Effects of oral propranolol in normal subjects The effects of oral propranolol were evaluated in 10 normal volunteers. The resting heart rate decreased from the mean control value of 68 ± 3.3 (SE) to 56 ± 2.8 beats per minute (bpm) on propranolol (p < 0.001, paired t test). Mean systolic blood pressure also decreased from 125 ± 5.0 to 114 ± 4.2 mm Hg (p < 0.03). Resting systolic time intervals were unaffected by propranolol. Mean maximal treadmill exercise tolerance time was not significantly altered by propranolol although the mean heart rate systolic blood pressure product at maximal exertion was markedly decreased (1.91 ± 0.17 vs 2.62 ± 0.17 X 10\ p < 0.004). The nonsignificant effect of oral propranolol on resting systolic time intervals and maximum exercise tolerance despite significant changes in heart rate and blood pressure at rest and during exercise stand in contrast to the reported effects of intravenous propranolol. Explanations for this difference between the effects of oral and intravenous propranolol in nprmal subjects are examined.
Martin M. LeWinter, M.D., Michael H. Crawford, M.D., Joel S. Karliner, M.D., and Robert A. O'Rourke, M.D. San Diego, Calif.
The Cardiovascular Division, Department of Medicine, University of California
The beta adrenergic blocker, propranolol (Indera!), has become an important therapeutic agent in the management of ischemic chest pain, arrhythmias, and hypertension. 14 Despite the widespread use of this drug, there is little information on the effects of oral propranolol therapy in patients with normal left ventricular function. In normal human subjects, substantial alterations in various parameters of exercise performance resulting from rapid intravenous administration of propranolol have been reported. 6 , 9 Since the metabolism of oral and intravenous propranolol differs, it might be exSupported in part by National Heart and Lung Institute Training Grant No. 05846·06. Received for publication Nov. 19, 1974. Accepted for publication March 24, 1975. Reprint requests to: Or. Robert A. O'Rourke, University Hos· pital. 225 W. Dickinson St., San Diego, Calif. 92103.
pected that the oral administration of propranolol would have different quantitative effects from those after intravenous administration, We therefore designed a protocol to examine the effects of oral propranolol on heart rate, systemic arterial pressure, systolic time intervals, maximal exercise tolerance, and left ventricular size in normal subjects. Methods
Our subjects were 10 volunteers, 6 men and 4 women, with an average age of 45.8 yr (range 31 to 59). All were in good health and with no history of cardiovascular or pulmonary disease. The 4 female subjects had a previous cardiac catheterization for atypical chest pain but all had normal left ventricular pressures, left ventricular volumes, and selective coronary arteriograms.
709
710
Clinical Pharmacology and Therapeutics
LeWinter et al.
72
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130 120 110
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100 90 80 70
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Fig. 1. A. Effect of propranolol on resting heart rate. B. Effects of propranolol on supine systolic and diastolic blood pressure. C!o first control period; P. propranolol period; C 2• second control period; NS. not significant.
The study consisted of 3 sequential 2-week periods. During the first 2 weeks, the subjects received a placebo. This was followed by propranolol for the next 2 wk and by placebo for the final 2 wk. The dose of propranolol was 160 mg daily (40 mg every 6 hr during the day and 40 mg at bedtime). Placebo was administered in an identical fashion. Blood samples for serum propranolol were obtained between 2 and 3 hr after the morning dose at the end of the 2-wk propranolol period. Propranolol serum levels were measured by a modification of the fluorometric method of Shand, Nuckolls, and Oates. 15 At the start of the study and at the end of each 2-wk period, the following measurements were made 1 to 3 hr after the morning dose of drug: (1) Unusual symptoms were recorded. (2) A physical examination was performed and the resting heart rate and systemic arterial pressure were measured. (3) The roentgenographic left heart dimen-
si on was determined by the method of Kazamias and associates. 1o The left heart dimension has been shown to correlate well with the angiographicaUy determined left ventricular end diastolic diameter, and in our laboratory the normal value is taken to be 44 ± 8 (2 SD) mm/m 2 body surface area (BSA). (4) Systolic time intervals were derived by the method of Weissler, Harris, and Schoenfeld. 18 (5) A maximal treadmill exercise test was performed by a modified Bruce protocol. 5 Maximum heart rate was determined by measuring the ECG recorded R-R interval, and blood pressure was measured at the termination of exercise by cuff sphygmomanometer. During the study no patients received any other drug than propranolol. The control measurements subsequently referred to relate to data obtained after the first 2 wk of placebo therapy and after the final 2 wk of placebo treatment. To minimize any effect of training or familiarity with the procedures, the measurements obtained in each subject on the first visit were excluded from the analysis of the data. All data were analyzed by the paired Student t test using the subject as his own control. 11 Results
The fixed daily dose of 160 mg of oral propranolol resulted in a mean serum level of 28 ng/ml with a range of 9 to 89 ng/ml. Supine resting heart rate fell from 68 ± 3.3 (± 1 SE) bpm during the control period to 56 ± 2.8 bpm during propranolol therapy (p < 0.001, Fig. 1, A). Mean systolic blood pressure decreased from a control value of 125 ± 5.0 mm Hg to 114 ± 4.2 mm Hg (p < 0.03), while mean diastolic blood pressure did not change significantly (Fig. 1, B). Average left ventricular ejection time index, pre-ejection period index, and the ratio of preejection period to the left ventricular ejection time did not change significantly during propranolol therapy. Compared to the first control period, mean maximal exercise tolerance did not change significantly on propranolol (Fig. 2, A). There was, however, a small but significant decline in mean maximal exercise tolerance on pro-
Oral propranolol in normals
Volume 17 Number 6
pranolol compared with the final control period (610 ± 37 vs 654 ± 37 sec, p < 0.004). When compared to both control periods, the mean heart rate-systolic blood pressure product at the completion of exercise decreased markedly on propranolol (both p < 0.004, Fig. 2, B).
The mean left heart dimension of 45.4 ± 1.9 mm/m 2 on propranolol was not significantly different from the control 44.4 ± 1. 9 mm/ m2. During the final 2-wk placebo period, none of the parameters followed differed from the initial placebo period. The mean maximal exercise tolerance increased to 654 sec from control value of 616 sec, but this was not statistically significant. No adverse reactions were attributable to propranolol. Discussion Our study indicates that in doses adequate to reduce the resting heart rate and systolic blood pressure, as well as to markedly diminish the heart rate and blood pressure response to maximal exercise, propranolol had little if any effect on maximal exercise tolerance, whereas after acute intravenous administration, a 40% reduction in maximal exercise tolerance has been reported. 6 This difference may be related to the mode of drug administration since when propranolol is given intravenously, there is less time for conversion of drug to active metabolites. 3 • !2 It has been shown that orally administered propranolol undergoes extensive hepatic metabolism and at least 16 separate metabolites have been identified. 4 , !6 Several of these metabolites have beta adrenergic blocking activity4, 7 but others have opposite effects.17 In contrast, intravenously administered propranolol seems to escape hepatic breakdown. 3 The differences in metabolite breakdown between oral and intravenous propranolol do not appear to explain the difference in exercise tolerance since the data indicate that our subjects exhibited substantial beta adrenergic blockade. It seems reasonable, therefore, to consider other explanations. One mechanism might be a conditioning effect occurring during chronic, but not acute, administration. Such conditioning effects are commonly observed after daily physical training for weeks! and are presumably
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Martin M. LeWinter, M.D., Michael H. Crawford, M.D., Joel S. Karliner, M.D., and Robert A. O'Rourke, M.D. San Diego, Calif.
The Cardiovascular Division, Department of Medicine, University of California
The beta adrenergic blocker, propranolol (Indera!), has become an important therapeutic agent in the management of ischemic chest pain, arrhythmias, and hypertension. 14 Despite the widespread use of this drug, there is little information on the effects of oral propranolol therapy in patients with normal left ventricular function. In normal human subjects, substantial alterations in various parameters of exercise performance resulting from rapid intravenous administration of propranolol have been reported. 6 , 9 Since the metabolism of oral and intravenous propranolol differs, it might be exSupported in part by National Heart and Lung Institute Training Grant No. 05846·06. Received for publication Nov. 19, 1974. Accepted for publication March 24, 1975. Reprint requests to: Or. Robert A. O'Rourke, University Hos· pital. 225 W. Dickinson St., San Diego, Calif. 92103.
pected that the oral administration of propranolol would have different quantitative effects from those after intravenous administration, We therefore designed a protocol to examine the effects of oral propranolol on heart rate, systemic arterial pressure, systolic time intervals, maximal exercise tolerance, and left ventricular size in normal subjects. Methods
Our subjects were 10 volunteers, 6 men and 4 women, with an average age of 45.8 yr (range 31 to 59). All were in good health and with no history of cardiovascular or pulmonary disease. The 4 female subjects had a previous cardiac catheterization for atypical chest pain but all had normal left ventricular pressures, left ventricular volumes, and selective coronary arteriograms.
709
710
Clinical Pharmacology and Therapeutics
LeWinter et al.
72
A
70 I-~
et: .Cl E
w .....
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c
(l)~
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68 66 64 62 60 58 56 54 52
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w
et:
~ (f) (f) w
et:
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0 0 0 --l
en
130 120 110
B
~
O=SYSTOLlC c=OIASTOLlC I=ISE
100 90 80 70
~
60 50
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p
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Fig. 1. A. Effect of propranolol on resting heart rate. B. Effects of propranolol on supine systolic and diastolic blood pressure. C!o first control period; P. propranolol period; C 2• second control period; NS. not significant.
The study consisted of 3 sequential 2-week periods. During the first 2 weeks, the subjects received a placebo. This was followed by propranolol for the next 2 wk and by placebo for the final 2 wk. The dose of propranolol was 160 mg daily (40 mg every 6 hr during the day and 40 mg at bedtime). Placebo was administered in an identical fashion. Blood samples for serum propranolol were obtained between 2 and 3 hr after the morning dose at the end of the 2-wk propranolol period. Propranolol serum levels were measured by a modification of the fluorometric method of Shand, Nuckolls, and Oates. 15 At the start of the study and at the end of each 2-wk period, the following measurements were made 1 to 3 hr after the morning dose of drug: (1) Unusual symptoms were recorded. (2) A physical examination was performed and the resting heart rate and systemic arterial pressure were measured. (3) The roentgenographic left heart dimen-
si on was determined by the method of Kazamias and associates. 1o The left heart dimension has been shown to correlate well with the angiographicaUy determined left ventricular end diastolic diameter, and in our laboratory the normal value is taken to be 44 ± 8 (2 SD) mm/m 2 body surface area (BSA). (4) Systolic time intervals were derived by the method of Weissler, Harris, and Schoenfeld. 18 (5) A maximal treadmill exercise test was performed by a modified Bruce protocol. 5 Maximum heart rate was determined by measuring the ECG recorded R-R interval, and blood pressure was measured at the termination of exercise by cuff sphygmomanometer. During the study no patients received any other drug than propranolol. The control measurements subsequently referred to relate to data obtained after the first 2 wk of placebo therapy and after the final 2 wk of placebo treatment. To minimize any effect of training or familiarity with the procedures, the measurements obtained in each subject on the first visit were excluded from the analysis of the data. All data were analyzed by the paired Student t test using the subject as his own control. 11 Results
The fixed daily dose of 160 mg of oral propranolol resulted in a mean serum level of 28 ng/ml with a range of 9 to 89 ng/ml. Supine resting heart rate fell from 68 ± 3.3 (± 1 SE) bpm during the control period to 56 ± 2.8 bpm during propranolol therapy (p < 0.001, Fig. 1, A). Mean systolic blood pressure decreased from a control value of 125 ± 5.0 mm Hg to 114 ± 4.2 mm Hg (p < 0.03), while mean diastolic blood pressure did not change significantly (Fig. 1, B). Average left ventricular ejection time index, pre-ejection period index, and the ratio of preejection period to the left ventricular ejection time did not change significantly during propranolol therapy. Compared to the first control period, mean maximal exercise tolerance did not change significantly on propranolol (Fig. 2, A). There was, however, a small but significant decline in mean maximal exercise tolerance on pro-
Oral propranolol in normals
Volume 17 Number 6
pranolol compared with the final control period (610 ± 37 vs 654 ± 37 sec, p < 0.004). When compared to both control periods, the mean heart rate-systolic blood pressure product at the completion of exercise decreased markedly on propranolol (both p < 0.004, Fig. 2, B).
The mean left heart dimension of 45.4 ± 1.9 mm/m 2 on propranolol was not significantly different from the control 44.4 ± 1. 9 mm/ m2. During the final 2-wk placebo period, none of the parameters followed differed from the initial placebo period. The mean maximal exercise tolerance increased to 654 sec from control value of 616 sec, but this was not statistically significant. No adverse reactions were attributable to propranolol. Discussion Our study indicates that in doses adequate to reduce the resting heart rate and systolic blood pressure, as well as to markedly diminish the heart rate and blood pressure response to maximal exercise, propranolol had little if any effect on maximal exercise tolerance, whereas after acute intravenous administration, a 40% reduction in maximal exercise tolerance has been reported. 6 This difference may be related to the mode of drug administration since when propranolol is given intravenously, there is less time for conversion of drug to active metabolites. 3 • !2 It has been shown that orally administered propranolol undergoes extensive hepatic metabolism and at least 16 separate metabolites have been identified. 4 , !6 Several of these metabolites have beta adrenergic blocking activity4, 7 but others have opposite effects.17 In contrast, intravenously administered propranolol seems to escape hepatic breakdown. 3 The differences in metabolite breakdown between oral and intravenous propranolol do not appear to explain the difference in exercise tolerance since the data indicate that our subjects exhibited substantial beta adrenergic blockade. It seems reasonable, therefore, to consider other explanations. One mechanism might be a conditioning effect occurring during chronic, but not acute, administration. Such conditioning effects are commonly observed after daily physical training for weeks! and are presumably
700 w~
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711
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680
~~ 660
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