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Medical therapy in the elderly
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Vol. 10. No.2
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August 19R7:29A-J4A
Medical Therapy in the Elderly J . ALAN HERD, MD, CO-CHAIR, ALASTAIR J. J. WOOD, MD, CO-CHAIR
JAMES BLUMENIHAL, PHD, JAMES E. DOUGHERTY, MD, FACC, RAYMOND HARRIS, MD, FACC
Pharmacotherapy The relative lack of information on the disposition or efficacy of cardiovascularand other drugs, as well as drug interactions, has been a major impediment in the drug treatment of elderly patients. This is because drugs have generally been studiedin healthy, young, normal, usually male, volunteers . A series of conferences addressing this problem has resulted in the inclusion of elderly patients in current trials of drug disposition, dose ranging and drug efficacy. However, inadequate information is available for a large number of already marketed drugs used in the elderly. Cardiovascular drugs, particularly those with narrow therapeutic ratios. should be studied in well designed clinical trials in appropriate older subjects so that proper guidelines for their use can be provided. In this categoryare antiarrhythmic agents, anticoagulant drugs, inotropic agents and the more potent antihypertensive drugs. Even when this information becomes available. the physician is still obligated to individualize drug treatment in the elderly, given the recognized variability of their response to drugs. An individual's response to a drug may be determined either by the way the drug is distributed in or excreted by the body (drug pharmacokinetic changes) or by the individual's sensitivity to the drug (pharmacodynamic changes).
Pharmacokinetic Changes With Aging Alterations with aging have been found in the ability to metabolize drugs, in drug distribution and in the renal excretion of drugs, all of which may influence plasma drug concentrations (1-5) . Renal excretion. For drugs principaJly excreted by the kidney. a reduction in. glomerular filtration rate may decrease the clearanceof the drug. Recent studies suggest that there is not an inevitable decrease in creatinine clearance with advancing age in healthy subjects. However, the clearance of renally excreted drugs is significantly reduced in theelderly. A well knownexample of such a drug is digoxin, whose renalclearance is lower in the elderly. This decreased clearance is associated with a reduced glomerular filtration rate and increased plasma digoxin concentrations, with an increased risk of toxicity. ttl I'IX7 by the American College of Cardiology
Hepatic metabolism, Hepatic drug metabolism may also be altered in the elderly, resulting in elevation in the plasma concentration of drugs whose principal route of metabolism is by the liver. For example, aging significantly reduces the hepatic clearance of propranolol, such that blood propranolol concentrations are twofold higher in older patients than in the young (5). Changes in drug metabolizing ability with aging are complex. Smokers metabolize many drugs more rapidly than do nonsmokers. The ability of cigarette smoking to induce hepatic drug metabolism appears to decrease with advancingage, so that smoking increases the clearance of highly metabolized drugs predominantly in the young. It appears that aging predominantly affects the oxidative metabolism of drugs, while those drugs whose principal route of metabolism is by synthetic pathways, such as conjugation, are relatively unaffected by aging (6). Drug clearance. Changes in drug clearance, whether due to altereddrug metabolism or to altered renal excretion, imply that drug dosage in elderly patients has to be chosen with great care, and that drug dosage has to be lower for those drugs whose clearance is reduced with aging. Pharmacodynamic Changes With Aging Altered responses to similar drug concentrations may occur either because of alterations in the sensitivity of the target organ to drug effect or because of alterations in the responsiveness of the compensatory reflexes that normally limit the hemodynamic effects of a drug. Both these alterations occur in the elderly. The beta-adrenergic receptor system is the best studied system in aging humans. The sensitivity of beta-adrenergic receptors in cardiac and vascular tissues to stimulation by beta-adrenergic agonists decreases with advancing age. Studies in humans have shown that the elderly are less sensitive to the chronotropic effects of isoproterenol. requiringa larger dose to produce the same increase in pulse rate achieved in younger persons (7). Also, the elderly require higher concentrations of propranolol to produce the same degree of beta-blockade (7) . Both in isolated vascular tissues and in vivo, vascular relaxation and response to beta-receptor agonists are decreased with advancing age (g). These changes produce alterations in response to drugs that interact directly with the affected re07J5-1 097/871$3 .50
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HERD ET AL MWrCAL THERAPY
ceptors; they also have indirect effects in decreasing the sensitivity of beta-receptor response because they impair compensatory reflexes. For example. when elderly patients receive vasodilator or antihypertensive agents. the reflex sympathetic stimulation, which such hypotension normally evokes. causes a diminished heart rate response.
Effe cts of Concomitant Disease s on Drug Therapy in rhe Elderly There is an increased likelihood with advancing age that patients have recognized or unrecognized concomitant diseases that may adversely affect their response to cardiovascular drugs. For example. it is important to consider that an elderly patient may have overt or silent coronary artery disease before prescribing a potent vasodilator such as minoxidil or hydralazine. The increased myocardial oxygen demand caused by minoxidil- or hydralazine-induced vasodilation and reflex tachycardia may precipitate angina pectoris or myocardial infarction. Any drug likely to produce a large postural decrease in blood pressure is inappropriate for elderly patients because of their diminished compensalary reflex responses. The risks of centrally acting antihypertensive drugs are unclear. It has been suggested that the elderly are more sensitive to the central nervous system depressant effects of drugs such as methyldopa; however. in a recent study of the treatment of hypertension in the elderly (EWPHE Study), methyldopa was well tolerated (9) .
Drug Interactions Because of the frequency with which elderly patients receive multiple medications, often from multiple sources, they are particularly likely to be subject to drug interactions. These interactions include interference by one drug with the absorption, distribution or excretion of another (pharmacokinetic interaction) as well as drug interaction at the receptor level. Perhaps the most common form of drug interaction occurs when two concomitantly administereddrugs have a similar effect, and thus produce additive pharmacologic actions. These actions are frequently not the primary pharmacologic effect of the drugs but are a secondary or unwanted effect, not anticipated by the physician. For example, if two drugs with mild sedative action are given together. the combined sedative effect may be severe. Unfortunately, drug side effects are often unrecognized in elderly patients because the patient' s signs or symptoms are ascribed either to the underlying disease or to " old age." Cardiac effects of noncardiac medications. The elderly are frequent users of analgesics, antacids, laxatives, antidepressants, sedatives, bronchodilators and ophthalmic beta-receptor blockers. Some of these agents are prescription drugs, but many others may be obtained over the counter.
Many of these agents have cardiac effects that may be deleterious to patients with occult or overt cardiac disorders. For example, the high sodium content of antacids may cause volume expansion and precipitate heart failure. Sympathomimetic bronchodilators increase heart rate and may be arrhythmogcnic: they may be especially deleterious in patients with coronary artery disease. unmasking or worsening angina pectoris and ventricular arrhythmias. Antidepressant agents can precipitate arrhythmias. The nonsteroid anti-inflammatory drugs are commonly used by elderly patients both as prescription and as nonprescription agents, These drugs interfere with prostaglandin synthesis and raise blood pressure by several mechanisms, including sodium retention. The effects may vary from drug to drug and from patient to patient. Simplification of drug regimens should be the goal for both elderly and young patients. However, at least in a trial of antihypertensive therapy. the elderly appeared to show as good compliance as did the young ( 10, ll).
Recommendations Drug therapy for elderly patients is based on principles similar to those used to choose therapy in the young. However, because of the greater risk of adverse drug reactions in the elderly. there should be more attention to possible unwanted drug effects. Specifically. greater care is needed in adjusting drug dosage in elderly patients because of their impaired ability to excrete some drugs. In addition, impaired homeostatic mechanisms may accentuate the response to normal concentrations of drugs. Because of all these changes. therapy in elderly patients should be started at lower doses than is usual in younger patients, and the dose should be advanced slowly if necessary. Drug response should be carefully monitored. Because elderly patients often receive multiple drugs, the physician should be alert to drug interactions and should also avoid the coadministration of drugs with similar effects. These effects may be subtle; for example, the coadministration of a benzodiazopine tranquilizer and a centrally acting antihypertensive drug such as methyldopa. may both produce sedation. Finally, the elderly may not recognize and frequently do not spontaneously complain of drug side effects; potential unwanted effects must be assessed by direct questioning.
Diet and Exercise Nutrition and physical activity both play important roles in maintaining normal cardiovascular function in the elderly and arc the major nonpharmacologic approaches to the treatment of hypertension and the prevention of coronary heart disease in individuals of all ages. Physical activity that is well maintained in elderly individuals is associated with
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lower blood pressure and more favorable metabolic characteristics than are observed in sedentary individuals (12). Thus, diet and exercise appear to have a profound influence on health and disease. Our concern is to determine the benefits and hazards of diet and exercise in the elderly.
Nutriti on in the Elderly There is a lack of consensus concerning recommended dietary allowances that might contribute to the health of the elderly, in part because individuals age at different rates. and various physiologic functions deteriorate in unpredictable ways. so that there is great heterogeneity of physiologic function and. presumably, of nutritional requirements in the elderly ( 13) . Furthermore, there are inevitableconsequences of disease and medical treatment on intake and absorption of essential nutrients. Nutritional requirements must also take into account that lean body mass declines continually throughout life, with an average loss of about 6.3% for each decade (14), and an increase of adipose tissue with age. Carbohydrate and fat metabolism . Aging has an effect on carbohydrate and fat metabolism and inevitably involves a decrease in glucose utilization after glucose loading (15). This appears to be associated with insulin antagonism: a rise in the level of plasma insulin has been observed. As a result, the glucose that is not metabolized through the glycolytic cycle is used for synthesis of triglycerides. Free fatty acids become the main source of energy supply. High circulating plasma levels of free fatty acids enhance the synthesis of triglycerides and very low density lipoproteins. High levels of free fatty acids may promote clinical complications of ischemic heart disease in elderly individuals. Dietary intervention for hyperlipidemia. With age. there is a rising incidence and prevalence of cardiovascular disease, As in young adults, elderly individuals with high levels of atherogenic lipids develop more cardiovascular disease (16). The success of several trials in reducing morbidity and mortality from coronary heart disease (17,18) has focused attention on lowering blood lipids as a preventive strategy, Deaths from myocardial infarction and progression of coronary lesions also were reduced when blood lipid levels were reduced by administration of cholestyramine or marked reduction in intake of saturated fat. The greatest benefits were observed in patients with a high ratio of total to high density lipoprotein cholesterol (18). Patients with these characteristics are the ones most likely to benefit from dietary intervention, Hypertension and nutritional risk factors. Hypertension, particularly isolated systolic hypertension, is common in elderly individuals. Although risk factors for the development of hypertension have not been well defined, a number of possibilities include obesity and dietary intake of sodium, potassium, calcium, fat and alcohol. All these risk factors may be classified as nutritional,
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Weight reduction. Weight reduction can reduce blood pressure independently of dietary sodium restriction (19,20), Small amounts of weight loss usually will lower blood pressure even in individuals who are not obese (21). Sodium restriction has been effective in lowering blood pressure in some individuals (22). Elderly individuals, particularly those with severe hypertension and low renin values, may respond to sodium restriction. Decreased fat intake or increased intake of polyunsaturated fatty acids also has been reported to reduce blood pressure (23), These data suggest that it is reasonable to moderately restrict sodium intake in the elderly to 75 to 100 mmollday. Dietary calcium intake should be maintained to prevent osteoporosis. Reduction of fat intake might have its greatest efficacy by lowering caloric intake and reducing obesity.
Physical Activity in the Elderly The effects of physical conditioning in the elderly have been compared in studies of individuals who are sedentary and those who are physically active (24). A progressive decline in maximal oxygen uptake is observed with age, but sedentary individuals have a 10to 20% decrement compared with active individuals of the same age (25,26), Elderly individuals who are physically active may have a greater endurance capacity than younger sedentary individuals, Other health characteristics are also well maintained in physically active elderly individuals. Endurance training. Endurance training also can improve the physical working capacity of sedentary elderly individuals (Table I). Maximal oxygen uptake increases (27,28) as evidence of endurance conditioning. Vigorous exercise in elderly individuals also appears associated with a reduced incidence of myocardial infarction. Paffenbarger et al. (29) reported the results of a physical activity survey of 16.936 Harvard male alumni aged 35 to 74 years, of whom 572 experienced heart attacks in 117,680 personyears of follow-up. Menwith a physical activity index < 2.000 kcal/week were at 65% higher risk than were classmates with a higher index. Although individuals aged 65 to 74 years had a higher rate of heart anack than those in younger age groups. individuals with a physical activity index > 2.000 kcal/week had less than half the rate of heart attack experienced by those with a physical activity index less than 500 kcallweek. Physically active elderly individuals had lower rates of heart attack than those who were sedentary. Regular exercise. Exercise training elicits beneficial physiologic and metabolic responses in skeletal muscle and the cardiopulmonary system, Prescription of regular exercise for elderly patients should consider the individual's maximal oxygen uptake. corrected for age, sex and lean body mass. Regular isotonic exercise. particularly walking, may have favorable physiologic and psychologic benefits in the elderly.
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Table 1. Results of Symptom-Limited Maximal Spiroergometry Before and After Systematic Bicycle Ergometer Training of 12 Weeks Duration* No. of Patients Max HR (min~l) Max work load (W) V0 2 max (ml min-I) ABEmax Submax HR (min-I) V E- max (I min-I)
12 12 8 10
12
Before Training 147 ± I3t III ± 36 1,623 ± 423 4.5 ± 1.I 135 ± 12
8
52 ± 18
After Training 147 129 1,856 5.6 125
± ± ± ± ±
16 29 480 1.4 14
p Value NS <0.01 <0.01 NS <0.5
60 ± 21
NS
*Eight women and four men aged 67 to 76 years (mean 71.1). tMean ± SD. ABEmax = maximaldifference between base excess at rest and during exhausting exercise; Max HR = maximal heart rate; Submax HR = heart rate at the same submaximal exercise level; VE~max = maximal ventilation; V0 2 max = maximal oxygen uptake. (Adapted from Haber P, et al. [28]).
Exercise Testing in the Elderly
Psychologic Benefits of Exercise
Exercise testing is safe and effective for the evaluation of cardiovascular status in elderly patients. The degree of ST depression during exercise testing is a reliable predictor of the extent of coronary artery disease (30). The extent of rise in systolic blood pressure during an exercise test is reported to be the single best predictor of subsequent morbidity and mortality (31). A low increase of the pressurerate product from rest to maximal exercise and OCCurrence of significant exercise-associated ventricular arrhythmias may identify a high risk group Of patients with substantially reduced probability for survival compared with patients without these responses. Elderly individuals respond to submaximal and maximal exercise tests similarly to younger individuals (30,32,33). However, maximal heart rate is significantly lower in patients >65 years of age. Systolic blood pressure is higher in older patients at rest and during exercise, but diastolic blood pressure is the same in both age groups. At the same intensity of exercise, heart rate tends to be lower and blood pressure higher in older than in younger individuals. Pharmacologic testing. It may be difficult for some elderly persons to perform a maximal exercise test because of physical limitations associated with orthopedic, neurologic or musculoskeletal conditions. Under these circumstances, diagnostic information can be obtained with pharmacologic testing, such as intravenous or oral dipyridamole administration during thallium imaging, to maximize coronary flow heterogeneity (34). Arm exercise testing. Another alternative to treadmill or bicycle ergometer exercise testing is an arm exercise test. Arm ergometry using a hand-cranked bicycle ergometer can help evaluate individuals with heart disease. In assessing the severity of coronary heart disease, arm ergometry can be combined with thallium scintigraphy (35).
Studies of the psychologic effects of aerobic exercise training (36) have shown that aerobic exercise can improve mood (37), reduce psychophysiologic responsivity to behavioral stressors (38,39) and improve self-esteem (40,41) in both the young and the old. In addition, aerobic exercise may improve cognitive functioning and psychomotor speed (42).
Dustman et al. (43) showed that older adults (55 to 70 years of age) achieved a 27% increase in maximal oxygen consumption after a 4 month aerobic exercise program. This was accompanied by improvement both in simple reaction time performance and in a measure of resistance to perceptual distraction (Stroop task). Thus, exercise may improve psychologic and cognitive functioning in the elderly.
Adherence to Prescribed Exercise Attitudes about exercise and health may influence adherence to cardiac rehabilitation exercise. Sidney and Shephard (44), studying the activity patterns of men and women 2:60 years of age found that elderly individuals seldom engage in heavy physical activity. Heart rates during continuous electrocardiographic recording indicated that elderly subjects overestimated the time spent on heavy physical activity, as compared with ratings by younger adults in similar studies. Attitudes toward physical activity may influence the compliance of elderly patients with exercise rehabilitation after myocardial infarction. Gori et al. (45) reported that only 12% of patients >65 years completed a 4 month program. Factors contributing to noncompliance. An important step in overcoming noncompliance involves identification of factors in both the individual and the environment that contribute to noncompliance. Compliance refers to the de-
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gree to which a person's behavior in taking medications. following a diet,exercising or executing otherlifestyle changes coincideswith medicalor health advice (46). Characteristics of a rehabilitation program, available social supports and perceptions of the treatment regimen have to be assessed. Although elderly cardiac patients are not at greater risk for noncompliance, a number of factors associated with noncompliance appear relevant for elderly cardiac patients. These include an increased complexity and duration of treatment. a high degree of behaviorchange required by the treatment, the patients's limited perception of personal vulnerability and the increased potential success of treatment contingent on compliance (47). The patient's comprehension of the treatment program appears to be the most important feature favoring compliance. Although few systematic efforts to increase compliance with cardiac rehabilitation interventions have been published, a variety of strategies for improving compliance are appropriate for elderly cardiac patients; these include convenience. tailoringof the exerciseregimen for older persons. delineationof goals specific for elderly patients and the like (48).
Education of the Elderly Cardiac Patient In planning health education programs for an elderly population, medical! social and cultural barriers to communication must be addressed for subsets of individuals . Impaired vision and hearing exemplify physical handicaps, and declining cognitive function and emotional instability are examples of mental problems, Other subsets of individuals may be fragile or have concomitant diseases, or both. The possible gains have to he weighed against risks of changing lifelong habits, creating anxiety and engendering negative reactions. Educational messages should convey a recognition of the patient's persunal worth. Suggestions for lifestyle interventions should be made in moderation and at levels compatible with the patient's prior experience and age. Promotion of a healthy lifestyle through smoking cessation. adequate diet. reduced alcohol intake and regular physical activity can provide important benefits to elderly patients who function at a marginal level. Also important are stress reduction , development of social support networks and simplification of daily life or work activities (49).
Summary Recommendations concerning nutrition and physical activity are an important part of health care in the elderly. There is increasingevidence that diet and exercise influence the development and progression of cardiovascular disease
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in the elderly as well as the young. Decreases in coronary risk factors can be achieved in the elderly by attention to proper diet and exercise.
References I. Triggs EJ. Nation RL. Pharmacokinetics in the aged. A review. J
Pharmacokinet Biopharm 1975;3:387-41 8. 2. Vestal RE. Drug use in the elderly: a review of problems and special considerations. Drugs 1978;16:358- 82. 3. Crooks J. O'Malley K, Stevenson IH. Pharmacokinetics in the elderly. Clin Pharmacokinet 1976;1:280-96 . 4. Paxton JW, Briant RH. Alphaj-acid glycoprotein concentrations and propranolol binding in elderly patients with acute illness. Br J Clin Phannacol 1984;18:806-10. 5. Vestal RE. Wood AJJ, Branch RA. Shand DG, Wilkinson GR. Effect of age and cigarette smoking on propranolol disposition. Clin Pharrnacol Ther 1979;26:8 -15 . 6. Kraus JW, Desmond PV. Marshall JP, Johnson RF, Schenker S, Wilkinson GR. Effects of aging and liver disease on disposition of lorazeparn. Clin Pharmacol Ther 1978;24:411-9. 7. Vestal RE. Wood AJ . Shand 00 . Reduced beta-adrenorcceptor sensitivity in the elderly. C1in Phannacol Ther 11)79;26:181-6. ll. Lakatta EG. Age-related alterations in the cardiovascular response to adrenergic mediated stress. Fed Proc 1980:39:3173- 7. 9. Amery A. Birkenhager W, Brixko P, et al. Mortality and morbidity results from the European Working Party on High Blood Pressure in the Elderly trial. Lancet 1985;1:1349-54 . 10. Hypertension Detection and Follow-up Program Cooperative Group. Five-year findings of the Hypertension Detection and Follow-up Program. I. Reduction in morbidity of persons with high blood pressure, including mild hypertension. JAMA 1979;242:2562- 71. II . Hypertension Detection and Follow-up Program Cooperative Group. Five-year findings of the Hypertension Detection and Follow-up Program. II. Mortality by race, sex. and age. JAMA 1979;242:2572-7 . 12. Larsson B. Renstrom P. Svardsudd K. et al. Health and ageing characteristics of highly physically active 65-year-old men. Eur Heart J 1984;5(suppl E):31-5. 13. Schneider EL. Vining EM, Hadley EC, Farnham SA. Recommended dietary allowances and the healthof the elderly. N Engl J Med 1986;314: 157-60 . 14. Forbes GB. The adult decline in lean body mass. Am Bioi 1976;48: 161-73. 15. Davidson MB. The effect of aging on carbohydrate metabolism: a review of the English literature and a practical approach to the diagnosis of diabetes mellitus in theelderly. Metabolism 1979;28:688-705. 16. Kannel WB, Gordon T. Evaluation of cardiovascular risk in the elderly: the Framingham Study. Bull NY Acad Med 1978:54:573- 91. 17. Lipid Research Clinics Program. The Lipid Research Clinics Coronary Primary Prevention Trial Results. I. Reduction in incidence of coronary heart disease. JMtA 1984;251:351··64. 18. Amtzenius AC, Kromhout D. Barth, JD, et al. Diet, lipoproteins. and the progression of coronary atherosclerosis. The Leidenlntervention Trial. N Engl J Med 1985;312:805-11. 19. Reisin E. Abel R. Modan M, et al. Effect of weight loss without salt restriction on the reduction of blood pressure in overweight hypertensive patients. N Engl J Ivkd 19782 98:1- 6. 20. Maxwell MH, Kushiro T, Dornfeld LP, Tuck ML, Waks AU. BP changes in obese hypertensive subjects during rapid weight loss. Comparison of restricted unchanged salt intake. Arch Intern Med 1984;144: 1581-4 . 21. Imai Y. Sato K. Abe K. et al. Effect of weight loss on blood pressure
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and drug consumption in normal weight patients. Hypertension 1986;8: 223-8. 22. Koolen MI, Van Brummelen P. Sodium sensitivity in essential hypertension: role of the renin-angiotension-aldosterone system and predictive value of an intravenous frusemide test. 1 Hypertens 1984;2: 55-9. 23. Puska P, Iacono 1M, Nissinen A, et al. Controlled, randomised trial of the effect of dietary fat on blood pressure. Lancet 1983;1:1-5. 24. Hossack KR, Bruc RA. Maximal cardiac function in sedentary normal men and women: comparison of age-related changes. 1 Appl Physiol 1982;53:799-804. 25. Wenger NK. Rehabilitation of the elderly cardiac patient. Cardiovasc Clin 1981;12:221-30. 26. Robinson S, Dill DB, Tzankoff SP, Wagner lA, Robinson RD. Longitudinal studies of aging in 37 men. 1 Appl Physiol 1975;38:263-7. 27. deVries HA. Physiological effects of an exercise training regimen upon men aged 52-88. 1 Gerontol 1970;25:325-36. 28. Haber P, Honiger B, Klicpera M, Niederberger M. Effects in elderly people 67-76 years of age of three-month endurance training on a bicycle ergometer. Eur Heart 1 1984;5(suppl E):37-9. 29. Paffenbarger RS. Wing AL, Hyde RT. Physical activity as an index of heart attack risk in college alumni. Am 1 Epidemiol 1978;108: 161-75. 30. Samek L, Betz P, Schnellbacher K. Exercise testing in elderly patients with coronary artery disease. Eur Heart 1 1984;5(suppl E):69-73. 31. Saunamaki KI. Early post-myocardial infarction exercise testing in subjects 70 years or more of age. Functional and prognostic evaluation. Eur Heart 1 1984;5(suppl E):93-6. 32. Cokkinos DV. Perrakis C, Diakoumakos N, Papantonakos A, Mamaki S. Cardiac function at treadmill exercise in various age groups. Eur Heart 1 1984;5(suppl E):41-5.
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35. Balady GD, Weiner DA. Rothendler lA, Ryan n. Arm exercisethallium imaging testing for the detection of coronary artery disease. 1 Am Coil Cardiol 1987;9:84-8. 36. Folkins CH. Sime WE. Physical fitness training and mental health. Am Psychol 1981;36:373-89. 37. Blumental lA, Williams RS, Needles TL, Wallace AG. Psychological changes accompany aerobic exercise in health middle-aged adults. Psychosom Med 1982;44:529-36. 38. Holmes DS, Roth DL. Influence of aerobic fitness on pulse rate and subjective response to stress. Psychophysiology 1985;22:525-9. 39. Sinyor D, Schwartz SG, Peronnet F, Brisson G, Seraganian P. Aerobic fitness level and reactivity to psychosocial stress: physiological, biochemical, and subjective responses. Psychosom Med 1983;45:205-17. 40. Hanson IS, Nedde UH. Long-term physical training effect in sedentary females. 1 Appl Physiol 1974;32:112-26. 41. Hilyer lC, Mitchell W. Effect of systematic physical fitness training combined with counseling on the self-concept of college students. 1 Counseling Psychol 1979;26:427-36. 42. Tornporowski PD. Ellis NR. Effects of exercise on cognitive processes: a review. Psychol Bull 1986;99:338-46. 43. Dustman RE, Ruhling RO, Russell EM, et al. Aerobic exercise training and improved neuropsychological function of older individuals. Neurobiol Aging 1984;5:35-42. 44. Sidney KH, Shephard Rl. Activity patterns of elderly men and women. 1 Gerontol 1977;32:25-32.
45. Gori P. Pivotti F, Mase N, Zucconi V, Scardi S. Compliance with cardiac rehabilitation in the elderly. Eur Heart 1 I984;5(suppl):109-111. 46. Haynes RB, Taylor DW, Sackett DL. Compliance in health care. Baltimore. MD: Johns Hopkins Press, 1979. 47. Blackwell B. Treatment adherence. Br 1 Psychiatry 1976;129:51331.
33. Gaul G. Stress testing in persons above the age of 65 years. Applicability and diagnostic value of a standardized maximal symptomlimited testing protocol. Eur Heart 1 1984;5(suppl E):51-3.
48. Epstein LH, Cluss PA. Behavioral medicine perspective on adherence to long-term medical regimens. 1 Consult Clin Psychol 1982;50:950-71.
34. Boucher CA, Brester DC, Darling RC. Okada RD. Strauss HW, Pohost GM. Determination of cardiac risk by dipyridamole-thallium imaging before peripheral vascular surgery. N Engl 1 Med 1985;312: 389-94.
49. Shephard Rl, Wenger NK. Furberg CD. Education of the aged cardiac patient. In: NK Wenger. ed. The Education of the Patient with Cardiac Disease in the Twenty-first Century. New York: Le Jacq, 1986, 406-9.
Vol. 10. No.2
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August 19R7:29A-J4A
Medical Therapy in the Elderly J . ALAN HERD, MD, CO-CHAIR, ALASTAIR J. J. WOOD, MD, CO-CHAIR
JAMES BLUMENIHAL, PHD, JAMES E. DOUGHERTY, MD, FACC, RAYMOND HARRIS, MD, FACC
Pharmacotherapy The relative lack of information on the disposition or efficacy of cardiovascularand other drugs, as well as drug interactions, has been a major impediment in the drug treatment of elderly patients. This is because drugs have generally been studiedin healthy, young, normal, usually male, volunteers . A series of conferences addressing this problem has resulted in the inclusion of elderly patients in current trials of drug disposition, dose ranging and drug efficacy. However, inadequate information is available for a large number of already marketed drugs used in the elderly. Cardiovascular drugs, particularly those with narrow therapeutic ratios. should be studied in well designed clinical trials in appropriate older subjects so that proper guidelines for their use can be provided. In this categoryare antiarrhythmic agents, anticoagulant drugs, inotropic agents and the more potent antihypertensive drugs. Even when this information becomes available. the physician is still obligated to individualize drug treatment in the elderly, given the recognized variability of their response to drugs. An individual's response to a drug may be determined either by the way the drug is distributed in or excreted by the body (drug pharmacokinetic changes) or by the individual's sensitivity to the drug (pharmacodynamic changes).
Pharmacokinetic Changes With Aging Alterations with aging have been found in the ability to metabolize drugs, in drug distribution and in the renal excretion of drugs, all of which may influence plasma drug concentrations (1-5) . Renal excretion. For drugs principaJly excreted by the kidney. a reduction in. glomerular filtration rate may decrease the clearanceof the drug. Recent studies suggest that there is not an inevitable decrease in creatinine clearance with advancing age in healthy subjects. However, the clearance of renally excreted drugs is significantly reduced in theelderly. A well knownexample of such a drug is digoxin, whose renalclearance is lower in the elderly. This decreased clearance is associated with a reduced glomerular filtration rate and increased plasma digoxin concentrations, with an increased risk of toxicity. ttl I'IX7 by the American College of Cardiology
Hepatic metabolism, Hepatic drug metabolism may also be altered in the elderly, resulting in elevation in the plasma concentration of drugs whose principal route of metabolism is by the liver. For example, aging significantly reduces the hepatic clearance of propranolol, such that blood propranolol concentrations are twofold higher in older patients than in the young (5). Changes in drug metabolizing ability with aging are complex. Smokers metabolize many drugs more rapidly than do nonsmokers. The ability of cigarette smoking to induce hepatic drug metabolism appears to decrease with advancingage, so that smoking increases the clearance of highly metabolized drugs predominantly in the young. It appears that aging predominantly affects the oxidative metabolism of drugs, while those drugs whose principal route of metabolism is by synthetic pathways, such as conjugation, are relatively unaffected by aging (6). Drug clearance. Changes in drug clearance, whether due to altereddrug metabolism or to altered renal excretion, imply that drug dosage in elderly patients has to be chosen with great care, and that drug dosage has to be lower for those drugs whose clearance is reduced with aging. Pharmacodynamic Changes With Aging Altered responses to similar drug concentrations may occur either because of alterations in the sensitivity of the target organ to drug effect or because of alterations in the responsiveness of the compensatory reflexes that normally limit the hemodynamic effects of a drug. Both these alterations occur in the elderly. The beta-adrenergic receptor system is the best studied system in aging humans. The sensitivity of beta-adrenergic receptors in cardiac and vascular tissues to stimulation by beta-adrenergic agonists decreases with advancing age. Studies in humans have shown that the elderly are less sensitive to the chronotropic effects of isoproterenol. requiringa larger dose to produce the same increase in pulse rate achieved in younger persons (7). Also, the elderly require higher concentrations of propranolol to produce the same degree of beta-blockade (7) . Both in isolated vascular tissues and in vivo, vascular relaxation and response to beta-receptor agonists are decreased with advancing age (g). These changes produce alterations in response to drugs that interact directly with the affected re07J5-1 097/871$3 .50
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HERD ET AL MWrCAL THERAPY
ceptors; they also have indirect effects in decreasing the sensitivity of beta-receptor response because they impair compensatory reflexes. For example. when elderly patients receive vasodilator or antihypertensive agents. the reflex sympathetic stimulation, which such hypotension normally evokes. causes a diminished heart rate response.
Effe cts of Concomitant Disease s on Drug Therapy in rhe Elderly There is an increased likelihood with advancing age that patients have recognized or unrecognized concomitant diseases that may adversely affect their response to cardiovascular drugs. For example. it is important to consider that an elderly patient may have overt or silent coronary artery disease before prescribing a potent vasodilator such as minoxidil or hydralazine. The increased myocardial oxygen demand caused by minoxidil- or hydralazine-induced vasodilation and reflex tachycardia may precipitate angina pectoris or myocardial infarction. Any drug likely to produce a large postural decrease in blood pressure is inappropriate for elderly patients because of their diminished compensalary reflex responses. The risks of centrally acting antihypertensive drugs are unclear. It has been suggested that the elderly are more sensitive to the central nervous system depressant effects of drugs such as methyldopa; however. in a recent study of the treatment of hypertension in the elderly (EWPHE Study), methyldopa was well tolerated (9) .
Drug Interactions Because of the frequency with which elderly patients receive multiple medications, often from multiple sources, they are particularly likely to be subject to drug interactions. These interactions include interference by one drug with the absorption, distribution or excretion of another (pharmacokinetic interaction) as well as drug interaction at the receptor level. Perhaps the most common form of drug interaction occurs when two concomitantly administereddrugs have a similar effect, and thus produce additive pharmacologic actions. These actions are frequently not the primary pharmacologic effect of the drugs but are a secondary or unwanted effect, not anticipated by the physician. For example, if two drugs with mild sedative action are given together. the combined sedative effect may be severe. Unfortunately, drug side effects are often unrecognized in elderly patients because the patient' s signs or symptoms are ascribed either to the underlying disease or to " old age." Cardiac effects of noncardiac medications. The elderly are frequent users of analgesics, antacids, laxatives, antidepressants, sedatives, bronchodilators and ophthalmic beta-receptor blockers. Some of these agents are prescription drugs, but many others may be obtained over the counter.
Many of these agents have cardiac effects that may be deleterious to patients with occult or overt cardiac disorders. For example, the high sodium content of antacids may cause volume expansion and precipitate heart failure. Sympathomimetic bronchodilators increase heart rate and may be arrhythmogcnic: they may be especially deleterious in patients with coronary artery disease. unmasking or worsening angina pectoris and ventricular arrhythmias. Antidepressant agents can precipitate arrhythmias. The nonsteroid anti-inflammatory drugs are commonly used by elderly patients both as prescription and as nonprescription agents, These drugs interfere with prostaglandin synthesis and raise blood pressure by several mechanisms, including sodium retention. The effects may vary from drug to drug and from patient to patient. Simplification of drug regimens should be the goal for both elderly and young patients. However, at least in a trial of antihypertensive therapy. the elderly appeared to show as good compliance as did the young ( 10, ll).
Recommendations Drug therapy for elderly patients is based on principles similar to those used to choose therapy in the young. However, because of the greater risk of adverse drug reactions in the elderly. there should be more attention to possible unwanted drug effects. Specifically. greater care is needed in adjusting drug dosage in elderly patients because of their impaired ability to excrete some drugs. In addition, impaired homeostatic mechanisms may accentuate the response to normal concentrations of drugs. Because of all these changes. therapy in elderly patients should be started at lower doses than is usual in younger patients, and the dose should be advanced slowly if necessary. Drug response should be carefully monitored. Because elderly patients often receive multiple drugs, the physician should be alert to drug interactions and should also avoid the coadministration of drugs with similar effects. These effects may be subtle; for example, the coadministration of a benzodiazopine tranquilizer and a centrally acting antihypertensive drug such as methyldopa. may both produce sedation. Finally, the elderly may not recognize and frequently do not spontaneously complain of drug side effects; potential unwanted effects must be assessed by direct questioning.
Diet and Exercise Nutrition and physical activity both play important roles in maintaining normal cardiovascular function in the elderly and arc the major nonpharmacologic approaches to the treatment of hypertension and the prevention of coronary heart disease in individuals of all ages. Physical activity that is well maintained in elderly individuals is associated with
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lower blood pressure and more favorable metabolic characteristics than are observed in sedentary individuals (12). Thus, diet and exercise appear to have a profound influence on health and disease. Our concern is to determine the benefits and hazards of diet and exercise in the elderly.
Nutriti on in the Elderly There is a lack of consensus concerning recommended dietary allowances that might contribute to the health of the elderly, in part because individuals age at different rates. and various physiologic functions deteriorate in unpredictable ways. so that there is great heterogeneity of physiologic function and. presumably, of nutritional requirements in the elderly ( 13) . Furthermore, there are inevitableconsequences of disease and medical treatment on intake and absorption of essential nutrients. Nutritional requirements must also take into account that lean body mass declines continually throughout life, with an average loss of about 6.3% for each decade (14), and an increase of adipose tissue with age. Carbohydrate and fat metabolism . Aging has an effect on carbohydrate and fat metabolism and inevitably involves a decrease in glucose utilization after glucose loading (15). This appears to be associated with insulin antagonism: a rise in the level of plasma insulin has been observed. As a result, the glucose that is not metabolized through the glycolytic cycle is used for synthesis of triglycerides. Free fatty acids become the main source of energy supply. High circulating plasma levels of free fatty acids enhance the synthesis of triglycerides and very low density lipoproteins. High levels of free fatty acids may promote clinical complications of ischemic heart disease in elderly individuals. Dietary intervention for hyperlipidemia. With age. there is a rising incidence and prevalence of cardiovascular disease, As in young adults, elderly individuals with high levels of atherogenic lipids develop more cardiovascular disease (16). The success of several trials in reducing morbidity and mortality from coronary heart disease (17,18) has focused attention on lowering blood lipids as a preventive strategy, Deaths from myocardial infarction and progression of coronary lesions also were reduced when blood lipid levels were reduced by administration of cholestyramine or marked reduction in intake of saturated fat. The greatest benefits were observed in patients with a high ratio of total to high density lipoprotein cholesterol (18). Patients with these characteristics are the ones most likely to benefit from dietary intervention, Hypertension and nutritional risk factors. Hypertension, particularly isolated systolic hypertension, is common in elderly individuals. Although risk factors for the development of hypertension have not been well defined, a number of possibilities include obesity and dietary intake of sodium, potassium, calcium, fat and alcohol. All these risk factors may be classified as nutritional,
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Weight reduction. Weight reduction can reduce blood pressure independently of dietary sodium restriction (19,20), Small amounts of weight loss usually will lower blood pressure even in individuals who are not obese (21). Sodium restriction has been effective in lowering blood pressure in some individuals (22). Elderly individuals, particularly those with severe hypertension and low renin values, may respond to sodium restriction. Decreased fat intake or increased intake of polyunsaturated fatty acids also has been reported to reduce blood pressure (23), These data suggest that it is reasonable to moderately restrict sodium intake in the elderly to 75 to 100 mmollday. Dietary calcium intake should be maintained to prevent osteoporosis. Reduction of fat intake might have its greatest efficacy by lowering caloric intake and reducing obesity.
Physical Activity in the Elderly The effects of physical conditioning in the elderly have been compared in studies of individuals who are sedentary and those who are physically active (24). A progressive decline in maximal oxygen uptake is observed with age, but sedentary individuals have a 10to 20% decrement compared with active individuals of the same age (25,26), Elderly individuals who are physically active may have a greater endurance capacity than younger sedentary individuals, Other health characteristics are also well maintained in physically active elderly individuals. Endurance training. Endurance training also can improve the physical working capacity of sedentary elderly individuals (Table I). Maximal oxygen uptake increases (27,28) as evidence of endurance conditioning. Vigorous exercise in elderly individuals also appears associated with a reduced incidence of myocardial infarction. Paffenbarger et al. (29) reported the results of a physical activity survey of 16.936 Harvard male alumni aged 35 to 74 years, of whom 572 experienced heart attacks in 117,680 personyears of follow-up. Menwith a physical activity index < 2.000 kcal/week were at 65% higher risk than were classmates with a higher index. Although individuals aged 65 to 74 years had a higher rate of heart anack than those in younger age groups. individuals with a physical activity index > 2.000 kcal/week had less than half the rate of heart attack experienced by those with a physical activity index less than 500 kcallweek. Physically active elderly individuals had lower rates of heart attack than those who were sedentary. Regular exercise. Exercise training elicits beneficial physiologic and metabolic responses in skeletal muscle and the cardiopulmonary system, Prescription of regular exercise for elderly patients should consider the individual's maximal oxygen uptake. corrected for age, sex and lean body mass. Regular isotonic exercise. particularly walking, may have favorable physiologic and psychologic benefits in the elderly.
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Table 1. Results of Symptom-Limited Maximal Spiroergometry Before and After Systematic Bicycle Ergometer Training of 12 Weeks Duration* No. of Patients Max HR (min~l) Max work load (W) V0 2 max (ml min-I) ABEmax Submax HR (min-I) V E- max (I min-I)
12 12 8 10
12
Before Training 147 ± I3t III ± 36 1,623 ± 423 4.5 ± 1.I 135 ± 12
8
52 ± 18
After Training 147 129 1,856 5.6 125
± ± ± ± ±
16 29 480 1.4 14
p Value NS <0.01 <0.01 NS <0.5
60 ± 21
NS
*Eight women and four men aged 67 to 76 years (mean 71.1). tMean ± SD. ABEmax = maximaldifference between base excess at rest and during exhausting exercise; Max HR = maximal heart rate; Submax HR = heart rate at the same submaximal exercise level; VE~max = maximal ventilation; V0 2 max = maximal oxygen uptake. (Adapted from Haber P, et al. [28]).
Exercise Testing in the Elderly
Psychologic Benefits of Exercise
Exercise testing is safe and effective for the evaluation of cardiovascular status in elderly patients. The degree of ST depression during exercise testing is a reliable predictor of the extent of coronary artery disease (30). The extent of rise in systolic blood pressure during an exercise test is reported to be the single best predictor of subsequent morbidity and mortality (31). A low increase of the pressurerate product from rest to maximal exercise and OCCurrence of significant exercise-associated ventricular arrhythmias may identify a high risk group Of patients with substantially reduced probability for survival compared with patients without these responses. Elderly individuals respond to submaximal and maximal exercise tests similarly to younger individuals (30,32,33). However, maximal heart rate is significantly lower in patients >65 years of age. Systolic blood pressure is higher in older patients at rest and during exercise, but diastolic blood pressure is the same in both age groups. At the same intensity of exercise, heart rate tends to be lower and blood pressure higher in older than in younger individuals. Pharmacologic testing. It may be difficult for some elderly persons to perform a maximal exercise test because of physical limitations associated with orthopedic, neurologic or musculoskeletal conditions. Under these circumstances, diagnostic information can be obtained with pharmacologic testing, such as intravenous or oral dipyridamole administration during thallium imaging, to maximize coronary flow heterogeneity (34). Arm exercise testing. Another alternative to treadmill or bicycle ergometer exercise testing is an arm exercise test. Arm ergometry using a hand-cranked bicycle ergometer can help evaluate individuals with heart disease. In assessing the severity of coronary heart disease, arm ergometry can be combined with thallium scintigraphy (35).
Studies of the psychologic effects of aerobic exercise training (36) have shown that aerobic exercise can improve mood (37), reduce psychophysiologic responsivity to behavioral stressors (38,39) and improve self-esteem (40,41) in both the young and the old. In addition, aerobic exercise may improve cognitive functioning and psychomotor speed (42).
Dustman et al. (43) showed that older adults (55 to 70 years of age) achieved a 27% increase in maximal oxygen consumption after a 4 month aerobic exercise program. This was accompanied by improvement both in simple reaction time performance and in a measure of resistance to perceptual distraction (Stroop task). Thus, exercise may improve psychologic and cognitive functioning in the elderly.
Adherence to Prescribed Exercise Attitudes about exercise and health may influence adherence to cardiac rehabilitation exercise. Sidney and Shephard (44), studying the activity patterns of men and women 2:60 years of age found that elderly individuals seldom engage in heavy physical activity. Heart rates during continuous electrocardiographic recording indicated that elderly subjects overestimated the time spent on heavy physical activity, as compared with ratings by younger adults in similar studies. Attitudes toward physical activity may influence the compliance of elderly patients with exercise rehabilitation after myocardial infarction. Gori et al. (45) reported that only 12% of patients >65 years completed a 4 month program. Factors contributing to noncompliance. An important step in overcoming noncompliance involves identification of factors in both the individual and the environment that contribute to noncompliance. Compliance refers to the de-
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gree to which a person's behavior in taking medications. following a diet,exercising or executing otherlifestyle changes coincideswith medicalor health advice (46). Characteristics of a rehabilitation program, available social supports and perceptions of the treatment regimen have to be assessed. Although elderly cardiac patients are not at greater risk for noncompliance, a number of factors associated with noncompliance appear relevant for elderly cardiac patients. These include an increased complexity and duration of treatment. a high degree of behaviorchange required by the treatment, the patients's limited perception of personal vulnerability and the increased potential success of treatment contingent on compliance (47). The patient's comprehension of the treatment program appears to be the most important feature favoring compliance. Although few systematic efforts to increase compliance with cardiac rehabilitation interventions have been published, a variety of strategies for improving compliance are appropriate for elderly cardiac patients; these include convenience. tailoringof the exerciseregimen for older persons. delineationof goals specific for elderly patients and the like (48).
Education of the Elderly Cardiac Patient In planning health education programs for an elderly population, medical! social and cultural barriers to communication must be addressed for subsets of individuals . Impaired vision and hearing exemplify physical handicaps, and declining cognitive function and emotional instability are examples of mental problems, Other subsets of individuals may be fragile or have concomitant diseases, or both. The possible gains have to he weighed against risks of changing lifelong habits, creating anxiety and engendering negative reactions. Educational messages should convey a recognition of the patient's persunal worth. Suggestions for lifestyle interventions should be made in moderation and at levels compatible with the patient's prior experience and age. Promotion of a healthy lifestyle through smoking cessation. adequate diet. reduced alcohol intake and regular physical activity can provide important benefits to elderly patients who function at a marginal level. Also important are stress reduction , development of social support networks and simplification of daily life or work activities (49).
Summary Recommendations concerning nutrition and physical activity are an important part of health care in the elderly. There is increasingevidence that diet and exercise influence the development and progression of cardiovascular disease
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in the elderly as well as the young. Decreases in coronary risk factors can be achieved in the elderly by attention to proper diet and exercise.
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