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Drugs in the Elderly
Symposium on Clinical Pharmacology of Symptom Control
Drugs in the Elderly Marcus M. Reidenberg, M.D. *
The elderly, as a group, receive more drugs per capita than the population as a whole,6 and their fraction of the population is increasing. The incidence of adverse drug reactions in hospitalized people increases with age, so that patients in the eighth and ninth decades of life have three times the incidence of observed adverse drug reactions than are observed in people below the age of 50. 10 Among the common drugs, digitalis causes a substantial fraction of these serious adverse reactions in the elderly. As a group, the elderly respond differently to many drugs than young people do. One needs to understand and correct for these differences by modifying usual treatment regimens. In this way, drug therapy for the elderly can be made more predictable and thereby safer and more effective.
PHARMACOKINETIC DIFFERENCES BETWEEN YOUNG AND OLD Absorption of Drugs Whereas some drugs are absorbed by active transport processes, most drugs are absorbed by passive diffusion. The drugs absorbed by active transport are usually nutrients or close analogs of nutrients. The absorption of galactose, calcium, thiamine, and iron has been found to decrease with aging. These drugs are all absorbed by active transport processes, indicating that this pathway of drug absorption is slowed in the elderly. Physiologic changes in the gastrointestinal tract of the elderly that might be expected to decrease drug absorption include decreased gastric acidity, decreased motility, and decreased splanchnic blood flow. Despite these changes, acetaminophen, aspirin, phenylbutazone, practolol, and sulfamethoxazole have been studied and found to be absorbed normally in the elderly. 3. 21 The absorption of other drugs, including indomethacin and propoxyphene, may also be unchanged in the elderly.I6 Thus, one can conclude that the vast majority of drugs that are absorbed by passive diffusion are absorbed normally by the elderly. *Professor of Pharmacology and Medicine, and Head, Division of Clinical Pharmacology, Comell University Medical College, New York, New York Medical Clinics of North America-Vol. 66, No. 5, September 1982
1073
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MARCUS M. REIDENBERG
Distribution of Drugs Body size decreases as people age, and this decreases the volume of distribution of drugs. This raises the concentration of a drug throughout the body if the dose is given on a per patient and not per kilogram of body weight basis. This failure to reduce customary doses of drugs to allow for the decreased body size of many elderly individuals is one of the factors contributing to the high frequency of adverse drug reactions in this population. The serum albumin level falls with aging.24 This can cause a decrease in the protein binding of many drugs which would require a change in the values for the therapeutic level. The reason is that the intensity of drug effect is related to the concentration of drug in plasma water since this concentration establishes the diffusion gradient to the site of action. The total drug concentration measured in the clinical laboratory includes the drug in plasma water plus the drug bound to the plasma proteins. A decrease in protein binding will lower the total (measured) drug concentration for any desired concentration in plasma water. Thus, to achieve the desired "therapeutic" concentration in plasma water, a lower total level must be achieved. For example, if serum albumin is 50 per cent of normal, then phenytoin (Dilantin) binding would be only 50 per cent of normal and "therapeutic" levels in such a patient would be close to 5 to 10 ILg per ml instead of the usual 10 to 20 ILg per ml. In general, one should lower the therapeutic range of highly protein-bound drugs for patients with hypoalbuminemia.
Metabolism of Drugs There are enormous differences between individuals in their rates of hepatic drug metabolism. In general, the elderly metabolize drugs more slowly than the young. For any specific elderly individual, however, the rate of drug metabolism may be anywhere in the range of the young. Thus, while an elderly person, on the average, should receive half to two thirds the dose of a metabolized drug that an average young person would receive, any specific elderly patient should have the dose of metabolized drug individualized in the same manner as one would for a young patient. Enzyme induction, the process of increasing the amount of drugoxidizing enzyme in the liver in response to inducing agents such as phenobarbital or smoking, is reduced in the elderly.19
Excretion of Drugs Many investigators, starting with Lewis and Alving in 1938,14 have observed a decline in renal function with aging. Kampmann et al. demonstrated a fall in endogenous creatinine formation rate as well. 13 Thus, as people age, their creatinine clearance falls while their serum creatinine level remains unchanged. For this reason, a serum creatinine level below 1. 5 mg per dl cannot be accepted as indicative of a normal glomerular filtration rate in an elderly person. For example, a group of women between 80 and 99 years old with serum creatinine values below 1.5 mg per dl (and averaging 1 mg per dl) had creatinine clearance values below 60 ml per min and averaged 40 ml per min. 13 This reduced renal function is severe
1075
DRUGS IN THE ELDERLY
enough to require significant reduction of dosage of drugs excreted by the kidney. Such drugs include aminoglycoside antibiotics, digoxin, procainamide, ethambutol, cimetidine, methotrexate, and some cephalosporins. Failure to reduce the dose of drugs excreted by the kidney for elderly people with "normal" serum creatinine levels is another major cause of adverse drug reactions in this population. The easiest way to correct for the decline in renal function is to estimate the glomerular filtration rate of the patient, then reduce the dose of the drug according to the recommendations for that drug for the renal function of the patient. Creatinine clearance can be estimated by the equation of Cockcroft and Gault: 4 Ccr in mllmin
(140 - age) (weight in kg) 72 X serum creatinine in mg/dl
This equation yields the creatinine clearance for men. The calculated value should be multiplied by 0.85 for women. If the patient is obese or edematous, then using an estimate of lean body weight would yield a closer estimate of glomerular filtration rate than using the measured weight.
Tissue Sensitivity to Drugs in the Elderly Many drugs act by combining with specific macromolecular components of tissues named drug receptors. This interaction of a drug with its receptor initiates the processes that lead to the response. A number of studies in both laboratory animals and in man have shown a decrease with age in the number of drug receptors for various hormones and their analogs. 18 Vestal, Wood, and Shand observed reduced responses to isoproterenol in the elderly, and an apparent cardiac resistance to propranolol as well. 22 While a decrease in the number of cardiac beta-adrenergic receptors might account for this drug resistance, their data on dose-response relationships suggest a decreased affinity of beta receptors for these drugs in the elderly rather than a decreased number of beta receptors in elderly hearts. Since the elderly do have an increased incidence of adverse reactions to propranolol, additional unidentified factors must alter their response to this drug. In contrast to the possible resistance of the elderly to drugs that act on specific receptors for hormones and their analogs, the elderly appear to be sensitive to a variety of drugs. Elderly people have a marked increase in their sensitivity to benzodiazepines that is not related to the pharmacokinetics of this group of drugs. In general, the metabolic clearance rate of thebenzodiazepines is normal or slightly slowed in the elderly. 8. 23 Yet these drugs have a much greater intensity of effect for any dose in the elderly than in the young. Two studies of the acute intravenous dose-response relationships of diazepam showed unequivocal sensitivity of the elderly nervous system to this drug. In one study of 19 patients receiving diazepam for sedation prior to peroral gastrointestinal endoscopy, it was observed that the dose required was inversely related to the age of the patient. 7 In the other study, 23 patients received diazepam in the dose required to achieve a uniform degree of sedation for cardioversion .. The dose averaged
1076
MARCUS M. REIDENBERG
0.2 mg per kg for the elderly and about 0.5 mg per kg for the middle aged. The plasma concentration of diazepam immediately after cardioversion was directly proportional to the dose (r=0.84, p < 0.001) and inversely proportional to the age (r = 0.56, p < 0.01), thus showing a strikingly increased sensitivity of the elderly to this drug. 17 The mechanism causing this increased tissue sensitivity of the elderly to benzodiazepines is unknown. This combination of a marked increase in central nervous system sensitivity with a modest decrease in metabolism rate leads to a high degree of susceptibility of the elderly to oversedation by the benzodiazepines. The elderly appear sensitive to the anticoagulant effects of warfarin. 20 In addition, they are more likely to develop bleeding complications of anticoagulant therapy than are younger patients. This may be due to the increasing frequency of complicating illnesses predisposing the elderly to bleed as well as to effects of aging itself.
SPECIAL PROBLEMS Drug-Induced Depression The problem of depression caused by drugs came to general medical attention after reserpine came into widespread use for hypertension. Other antihypertensive drugs, benzodiazepines, levodopa, digitalis, indomethacin, corticosteroids, and phenothiazines have also been reported to cause depression. 1 Many other drugs have also been associated with depression. In addition to depression, dementia and oversedation can also result from treatment with drugs that have sedating actions or side effects. Excessive sedation or depression caused by multiple concurrently administered drugs (including alcohol) coupled with the increased sensitivity of the aged central nervous system is probably one of the most common adverse drug reactions or interactions in the elderly.
Drug-Induced Dementia There is evidence of a decrease in cholinergic activity of the brain of elderly people with Alzheimer's disease. It is also known that scopolamine, an anticholinergic drug active in the central nervous system, can impair the recent memory and mental functioning of even normal healthy individuals. Thus, one must question the extent to which anticholinergic drugs contribute to the dementia of the elderly who take them. In addition to atropine and scopolamine, drugs with anticholinergic activity include the tricyclic antidepressants, the antihistamines, and the phenothiazines. Scopolamine and antihistamines are present in over-the-counter sleep medicine, and antihistamines are in nonprescription preparations for symptomatic relief of colds and rhinitis. Thus, elderly patients may be receiving centrally acting anticholinergic drugs from a variety of sources with additive deleterious effect on their mental function.
Digitalis Toxicity While much has recently been written about the cardiac toxicity of digitalis preparations, little attention has been paid to the toxic effects of
1077
DRUGS IN THE ELDERLY
this group of drugs on the central nervous system. "Therapeutic" and "toxic" levels of the glycosides refer only to cardiac toxicity, not to neurotoxicity. Symptoms of digitalis toxicity can include fatigue, weakness, psychic disturbance including delirium, impaired vision including difficulty reading, anorexia, and nausea. These symptoms can occur at glycoside levels below the "toxic" range. Elderly patients in sinus rhythm without enlarged hearts who are receiving digitalis should periodically have their need for this drug re-evaluated.
Compliance with Therapeutic Regimens The general problem of patients not taking their medicine as prescribed, noncompliance, is now fully acknowledged as a problem of medical practice. 9 ,11 There are some special problems of compliance for the elderly. One particular problem is that of confusion. An elderly patient is often expected to take multiple drugs on different time schedules even though some of the drugs impair an already deteriorated memory. It is hardly surprising that compliance is a problem in outpatient geriatric practice. Mechanical aids to the patient's memory help to solve this problem. Another problem of the elderly is poor vision. A look at the label on a bottle of medicine as dispensed from a local pharmacy will reveal how difficult it can be to find the directions for use on the label, let alone actually read them. Directing the pharmacist to type the directions in all capital letters and developing other ways of helping the patient with poor vision see what is necessary for proper compliance will aid with this problem. Child-proof containers are often difficult or impossible for elderly patients with arthritis to open. Avoiding them when no small children are . in the household can help. The overall cost of medication can often deter a patient from taking what has been prescribed. Frankly discussing cost of medications with a patient may bring to light information that a patient would not otherwise volunteer. Compliance can be significantly improved in the elderly if supervision of their medication can be arranged.
CONCLUSIONS In some respects the elderly as a group differ from young and middleaged people in their responses to drugs. Their rate of drug metabolism is a little slower on the average, so they need slightly reduced doses of metabolized drugs. Their renal function is reduced, often without an increase in their serum creatinine level, because their endogenous creatinine formation rate is also reduced. This requires reduction in dosage of excreted drugs. Their nervous systems are unusually sensitive to the depressant effects of benzodiazepines and possibly other drugs. They also have more problems complying with therapeutic regimens than younger people. By understanding and allowing for these differences, therapeutics for older patients can be made safer and more effective.
1078
MARC.VS M. REIDENBERG
REFERENCES 1. Anonymous: Drug-induced depression. Lancet, 2:1333-1334, 1977. 2. Bender, A. D.: Effect of age on intestinal absorption: Implications for drug absorption in the elderly. J. Am. Geriatr. Soc., 16:1331-1339, 1968. 3. Castled en, C. M., Volans, C. N., and Raymond, K.: The effect of ageing on drug absorption from the gut. Age Aging, 6:1938-1943, 1977. 4. Cockcroft, D. W., and Gault, M. H.: Prediction of creatinine clearance from serum creatinine. Nephron, 16:31-41, 1976. 5. Crooks, J., O'Malley, K., and Stevenson, I. H.: Pharmacokinetics in the elderly. Clin. Pharmacokinet., 1 :280-296, 1976. 6. Drugs and the elderly. Editorial. Lancet, 2:693-694, 1977. 7. Giles, H. G., MacLeod, S. M., Wright, J. R., et al.: Influence of age and previous use on diazepam dosage required for endoscopy. Can. Med. Assoc. J., 118:513-514, 1978. 8. Greenblatt, D. J., Alien, M. D., Harmetz, J. S., et a!.: Determinants of diazepam disposition in humans. Clin. Pharmacol. Ther., 27:301-312, 1980. 9. Haynes, R. B., Taylor, D. W., and Sackett, D. L. (eds.): Compliance in Health Care. Baltimore, The Johns Hopkins University Press, 1979. 10. Hurwitz, N.: Predisposing factors in adverse reactions to drugs. Br. Med. J., 1:536-539, 1969. 11. Hussar, D. A.: Patient noncompliance. J. Am. Pharm. Assoc., 15:8-16, 1975. 12. Kampmann, J. P., and Molholm Hansen, J. D.: Renal excretion of drugs. In Crooks, J., and Stevenson, I. H. (eds.): Drugs and the Elderly. Baltimore, University Park Press, 1979, pp. 77-87. 13. Kampmann, J., Siersback-Nielsen, K., Kristensen, M., eta!.: Rapid evaluation of creatinine clearance. Acta Med. Scand., 196:517-520, 1974. 14. Lewis, W. H., and Alving, A. S.: Changes with age in the renal function of adult men. Am. J. Physiol., 123:500-515, 1938. 15. Morris, L. A., and Halperin, J. A.: Effects of written drug information on patient knowledge and compliance: A literature review. Am. J. Public Health, 69:47-52, 1979. 16. Ouslander, J. B.: Drug therapy in the elderly. Ann. Intern. Med., 95:711-722, 1981. 17. Reidenberg, M. M., Levy, M., Warner, H., et al.: Relationship between diazepam dose, plasma level, age, and central nervous system depression. Clin. Pharmacol. Ther., 23:371-374, 1978. 18. Roth, G. S.: Hormone receptor changes during adulthood and senescence: Significance for aging research. Fed. Proc., 38:1910-1914, 1979. 19. Salem, S. A. M., Rajjayabun, P., Shepherd, A. M. M., et al.: Reduced induction of drug metabolism in the elderly. Age Aging, 7:68-73, 1978. 20. Shepherd, A. M. M., Hewick, D. S., Moreland, T. A., et al.: Age as a determinant of sensitivity to warfarin. Br. J. Clin. Pharmacol., 4:315-320, 1977. 21. Triggs, E. J., Nation, R. L., Long, A., et a!.: Pharmacokinetics in the elderly. Eur. J. Clin. Pharmacol., 8:55-62, 1975. 22. Vestal, R. E., Wood, A. J. J., and Shand, D. G.: Reduced adrenoceptor sensitivity in the elderly. Clin. Pharmacol. Ther., 26:181-186, 1979. 23. Wilkinson, G. R.: The effects of aging on the disposition of benzodiazepines in man. In Crooks, J., and Stevenson, 1. H. (eds.): Drugs and the Elderly. Baltimore, University Park Press, 1979, pp. 103-116. 24. Woodford-Williams, E., Alvares, A. S., Webster, D., et al.: Serum protein patterns in normal and pathological ageing. Gerontologia, 10:86-99, 1964. Division of Clinical Pharmacology Cornell University Medical College 525 East 68th Street New York, New York 10021
Drugs in the Elderly Marcus M. Reidenberg, M.D. *
The elderly, as a group, receive more drugs per capita than the population as a whole,6 and their fraction of the population is increasing. The incidence of adverse drug reactions in hospitalized people increases with age, so that patients in the eighth and ninth decades of life have three times the incidence of observed adverse drug reactions than are observed in people below the age of 50. 10 Among the common drugs, digitalis causes a substantial fraction of these serious adverse reactions in the elderly. As a group, the elderly respond differently to many drugs than young people do. One needs to understand and correct for these differences by modifying usual treatment regimens. In this way, drug therapy for the elderly can be made more predictable and thereby safer and more effective.
PHARMACOKINETIC DIFFERENCES BETWEEN YOUNG AND OLD Absorption of Drugs Whereas some drugs are absorbed by active transport processes, most drugs are absorbed by passive diffusion. The drugs absorbed by active transport are usually nutrients or close analogs of nutrients. The absorption of galactose, calcium, thiamine, and iron has been found to decrease with aging. These drugs are all absorbed by active transport processes, indicating that this pathway of drug absorption is slowed in the elderly. Physiologic changes in the gastrointestinal tract of the elderly that might be expected to decrease drug absorption include decreased gastric acidity, decreased motility, and decreased splanchnic blood flow. Despite these changes, acetaminophen, aspirin, phenylbutazone, practolol, and sulfamethoxazole have been studied and found to be absorbed normally in the elderly. 3. 21 The absorption of other drugs, including indomethacin and propoxyphene, may also be unchanged in the elderly.I6 Thus, one can conclude that the vast majority of drugs that are absorbed by passive diffusion are absorbed normally by the elderly. *Professor of Pharmacology and Medicine, and Head, Division of Clinical Pharmacology, Comell University Medical College, New York, New York Medical Clinics of North America-Vol. 66, No. 5, September 1982
1073
1074
MARCUS M. REIDENBERG
Distribution of Drugs Body size decreases as people age, and this decreases the volume of distribution of drugs. This raises the concentration of a drug throughout the body if the dose is given on a per patient and not per kilogram of body weight basis. This failure to reduce customary doses of drugs to allow for the decreased body size of many elderly individuals is one of the factors contributing to the high frequency of adverse drug reactions in this population. The serum albumin level falls with aging.24 This can cause a decrease in the protein binding of many drugs which would require a change in the values for the therapeutic level. The reason is that the intensity of drug effect is related to the concentration of drug in plasma water since this concentration establishes the diffusion gradient to the site of action. The total drug concentration measured in the clinical laboratory includes the drug in plasma water plus the drug bound to the plasma proteins. A decrease in protein binding will lower the total (measured) drug concentration for any desired concentration in plasma water. Thus, to achieve the desired "therapeutic" concentration in plasma water, a lower total level must be achieved. For example, if serum albumin is 50 per cent of normal, then phenytoin (Dilantin) binding would be only 50 per cent of normal and "therapeutic" levels in such a patient would be close to 5 to 10 ILg per ml instead of the usual 10 to 20 ILg per ml. In general, one should lower the therapeutic range of highly protein-bound drugs for patients with hypoalbuminemia.
Metabolism of Drugs There are enormous differences between individuals in their rates of hepatic drug metabolism. In general, the elderly metabolize drugs more slowly than the young. For any specific elderly individual, however, the rate of drug metabolism may be anywhere in the range of the young. Thus, while an elderly person, on the average, should receive half to two thirds the dose of a metabolized drug that an average young person would receive, any specific elderly patient should have the dose of metabolized drug individualized in the same manner as one would for a young patient. Enzyme induction, the process of increasing the amount of drugoxidizing enzyme in the liver in response to inducing agents such as phenobarbital or smoking, is reduced in the elderly.19
Excretion of Drugs Many investigators, starting with Lewis and Alving in 1938,14 have observed a decline in renal function with aging. Kampmann et al. demonstrated a fall in endogenous creatinine formation rate as well. 13 Thus, as people age, their creatinine clearance falls while their serum creatinine level remains unchanged. For this reason, a serum creatinine level below 1. 5 mg per dl cannot be accepted as indicative of a normal glomerular filtration rate in an elderly person. For example, a group of women between 80 and 99 years old with serum creatinine values below 1.5 mg per dl (and averaging 1 mg per dl) had creatinine clearance values below 60 ml per min and averaged 40 ml per min. 13 This reduced renal function is severe
1075
DRUGS IN THE ELDERLY
enough to require significant reduction of dosage of drugs excreted by the kidney. Such drugs include aminoglycoside antibiotics, digoxin, procainamide, ethambutol, cimetidine, methotrexate, and some cephalosporins. Failure to reduce the dose of drugs excreted by the kidney for elderly people with "normal" serum creatinine levels is another major cause of adverse drug reactions in this population. The easiest way to correct for the decline in renal function is to estimate the glomerular filtration rate of the patient, then reduce the dose of the drug according to the recommendations for that drug for the renal function of the patient. Creatinine clearance can be estimated by the equation of Cockcroft and Gault: 4 Ccr in mllmin
(140 - age) (weight in kg) 72 X serum creatinine in mg/dl
This equation yields the creatinine clearance for men. The calculated value should be multiplied by 0.85 for women. If the patient is obese or edematous, then using an estimate of lean body weight would yield a closer estimate of glomerular filtration rate than using the measured weight.
Tissue Sensitivity to Drugs in the Elderly Many drugs act by combining with specific macromolecular components of tissues named drug receptors. This interaction of a drug with its receptor initiates the processes that lead to the response. A number of studies in both laboratory animals and in man have shown a decrease with age in the number of drug receptors for various hormones and their analogs. 18 Vestal, Wood, and Shand observed reduced responses to isoproterenol in the elderly, and an apparent cardiac resistance to propranolol as well. 22 While a decrease in the number of cardiac beta-adrenergic receptors might account for this drug resistance, their data on dose-response relationships suggest a decreased affinity of beta receptors for these drugs in the elderly rather than a decreased number of beta receptors in elderly hearts. Since the elderly do have an increased incidence of adverse reactions to propranolol, additional unidentified factors must alter their response to this drug. In contrast to the possible resistance of the elderly to drugs that act on specific receptors for hormones and their analogs, the elderly appear to be sensitive to a variety of drugs. Elderly people have a marked increase in their sensitivity to benzodiazepines that is not related to the pharmacokinetics of this group of drugs. In general, the metabolic clearance rate of thebenzodiazepines is normal or slightly slowed in the elderly. 8. 23 Yet these drugs have a much greater intensity of effect for any dose in the elderly than in the young. Two studies of the acute intravenous dose-response relationships of diazepam showed unequivocal sensitivity of the elderly nervous system to this drug. In one study of 19 patients receiving diazepam for sedation prior to peroral gastrointestinal endoscopy, it was observed that the dose required was inversely related to the age of the patient. 7 In the other study, 23 patients received diazepam in the dose required to achieve a uniform degree of sedation for cardioversion .. The dose averaged
1076
MARCUS M. REIDENBERG
0.2 mg per kg for the elderly and about 0.5 mg per kg for the middle aged. The plasma concentration of diazepam immediately after cardioversion was directly proportional to the dose (r=0.84, p < 0.001) and inversely proportional to the age (r = 0.56, p < 0.01), thus showing a strikingly increased sensitivity of the elderly to this drug. 17 The mechanism causing this increased tissue sensitivity of the elderly to benzodiazepines is unknown. This combination of a marked increase in central nervous system sensitivity with a modest decrease in metabolism rate leads to a high degree of susceptibility of the elderly to oversedation by the benzodiazepines. The elderly appear sensitive to the anticoagulant effects of warfarin. 20 In addition, they are more likely to develop bleeding complications of anticoagulant therapy than are younger patients. This may be due to the increasing frequency of complicating illnesses predisposing the elderly to bleed as well as to effects of aging itself.
SPECIAL PROBLEMS Drug-Induced Depression The problem of depression caused by drugs came to general medical attention after reserpine came into widespread use for hypertension. Other antihypertensive drugs, benzodiazepines, levodopa, digitalis, indomethacin, corticosteroids, and phenothiazines have also been reported to cause depression. 1 Many other drugs have also been associated with depression. In addition to depression, dementia and oversedation can also result from treatment with drugs that have sedating actions or side effects. Excessive sedation or depression caused by multiple concurrently administered drugs (including alcohol) coupled with the increased sensitivity of the aged central nervous system is probably one of the most common adverse drug reactions or interactions in the elderly.
Drug-Induced Dementia There is evidence of a decrease in cholinergic activity of the brain of elderly people with Alzheimer's disease. It is also known that scopolamine, an anticholinergic drug active in the central nervous system, can impair the recent memory and mental functioning of even normal healthy individuals. Thus, one must question the extent to which anticholinergic drugs contribute to the dementia of the elderly who take them. In addition to atropine and scopolamine, drugs with anticholinergic activity include the tricyclic antidepressants, the antihistamines, and the phenothiazines. Scopolamine and antihistamines are present in over-the-counter sleep medicine, and antihistamines are in nonprescription preparations for symptomatic relief of colds and rhinitis. Thus, elderly patients may be receiving centrally acting anticholinergic drugs from a variety of sources with additive deleterious effect on their mental function.
Digitalis Toxicity While much has recently been written about the cardiac toxicity of digitalis preparations, little attention has been paid to the toxic effects of
1077
DRUGS IN THE ELDERLY
this group of drugs on the central nervous system. "Therapeutic" and "toxic" levels of the glycosides refer only to cardiac toxicity, not to neurotoxicity. Symptoms of digitalis toxicity can include fatigue, weakness, psychic disturbance including delirium, impaired vision including difficulty reading, anorexia, and nausea. These symptoms can occur at glycoside levels below the "toxic" range. Elderly patients in sinus rhythm without enlarged hearts who are receiving digitalis should periodically have their need for this drug re-evaluated.
Compliance with Therapeutic Regimens The general problem of patients not taking their medicine as prescribed, noncompliance, is now fully acknowledged as a problem of medical practice. 9 ,11 There are some special problems of compliance for the elderly. One particular problem is that of confusion. An elderly patient is often expected to take multiple drugs on different time schedules even though some of the drugs impair an already deteriorated memory. It is hardly surprising that compliance is a problem in outpatient geriatric practice. Mechanical aids to the patient's memory help to solve this problem. Another problem of the elderly is poor vision. A look at the label on a bottle of medicine as dispensed from a local pharmacy will reveal how difficult it can be to find the directions for use on the label, let alone actually read them. Directing the pharmacist to type the directions in all capital letters and developing other ways of helping the patient with poor vision see what is necessary for proper compliance will aid with this problem. Child-proof containers are often difficult or impossible for elderly patients with arthritis to open. Avoiding them when no small children are . in the household can help. The overall cost of medication can often deter a patient from taking what has been prescribed. Frankly discussing cost of medications with a patient may bring to light information that a patient would not otherwise volunteer. Compliance can be significantly improved in the elderly if supervision of their medication can be arranged.
CONCLUSIONS In some respects the elderly as a group differ from young and middleaged people in their responses to drugs. Their rate of drug metabolism is a little slower on the average, so they need slightly reduced doses of metabolized drugs. Their renal function is reduced, often without an increase in their serum creatinine level, because their endogenous creatinine formation rate is also reduced. This requires reduction in dosage of excreted drugs. Their nervous systems are unusually sensitive to the depressant effects of benzodiazepines and possibly other drugs. They also have more problems complying with therapeutic regimens than younger people. By understanding and allowing for these differences, therapeutics for older patients can be made safer and more effective.
1078
MARC.VS M. REIDENBERG
REFERENCES 1. Anonymous: Drug-induced depression. Lancet, 2:1333-1334, 1977. 2. Bender, A. D.: Effect of age on intestinal absorption: Implications for drug absorption in the elderly. J. Am. Geriatr. Soc., 16:1331-1339, 1968. 3. Castled en, C. M., Volans, C. N., and Raymond, K.: The effect of ageing on drug absorption from the gut. Age Aging, 6:1938-1943, 1977. 4. Cockcroft, D. W., and Gault, M. H.: Prediction of creatinine clearance from serum creatinine. Nephron, 16:31-41, 1976. 5. Crooks, J., O'Malley, K., and Stevenson, I. H.: Pharmacokinetics in the elderly. Clin. Pharmacokinet., 1 :280-296, 1976. 6. Drugs and the elderly. Editorial. Lancet, 2:693-694, 1977. 7. Giles, H. G., MacLeod, S. M., Wright, J. R., et al.: Influence of age and previous use on diazepam dosage required for endoscopy. Can. Med. Assoc. J., 118:513-514, 1978. 8. Greenblatt, D. J., Alien, M. D., Harmetz, J. S., et a!.: Determinants of diazepam disposition in humans. Clin. Pharmacol. Ther., 27:301-312, 1980. 9. Haynes, R. B., Taylor, D. W., and Sackett, D. L. (eds.): Compliance in Health Care. Baltimore, The Johns Hopkins University Press, 1979. 10. Hurwitz, N.: Predisposing factors in adverse reactions to drugs. Br. Med. J., 1:536-539, 1969. 11. Hussar, D. A.: Patient noncompliance. J. Am. Pharm. Assoc., 15:8-16, 1975. 12. Kampmann, J. P., and Molholm Hansen, J. D.: Renal excretion of drugs. In Crooks, J., and Stevenson, I. H. (eds.): Drugs and the Elderly. Baltimore, University Park Press, 1979, pp. 77-87. 13. Kampmann, J., Siersback-Nielsen, K., Kristensen, M., eta!.: Rapid evaluation of creatinine clearance. Acta Med. Scand., 196:517-520, 1974. 14. Lewis, W. H., and Alving, A. S.: Changes with age in the renal function of adult men. Am. J. Physiol., 123:500-515, 1938. 15. Morris, L. A., and Halperin, J. A.: Effects of written drug information on patient knowledge and compliance: A literature review. Am. J. Public Health, 69:47-52, 1979. 16. Ouslander, J. B.: Drug therapy in the elderly. Ann. Intern. Med., 95:711-722, 1981. 17. Reidenberg, M. M., Levy, M., Warner, H., et al.: Relationship between diazepam dose, plasma level, age, and central nervous system depression. Clin. Pharmacol. Ther., 23:371-374, 1978. 18. Roth, G. S.: Hormone receptor changes during adulthood and senescence: Significance for aging research. Fed. Proc., 38:1910-1914, 1979. 19. Salem, S. A. M., Rajjayabun, P., Shepherd, A. M. M., et al.: Reduced induction of drug metabolism in the elderly. Age Aging, 7:68-73, 1978. 20. Shepherd, A. M. M., Hewick, D. S., Moreland, T. A., et al.: Age as a determinant of sensitivity to warfarin. Br. J. Clin. Pharmacol., 4:315-320, 1977. 21. Triggs, E. J., Nation, R. L., Long, A., et a!.: Pharmacokinetics in the elderly. Eur. J. Clin. Pharmacol., 8:55-62, 1975. 22. Vestal, R. E., Wood, A. J. J., and Shand, D. G.: Reduced adrenoceptor sensitivity in the elderly. Clin. Pharmacol. Ther., 26:181-186, 1979. 23. Wilkinson, G. R.: The effects of aging on the disposition of benzodiazepines in man. In Crooks, J., and Stevenson, 1. H. (eds.): Drugs and the Elderly. Baltimore, University Park Press, 1979, pp. 103-116. 24. Woodford-Williams, E., Alvares, A. S., Webster, D., et al.: Serum protein patterns in normal and pathological ageing. Gerontologia, 10:86-99, 1964. Division of Clinical Pharmacology Cornell University Medical College 525 East 68th Street New York, New York 10021