Reprinted from ANGIOLOGY Vol. 26, No.4 April, 1975 Printed in U.S.A. Copyright © 1975
EFFECT OF BETA ADRENERGIC BLOCKING AGENTS (ALPRENOLOL AND PROPRANOLOL) IN ESSENTIAL HYPERTENSION BIJAN NIK-AKHTAR, M.D., F.I.C.A.,* MOHAMAD-ALI RASHED, M.D.** MANIJEH KHAKPOUR, M.D.*** .
AND
INTRODUCTION
Since recent studies indicated that young hypertensive individuals with or moderate hypertension present normal peripheral resistance but increased cardiac output (1-5) therefore, it was believed that in some cases, the cause of central nature, causing an increase in the pumping capacity of the heart by hyperactivity of the systemic nervous system. Since Alqvist (6) advanced his theory that sympathetic nervous system exert on two different receptors as the alpha-receptor which is connected with
slight
excitory mechanism and beta-receptor which primarily exert an inhibitory function with one important exception that the purely excitatory effect on the heart is mediated through beta-receptors. Judging from these observations, some investigators focused their interests to the fact that beta-receptor blocking agents may be of therapeutic value in hypertensive patients (7-10). Prichard and Gillam (11), found propranolol given in individualized and often extremely high doses to be a very active antihypertensive agents of the same potency as Guanethidine and Methyldopa with the exception that beta-blockers do not produce postural hypertension. Furberg and Michaelson (7), also found out that antihypertensive effect of alprenolol, a beta-adrenergic blocking agent was considered as moderate. In order to evaluate and compare the antihypertensive effect of alprenolol and propranolol in hypertensive subjects, we used these two drugs as the sole antihypertensive drugs on out patients with essential arterial hypertension in two parallel double blind studies and investigated their therapeutic effects on hypertension running for two years. MATERIALS AND METHODS
Our medical clinic had 17330 patients registered as of July 1, 1968, of which 3320 individuals were hypertensive with varying etiology. From that time all registrants at the clinic have received a complete initial examination at the time of entry. During this examination a single measurement of blood pressure was obtained routinely by the clinic staff physicians and nurses, who were not asked to modify their usual method of casual blood pressure measurement. All From Department of Medicine, School Tehran University, Tehran, Iran. Health, *
of
Medicine, Tehran University,
and School of Public
Associate Professor of Medicine. * Associate Professor of Medicine. ***Associate Professor of Public Health.
*
339
Downloaded from ang.sagepub.com at UNIV OF WESTERN ONTARIO on June 9, 2015
.
340
blood pressure measurements followed the technique used by Mial (12). Reading were taken from the right arm with subject in spine, sitting, and standing positions after a wait of 5 minutes. A 23 x 13 cm. cuff with nylon-hooket binding was used with a mercury sphygmomanometer. Diastolic pressure was defined as that at which muffling of sounds preceded their disappearance. The records of those persons who had an initial systolic blood pressure of 160 mmHg or greater and diastolic pressure of 90 mmHg or higher were selected for special review of the subsequent two blood pressure determinations, whenever they were recorded. Screening began in July 1968. Pressure recorded when a subject was febrile or physically or mentally distressed or had other medical conditions including aortic valvular diseases, anemia, hyperthyroidism, were discarded. All those with diastolic pressure at or over 100 mmHg, were followed up with at least two readings. Those with three or more readings at or above Pickering’s level were investigated by examination of the heart and fundi, E.C.G., chest X-ray, urine for protein and glucose, blood nitrogen, uric acid and cholestrol, catecholamine, 17-keto and hydroxy-steroids, renal angiography, intravenous pyelography and renal biopsy. The distribution of the mean systolic and diastolic blood pressure in all subjects according to the age was consistent with the belief that systolic blood pressure rises with age in both sexes. Utilizing the initial blood pressure determinations, 3320 subjects met the criteria for isolated systolic, diastolic, or combined systolic and diastolic hypertension. One hundred seven subjects were isolated and diagnosed as essential hypertension, after a complete physical and laboratory work up failed to reveal any cause for hypertension. Of these hypertensive subjects 45 were tried on propranolol and 62 on alprenolol respectively. Laboratory analysis were performed according to the routine methods used at our clinic. These comprised of red blood cell and white blood cell count, platelets, bilirubin, alkaline phosphatase, uric acid, urinalysis, fasting blood sugar, blood urea, creatinine, serum glutamic and oxalo acetic transaminase. more
RESULTS
tried in
series
comprised of
patients and propranolol study that 50 mg of induces about the 100 same blockade as propranolol mg alprenolol orally, therefore, dosage of alprenolol was commenced at 100 mg daily in four divided doses, and each dose was increased by 25 mg after two weeks and by another 25 mg after four weeks. The starting dose of propranolol was usually 80 mg daily in four divided doses increasing at weekly intervals to 160-320 mg daily. Further increases were made at two weekly intervals to 400-800 mg daily when higher doses were required. After a period of several weeks (4-13 weeks) both alprenolol and propranolol reduced systolic and diastolic blood pressure in supine, sitting and standing positions. The systolic pressure being decreased by about 20 mmHg and
Alprenolol
was
tried
on
was
45
one
patients (Table I, II). Based
on
62
earlier
Downloaded from ang.sagepub.com at UNIV OF WESTERN ONTARIO on June 9, 2015
341 diastolic pressure by about 7 mmHg in series used alprenolol and reduction in systolic pressure being decreased by 25 mmHg and diastolic pressure about 10 mmHg in group using propranolol (Table IV). No significant adverse effect or change in results of laboratory tests were noted during treatment. Side effect such as dizziness was noted in 10 women and 3 men. Marked bradycardia in group using propranolol was also noted when the dosage was increased to 400 mg daily. The following results have been obtained during such therapy: 1-Propranolol and alprenolol if given in individualized and often extremely high doses for a long time (from 4-13 weeks) are proved to be very active antihypertensive agents. 2-The gradual onset of their antihypertensive effect appeared after several weeks were similar in both groups using propranolol and alprenolol. 3-The reduction in blood pressure were noted in both systolic and diastolic pressure with the average reduction of 20 mmHg for systolic and 5-7 mmHg for diastolic pressure. 4-The antihypertensive effect of propranolol and alprenolol was found to be more pronounced during exercise than at rest. 5-The heart rate
propranolol
was
group and 7-10 in
reduced from 7-15 per minute (10-15 in group as shown in Table III. Marked
alprenolol
TABLE I Characteristics of patients
population
TABLE II
Changes in
+
L.V.H.
=
Left Venticular
eye
ground and cardiac size
Hypertrophy
Downloaded from ang.sagepub.com at UNIV OF WESTERN ONTARIO on June 9, 2015
342
bradycardia (56 per minute) was noted in one patient when alprenolol was increased to 800 mg daily. 6-There was no remarkable changes in laboratory results attributed to the use of these two drugs, except slight elevation of uric acid (3-4 mg%) was noted in 6 individuals who were taking propranolol and in 3 who were taking alprenolol up to 400 mg and 800 mg respectively. 7-It was quite remarkable that the antihypertensive effect of these two drugs were more pronounced during exercise than at rest and in individuals under the age of 40 comparing with those who were over the age of 40. 8-The response in those who had enlarged heart was more pronounced than those who had normal cardiac size. 9-It was also noted that propranolol reduces blood pressure about the same magnitude as alprenolol with the half dosage (20-25 mmHg for systolic and 7-10 mmHg for diastolic pressure in both groups). DISCUSSION
The favourable effects of beta-adrenergic blocking agents in angina pectoris and various cardiac arrhythmias have been documented in several clinical trials (13-14), but during recent years an antihypertensive effect with beta-adrenergic blocking agents such as propranolol (11, 12, 15) and alprenolol (7), has been noted in those patients when beta-adrenergic blockers were tried. In most studies, the beta-blockers were given in moderate dosage and was found to have an antihypertensive effectiveness of about the same order of magnitude as that of the thiazide diuretics (8, 15, 16). Prichard and Gillam (11) found propranolol and Furberg and Michaelson (7) found alprenolol given in individualized and often extremely high doses to be very active antihypertensive agents. Weal (17), Shineburne (18), and Prichard (9), found that the reduction of the blood pressure during beta-adrenergic blocking therapy is due to cardiac effects of these drugs rather than to the effects on the blood vessels. TABLE III
Results
.
of heart
rate
TABLE IV
Results of arterial blood pressure
drop
Downloaded from ang.sagepub.com at UNIV OF WESTERN ONTARIO on June 9, 2015
343
The correlation between the reduction in heart rate and blood pressure during exercise in hypertensive patients during alprenolol and propranolol treatment gives further support for such an interpretation. Furberg (19), has shown that the effect of beta-blockers of the heart during exercise, was generally most pronounced in subjects with signs of a hypertensive circulation and least in those with signs of hypokinetic circulation. Judging from these observations, antihypertensive effects of propranolol and alprenolol would be expected primarily in patients without evidence of organic cardiac damage. We regard the antihypertensive effect of these drugs as moderate in patients with essential hypertension. SUMMARY
The antihypertensive effect of two adrenergic blocking agents (Alprenolol and Propranolol) have been studied in a group of 107 patients with essential
hypertension. A significant reduction of 20 mmHg in the systolic blood pressure was recorded for the group using Alprenolol and 25 mmHg in the group using
Propranolol. The corresponding decrease of 7-10 mmHg in the diastolic blood pressure for the entire group was also significant. These two drugs may be of therapeutic value in essential hypertension, independently or in combination with other antihypertensive drugs. B. Nik-Akhtar
Department of Medicine School of Medicine Tehran Uniuersity Tehran, Iran REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19.
Bello, C. T., Sevy, R. W. and Harakal, C. (1965), Amer. J. Med. Sci. 250: 24 Bello, C. T., Sevy, R. W., Harkal, C. and Hillyer, P. N. (1967), Amer. J. Med. Sci. 253: 194 Finkelman, S., Wreel, M. and Agrest, A. (1965), Circulation 31: 356 Kuramoto, K., Murata, K., Yazaki, Y., Ikeda, M. and Nakao, K. (1968), Jap. Circulat. J. (En) 32: 9811 Lund-Johnsen, P. (1967), Acta Med. Scand. Suppl. 482 Alqvist, R. P. (1948), Amer. J. Physiol. 153: 586 Furberg, G. C. and Michaealson, G. (1969), Acta Med. Scand. 186: 447 Paterson, G. W. and Dollery, C. T. (1966), Lancet 2: 1148 Prichard, B. N. C. and Gillam, P. M. S. (1964), Brit. Med. J. 2: 725 Richards, A. (1966), Amer. J. Cardiol. 18: 384 Prichard, B. N. S. and Gillam, P. M. S. (1969), Brit. Med. J. 1: 7 Miall, W. E. and Oldham, P. D. (1958), Clin. Sci. 17: 409 Bjorntorp, P. (1967), Acta Med. Scand. 182: 285 Bjorntrop, P. (1968), Acta Med. Scand. 184: 259 Frohlich, E. C., Tarazi, R. C., Dustan, H. P. and Page, I. H. (1968), Circulation 37: 417 Dorph, S. and Binder, C. (1969), Acta Med. Scand. 185: 445 Weal, H. J. (1966), Clin. Pharmacol. Therap. 7: 558 Shineburne, E., Fleming, G. and Harmer, J. (1967), Lancet 2: 1217 Furberg, G. C. (1967), Acta Med. Scand. 182, 119
Downloaded from ang.sagepub.com at UNIV OF WESTERN ONTARIO on June 9, 2015
_
EFFECT OF BETA ADRENERGIC BLOCKING AGENTS (ALPRENOLOL AND PROPRANOLOL) IN ESSENTIAL HYPERTENSION BIJAN NIK-AKHTAR, M.D., F.I.C.A.,* MOHAMAD-ALI RASHED, M.D.** MANIJEH KHAKPOUR, M.D.*** .
AND
INTRODUCTION
Since recent studies indicated that young hypertensive individuals with or moderate hypertension present normal peripheral resistance but increased cardiac output (1-5) therefore, it was believed that in some cases, the cause of central nature, causing an increase in the pumping capacity of the heart by hyperactivity of the systemic nervous system. Since Alqvist (6) advanced his theory that sympathetic nervous system exert on two different receptors as the alpha-receptor which is connected with
slight
excitory mechanism and beta-receptor which primarily exert an inhibitory function with one important exception that the purely excitatory effect on the heart is mediated through beta-receptors. Judging from these observations, some investigators focused their interests to the fact that beta-receptor blocking agents may be of therapeutic value in hypertensive patients (7-10). Prichard and Gillam (11), found propranolol given in individualized and often extremely high doses to be a very active antihypertensive agents of the same potency as Guanethidine and Methyldopa with the exception that beta-blockers do not produce postural hypertension. Furberg and Michaelson (7), also found out that antihypertensive effect of alprenolol, a beta-adrenergic blocking agent was considered as moderate. In order to evaluate and compare the antihypertensive effect of alprenolol and propranolol in hypertensive subjects, we used these two drugs as the sole antihypertensive drugs on out patients with essential arterial hypertension in two parallel double blind studies and investigated their therapeutic effects on hypertension running for two years. MATERIALS AND METHODS
Our medical clinic had 17330 patients registered as of July 1, 1968, of which 3320 individuals were hypertensive with varying etiology. From that time all registrants at the clinic have received a complete initial examination at the time of entry. During this examination a single measurement of blood pressure was obtained routinely by the clinic staff physicians and nurses, who were not asked to modify their usual method of casual blood pressure measurement. All From Department of Medicine, School Tehran University, Tehran, Iran. Health, *
of
Medicine, Tehran University,
and School of Public
Associate Professor of Medicine. * Associate Professor of Medicine. ***Associate Professor of Public Health.
*
339
Downloaded from ang.sagepub.com at UNIV OF WESTERN ONTARIO on June 9, 2015
.
340
blood pressure measurements followed the technique used by Mial (12). Reading were taken from the right arm with subject in spine, sitting, and standing positions after a wait of 5 minutes. A 23 x 13 cm. cuff with nylon-hooket binding was used with a mercury sphygmomanometer. Diastolic pressure was defined as that at which muffling of sounds preceded their disappearance. The records of those persons who had an initial systolic blood pressure of 160 mmHg or greater and diastolic pressure of 90 mmHg or higher were selected for special review of the subsequent two blood pressure determinations, whenever they were recorded. Screening began in July 1968. Pressure recorded when a subject was febrile or physically or mentally distressed or had other medical conditions including aortic valvular diseases, anemia, hyperthyroidism, were discarded. All those with diastolic pressure at or over 100 mmHg, were followed up with at least two readings. Those with three or more readings at or above Pickering’s level were investigated by examination of the heart and fundi, E.C.G., chest X-ray, urine for protein and glucose, blood nitrogen, uric acid and cholestrol, catecholamine, 17-keto and hydroxy-steroids, renal angiography, intravenous pyelography and renal biopsy. The distribution of the mean systolic and diastolic blood pressure in all subjects according to the age was consistent with the belief that systolic blood pressure rises with age in both sexes. Utilizing the initial blood pressure determinations, 3320 subjects met the criteria for isolated systolic, diastolic, or combined systolic and diastolic hypertension. One hundred seven subjects were isolated and diagnosed as essential hypertension, after a complete physical and laboratory work up failed to reveal any cause for hypertension. Of these hypertensive subjects 45 were tried on propranolol and 62 on alprenolol respectively. Laboratory analysis were performed according to the routine methods used at our clinic. These comprised of red blood cell and white blood cell count, platelets, bilirubin, alkaline phosphatase, uric acid, urinalysis, fasting blood sugar, blood urea, creatinine, serum glutamic and oxalo acetic transaminase. more
RESULTS
tried in
series
comprised of
patients and propranolol study that 50 mg of induces about the 100 same blockade as propranolol mg alprenolol orally, therefore, dosage of alprenolol was commenced at 100 mg daily in four divided doses, and each dose was increased by 25 mg after two weeks and by another 25 mg after four weeks. The starting dose of propranolol was usually 80 mg daily in four divided doses increasing at weekly intervals to 160-320 mg daily. Further increases were made at two weekly intervals to 400-800 mg daily when higher doses were required. After a period of several weeks (4-13 weeks) both alprenolol and propranolol reduced systolic and diastolic blood pressure in supine, sitting and standing positions. The systolic pressure being decreased by about 20 mmHg and
Alprenolol
was
tried
on
was
45
one
patients (Table I, II). Based
on
62
earlier
Downloaded from ang.sagepub.com at UNIV OF WESTERN ONTARIO on June 9, 2015
341 diastolic pressure by about 7 mmHg in series used alprenolol and reduction in systolic pressure being decreased by 25 mmHg and diastolic pressure about 10 mmHg in group using propranolol (Table IV). No significant adverse effect or change in results of laboratory tests were noted during treatment. Side effect such as dizziness was noted in 10 women and 3 men. Marked bradycardia in group using propranolol was also noted when the dosage was increased to 400 mg daily. The following results have been obtained during such therapy: 1-Propranolol and alprenolol if given in individualized and often extremely high doses for a long time (from 4-13 weeks) are proved to be very active antihypertensive agents. 2-The gradual onset of their antihypertensive effect appeared after several weeks were similar in both groups using propranolol and alprenolol. 3-The reduction in blood pressure were noted in both systolic and diastolic pressure with the average reduction of 20 mmHg for systolic and 5-7 mmHg for diastolic pressure. 4-The antihypertensive effect of propranolol and alprenolol was found to be more pronounced during exercise than at rest. 5-The heart rate
propranolol
was
group and 7-10 in
reduced from 7-15 per minute (10-15 in group as shown in Table III. Marked
alprenolol
TABLE I Characteristics of patients
population
TABLE II
Changes in
+
L.V.H.
=
Left Venticular
eye
ground and cardiac size
Hypertrophy
Downloaded from ang.sagepub.com at UNIV OF WESTERN ONTARIO on June 9, 2015
342
bradycardia (56 per minute) was noted in one patient when alprenolol was increased to 800 mg daily. 6-There was no remarkable changes in laboratory results attributed to the use of these two drugs, except slight elevation of uric acid (3-4 mg%) was noted in 6 individuals who were taking propranolol and in 3 who were taking alprenolol up to 400 mg and 800 mg respectively. 7-It was quite remarkable that the antihypertensive effect of these two drugs were more pronounced during exercise than at rest and in individuals under the age of 40 comparing with those who were over the age of 40. 8-The response in those who had enlarged heart was more pronounced than those who had normal cardiac size. 9-It was also noted that propranolol reduces blood pressure about the same magnitude as alprenolol with the half dosage (20-25 mmHg for systolic and 7-10 mmHg for diastolic pressure in both groups). DISCUSSION
The favourable effects of beta-adrenergic blocking agents in angina pectoris and various cardiac arrhythmias have been documented in several clinical trials (13-14), but during recent years an antihypertensive effect with beta-adrenergic blocking agents such as propranolol (11, 12, 15) and alprenolol (7), has been noted in those patients when beta-adrenergic blockers were tried. In most studies, the beta-blockers were given in moderate dosage and was found to have an antihypertensive effectiveness of about the same order of magnitude as that of the thiazide diuretics (8, 15, 16). Prichard and Gillam (11) found propranolol and Furberg and Michaelson (7) found alprenolol given in individualized and often extremely high doses to be very active antihypertensive agents. Weal (17), Shineburne (18), and Prichard (9), found that the reduction of the blood pressure during beta-adrenergic blocking therapy is due to cardiac effects of these drugs rather than to the effects on the blood vessels. TABLE III
Results
.
of heart
rate
TABLE IV
Results of arterial blood pressure
drop
Downloaded from ang.sagepub.com at UNIV OF WESTERN ONTARIO on June 9, 2015
343
The correlation between the reduction in heart rate and blood pressure during exercise in hypertensive patients during alprenolol and propranolol treatment gives further support for such an interpretation. Furberg (19), has shown that the effect of beta-blockers of the heart during exercise, was generally most pronounced in subjects with signs of a hypertensive circulation and least in those with signs of hypokinetic circulation. Judging from these observations, antihypertensive effects of propranolol and alprenolol would be expected primarily in patients without evidence of organic cardiac damage. We regard the antihypertensive effect of these drugs as moderate in patients with essential hypertension. SUMMARY
The antihypertensive effect of two adrenergic blocking agents (Alprenolol and Propranolol) have been studied in a group of 107 patients with essential
hypertension. A significant reduction of 20 mmHg in the systolic blood pressure was recorded for the group using Alprenolol and 25 mmHg in the group using
Propranolol. The corresponding decrease of 7-10 mmHg in the diastolic blood pressure for the entire group was also significant. These two drugs may be of therapeutic value in essential hypertension, independently or in combination with other antihypertensive drugs. B. Nik-Akhtar
Department of Medicine School of Medicine Tehran Uniuersity Tehran, Iran REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19.
Bello, C. T., Sevy, R. W. and Harakal, C. (1965), Amer. J. Med. Sci. 250: 24 Bello, C. T., Sevy, R. W., Harkal, C. and Hillyer, P. N. (1967), Amer. J. Med. Sci. 253: 194 Finkelman, S., Wreel, M. and Agrest, A. (1965), Circulation 31: 356 Kuramoto, K., Murata, K., Yazaki, Y., Ikeda, M. and Nakao, K. (1968), Jap. Circulat. J. (En) 32: 9811 Lund-Johnsen, P. (1967), Acta Med. Scand. Suppl. 482 Alqvist, R. P. (1948), Amer. J. Physiol. 153: 586 Furberg, G. C. and Michaealson, G. (1969), Acta Med. Scand. 186: 447 Paterson, G. W. and Dollery, C. T. (1966), Lancet 2: 1148 Prichard, B. N. C. and Gillam, P. M. S. (1964), Brit. Med. J. 2: 725 Richards, A. (1966), Amer. J. Cardiol. 18: 384 Prichard, B. N. S. and Gillam, P. M. S. (1969), Brit. Med. J. 1: 7 Miall, W. E. and Oldham, P. D. (1958), Clin. Sci. 17: 409 Bjorntorp, P. (1967), Acta Med. Scand. 182: 285 Bjorntrop, P. (1968), Acta Med. Scand. 184: 259 Frohlich, E. C., Tarazi, R. C., Dustan, H. P. and Page, I. H. (1968), Circulation 37: 417 Dorph, S. and Binder, C. (1969), Acta Med. Scand. 185: 445 Weal, H. J. (1966), Clin. Pharmacol. Therap. 7: 558 Shineburne, E., Fleming, G. and Harmer, J. (1967), Lancet 2: 1217 Furberg, G. C. (1967), Acta Med. Scand. 182, 119
Downloaded from ang.sagepub.com at UNIV OF WESTERN ONTARIO on June 9, 2015
_
