Br. J. clin Pharmac, (1979) 8, 107S IllS
COMPARATIVE HAEMODYNAMIC EFFECTS OF LABETALOL, TIMOLOL, PRAZOSIN AND THE COMBINATION OF TOLAMOLOL AND PRAZOSIN PER LUND-JOHANSEN Medical Department, University of Bergen, School of Medicine, Haukeland Sykehus, Bergen, Norway
1 Four groups of patients with previously untreated essential hypertension in WHO stage I were treated either with timolol (n = 16), or prazosin (n = 13) or prazosin plus tolamolol (n = 12), or labetalol (n = 15). 2 Oxygen consumption, heart rate, cardiac output (Cardiogreen) and intraarterial brachial BP were recorded at rest in the supine and sitting position and during steady-state work at 50, 100 and 150 W before treatment and after 1 yr on drug therapy. 3 All regimes induced significant decrease in arterial BP at rest as well as during exercise. 4 BP reduction was achieved through different haemodynamic mechanisms. In the timolol group BP reduction was associated with a marked decrease in heart rate and cardiac output but no decrease in total peripheral resistance. In the prazosin group there was a significant decrease in total peripheral resistance at rest as well as during exercise. During exercise the cardiac index was higher than before treatment. In the groups treated with prazosin plus tolamolol or labetalol alone the changes were rather similar. There was a significant decrease in total peripheral resistance at rest, supine and during exercise. Heart rate was decreased, but much less than by the use of a pure fl-blocker alone. Due to a compensatory increase in stroke volume, particularly during muscular exercise, the cardiac index was reduced much less than in the group treated with timolol. 5 The results indicate that the haemodynamic long-term effects of labetalol differ from those seen after long-term therapy on prazosin or f-adrenoceptor blockers and resemble those seen after combined treatment with both a- and P-adrenoceptor blockers. 6 The clinical significance of these differences is briefly discussed.
Introduction
FROM a clinical point of view a useful antihypertensive agent should induce a significant decrease in BP in most patients, without any side-effects. However, at least theoretically it could also be an advantage if the drug reduced BP through correction of the haemodynamic disturbances responsible for the increased BP. Practically all hypertensive patients in whom drug treatment is found indicated, demonstrate an increase in total peripheral resistance as the dominating haemodynamic disorder. At rest the cardiac output is normal or subnormal, but during muscular exercise it is too low due to insufficient increase in stroke volume (Lund-Johansen, 1967). The various antihypertensive drugs reduce BP through very different haemodynamic mechanisms (reviewed in LundJohansen, 1978). In recent years drugs interfering with a- or ,Badrenoceptors or both have been increasingly used in treatment of hypertension. The purpose of this paper
0306-5251/79/170107-05 $01.00
is to compare the haemodynamic long-term effects induced by such drugs. The results obtained in four groups of patients treated either with timolol, prazosin, prazosin plus tolamolol or labetalol will be presented. As the results have been published previously in separate papers (Lund-Johansen, 1976, 1974, 1977; Lund-Johansen & Bakke, 1979), the results are summarized in this paper. Methods
Fifty-six males with previously untreated essential hypertension in WHO stage I were studied. Secondary hypertension was excluded by usual routine procedures and all were without symptoms. The hypertension was usually discovered by routine control and confirmed by later visits to the outpatient clinic at Medical Department A, Haukeland Hospital. C) Macmillan Journals Ltd 1979
108S PER LUND-JOHANSEN
All subjects were studied haemodynamically in strictly standardized conditions at rest, supine and sitting, and during bicycling in steady state at 50, 100 and 150 W. Oxygen consumption was measured using a Douglas bag and the microScholander technique; intraarterial BP (brachial artery) and heart rate (HR) were measured continuously and cardiac output (Cardiogreen) was measured in duplicate in each situation. The methods have been described previously in detail (Lund-Johansen, 1967). The subjects were informed about the nature and the purpose of the study and consent was obtained from all. After a treatment period of 11-12 months the haemodynamic study was repeated. The difference between the haemodynamic results at the first and the second study was tested for statistical significance using Student's t-test (paired sample test). Treatment
Sixteen patients (mean age 47 y) were treated with timolol (dose 10-30 mg daily; mean 17.5 mg), 13 (mean age 42 y) with prazosin (dose 3.0-7.5 mg daily; mean 4 mg), 12 (mean age 47 y) with prazosin plus tolamolol (dose of prazosin 1.5-6.0 mg daily; mean 4.0 mg; dose of tolamolol 150-300 mg daily; mean 200 mg), and 15 (mean age 47 y) were treated with labetalol (dose 200-800 mg daily; mean 453 mg). The dose was adjusted according to the response, aiming at a casual BP of < 140/90 mm Hg without sideeffects. No other drugs or any diet restriction were given. On the day of the second haemodynamic study all patients took their usual morning dose at 0700. The haemodynamic study was carried out between 0900 and 1200.
Results 'Non-responders' and side-effects Three patients in the prazosin group and one patient in the prazosin plus tolamolol group were excluded because of unsatisfactory BP reduction (diastolic BP remained above 100 mmH$ in spite of dose increase). No severe side-effects were seen in any of the groups and no subject had to be withdrawn because of sideeffects. In the timolol group three patients experienced pronounced fatigue during the first 2-3 weeks. In the prazosin group there were no sideeffects. In the prazosin plus tolamolol group one subject experienced the first dose syncope reaction. Later doses were tolerated. In the labetalol group three patients complained of dizziness and feeling of fatigue during the initial 1-2 weeks of treatment. Two of these patients almost syncopated when resting sitting after the 150 W exercise load at the last
haemodynamic study. (After the study was completed tolamolol was removed from clinical trials due to possible carcinogenic effect seen in high dose studies in animals.) Casual blood pressure
The sitting casual BP fell in all subjects in all groups. Mean values decreased from 171/114 mmHg to 142/97 mmHg in the timolol group, from 170/120 mm Hg to 137/97 mmHg in the prazosin group, from 170/115 to 129/89 mmHg in the prazosin plus tolamolol group, and from 167/110 mmHg to 134/88 mmHg in the labetalol group. Haemodynamic changes At the pretreatment study all patients had increased total peripheral resistance at rest and during exercise, and the cardiac index during exercise was subnormal. Mean arterial pressure (MAP)
MAP was reduced significantly at rest as well as during exercise in all four groups. At rest (sitting) the decrease in MAP was 17% with timolol, 13% with prazosin, 20% with prazosin plus tolamolol, and 23% with labetalol. An analysis of the haemodynamic changes showed that the mechanism behind the decrease in BP differed in the four groups. Figures 1, 2, 3 and 4 show the relative changes in MAP, total peripheral resistance index, cardiac index and heart rate at rest sitting and during the 100 W exercise level in the four groups. In the timolol group BP reduction was associated with a marked decrease (approximately 28%) in cardiac index at rest as well as during exercise and also with a marked decrease in heart rate (approximately 27%). The post-treatment total peripheral resistance was higher than before treatment at rest as well as during exercise (Figure 1). Patients treated with prazosin showed a very different haemodynamic pattern (Figure 2). The reduction in MAP was associated with a significant decrease in total peripheral resistance at rest as well as during exercise. During exercise the decrease in resistance was 22%. The cardiac index at rest sitting tended to be higher than before treatment. During exercise the post-treatment cardiac index was significantly higher than before treatment due to an
increase in stroke volutme. Heart rate did not show any significant changes. Figure 3 shows the combination of prazosin plus the cardioselective fi-adrenoceptor blocker tolamolol. The decrease in MAP was greater than in the group treated with prazosin alone (20% compared with 13% at rest sitting). The total peripheral resistance was unchanged during rest sitting, but the post-treatment
HAEMODYNAMIC EFFECTS Rest, sitting 20w-
L
101F u)
a) 0)
10OW
T7
Rest, sitting I
109S
100W
**
.0.
cc
e)
14
COMPARATIVE HAEMODYNAMIC EFFECTS OF LABETALOL, TIMOLOL, PRAZOSIN AND THE COMBINATION OF TOLAMOLOL AND PRAZOSIN PER LUND-JOHANSEN Medical Department, University of Bergen, School of Medicine, Haukeland Sykehus, Bergen, Norway
1 Four groups of patients with previously untreated essential hypertension in WHO stage I were treated either with timolol (n = 16), or prazosin (n = 13) or prazosin plus tolamolol (n = 12), or labetalol (n = 15). 2 Oxygen consumption, heart rate, cardiac output (Cardiogreen) and intraarterial brachial BP were recorded at rest in the supine and sitting position and during steady-state work at 50, 100 and 150 W before treatment and after 1 yr on drug therapy. 3 All regimes induced significant decrease in arterial BP at rest as well as during exercise. 4 BP reduction was achieved through different haemodynamic mechanisms. In the timolol group BP reduction was associated with a marked decrease in heart rate and cardiac output but no decrease in total peripheral resistance. In the prazosin group there was a significant decrease in total peripheral resistance at rest as well as during exercise. During exercise the cardiac index was higher than before treatment. In the groups treated with prazosin plus tolamolol or labetalol alone the changes were rather similar. There was a significant decrease in total peripheral resistance at rest, supine and during exercise. Heart rate was decreased, but much less than by the use of a pure fl-blocker alone. Due to a compensatory increase in stroke volume, particularly during muscular exercise, the cardiac index was reduced much less than in the group treated with timolol. 5 The results indicate that the haemodynamic long-term effects of labetalol differ from those seen after long-term therapy on prazosin or f-adrenoceptor blockers and resemble those seen after combined treatment with both a- and P-adrenoceptor blockers. 6 The clinical significance of these differences is briefly discussed.
Introduction
FROM a clinical point of view a useful antihypertensive agent should induce a significant decrease in BP in most patients, without any side-effects. However, at least theoretically it could also be an advantage if the drug reduced BP through correction of the haemodynamic disturbances responsible for the increased BP. Practically all hypertensive patients in whom drug treatment is found indicated, demonstrate an increase in total peripheral resistance as the dominating haemodynamic disorder. At rest the cardiac output is normal or subnormal, but during muscular exercise it is too low due to insufficient increase in stroke volume (Lund-Johansen, 1967). The various antihypertensive drugs reduce BP through very different haemodynamic mechanisms (reviewed in LundJohansen, 1978). In recent years drugs interfering with a- or ,Badrenoceptors or both have been increasingly used in treatment of hypertension. The purpose of this paper
0306-5251/79/170107-05 $01.00
is to compare the haemodynamic long-term effects induced by such drugs. The results obtained in four groups of patients treated either with timolol, prazosin, prazosin plus tolamolol or labetalol will be presented. As the results have been published previously in separate papers (Lund-Johansen, 1976, 1974, 1977; Lund-Johansen & Bakke, 1979), the results are summarized in this paper. Methods
Fifty-six males with previously untreated essential hypertension in WHO stage I were studied. Secondary hypertension was excluded by usual routine procedures and all were without symptoms. The hypertension was usually discovered by routine control and confirmed by later visits to the outpatient clinic at Medical Department A, Haukeland Hospital. C) Macmillan Journals Ltd 1979
108S PER LUND-JOHANSEN
All subjects were studied haemodynamically in strictly standardized conditions at rest, supine and sitting, and during bicycling in steady state at 50, 100 and 150 W. Oxygen consumption was measured using a Douglas bag and the microScholander technique; intraarterial BP (brachial artery) and heart rate (HR) were measured continuously and cardiac output (Cardiogreen) was measured in duplicate in each situation. The methods have been described previously in detail (Lund-Johansen, 1967). The subjects were informed about the nature and the purpose of the study and consent was obtained from all. After a treatment period of 11-12 months the haemodynamic study was repeated. The difference between the haemodynamic results at the first and the second study was tested for statistical significance using Student's t-test (paired sample test). Treatment
Sixteen patients (mean age 47 y) were treated with timolol (dose 10-30 mg daily; mean 17.5 mg), 13 (mean age 42 y) with prazosin (dose 3.0-7.5 mg daily; mean 4 mg), 12 (mean age 47 y) with prazosin plus tolamolol (dose of prazosin 1.5-6.0 mg daily; mean 4.0 mg; dose of tolamolol 150-300 mg daily; mean 200 mg), and 15 (mean age 47 y) were treated with labetalol (dose 200-800 mg daily; mean 453 mg). The dose was adjusted according to the response, aiming at a casual BP of < 140/90 mm Hg without sideeffects. No other drugs or any diet restriction were given. On the day of the second haemodynamic study all patients took their usual morning dose at 0700. The haemodynamic study was carried out between 0900 and 1200.
Results 'Non-responders' and side-effects Three patients in the prazosin group and one patient in the prazosin plus tolamolol group were excluded because of unsatisfactory BP reduction (diastolic BP remained above 100 mmH$ in spite of dose increase). No severe side-effects were seen in any of the groups and no subject had to be withdrawn because of sideeffects. In the timolol group three patients experienced pronounced fatigue during the first 2-3 weeks. In the prazosin group there were no sideeffects. In the prazosin plus tolamolol group one subject experienced the first dose syncope reaction. Later doses were tolerated. In the labetalol group three patients complained of dizziness and feeling of fatigue during the initial 1-2 weeks of treatment. Two of these patients almost syncopated when resting sitting after the 150 W exercise load at the last
haemodynamic study. (After the study was completed tolamolol was removed from clinical trials due to possible carcinogenic effect seen in high dose studies in animals.) Casual blood pressure
The sitting casual BP fell in all subjects in all groups. Mean values decreased from 171/114 mmHg to 142/97 mmHg in the timolol group, from 170/120 mm Hg to 137/97 mmHg in the prazosin group, from 170/115 to 129/89 mmHg in the prazosin plus tolamolol group, and from 167/110 mmHg to 134/88 mmHg in the labetalol group. Haemodynamic changes At the pretreatment study all patients had increased total peripheral resistance at rest and during exercise, and the cardiac index during exercise was subnormal. Mean arterial pressure (MAP)
MAP was reduced significantly at rest as well as during exercise in all four groups. At rest (sitting) the decrease in MAP was 17% with timolol, 13% with prazosin, 20% with prazosin plus tolamolol, and 23% with labetalol. An analysis of the haemodynamic changes showed that the mechanism behind the decrease in BP differed in the four groups. Figures 1, 2, 3 and 4 show the relative changes in MAP, total peripheral resistance index, cardiac index and heart rate at rest sitting and during the 100 W exercise level in the four groups. In the timolol group BP reduction was associated with a marked decrease (approximately 28%) in cardiac index at rest as well as during exercise and also with a marked decrease in heart rate (approximately 27%). The post-treatment total peripheral resistance was higher than before treatment at rest as well as during exercise (Figure 1). Patients treated with prazosin showed a very different haemodynamic pattern (Figure 2). The reduction in MAP was associated with a significant decrease in total peripheral resistance at rest as well as during exercise. During exercise the decrease in resistance was 22%. The cardiac index at rest sitting tended to be higher than before treatment. During exercise the post-treatment cardiac index was significantly higher than before treatment due to an
increase in stroke volutme. Heart rate did not show any significant changes. Figure 3 shows the combination of prazosin plus the cardioselective fi-adrenoceptor blocker tolamolol. The decrease in MAP was greater than in the group treated with prazosin alone (20% compared with 13% at rest sitting). The total peripheral resistance was unchanged during rest sitting, but the post-treatment
HAEMODYNAMIC EFFECTS Rest, sitting 20w-
L
101F u)
a) 0)
10OW
T7
Rest, sitting I
109S
100W
**
.0.
cc
e)
14
