DIURETICS, P-BLOCKERS OR BOTH AS TREATMENT FOR ESSENTIAL HYPERTENSION KLAUS 0. STUMPE AND A. OVERLACK Medizinische Universitats-Poliklinik Bonn, West Germany
1 Patients with borderline (group I) and sustained hypertension (group II) were treated with 3-blocking drugs, diuretics and the combination of both. In the two groups of patients the antihypertensive effectiveness of both short-term intravenous or chronically oral propranolol was directly related to the extent to which the drug produced an absolute reduction in plasma renin activity (PRA). No such a correlation could be obtained with pindolol. In group I following ,B-blockade, day-night profiles of PRA were similar to those observed in group II before treatment. Thus, in this latter subgroup, low renin profiles might reflect reduced ,3-adrenergic
activity. 2 When the chronically 13-blockaded patients were changed to chronic diuretic therapy it became evident that young hypertensive patients of group II showed a more pronounced BP response than the patients of group I. In those patients of group II in whom pressure was not controlled by the diuretic alone, combination with a 13-blocker led to pressure normalization. 3 The 13-blocking drug induced reduction in pressure was greater in the 25-35 yr olds, than in those older than 55. In contrast, the antihypertensive effect of the diuretic was more pronounced in the 55-70 yr olds than in those younger than 40. 4 It is concluded that sympathetic nervous system activity mainly determined PRA as well as antihypertensive effectiveness of both the P-blockers and the diuretics. As to outpatient management it is proposed that with the exception of young borderline hypertensives who seem to respond best to 13-blockers, initial antihypertensive drug therapy may consist of a diuretic agent. If the antihypertensive effect of the diuretic is insufficient, combination with a P-blocking drug could be used to achieve the best effect.
Introduction INHIBITION of adrenergic nervous activity as well as control of sodium metabolism by diuretics play central roles in the management of hypertension. Among adrenergic inhibitors P-receptor antagonists offer the most important approach to modern antihypertensive therapy. As these drugs act only on 13receptors, side-effects associated with a-receptor blockade, such as orthostatic hypertension, stuffy nose, and sexual dysfunction in the male, are uncommon. Thus, with 13-receptor blockade alone or in combination with a diuretic the physician has the opportunity both to attain the desired hypotensive efficacy with minimal side effects and to improve
patient compliance with antihypertensive regimens. Although the consensus seems to be that 13blockers and diuretic drugs, alone or in combination, are an effective form of therapy irrespective of which agents are used (BUhleret al., 1975; Davidson et al., 1976; Dustan et al., 1974; Hamer, 1976; Morgan et al., 1974; Stumpe & Kolloch, 1976), the question of prediction of response remains unsolved. There is no simple clinical analysis to predict a patient's response to either a 13-blocking drug or diuretic. Whichever
0306-5251/79/140189-09$01.00 3
agent is used as principal therapy, there will be a significant decline in BP in some patients and little or no decline in others. This remains the trial and error element in the treatment of each hypertensive
patient. The purpose of this paper is to present some data which were obtained in essential hypertensive patients who were treated with either a 13-blocking drug, a diuretic, or a combination of both. Besides evaluation of the antihypertensive responses we tried to find which factors might determine the antihypertensive efficacy of these drugs and might be helpful in predicting a reduction in BP. In a first series of experiments we re-evaluated the antihypertensive efficacy of propranolol and pindolol in relation to their renin suppressive effect. To exclude episodic secretions of renin as a cause of the reported dissociation between PRA and arterial BP with treatment, measurements were made in all patients every 30 min over a 10-h period during continuous recumbency (Stumpe et al., 1976). The studies were carried out using 46 male patients with essential hypertension. They ranged in age from 21© Macmillan Journals Ltd.
190S
K.O. STUMPE & A. OVERLACK
a
0)
I
E E
Heart rate (beats/min)
76 69 71 +3.8 t3.9 ±3.3
72 71 79 ±4.4 ±3.7 ±3.1
76 65 ±3.5 ±4.1
66 ±3.8
4 -c
0-
3 2
c:
2100 2400 0300 0600 2100 2400 0300 0600 2100 2400 0300 0600
Time Figure 1 Effect of intravenous administration of propranolol or pindolol on arterial pressure (RR), heart rate and PRA in patients with borderline hypertension. PRA and arterial BPs were measured during continuous recumbency every 30 min during a 1 0-h period beginning at 2000 after 7 h of bed rest. a, Control; b, pindolol 1.2 pg/min/kg i.v.; c, propranolol 2.5 lAg/min/kg i.v. n= 11. Mean+s.e.
30 yr and had never taken antihypertensive drugs. The elevation in BP was classified as sustained hypertension or borderline hypertension on the basis of repeated measurements. In all patients with sustained hypertension, the average BP during several outpatient visits was greater than 160/95 mmHg. In patients with borderline hypertension, the average pressure in these conditions generally ranged from 140/90 to 160/95 mmHg, although occasional values were sometimes greater than 160/100 mmHg and sometimes less than 140/90 mmHg. Short-term P-receptor blockade
Borderline hypertension After a 1-h infusion of pindolol or propranolol, prompt and striking reductions of both systolic and
diastolic BP occurred in all patients with borderline hypertension (P
1 Patients with borderline (group I) and sustained hypertension (group II) were treated with 3-blocking drugs, diuretics and the combination of both. In the two groups of patients the antihypertensive effectiveness of both short-term intravenous or chronically oral propranolol was directly related to the extent to which the drug produced an absolute reduction in plasma renin activity (PRA). No such a correlation could be obtained with pindolol. In group I following ,B-blockade, day-night profiles of PRA were similar to those observed in group II before treatment. Thus, in this latter subgroup, low renin profiles might reflect reduced ,3-adrenergic
activity. 2 When the chronically 13-blockaded patients were changed to chronic diuretic therapy it became evident that young hypertensive patients of group II showed a more pronounced BP response than the patients of group I. In those patients of group II in whom pressure was not controlled by the diuretic alone, combination with a 13-blocker led to pressure normalization. 3 The 13-blocking drug induced reduction in pressure was greater in the 25-35 yr olds, than in those older than 55. In contrast, the antihypertensive effect of the diuretic was more pronounced in the 55-70 yr olds than in those younger than 40. 4 It is concluded that sympathetic nervous system activity mainly determined PRA as well as antihypertensive effectiveness of both the P-blockers and the diuretics. As to outpatient management it is proposed that with the exception of young borderline hypertensives who seem to respond best to 13-blockers, initial antihypertensive drug therapy may consist of a diuretic agent. If the antihypertensive effect of the diuretic is insufficient, combination with a P-blocking drug could be used to achieve the best effect.
Introduction INHIBITION of adrenergic nervous activity as well as control of sodium metabolism by diuretics play central roles in the management of hypertension. Among adrenergic inhibitors P-receptor antagonists offer the most important approach to modern antihypertensive therapy. As these drugs act only on 13receptors, side-effects associated with a-receptor blockade, such as orthostatic hypertension, stuffy nose, and sexual dysfunction in the male, are uncommon. Thus, with 13-receptor blockade alone or in combination with a diuretic the physician has the opportunity both to attain the desired hypotensive efficacy with minimal side effects and to improve
patient compliance with antihypertensive regimens. Although the consensus seems to be that 13blockers and diuretic drugs, alone or in combination, are an effective form of therapy irrespective of which agents are used (BUhleret al., 1975; Davidson et al., 1976; Dustan et al., 1974; Hamer, 1976; Morgan et al., 1974; Stumpe & Kolloch, 1976), the question of prediction of response remains unsolved. There is no simple clinical analysis to predict a patient's response to either a 13-blocking drug or diuretic. Whichever
0306-5251/79/140189-09$01.00 3
agent is used as principal therapy, there will be a significant decline in BP in some patients and little or no decline in others. This remains the trial and error element in the treatment of each hypertensive
patient. The purpose of this paper is to present some data which were obtained in essential hypertensive patients who were treated with either a 13-blocking drug, a diuretic, or a combination of both. Besides evaluation of the antihypertensive responses we tried to find which factors might determine the antihypertensive efficacy of these drugs and might be helpful in predicting a reduction in BP. In a first series of experiments we re-evaluated the antihypertensive efficacy of propranolol and pindolol in relation to their renin suppressive effect. To exclude episodic secretions of renin as a cause of the reported dissociation between PRA and arterial BP with treatment, measurements were made in all patients every 30 min over a 10-h period during continuous recumbency (Stumpe et al., 1976). The studies were carried out using 46 male patients with essential hypertension. They ranged in age from 21© Macmillan Journals Ltd.
190S
K.O. STUMPE & A. OVERLACK
a
0)
I
E E
Heart rate (beats/min)
76 69 71 +3.8 t3.9 ±3.3
72 71 79 ±4.4 ±3.7 ±3.1
76 65 ±3.5 ±4.1
66 ±3.8
4 -c
0-
3 2
c:
2100 2400 0300 0600 2100 2400 0300 0600 2100 2400 0300 0600
Time Figure 1 Effect of intravenous administration of propranolol or pindolol on arterial pressure (RR), heart rate and PRA in patients with borderline hypertension. PRA and arterial BPs were measured during continuous recumbency every 30 min during a 1 0-h period beginning at 2000 after 7 h of bed rest. a, Control; b, pindolol 1.2 pg/min/kg i.v.; c, propranolol 2.5 lAg/min/kg i.v. n= 11. Mean+s.e.
30 yr and had never taken antihypertensive drugs. The elevation in BP was classified as sustained hypertension or borderline hypertension on the basis of repeated measurements. In all patients with sustained hypertension, the average BP during several outpatient visits was greater than 160/95 mmHg. In patients with borderline hypertension, the average pressure in these conditions generally ranged from 140/90 to 160/95 mmHg, although occasional values were sometimes greater than 160/100 mmHg and sometimes less than 140/90 mmHg. Short-term P-receptor blockade
Borderline hypertension After a 1-h infusion of pindolol or propranolol, prompt and striking reductions of both systolic and
diastolic BP occurred in all patients with borderline hypertension (P
