Br. J. clin. Pharmac. (1979), 7, 169-174
HAEMODYNAMIC EFFECTS AND PLASMA CONCENTRATIONS OF LABETALOL DURING LONG-TERM TREATMENT OF ESSENTIAL HYPERTENSION P. LUND-JOHANSEN & 0. M. BAKKE Medical Department A and Clinical Pharmacology Unit, Laboratory of Clinical Biochemistry, University of Bergen, School of Medicine, Haukeland Sykehus, Bergen, Norway
I Fifteen men with untreated essential hypertension in WHO stage 1 were studied on an outpatient basis to evaluate the haemodynamic long-term effect of a new a- and P-adrenergic receptor blocker, labetalol. 2 Oxygen consumption, heart rate, cardiac output (Cardiogreen) and intraarterial brachial pressure were recorded at rest in a supine and sitting position, and during steady state work at 300, 600 and 900 kpm/min. 3 The subjects were treated with labetalol (dose 200-800 mg/day) as the sole drug for 1 year. The haemodynamic study was then repeated and the concentration of labetalol in plasma 2-2.5 h after the morning dose was measured. 4 Mean arterial blood pressure was reduced approximately 23% at rest and 21% during exercise. The heart rate was decreased 15% at rest and 16% during exercise. There was a compensatory increase in the stroke volume and consequently the cardiac index was reduced less than the heart rate, 7% at rest supine and 10% during exercise. There was a significant decrease in total peripheral resistance at rest supine (16%) and during exercise (12%). 5 No serious side-effects were seen, but two subjects almost syncopated in the sitting position after the 900 kpm/min work load at the restudy. 6 There was no correlation between the plasma concentration and the effect of labetalol. 7 The haemodynamic changes differ from those seen after long-term therapy with drugs possessing only ,-adrenoceptor blocking properties, and agree well with what should be expected with a drug which possesses both a- and ,-adrenoceptor blocking properties.
Introduction Labetalol is a relatively new antihypertensive drug with both a-adrenergic and P-adrenergic receptor blocking properties (Brittain & Levy, 1976; Richards, 1976). The drug has proved useful in severe (Dargie, Dollery & Daniel, 1976) and moderate (Bolli, WaalManning, Wood & Simpson, 1976; Kane & Gregg, 1976; Prichard & Boakes, 1976) hypertension. Studies of the acute haemodynamic effects have shown that at rest in the supine position the reduction in blood pressure is associated with a marked decrease in total peripheral resistance without any significant changes in cardiac output (Joekes & Thompson, 1976; Koch, 1976a). During exercise, however, cardiac output is also reduced (Koch, 1976a). The few long-term studies that have been published suggest that the haemodynamic profile observed after acute administration is maintained during prolonged treatment (Koch, 1976b; Edwards & Raftery, 1976).
The purpose of this work was to study the haemodynamic changes at rest and during exercise induced by 1 year of treatment with labetalol as the sole drug in subjects with mild to moderate essential hypertension. We also wanted to investigate the relationship between the dose, the plasma concentration and the blood pressure and haemodynamic effects of labetalol. Methods
The study included fifteen men, aged 24 to 60 years (mean 47.5 years) with untreated essential hypertension in WHO stage I (World Health Organization, technical report series 231). Secondary hypertension was excluded by the usual routine procedures (Lund-Johansen, 1967). All were without
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P. LUND-JOHANSEN & O.M. BAKKE
symptoms, the hypertension being discovered by routine control by a health officer and established by at least three visits to the outpatient clinic at the Medical Department A, Haukeland Hospital. The mean value and s.d. for body-weight and body surface area (BSA) before treatment were 77.1 ±8.6 kg and 1.94 + 0.11 M2. After 1 year on therapy the bodyweight was not significantly changed. The subjects were studied haemodynamically during strictly standardized conditions at rest supine and sitting and during bicycling in steady state at 300, 600 and 900 kpm/min. Oxygen consumption was measured by a Douglas bag and micro Scholander technique. The intraarterial pressure (brachial artery) and heart rate (HR) were measured continuously and the cardiac output (Cardiogreen) was measured in duplicate in each situation. The methods have been described previously in detail (Lund-Johansen, 1967, 1974). After the 900 kpm/min work load the patients rested in the sitting position for 5 min with continuous monitoring of blood pressure and heart rate to study possible postexercise blood pressure reduction. The subjects were informed about the nature and the purpose of the study and consent was obtained from all. All studies were made on an out-patient basis. After a treatment period of 11 to 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 the Student's t-test (paired sample test). A sample of arterial blood (5 ml) was collected in a heparinized tube from all of the patients except one during the second haemodynamic study 2-2.5 h after the morning dose. At this time the peak concentration is expected after oral administration of labetalol (Richards, Maconochie, Bland, Hopkins, Woodings & Martin, 1977). The plasma was separated and stored at - 200C until taken for analysis. The concentration of labetalol was determined by the fluorimetric method of Richards et al. (1977) as modified by Nyegaard & Co A/S, Oslo, Norway (personal communication). According to this modffication ethyl acetate was used instead of chloroform for extraction and the fluorescence was read at 425 nm (Ex 345 nm). Calibration curves were prepared from serum containing 50-1000 ng labetalol/ml. Treatment
The patients received tablets of labetalol (100 mg) at 07.00 and 17.00 h. Five patients continued with 200 mg daily, in five the dose was increased to 400 mg, in one to 600 mg and in four to 800 mg daily, aining at a sitting casual blood pressure < 140/90 mmHg. No other drugs and no diet restriction were given. On the day of the second haemodynamic study the patients took their usual morning dose at 07.00 h. The
haemodynamic study was performed between 09.00 and 12.00h.
Side-effects Three patients complained of dizziness and feeling of fatigue during the initial 1-2 weeks of treatment, one particularly when raising quickly from bent position with head down. The remaining patients had no sideeffects, particularly no orthostatic reactions. However, two patients almost syncopated when sitting in the ergometer chair resting after the 900 kpm/min work load. In both subjects, who had behaved perfectly normally during the whole procedure, there was a rapid fall in the blood pressure in the sitting position after the last work test. (This type of reaction has not been seen in our laboratory among more than 200 hypertensive patients participating in similar experiments with or without drugs). Results
Casual blood pressure and heart rate The casual blood pressure (sitting) decreased in all subjects during treatment, the mean value from 167/110 mmHg before starting to 134/88 mmHg at the last control shortly before the second haemodynamic study. The mean heart rate decreased from 82 to 68 beats/min. There were no orthostatic reactions during the casual follow-up and the mean value of standing blood pressure at the last control was 131/87mmHg.
Haemodynamic data The haemodynamic data are shown in Tables 1 and 2 and Figure 1. The oxygen consumption (VO2) did not change significantly at rest. During exercise the V02 was higher after therapy, the increase at the 300 and 600 kpm/min work load almost reached statistical significance. Cardiac index A reduction in cardiac index was observed at rest as well as during exercise. At rest in the supine position the decrease was only 7% (NS). The decrease at rest sitting was 14% (highly significant) and during excercise approximately 10% (significant).
Heart rate
The post-treatment heart rates were reduced in all but one subject at rest and in all subjects during exercise. The reduction in heart rate was 15% at rest and
HAEMODYNAMICS OF LABETALOL IN HYPERTENSION Table 1 Oxygen consumption (V02), cardiac index (Cl), stroke index (SI) and heart rate (HR) before (1) and during (2) therapy, mean difference (2-1) the P value of paired sample test Rest
Supine 1 2
Sitting 1 2
V02 (ml min-1 m-2) Mean s.d. 2-1
-1
p Cl (I min-' m-2)
Mean s.d. 2-1 p Si (ml stroke -1 m-2) Mean s.d. 2-1 p HR (beat min-1) Mean s.d. 2-1 p
156 19.7
157 24.2
NS
3.15 2.93 0.44 0.40 -0.22 NS
2.67 2.29 0.31 0.33 -0.38
300 2
1
Work (kpm/min) 600 1 2
900
2
563 603 825 881 1241 1261 38.3 63.6 71.2 101.7 136.0 168.5 +40 +56 +20 < 0.05 < 0.05 NS 6.94 6.28 1.12 0.99 -0.66
HAEMODYNAMIC EFFECTS AND PLASMA CONCENTRATIONS OF LABETALOL DURING LONG-TERM TREATMENT OF ESSENTIAL HYPERTENSION P. LUND-JOHANSEN & 0. M. BAKKE Medical Department A and Clinical Pharmacology Unit, Laboratory of Clinical Biochemistry, University of Bergen, School of Medicine, Haukeland Sykehus, Bergen, Norway
I Fifteen men with untreated essential hypertension in WHO stage 1 were studied on an outpatient basis to evaluate the haemodynamic long-term effect of a new a- and P-adrenergic receptor blocker, labetalol. 2 Oxygen consumption, heart rate, cardiac output (Cardiogreen) and intraarterial brachial pressure were recorded at rest in a supine and sitting position, and during steady state work at 300, 600 and 900 kpm/min. 3 The subjects were treated with labetalol (dose 200-800 mg/day) as the sole drug for 1 year. The haemodynamic study was then repeated and the concentration of labetalol in plasma 2-2.5 h after the morning dose was measured. 4 Mean arterial blood pressure was reduced approximately 23% at rest and 21% during exercise. The heart rate was decreased 15% at rest and 16% during exercise. There was a compensatory increase in the stroke volume and consequently the cardiac index was reduced less than the heart rate, 7% at rest supine and 10% during exercise. There was a significant decrease in total peripheral resistance at rest supine (16%) and during exercise (12%). 5 No serious side-effects were seen, but two subjects almost syncopated in the sitting position after the 900 kpm/min work load at the restudy. 6 There was no correlation between the plasma concentration and the effect of labetalol. 7 The haemodynamic changes differ from those seen after long-term therapy with drugs possessing only ,-adrenoceptor blocking properties, and agree well with what should be expected with a drug which possesses both a- and ,-adrenoceptor blocking properties.
Introduction Labetalol is a relatively new antihypertensive drug with both a-adrenergic and P-adrenergic receptor blocking properties (Brittain & Levy, 1976; Richards, 1976). The drug has proved useful in severe (Dargie, Dollery & Daniel, 1976) and moderate (Bolli, WaalManning, Wood & Simpson, 1976; Kane & Gregg, 1976; Prichard & Boakes, 1976) hypertension. Studies of the acute haemodynamic effects have shown that at rest in the supine position the reduction in blood pressure is associated with a marked decrease in total peripheral resistance without any significant changes in cardiac output (Joekes & Thompson, 1976; Koch, 1976a). During exercise, however, cardiac output is also reduced (Koch, 1976a). The few long-term studies that have been published suggest that the haemodynamic profile observed after acute administration is maintained during prolonged treatment (Koch, 1976b; Edwards & Raftery, 1976).
The purpose of this work was to study the haemodynamic changes at rest and during exercise induced by 1 year of treatment with labetalol as the sole drug in subjects with mild to moderate essential hypertension. We also wanted to investigate the relationship between the dose, the plasma concentration and the blood pressure and haemodynamic effects of labetalol. Methods
The study included fifteen men, aged 24 to 60 years (mean 47.5 years) with untreated essential hypertension in WHO stage I (World Health Organization, technical report series 231). Secondary hypertension was excluded by the usual routine procedures (Lund-Johansen, 1967). All were without
170
P. LUND-JOHANSEN & O.M. BAKKE
symptoms, the hypertension being discovered by routine control by a health officer and established by at least three visits to the outpatient clinic at the Medical Department A, Haukeland Hospital. The mean value and s.d. for body-weight and body surface area (BSA) before treatment were 77.1 ±8.6 kg and 1.94 + 0.11 M2. After 1 year on therapy the bodyweight was not significantly changed. The subjects were studied haemodynamically during strictly standardized conditions at rest supine and sitting and during bicycling in steady state at 300, 600 and 900 kpm/min. Oxygen consumption was measured by a Douglas bag and micro Scholander technique. The intraarterial pressure (brachial artery) and heart rate (HR) were measured continuously and the cardiac output (Cardiogreen) was measured in duplicate in each situation. The methods have been described previously in detail (Lund-Johansen, 1967, 1974). After the 900 kpm/min work load the patients rested in the sitting position for 5 min with continuous monitoring of blood pressure and heart rate to study possible postexercise blood pressure reduction. The subjects were informed about the nature and the purpose of the study and consent was obtained from all. All studies were made on an out-patient basis. After a treatment period of 11 to 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 the Student's t-test (paired sample test). A sample of arterial blood (5 ml) was collected in a heparinized tube from all of the patients except one during the second haemodynamic study 2-2.5 h after the morning dose. At this time the peak concentration is expected after oral administration of labetalol (Richards, Maconochie, Bland, Hopkins, Woodings & Martin, 1977). The plasma was separated and stored at - 200C until taken for analysis. The concentration of labetalol was determined by the fluorimetric method of Richards et al. (1977) as modified by Nyegaard & Co A/S, Oslo, Norway (personal communication). According to this modffication ethyl acetate was used instead of chloroform for extraction and the fluorescence was read at 425 nm (Ex 345 nm). Calibration curves were prepared from serum containing 50-1000 ng labetalol/ml. Treatment
The patients received tablets of labetalol (100 mg) at 07.00 and 17.00 h. Five patients continued with 200 mg daily, in five the dose was increased to 400 mg, in one to 600 mg and in four to 800 mg daily, aining at a sitting casual blood pressure < 140/90 mmHg. No other drugs and no diet restriction were given. On the day of the second haemodynamic study the patients took their usual morning dose at 07.00 h. The
haemodynamic study was performed between 09.00 and 12.00h.
Side-effects Three patients complained of dizziness and feeling of fatigue during the initial 1-2 weeks of treatment, one particularly when raising quickly from bent position with head down. The remaining patients had no sideeffects, particularly no orthostatic reactions. However, two patients almost syncopated when sitting in the ergometer chair resting after the 900 kpm/min work load. In both subjects, who had behaved perfectly normally during the whole procedure, there was a rapid fall in the blood pressure in the sitting position after the last work test. (This type of reaction has not been seen in our laboratory among more than 200 hypertensive patients participating in similar experiments with or without drugs). Results
Casual blood pressure and heart rate The casual blood pressure (sitting) decreased in all subjects during treatment, the mean value from 167/110 mmHg before starting to 134/88 mmHg at the last control shortly before the second haemodynamic study. The mean heart rate decreased from 82 to 68 beats/min. There were no orthostatic reactions during the casual follow-up and the mean value of standing blood pressure at the last control was 131/87mmHg.
Haemodynamic data The haemodynamic data are shown in Tables 1 and 2 and Figure 1. The oxygen consumption (VO2) did not change significantly at rest. During exercise the V02 was higher after therapy, the increase at the 300 and 600 kpm/min work load almost reached statistical significance. Cardiac index A reduction in cardiac index was observed at rest as well as during exercise. At rest in the supine position the decrease was only 7% (NS). The decrease at rest sitting was 14% (highly significant) and during excercise approximately 10% (significant).
Heart rate
The post-treatment heart rates were reduced in all but one subject at rest and in all subjects during exercise. The reduction in heart rate was 15% at rest and
HAEMODYNAMICS OF LABETALOL IN HYPERTENSION Table 1 Oxygen consumption (V02), cardiac index (Cl), stroke index (SI) and heart rate (HR) before (1) and during (2) therapy, mean difference (2-1) the P value of paired sample test Rest
Supine 1 2
Sitting 1 2
V02 (ml min-1 m-2) Mean s.d. 2-1
-1
p Cl (I min-' m-2)
Mean s.d. 2-1 p Si (ml stroke -1 m-2) Mean s.d. 2-1 p HR (beat min-1) Mean s.d. 2-1 p
156 19.7
157 24.2
NS
3.15 2.93 0.44 0.40 -0.22 NS
2.67 2.29 0.31 0.33 -0.38
300 2
1
Work (kpm/min) 600 1 2
900
2
563 603 825 881 1241 1261 38.3 63.6 71.2 101.7 136.0 168.5 +40 +56 +20 < 0.05 < 0.05 NS 6.94 6.28 1.12 0.99 -0.66
