This article is one of a series on topics in primary care in which common diagnostic or therapeutic problems encountered in primary care practice are presented. Physicians interested in contributing to the series are encouraged to contact the series' editors. STEPHEN J. McPHEE, MD TERRIE MENDELSON, MD Assistant Editors

Medications in older patients.

Adverse drug reactions are common in persons aged 65 and older and are associated with increased morbidity and mortality. A heightened susceptibility ...
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