JOURNAL OF THE AMERICAN GERIATRICS SOCIETY Copyright 01979 by the American Geriatrics Society
Vol. XXVII, No. 8 Printed in U.S.A.
Drug Use in a Geriatric Population WILLIAM E. HALE, MD*, RONALD G. MARKS, P h D t and RONALD B. STEWART, MS**
Dunedin Program, Dunedin, and the Departments of Statistics and Clinical Pharmacy, University of Florida, Gainesuille, Florida ABSTRACT: Drug usage was studied in a geriatric hypertension-screening program. A questionnaire was used to collect the required information from patients visiting the clinic during three successive years. The study included 1,711 patients, of whom 76.6 percent were regularly using a drug preparation. A consistent increase was noted in the average number of drug categories used with increasing age, from 1.6 in patients under 70 to 2.6 in patients over 84 years old. The most common drug categories involved were antihypertensive agents, cardiovascular drugs, vitamins, and internal analgesics. a repetitive basis. If a participant withdraws from the program, he will be replaced from a waiting list of 450 persons. To date, approximately 2,030 persons have been followed for the entire 3.5 years of the program. One week prior to their clinic visit, a letter is sent to remind patients of their appointment. Enclosed is a detailed questionnaire which the patients are expected to complete before their visit. The form consists of 174 questions dealing with such items as family history, dietary habits, past illnesses, present symptoms, and drug history. Upon the patient’s arrival at the clinic, the questionnaire is reviewed with the patient by a registered nurse and any difficulties are clarified. Multiple blood pressure determinations are made, the carotid areas are auscultated, an electrocardiogram is performed, and a blood sample is obtained for SMA-23 analysis and a hemogram. Patients are asked if they are regularly taking any medicines, and a check list of 34 drug categories is provided to prompt their memory. A maximum of 10 drug classes can be recorded for a single patient. If a patient is taking more than one drug in a given class, it is recorded only once. For example, if a patient is using chlordiazepoxide, thioridazine and diazepam, the record would show only the use of tranquilizers. For the purpose of this paper, drugs were grouped into 22 therapeutic categories, according to the World Health Organization system (7).
Studies in both outpatients and inpatients have shown that drug misuse and adverse drug reactions constitute a significant public health problem (1-3). The incidence of adverse drug reactions as a cause of admission to hospitals has ranged from 2 to 6 percent (4). The elderly are at greater risk for drug-induced illness than are younger patients (5, 6). It has not been determined whether this increased risk results from increased use of drugs or from increased sensitivity to them. Since few studies have been made in ambulatory settings to determine the pattern of drug use among elderly patients, we decided to employ relevant information collected in a geriatric hypertension-screening program. The findings are described in this paper. METHODS The Dunedin Program was initiated on July 7, 1975. Its purpose is to screen elderly patients for the presence of hypertension and other disorders and to encourage the patients to seek appropriate medical care for the detected illnesses. The clinic is located in Dunedin, Florida, a large retirement area located near St. Petersburg and Clearwater. Any person over 65 years of age, regardless of economic status, may enter the program. A maximum of 3,162 persons have been seen annually on * Address for reprint requests: William E. Hale, MD, Director, Dunedin Program, Dunedin, FL 33528. t Assistant Professor of Statistics, Biostatistics Unit, Department of Statistics, University of Florida, Gainesville. * * Address for correspondence: Ronald B. Stewart, MS, Associate Professor and Chairman, Department of Clinical Pharmacy, College of Pharmacy (Box J-4), J. Hillis Miller Health Center, University of Florida, Gainesville, FL 32610.
RESULTS All patients (a total of 1,711) who visited the
374
August 1979
DRUG USE IN A GERIATRIC POPULATION TABLE 1 Drug Use among Patients in the Dunedin Program, by Sex All Patients
Men Women Totals
Patients Using Drugs
No.
%
636 1,075 ___ 1,711
37.2 62.8 100.0
clinic for their third evaluation during the period from August 1, 1977 to October 4, 1978 were included in this study. As shown in Table 1, 1,075 (62.8 percent) of these patients were women. The chi-square test indicated that a significantly higher proportion of women (79.4 percent) were using drugs compared to men (72.0 percent) (p < .0005). Table 2 is a summary of drug usage by patients in various age categories. The chi-square test showed a consistent increase in the percentage of patients using at least one drug, ranging from the age group “under 70” to the group “over 84” (p < .005). When all age groups were considered, 76.6 percent of the patients were regularly using some form of drug preparation. By age 85, more than 85 percent of the patients reported the use of at least one drug on a regular basis. The average number of drug classes used by patients in the different age groups is shown in Table 3. There was a consistent increase in the average number of drug classes used with increasing age, from 1.6 in the under-70 age group to 2.6 in the over-84 group. The average numbers of drug classes in the five age groups were compared by means of a one-way analysis of variance. The results were statistically significant (p < .0001), implying that not all the age groups used the same number of drug classes. Duncan’s multiple comparison procedure (adjusted for unequal group sizes) was employed to determine which groups differed. In Table 3, the groups which did not differ are connected by a common vertical line on the right. The conclusion was that the over-84 age group was using more classes of drugs than were any of the other groups. It should be emphasized that these figures do not represent the total number of different drugs, but rather the number of different drug categories. Men used an average of 1.7 drug classes compared to an average of 2.0 used by women. A twosample Z test showed that women used a greater number of drug classes than did men (statistically significant, p < .0005). The frequency of use of 22 drug classes by both men and women is shown in Table 4.Women used
No. 458 854 __ 1.312
Patients Not Using Drugs
76
72.0 79.4 76.6
~
No. 178 22 1 399
%
28.0 20.6 __ 23.3
TABLE 2 Drug Use among Patients in the Dunedin Program, by Age Age Group (WS)
Under 70 70-74 75-79 80-84 Over 84 Totals
Patients Using at Least One Drug
Total Patients in Age Group
No.
56
No.
217 463 354 209 66 .- 1,309
72.6 73.6 78.7 82.3 85.7 76.6
299 629 450 254 7 7 1.709
%
_______
17.5 36.8 26.3 14.9 4.5 ’00.0
TABLE 3 Comparison of Drug Categories Used by Patients of Various Ages
Ape Grow (vrs)
Average Number of Drug Categories Used
Under 70 70-74 75-79 80-84 Over 84
1.6 2.1 2.6
antihypertensive agents, laxatives, hormones, analgesics, vitamins and thyroid preparations with significantly greater frequency than did men (chisquare test). Men were more likely to use cardiovascular dilators, anticoagulants, and drugs for the treatment of cardiac disease or gout. DISCUSSION The results of this study showed that 76.6 percent of the patients were regularly using drugs, and the average patient was regularly using 1.9 drug classes. The number of drug classes increased with advancing age. According to HEW statistics (8), approximately 80 percent of the elderly, in comparison with 40 percent of patients under 65, have one or more chronic disorders. The existence of multiple acute and chronic disorders in this age group probably is a major factor in the increased use of drugs. The most common classes of drugs used by the older population of patients were antihypertensive agents (30.7 percent), vitamins (26.7 percent), car-
375
Vol. XXVII
HALE, MARKS AND STEWART TABLE 4 Therapeutic Classes of Drugs Used by Patients in the Dunedin Program-Distribution Sex Distribution of Patients Using Drug Category Men ( N = 636)
Women ( N = 1075)
by Sex
Total Patients Using Drug Category ( N = 1711)
~
Therapeutic Class Hypnotics Tranquilizers Sedatives Antidepressants Cardiovascular drugs (dilators) Congestive heart failure and antiarrhythmic drugs Antihypertensive agents Pulmonary drugs Diuretics Antacids Laxatives Antisecretory drugs Antihistamines Hormones Analgesics Steroids Vitamins Uric acid regulators Anticoagulants Thyroid preparations Diabetes regulators Other
76
No.
B
No.
11 14 117
6.4 9.5 1.0 1.3 10.8
33 46 5 6 101
5.1 7.2 0.7 0.9 15.8
102 149 16 20 218
5.9 8.7 0.9 1.1 12.7*
133
12.4
128
20.1
26 1
15.3*
361 10 103 67 115 10 12 42 299 15 322 16 7 87 32 196
33.6 0.9 9.6 6.2 10.6 0.9 1.1 3.9 27.8 1.3 29.9 1.4 0.6 8.1 2.9 18.2
164 14 58 37 41 9 8 9 113 11 135 39 17 15 19 84
25.8 2.2 9.1 5.8 6.4 1.4 1.2 1.4 17.7 1.7 21.2 6.1 2.6 2.3 2.9 13.2
525 24 161 104 156 19 20 51 412 26 457 55 24 102 51 280
30.7' 1.4 9.4 6.0 9.1* 1.1 1.1 2.9' 24.0* 1.5 26.7. 3.2* 1.4* 5.9* 2.9 16.3*
No. 69 103
* Significant difference (p < .01).
diac drugs (15.3 percent), cardiovascular dilators (12.7 percent), laxatives (9.1 percent), and tranquilizers (8.7 percent). In a 1974 randomized study (9) conducted in 288 nursing homes, it was found that the most commonly prescribed drugs were laxatives (58.1 percent), analgesics (51.3 percent), tranquilizers (46.9 percent), vitamins (34.1 percent), sedative-hypnotics (34.7 percent), and cardiac drugs (29.1 percent). Clearly, there are major differences in the health status of patients in extended care facilities compared to the health status of ambulatory patients seen in the Dunedin Program. It is noteworthy, however, that the use of cardiac drugs and vitamins was similar in both populations studied, but there was a dramatic preponderance in the use of laxatives, analgesics, tranquilizers and sedative-hypnotic drugs for patients in extended care facilities. Several limitations are apparent in this study. Questionnaire reports on the use of drugs were dependent upon the patient's memory. To minimize this factor, questionnaires were mailed to the patients one week in advance of their appointment so that they could record the drugs they used. The patients were from a retirement area in Southwest Florida, and therefore were not representative of all geriatric patients. Moreover, it was difficult to classify many drugs into appropriate therapeutic
376
categories without knowing the intent of the prescribing physician. The findings indicate that one factor that may predispose elderly patients to the development of drug-induced illness is the increased use of drugs. Other investigators have shown that elderly patients are more sensitive to the pharmacologic effects of drugs, probably as a result of decreased ability to metabolize and excrete these compounds (6, 10-12). Results of this study and several others confirm that older patients commonly receive numerous pharmacologic agents, with the potential for therapeutic duplication (13-15). Therefore, one would expect such problems as noncompliance, drugdrug or drug-disease interactions, and adverse drug reactions to be a major concern for the aged. Physicians should evaluate carefully the need for drugs in elderly patients, and the possible complications of prescribed therapy. REFERENCES 1. Miller RR: Hospital admissions due to adverse drug reactions, Arch Int Med 134: 219, 1974. 2. McKenney JM and Harrison WL: Drug-related hospital admissions, Am J Hosp Pharm 33: 792, 1976. 3. Kellaway GSM and McCrae E: Intensive monitoring for
adverse drug effects in patients discharged from acute medical wards, N Zealand Med J 78: 525, 1973.
August 1979
DRUG USE IN A GERIATRIC POPULATION
4. Gardner P and Cluff LE: The epidemiology of adverse drug reactions: a review and perspective, Johns Hopkins Med J 126: 77, 1970. 5. Caranasos G, Stewart RB and Cluff LE: Drug induced illness leading to hospitalization, JAMA 228: 713, 1974. 6. Reidenberg MM et al: Relationship between diazepam dose, plasma level, age, and central nervous system depression, Clin Pharmacol Therap 23: 371, 1978. 7. Helling M and Venulet J : Drug recording and classification by the WHO Research Center for International Monitoring of Adverse Reactions to Drugs, Methods Inform Med 13: 169, 1974. 8. US Dept. of HEW, Task Force on Prescription Drugs: T h e Drug Users. Washington, DC, US Govt. Printing Office, 1968. 9. US Dept. of HEW. Office of Long Term Care: Physician’s Drug Prescribing Patterns in Skilled Nursing Facilities. Publication No. 76-50050. Washington, DC, US Govt. Printing Office, 1976.
10. Boethius G and Sjogvist F: Doses and dosage intervals of drugs. Clinical practice and pharmacokinetic principles, Clin Pharmacol Therap 24: 255, 1978. 11. Greenblatt D J , Allen M D and Shader RI: Toxicity of highdose flurazepam in the elderly, Clin Pharmacol Therap 21: 355, 1977. 12. Greenblatt D J and Allen MD: Toxicity of nitrazepam in the elderly, Brit J Clin Pharm 5: 407, 1978. 13. Guttmann D: A Study of Legal Drug Use by Older Americans. US Dept. of HEW. Washington, DC, US Govt. Printing Office, 1977. 14. US Dept. of HEW, National Center for Health Statistics: Prescribed and Nonprescribed Medicines; Type and Use of Medicines, United States, 1964-65. Publication No:1000, Series 10, No. 39. Washington, DC, US Govt. Printing Office, 1967. 15. Kalchthaler T , Coccaro E and Lichtiger S: Incidence of polypharmacy in a long-term care facility, J Am Geriatrics SOC25: 308, 1977.
377
Vol. XXVII, No. 8 Printed in U.S.A.
Drug Use in a Geriatric Population WILLIAM E. HALE, MD*, RONALD G. MARKS, P h D t and RONALD B. STEWART, MS**
Dunedin Program, Dunedin, and the Departments of Statistics and Clinical Pharmacy, University of Florida, Gainesuille, Florida ABSTRACT: Drug usage was studied in a geriatric hypertension-screening program. A questionnaire was used to collect the required information from patients visiting the clinic during three successive years. The study included 1,711 patients, of whom 76.6 percent were regularly using a drug preparation. A consistent increase was noted in the average number of drug categories used with increasing age, from 1.6 in patients under 70 to 2.6 in patients over 84 years old. The most common drug categories involved were antihypertensive agents, cardiovascular drugs, vitamins, and internal analgesics. a repetitive basis. If a participant withdraws from the program, he will be replaced from a waiting list of 450 persons. To date, approximately 2,030 persons have been followed for the entire 3.5 years of the program. One week prior to their clinic visit, a letter is sent to remind patients of their appointment. Enclosed is a detailed questionnaire which the patients are expected to complete before their visit. The form consists of 174 questions dealing with such items as family history, dietary habits, past illnesses, present symptoms, and drug history. Upon the patient’s arrival at the clinic, the questionnaire is reviewed with the patient by a registered nurse and any difficulties are clarified. Multiple blood pressure determinations are made, the carotid areas are auscultated, an electrocardiogram is performed, and a blood sample is obtained for SMA-23 analysis and a hemogram. Patients are asked if they are regularly taking any medicines, and a check list of 34 drug categories is provided to prompt their memory. A maximum of 10 drug classes can be recorded for a single patient. If a patient is taking more than one drug in a given class, it is recorded only once. For example, if a patient is using chlordiazepoxide, thioridazine and diazepam, the record would show only the use of tranquilizers. For the purpose of this paper, drugs were grouped into 22 therapeutic categories, according to the World Health Organization system (7).
Studies in both outpatients and inpatients have shown that drug misuse and adverse drug reactions constitute a significant public health problem (1-3). The incidence of adverse drug reactions as a cause of admission to hospitals has ranged from 2 to 6 percent (4). The elderly are at greater risk for drug-induced illness than are younger patients (5, 6). It has not been determined whether this increased risk results from increased use of drugs or from increased sensitivity to them. Since few studies have been made in ambulatory settings to determine the pattern of drug use among elderly patients, we decided to employ relevant information collected in a geriatric hypertension-screening program. The findings are described in this paper. METHODS The Dunedin Program was initiated on July 7, 1975. Its purpose is to screen elderly patients for the presence of hypertension and other disorders and to encourage the patients to seek appropriate medical care for the detected illnesses. The clinic is located in Dunedin, Florida, a large retirement area located near St. Petersburg and Clearwater. Any person over 65 years of age, regardless of economic status, may enter the program. A maximum of 3,162 persons have been seen annually on * Address for reprint requests: William E. Hale, MD, Director, Dunedin Program, Dunedin, FL 33528. t Assistant Professor of Statistics, Biostatistics Unit, Department of Statistics, University of Florida, Gainesville. * * Address for correspondence: Ronald B. Stewart, MS, Associate Professor and Chairman, Department of Clinical Pharmacy, College of Pharmacy (Box J-4), J. Hillis Miller Health Center, University of Florida, Gainesville, FL 32610.
RESULTS All patients (a total of 1,711) who visited the
374
August 1979
DRUG USE IN A GERIATRIC POPULATION TABLE 1 Drug Use among Patients in the Dunedin Program, by Sex All Patients
Men Women Totals
Patients Using Drugs
No.
%
636 1,075 ___ 1,711
37.2 62.8 100.0
clinic for their third evaluation during the period from August 1, 1977 to October 4, 1978 were included in this study. As shown in Table 1, 1,075 (62.8 percent) of these patients were women. The chi-square test indicated that a significantly higher proportion of women (79.4 percent) were using drugs compared to men (72.0 percent) (p < .0005). Table 2 is a summary of drug usage by patients in various age categories. The chi-square test showed a consistent increase in the percentage of patients using at least one drug, ranging from the age group “under 70” to the group “over 84” (p < .005). When all age groups were considered, 76.6 percent of the patients were regularly using some form of drug preparation. By age 85, more than 85 percent of the patients reported the use of at least one drug on a regular basis. The average number of drug classes used by patients in the different age groups is shown in Table 3. There was a consistent increase in the average number of drug classes used with increasing age, from 1.6 in the under-70 age group to 2.6 in the over-84 group. The average numbers of drug classes in the five age groups were compared by means of a one-way analysis of variance. The results were statistically significant (p < .0001), implying that not all the age groups used the same number of drug classes. Duncan’s multiple comparison procedure (adjusted for unequal group sizes) was employed to determine which groups differed. In Table 3, the groups which did not differ are connected by a common vertical line on the right. The conclusion was that the over-84 age group was using more classes of drugs than were any of the other groups. It should be emphasized that these figures do not represent the total number of different drugs, but rather the number of different drug categories. Men used an average of 1.7 drug classes compared to an average of 2.0 used by women. A twosample Z test showed that women used a greater number of drug classes than did men (statistically significant, p < .0005). The frequency of use of 22 drug classes by both men and women is shown in Table 4.Women used
No. 458 854 __ 1.312
Patients Not Using Drugs
76
72.0 79.4 76.6
~
No. 178 22 1 399
%
28.0 20.6 __ 23.3
TABLE 2 Drug Use among Patients in the Dunedin Program, by Age Age Group (WS)
Under 70 70-74 75-79 80-84 Over 84 Totals
Patients Using at Least One Drug
Total Patients in Age Group
No.
56
No.
217 463 354 209 66 .- 1,309
72.6 73.6 78.7 82.3 85.7 76.6
299 629 450 254 7 7 1.709
%
_______
17.5 36.8 26.3 14.9 4.5 ’00.0
TABLE 3 Comparison of Drug Categories Used by Patients of Various Ages
Ape Grow (vrs)
Average Number of Drug Categories Used
Under 70 70-74 75-79 80-84 Over 84
1.6 2.1 2.6
antihypertensive agents, laxatives, hormones, analgesics, vitamins and thyroid preparations with significantly greater frequency than did men (chisquare test). Men were more likely to use cardiovascular dilators, anticoagulants, and drugs for the treatment of cardiac disease or gout. DISCUSSION The results of this study showed that 76.6 percent of the patients were regularly using drugs, and the average patient was regularly using 1.9 drug classes. The number of drug classes increased with advancing age. According to HEW statistics (8), approximately 80 percent of the elderly, in comparison with 40 percent of patients under 65, have one or more chronic disorders. The existence of multiple acute and chronic disorders in this age group probably is a major factor in the increased use of drugs. The most common classes of drugs used by the older population of patients were antihypertensive agents (30.7 percent), vitamins (26.7 percent), car-
375
Vol. XXVII
HALE, MARKS AND STEWART TABLE 4 Therapeutic Classes of Drugs Used by Patients in the Dunedin Program-Distribution Sex Distribution of Patients Using Drug Category Men ( N = 636)
Women ( N = 1075)
by Sex
Total Patients Using Drug Category ( N = 1711)
~
Therapeutic Class Hypnotics Tranquilizers Sedatives Antidepressants Cardiovascular drugs (dilators) Congestive heart failure and antiarrhythmic drugs Antihypertensive agents Pulmonary drugs Diuretics Antacids Laxatives Antisecretory drugs Antihistamines Hormones Analgesics Steroids Vitamins Uric acid regulators Anticoagulants Thyroid preparations Diabetes regulators Other
76
No.
B
No.
11 14 117
6.4 9.5 1.0 1.3 10.8
33 46 5 6 101
5.1 7.2 0.7 0.9 15.8
102 149 16 20 218
5.9 8.7 0.9 1.1 12.7*
133
12.4
128
20.1
26 1
15.3*
361 10 103 67 115 10 12 42 299 15 322 16 7 87 32 196
33.6 0.9 9.6 6.2 10.6 0.9 1.1 3.9 27.8 1.3 29.9 1.4 0.6 8.1 2.9 18.2
164 14 58 37 41 9 8 9 113 11 135 39 17 15 19 84
25.8 2.2 9.1 5.8 6.4 1.4 1.2 1.4 17.7 1.7 21.2 6.1 2.6 2.3 2.9 13.2
525 24 161 104 156 19 20 51 412 26 457 55 24 102 51 280
30.7' 1.4 9.4 6.0 9.1* 1.1 1.1 2.9' 24.0* 1.5 26.7. 3.2* 1.4* 5.9* 2.9 16.3*
No. 69 103
* Significant difference (p < .01).
diac drugs (15.3 percent), cardiovascular dilators (12.7 percent), laxatives (9.1 percent), and tranquilizers (8.7 percent). In a 1974 randomized study (9) conducted in 288 nursing homes, it was found that the most commonly prescribed drugs were laxatives (58.1 percent), analgesics (51.3 percent), tranquilizers (46.9 percent), vitamins (34.1 percent), sedative-hypnotics (34.7 percent), and cardiac drugs (29.1 percent). Clearly, there are major differences in the health status of patients in extended care facilities compared to the health status of ambulatory patients seen in the Dunedin Program. It is noteworthy, however, that the use of cardiac drugs and vitamins was similar in both populations studied, but there was a dramatic preponderance in the use of laxatives, analgesics, tranquilizers and sedative-hypnotic drugs for patients in extended care facilities. Several limitations are apparent in this study. Questionnaire reports on the use of drugs were dependent upon the patient's memory. To minimize this factor, questionnaires were mailed to the patients one week in advance of their appointment so that they could record the drugs they used. The patients were from a retirement area in Southwest Florida, and therefore were not representative of all geriatric patients. Moreover, it was difficult to classify many drugs into appropriate therapeutic
376
categories without knowing the intent of the prescribing physician. The findings indicate that one factor that may predispose elderly patients to the development of drug-induced illness is the increased use of drugs. Other investigators have shown that elderly patients are more sensitive to the pharmacologic effects of drugs, probably as a result of decreased ability to metabolize and excrete these compounds (6, 10-12). Results of this study and several others confirm that older patients commonly receive numerous pharmacologic agents, with the potential for therapeutic duplication (13-15). Therefore, one would expect such problems as noncompliance, drugdrug or drug-disease interactions, and adverse drug reactions to be a major concern for the aged. Physicians should evaluate carefully the need for drugs in elderly patients, and the possible complications of prescribed therapy. REFERENCES 1. Miller RR: Hospital admissions due to adverse drug reactions, Arch Int Med 134: 219, 1974. 2. McKenney JM and Harrison WL: Drug-related hospital admissions, Am J Hosp Pharm 33: 792, 1976. 3. Kellaway GSM and McCrae E: Intensive monitoring for
adverse drug effects in patients discharged from acute medical wards, N Zealand Med J 78: 525, 1973.
August 1979
DRUG USE IN A GERIATRIC POPULATION
4. Gardner P and Cluff LE: The epidemiology of adverse drug reactions: a review and perspective, Johns Hopkins Med J 126: 77, 1970. 5. Caranasos G, Stewart RB and Cluff LE: Drug induced illness leading to hospitalization, JAMA 228: 713, 1974. 6. Reidenberg MM et al: Relationship between diazepam dose, plasma level, age, and central nervous system depression, Clin Pharmacol Therap 23: 371, 1978. 7. Helling M and Venulet J : Drug recording and classification by the WHO Research Center for International Monitoring of Adverse Reactions to Drugs, Methods Inform Med 13: 169, 1974. 8. US Dept. of HEW, Task Force on Prescription Drugs: T h e Drug Users. Washington, DC, US Govt. Printing Office, 1968. 9. US Dept. of HEW. Office of Long Term Care: Physician’s Drug Prescribing Patterns in Skilled Nursing Facilities. Publication No. 76-50050. Washington, DC, US Govt. Printing Office, 1976.
10. Boethius G and Sjogvist F: Doses and dosage intervals of drugs. Clinical practice and pharmacokinetic principles, Clin Pharmacol Therap 24: 255, 1978. 11. Greenblatt D J , Allen M D and Shader RI: Toxicity of highdose flurazepam in the elderly, Clin Pharmacol Therap 21: 355, 1977. 12. Greenblatt D J and Allen MD: Toxicity of nitrazepam in the elderly, Brit J Clin Pharm 5: 407, 1978. 13. Guttmann D: A Study of Legal Drug Use by Older Americans. US Dept. of HEW. Washington, DC, US Govt. Printing Office, 1977. 14. US Dept. of HEW, National Center for Health Statistics: Prescribed and Nonprescribed Medicines; Type and Use of Medicines, United States, 1964-65. Publication No:1000, Series 10, No. 39. Washington, DC, US Govt. Printing Office, 1967. 15. Kalchthaler T , Coccaro E and Lichtiger S: Incidence of polypharmacy in a long-term care facility, J Am Geriatrics SOC25: 308, 1977.
377
