Isoprenaline dose‐response curves plotting increases in heart rate before and after labetalol are suggestive of competitive antagonism at beta‐adrenoceptor sites. Phenylephrine dose‐response curves using increases in systolic pressure before and after labetalol are suggestive of competitive antagonism at alpha‐adrenoceptor sites. The ratio of alpha:beta‐adrenoceptor antagonism induced by labetalol is approximately 1:3. Peak pharmacological responses after a single oral dose of labetalol (400 mg) occurred between 90‐120 min after administration.
Labetalol 1.5 mg/kg administered intravenously to normal subjects in the supine position produced an immediate mean fall in systolic (16%) and diastolic (25%) blood pressure with a concomitant increase in heart rate (12%). After graded exercise, intravenous labetalol inhibited increases in heart rate and blood pressure.Isoprenaline log dose response curves of increase in heart rate and reduction in diastolic pressure after intravenous labetalol shifted to the right in a parallel manner compared with pre-labetalol response curves suggestive of competitive antagonism at beta-adrenoceptor sites. Similarly, phenylephrine dose response curves of increase in systolic pressure before and after intravenous labetalol were suggestive of competitive antagonism at alpha-adrenoceptor sites. The ratio of relative potency alpha: beta adrenoceptor antagonism after intravenous labetalol was approximately 1: 7, whereas in the same subjects after oral labetalol the ratio was approximately 1: 3 as previously reported.Using the inhibition of isoprenaline tachycardia to estimate the potency of the beta-adrenoceptor antagonism of labetalol relative to that of propranolol the potency ratio was 1: 6. However, using inhibition of Valsalva tachycardia as the index, the estimated ratio was approximately 1 :3. Estimates of relative potency using inhibition of tilt tachycardia were complicated by the additional effects upon blood pressure after labetalol not seen after propranolol.Labetalol produced adrenoceptor blockade at both alpha and beta sites in man sufficient to explain its therapeutic antihypertensive effect.Labetalol is a compound possessing combined alpha and beta adrenoceptor antagonist properties (Farmer et al., 1972). Consequently it has been assessed in clinical practice as an antihypertensive agent. Prichard et al. (1975) and Koch (1976)
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.
1In healthy male volunteers after single oral doses, AH 5158 produced inhibition of exercise induced tachycardia, falls in systolic and diastolic pressure at rest and in response to exercise, which are probably related to combined f-and a-adrenoceptor antagonism. 2 At increasing doses from 100 mg to 400 mg there exists a dose related antagonistic effect, though the dominant effect of,-adrenoceptor antagonism is more easily demonstrable than is a antagonism. 3 As indicated by the pattern of pharmacological effects, absorption of the oral drug is good and the duration of action of a 400 mg dose is approximately 8 hours. 4 Despite being administered in j3-adrenoceptor blocking doses, AH 5158 had no adverse effects upon peak expiratory flow at rest or in response to exercise.
5It is concluded that the pharmacological profile of this combined a-and ,B-adrenoceptor antagonism suggests a potential therapeutic role as an antihypertensive drug.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.