European Journal of Clinical Pharmacology
Europ. J. clin. Pharmacol. 11, 85-90 (1977)
@ by Springer-Verlag 1977
Relationship between Plasma Concentrations and Pharmacological Effects of Labetalol D. A. Richards, J. G. Maconochie, R. E. Bland, R. Hopkins, E. P. Woodings and L. E. Martin Medical Division and Biochemistry Department, Alien and Hanburys Research Limited, Ware, Hertfordshire, England
Summary. In healthy normal subjects following the administration of labetalol the pharmacological effects were measured and compared with the plasma concentrations achieved. The inhibition of exercise induced tachycardia and inhibition of exercise induced increases in systolic pressure were significantly related to the administered dose of labetalol. Labetalol was rapidly absorbed from the gastrointestinal tract and peak plasma concentrations occurred two hours after oral administration. There was a linear correlation (r = 0.84) between the logarithm of the plasma concentration and the maximum inhibition of exercise tachycardia at two hours. After intravenous administration there was an immediate reduction in systolic and diastolic blood pressure with a concomitant small increase in heart rate. There was a rapid decline in the associated plasma concentration but the pharmacological effects were maintained in excess of two hours. Our findings are consistent with those of others who have studied the relationship between pharmacological events and plasma concentrations after single doses of other adrenoceptor blocking drugs. Key words: Labetalol, blood pressure, heart rate, plasma concentration.
It has been established with various beta blocking drugs that their ability to inhibit exercise induced tachycardia correlates with plasma concentration of drug. Ablad et al. [1] has described the relationship in respect of alprenolol; Hicks et al. [2] for pindolol, Fitzgerald and Scales [3] for practolol and Brown et al. [4] for sotalol. Faulkner et al. [5] have correlated the pharmacokinetics and pharmacological events following tolamolol with plasma concentration of drug.
Labetalol is a combined alpha and beta adrenoceptor antagonist currently being evaluated as an antihypertensive agent [6, 7]. In man the beta adrenoceptor antagonist effect of the drug is greater than that of the alpha adrenoceptor antagonism, approximately in the ratio of 3:1 beta to alpha [8]. Having previously shown that labetalol was a beta adrenoceptot blocking drug in man [9] we attempted to correlate measured pharmacological events with the plasma concentration following single oral doses of 100, 200 and 400 mg. In addition, we examined the relationship between the plasma concentration of labetalol when administered intravenously with the immediate changes in cardiovascular parameters. Both studies were conducted on normal healthy males.
Method
Oral Study Five healthy male subjects aged 22-44 years each weighing 64-74 kg took part in this study. Each subject presented in the laboratory at the beginning of the day having had only a very light breakfast without tea or coffee. Chest electrodes were attached and heart rate was measured using a Narco biosystems biotachometer with a paper print out of heart rate on to a Devices-2-channel recorder. After a period sitting at rest, recordings of heart rate were made at intervals until the rate was stable. At this point a reading of the heart rate at rest was taken from the biotachometer followed by measurements of systolic and diastolic blood pressure using a solid state electrosphygrnomanometer taken after the subjects had stood for one minute and repeated after they had sat for a further minute. We chose the electrosphygmomanometer for recording blood pressure since, al-
86
D.A. Richardset al.: PlasmaConcentrationand Effectsof Labetalol lOOmg
30.
200mg
,/
r
I
T
Reduction in 20heart
[
rate bts/min
400mg
IO-
1
150-
Plasma IOO. concentration
ng/ml
50-
'I
F
r
2
3
J
5
0
1
2
3
5
0
1
2
3
5
TIME-hours
Fig. 1. Relationship between mean (_+ SEM) plasma concentrations (0) of labetalol taken at hourly intervals for 5 h and reductions in mean ( + SEM) heart rate (x) after exercise in five normal subjects
30
25
o/1"= "84 • o " P
Europ. J. clin. Pharmacol. 11, 85-90 (1977)
@ by Springer-Verlag 1977
Relationship between Plasma Concentrations and Pharmacological Effects of Labetalol D. A. Richards, J. G. Maconochie, R. E. Bland, R. Hopkins, E. P. Woodings and L. E. Martin Medical Division and Biochemistry Department, Alien and Hanburys Research Limited, Ware, Hertfordshire, England
Summary. In healthy normal subjects following the administration of labetalol the pharmacological effects were measured and compared with the plasma concentrations achieved. The inhibition of exercise induced tachycardia and inhibition of exercise induced increases in systolic pressure were significantly related to the administered dose of labetalol. Labetalol was rapidly absorbed from the gastrointestinal tract and peak plasma concentrations occurred two hours after oral administration. There was a linear correlation (r = 0.84) between the logarithm of the plasma concentration and the maximum inhibition of exercise tachycardia at two hours. After intravenous administration there was an immediate reduction in systolic and diastolic blood pressure with a concomitant small increase in heart rate. There was a rapid decline in the associated plasma concentration but the pharmacological effects were maintained in excess of two hours. Our findings are consistent with those of others who have studied the relationship between pharmacological events and plasma concentrations after single doses of other adrenoceptor blocking drugs. Key words: Labetalol, blood pressure, heart rate, plasma concentration.
It has been established with various beta blocking drugs that their ability to inhibit exercise induced tachycardia correlates with plasma concentration of drug. Ablad et al. [1] has described the relationship in respect of alprenolol; Hicks et al. [2] for pindolol, Fitzgerald and Scales [3] for practolol and Brown et al. [4] for sotalol. Faulkner et al. [5] have correlated the pharmacokinetics and pharmacological events following tolamolol with plasma concentration of drug.
Labetalol is a combined alpha and beta adrenoceptor antagonist currently being evaluated as an antihypertensive agent [6, 7]. In man the beta adrenoceptor antagonist effect of the drug is greater than that of the alpha adrenoceptor antagonism, approximately in the ratio of 3:1 beta to alpha [8]. Having previously shown that labetalol was a beta adrenoceptot blocking drug in man [9] we attempted to correlate measured pharmacological events with the plasma concentration following single oral doses of 100, 200 and 400 mg. In addition, we examined the relationship between the plasma concentration of labetalol when administered intravenously with the immediate changes in cardiovascular parameters. Both studies were conducted on normal healthy males.
Method
Oral Study Five healthy male subjects aged 22-44 years each weighing 64-74 kg took part in this study. Each subject presented in the laboratory at the beginning of the day having had only a very light breakfast without tea or coffee. Chest electrodes were attached and heart rate was measured using a Narco biosystems biotachometer with a paper print out of heart rate on to a Devices-2-channel recorder. After a period sitting at rest, recordings of heart rate were made at intervals until the rate was stable. At this point a reading of the heart rate at rest was taken from the biotachometer followed by measurements of systolic and diastolic blood pressure using a solid state electrosphygrnomanometer taken after the subjects had stood for one minute and repeated after they had sat for a further minute. We chose the electrosphygmomanometer for recording blood pressure since, al-
86
D.A. Richardset al.: PlasmaConcentrationand Effectsof Labetalol lOOmg
30.
200mg
,/
r
I
T
Reduction in 20heart
[
rate bts/min
400mg
IO-
1
150-
Plasma IOO. concentration
ng/ml
50-
'I
F
r
2
3
J
5
0
1
2
3
5
0
1
2
3
5
TIME-hours
Fig. 1. Relationship between mean (_+ SEM) plasma concentrations (0) of labetalol taken at hourly intervals for 5 h and reductions in mean ( + SEM) heart rate (x) after exercise in five normal subjects
30
25
o/1"= "84 • o " P
