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As detailed information on the pharmacokinetics (PK) of labetalol in pregnant people are lacking, the aims of this study were: (1) to build a physiologically based PK (PBPK) model of labetalol in non-pregnant individuals that incorporates different CYP2C19 genotypes (specifically, *1/*1, *1/*2 or *3, *2/*2, and *17/*17); (2) to translate this model to the second and third trimester of pregnancy; and (3) to combine the model with a previously published direct pharmacodynamic (PD) model to predict the blood pressure lowering effect of labetalol in the third trimester. Clinical data for model evaluation was obtained from the scientific literature. In non-pregnant populations, the mean ratios of simulated versus observed peak concentration (C max ), time to reach C max (T max ), and exposure (area under the plasma concentration-time curve, AUC) were 0.94, 0.82, and 1.16, respectively. The pregnancy PBPK model captured the observed PK adequately, but clearance was slightly underestimated with mean ratios of simulated versus observed C max , T max , and AUC of 1.28, 1.30, and 1.39, respectively. The results suggested that pregnant people with CYP2C19 *2/*2 alleles have similar labetalol exposure and trough levels compared to non-pregnant controls, whereas those with other alleles were found to have increased exposure and trough concentrations. Importantly, the pregnancy PBPK/PD model predicted that, despite increased exposure in some genotypes, the blood pressure lowering effect was broadly comparable across all genotypes. In view of the large inter-individual variability and the potentially increasing blood pressure during pregnancy, patients may need to be closely monitored for achieving optimal therapeutic effects and avoiding adverse events., (© 2024, The American College of Clinical Pharmacology.)

1. The agonistic and antagonistic effects of labetalol, the alpha1- and beta-adrenoceptor antagonist, were studied on beta3-adrenoceptors in the guinea-pig gastric fundus. 2. Labetalol caused a concentration-dependent relaxation with a pD2 value of 5.58 +/- 0.09 and an intrinsic activity of 0.64 +/- 0.06, which was not affected by pretreatment with both the selective beta1-adrenoceptor antagonist, (+/-)-atenolol (100 microM), and the selective beta2-adrenoceptor antagonist, (+/-)-butoxamine (100 microM). 3. However, the non-selective beta1-, beta2- and beta3-adrenoceptor antagonist, (+/-)-bupranolol (3-30 microM), shifted the concentration-response curve of labetalol to the right (pA2 value=5.97 +/- 0.08). 4. In the presence of (+/-)-atenolol (100 microM) and (+/-)-butoxamine (100 microM), relaxations to catecholamines [(-)-isoprenaline, (-)-noradrenaline and (-)-adrenaline], to the selective beta3-adrenoceptor agonist, BRL37344, and to the non-conventional partial beta3-adrenoceptor agonist, (+/-)-CGP12177A, were weakly antagonized by labetalol (10 microM). 5. These results indicate that labetalol, the arylethanolamine, acts as a partial agonist on beta3-adrenoceptors in the guinea-pig gastric fundus.

Twelve healthy male subjects completed this randomized, placebo controlled, four-period crossover trial to determine the effect of verapamil, diltiazem, and labetalol on the bioavailability and metabolism of imipramine. Subjects received a 7-day course of one of four treatments; verapamil (120 mg every 8 hr), diltiazem (90 mg every 8 hr), labetalol (200 mg every 12 hr), or placebo (every 12 hr) during each study period. Imipramine (100 mg) was administered orally on the morning of day 4 of each study period. Plasma and urine samples were collected periodically over the ensuing 96 hours. Samples were assayed by HPLC for imipramine, desipramine, 2-hydroxyimipramine, and 2-hydroxydesipramine. Verapamil, diltiazem, and labetalol increased imipramine area under the plasma concentration time curve (relative bioavailability) as compared with placebo by 15%, 30%, and 53%, respectively. Verapamil and diltiazem did not demonstrate consistent changes in the formation of the measured metabolites. Labetalol caused a significant decrease in the amount of imipramine metabolized to 2-hydroxyimipramine (mean decrease: 22%) and from desipramine to 2-hydroxydesipramine (mean decrease: 8%). The molar ratios of plasma AUC of 2-hydroxyimipramine and 2-hydroxydesipramine to the parent compounds were significantly decreased. Since these metabolic processes are dependent on the cytochrome P450IID6 isozyme, these data suggest that labetalol decreases the oral clearance of imipramine by inhibiting this system. All three of these commonly used agents decreased the oral clearance of imipramine. These drug interactions could lead to elevated imipramine concentrations and have the potential for clinically important adverse events.

1. The purpose of the present study was to investigate the acute (single injection), direct (chronic treatment) and the long-lasting effects after exposure to the alpha 1/beta-adrenoceptor antagonist labetalol during rat brain development on adrenoceptors and monoamine metabolism. 2. In 10-day-old rat pups, subcutaneously administered labetalol (10 mg kg-1) passed the blood-brain barrier, reaching a level of 2.1 micrograms g-1 tissue in the brain 90 min after injection. 3. Chronic labetalol treatment (10 mg kg-1, s.c., twice daily) during the first 10 days of life significantly increased alpha 1-adrenoceptor binding in the hypothalamus (+39%), but not in the occipital cortex. 4. This chronic postnatal labetalol treatment did not result in long-lasting changes in alpha 1- and beta-receptors measured on day 60. 5. A single labetalol injection (10 mg kg-1, s.c.) on postnatal day 10 significantly increased noradrenaline (NA) metabolism in all brain regions tested (+25 to 105%), but had no effects on 5-hydroxytryptamine (5-HT) or dopamine metabolism. 6. Chronic labetalol treatment between postnatal (PN) days 1 and 10 also increased NA metabolism on PN 10 (3-methoxy-4-hydroxyphenylglycol (MHPG)/NA, +20 to 100%), suggesting that tolerance to the acute effect of labetalol did not occur. A slight increase in 5-HT metabolism (20%) was induced by the chronic labetalol treatment in the hippocampus and meso-limbic system. 7. In general, long-lasting effects on NA metabolism could not be detected on day 60 more than one month after the treatment. However, 5-HT metabolism was significantly increased in all four brain regions measured (+20 to 70%). 8. We conclude that chronic labetalol exposure during early postnatal rat brain development does not cause long-lasting changes in beta-receptor number or NA metabolism, but appears to be critical for the rate of 5-HT metabolism in later life.

1. We compared the alpha 1-, alpha 2- and beta 1-adrenoceptor blocking potencies of labetalol with those of its two stereoisomers (RR and SR) in pithed rats and in homogenized rat cerebral cortex and heart. 2. In pithed rats, labetalol and the RR-SR combination were given orally either at doses of 25 and 50 mg kg-1 body wt. or intravenously at doses of 1 and 5 mg kg-1 body wt. Prazosin 4 and 20 micrograms kg-1 body wt. and propranolol 1 and 5 mg kg-1 body wt., were given intravenously for comparison studies of potency at alpha 1- and beta 1-adrenoceptors, respectively. Effects were studied before and after i.v. administration of either phenylephrine (at doses which increased the mean arterial pressure by approximately 80 mmHg) or isoprenaline (at doses that increased heart rate by approximately 100 beats min-1). 3. In pithed rats, labetalol and the RR-SR combination antagonized, in a dose-dependent manner, the pressor effect of phenylephrine (P less than 0.05) and the chronotropic effect of isoprenaline (P less than 0.05). Following both oral and intravenous dosing, the RR-SR combination was twice potent as labetalol in terms of alpha 1- and beta 1-adrenoceptor antagonism at equivalent doses. 4. Labetalol and the enantiomers lacked affinity at alpha 2-adrenoceptors while at alpha 1-adrenoceptors the order of potency was prazosin much greater than RR-SR greater than labetalol. At beta 1-adrenoceptors, the affinity of the compound RR-SR was about 3 times that of labetalol.5. As labetalol is a mixture of active (RR and SR) and inactive (SS and SR) enantiomers (in terms of alpha and beta receptor actions), the combination of RR and SR may be a valuable substitute for labetalol in the treatment of systemic hypertension. Although the potential for non-specific side effects (common to all four enantiomers) could be expected to be diminished, recent reports by postmarketing surveillance indicate that the RR isomer (dilevalol) can induce liver toxicity. Interestingly, labetalol is devoid of this effect; whether the combination of RR and SR enantiomers could be of clinical importance warrants further investigation.

Labetalol pharmacokinetics and pharmacodynamics were evaluated in nine subjects before and during enzyme inhibition with cimetidine. Pharmacologic response was assessed by use of standardized treadmill tests during 24 hours after administration of oral labetalol. Oral clearance of labetalol decreased with cimetidine administration (58.7 +/- 23.3 to 32.9 +/- 13.2 ml/min/kg; p less than 0.05), thereby causing a 79% increase in area under the curve. Labetalol systemic clearance also decreased (23.2 +/- 5.3 to 17.7 +/- 3.7 ml/min/kg; p less than 0.05), but the volume of distribution was unchanged. Labetalol caused significant beta-blockade for 8 hours after the last oral dose, but cimetidine did not alter pharmacologic response. The Emax model provided a good description of the concentration-effect relationship. At peak labetalol concentrations after oral administration, (R,R)-labetalol concentrations were significantly lower than those of the other three stereoisomers (p less than 0.05). Cimetidine caused an increase in the concentrations of each stereoisomer, but the difference was significant (p less than 0.05) for only the (S,R)-, (S,S)-, and (R,S)-isomers. This first evidence of labetalol stereoselective disposition is consistent with the findings of previous (R,R)-labetalol pharmacokinetic studies and with previous pharmacodynamic investigations of labetalol and (R,R)-labetalol.

1. The purpose of the present study was to investigate the haemodynamic, electrophysiological and antiarrhythmic effects of labetalol in the late reperfusion phase after myocardial infarction in conscious dogs. 2. Labetalol was administered in cumulative doses (0.5, 1 and 3 mg kg-1 90 min-1, i.v.). Compared to control the systolic blood pressure was significantly decreased 20 min after 0.5, 1 and 3 mg kg-1 and up to 30 min after 3 mg kg-1 labetalol. The diastolic blood pressure was significantly decreased 20 and 30 min after 0.5 and 3 mg kg-1 but was not significantly altered after 1 mg kg-1 labetalol. 3. Labetalol significantly increased the PQ, QRS, QT and QTc intervals, the 2:1 AV-conduction point, the ventricular effective refractory periods and the intraventricular conduction time from the apex of the right ventricle to the infarcted LAD-area. With the exception of the alterations in the PQ interval and 2:1 AV-conduction point the effects described above were dose-dependent. 4. Labetalol was active against arrhythmias induced by programmed electrical stimulation. This effect was already present after the lowest dose (0.5 mg kg-1). 5. The good antiarrhythmic activity of labetalol in this study can be explained by the adrenoceptor blocking properties and both the class I and III activity of this drug. Labetalol may be of potential benefit in controlling arrhythmias arising following myocardial infarction.

Cats anesthetized with alpha chloralose received saline or dilevalol (1 mg/kg, IV) during a 10-minute infusion. Fifteen minutes later, the left anterior descending coronary artery was subjected to coronary occlusion 2 mm below its origin. Regional differences in the beta receptor densities were found for the atria and ventricles and for the areas within the left ventricle in cats with no coronary occlusion and dilevalol or saline. The variation in beta receptor density distribution may be related to functional differences. Coronary occlusion and saline or dilevalol did not modify the myocardial beta receptor density regional distribution. Mean times to arrhythmia and death in five saline cats were 5.8 +/- 3.6 (N = 3) and 5.4 (N = 2) minutes; three cats were killed 6 hours after coronary occlusion. In five dilevalol cats the times to arrhythmia and death were 2.2 +/- 0.8 (N = 5) and 75.9 +/- 70.7 (N = 4); 1 cat was killed. Dilevalol induced a significant decrease in blood pressure and heart rate prior to coronary occlusion. Coronary occlusion decreased blood pressure and heart rate in both groups. Twenty-five minutes after dilevalol but prior to coronary occlusion, postganglionic cardiac sympathetic neural discharge decreased to 81%. In the minutes prior to arrhythmia, postganglionic cardiac sympathetic neural discharge was 95% and was significantly increased to 121% 3 minutes after coronary occlusion. The postganglionic cardiac sympathetic neural discharge values after coronary occlusion were similar to those in the saline cats. Dilevalol depressed postganglionic cardiac sympathetic neural discharge prior to coronary occlusion but did not prevent the nonuniform (i.e., increases, decreases, or no change) discharge in the postganglionic cardiac sympathetic neural discharge associated with coronary occlusion-induced arrhythmia. Norepinephrine and epinephrine values in saline cats increased the first 5 minutes after coronary occlusion; this increase was associated with arrhythmia. Norepinephrine and epinephrine values from minute 15 to minute 360 did not differ from control. Dilevalol prevented the increase in norepinephrine and epinephrine levels associated with arrhythmia and death.

beta-Adrenergic blockade after single, oral doses of labetalol or propranolol was evaluated in a double-blind, placebo-controlled study by an isoproterenol sensitivity test and handgrip exercise in 10 healthy men. The tests were performed with subjects resting in a supine position. At the doses used, there was no effect on heart rate and blood pressure in either the resting position or in the isometric exercise phase. It is possible that exercise-induced changes in blood pressure and heart rate were reduced by higher vagal tone in this young group tested in the supine position. Isoproterenol increased heart rate and reduced diastolic blood pressure in a dose-dependent manner. The dose of isoproterenol at which heart rate increased 25 bpm above the resting rate (CD25; 1.36 +/- 0.18 microgram) was of the order of that at which diastolic blood pressure fell 25 mm Hg from baseline (HD25; 1.07 +/- 0.07 microgram). There was a significant positive correlation between CD25 and HD25 in the 10 subjects. Propranolol and labetalol induced a dose-dependent, parallel shift to the right in the dose-response curves of isoproterenol effects on heart rate and diastolic blood pressure, indicating that both drugs are nonselective, competitive antagonists of beta-adrenergic receptors. On the average, propranolol was 17 and 19 times more potent than labetalol in antagonizing the chronotropic and hypotensive actions of isoproterenol, respectively.

1. AH 5158, 5-(1-hydroxy-2-((1-methyl-3-phenylpropyl)amino)ethyl)salicylamide, competitively antagonised phenylephrine-induced vasopressor responses in anaesthetized dogs, thus confirming that the drug possesses alpha-adrenoceptor blocking activity. 2. In contrast, AH 5158 was a relatively ineffective antagonist of vasopressor responses to noradrenaline in anesthetized dogs. Thus, at the lowest dose-level tested (1 mg/kg) AH 5158 abolished the increase in pulse width caused by noradrenaline, but otherwise had little or no blocking effect in doses as high as 10 mg/kg. Propranolol (0.1 mg/kg) also abolished the increase in pulse width caused by noradrenaline. With both drugs this effect is thought to be a consequence of blockade of the beta-adrenoceptor-mediated cardia stimulant action of noradrenaline. 3. The interaction between AH 5158 and noradrenaline in spinal dogs, anaesthetized cats and pithed rats was very similar to that seen in anaesthetized dogs. 4. Noradrenaline pressor responses were effectively antagonized by AH 5158 in anaesthetized dogs pretreated with cocaine. The degree of block was similar to that obtained when phenylephrine was the agonist in untreated dogs. 5. These results are consistent with the hypothesis that AH 5158 blocks a cocaine-sensitive inactivation process for noradrenaline in addition to blocking alpha- and beta-adrenoceptors. The resultant increase in the level of circulating noradrenaline would tend to counteract the adrenoceptor blocking action of the drug. 6. The implications of these findings are discussed.

At rest supine acute intravenous administration of the combined adrenergic alpha- and beta-receptor blocking compound labetalol (1 mg/kg body weight) to young, healthy, male subjects, produced a clear-cut fall in arterial blood pressure. During dynamic forearm exercise, forearm blood flow decreased by 17.2%, and calculated vascular resistance increased by 11.3% after labetalol. Forearm oxygen uptake decreased (14.6%), suggesting an increased mechanical efficiency. Lactate release from the exercising forearm decreased (17.6%), probably because of the beta-receptor blockade. Forearm uptake of glucose and free fatty acids remained unchanged. Arterial blood glucose concentration attained a higher level after labetalol. Arterial plasma concentration of FFA was reduced during exercise and post-exercise probably because beta-receptor mediated lipolysis was antagonized.

Because of results in animal experiments which demonstrated a partial beta 2-adrenoceptor activity of labetalol on rat uterine smooth muscle the present study was conducted in human preparations. The following results were obtained: 1. Rhythmic uterine contractions with a defined steady-state amplitude and frequency were elicited spontaneously and after methylergometrine. 2. Labetalol reduced amplitude of contractions dose-dependently after 3 h of incubation. Frequency was unaffected. 3. The tocolytic effect of labetalol is apparent only at high concentrations, above those used in the treatment of hypertension. 4. Neither beta 2-specific adrenoceptor blockade with ICI 118,551 nor alpha-blockade with phentolamine changed amplitude of contraction, either alone or in combination with labetalol. 5. Labetalol has little tocolytic effect on human myometrium in vitro. This effect is unrelated to alpha- or beta-antagonism, but seems to depend on a direct smooth muscle depressant effect. In conclusion, from the present in vitro experiments using human myometrial preparations, it seems unlikely that labetalol would interfere with the normal process of labor when used for the treatment of pregnancy hypertension.

The pharmacokinetics and pharmacodynamics of dilevalol, the R,R stereoisomer of labetalol, were evaluated in nine subjects. Dilevalol was given as a single 50 mg intravenous dose and as a 400 mg daily oral dose for 7 days. To study the effects of hepatic enzyme inhibition, each subject received dilevalol in the presence of and absence of cimetidine. Cardiac beta-blockade was assessed by use of standardized treadmill tests for 48 hours after oral dilevalol. The three-compartment model analysis showed that systemic clearance (29.8 +/- 5.7 ml/min/kg), volume of distribution (16.6 +/- 4.1 L/kg), and terminal half-life (11.7 +/- 2.7 hours) were not altered by cimetidine. However, there was a 20% increase in the area under the curve (p less than 0.05) and an 11% increase in systemic bioavailability (p less than 0.05) after oral administration. Dilevalol caused significant cardiac beta-blockade for more than 24 hours, but these effects were not altered by cimetidine. The pharmacokinetic changes are consistent with a decrease in first-pass extraction of a high clearance drug.

Twenty young (45 years or younger) and 20 older (55 years or older) adult patients with mild hypertension were enrolled in this study to compare the hemodynamic effects of labetalol versus placebo in two age groups. Ten patients in each group were randomly assigned to receive either a single oral dose of labetalol (200 mg) or placebo. Hemodynamic parameters were recorded immediately before and two hours after ingestion. Labetalol was more effective than placebo in significantly lowering systolic blood pressure (-11 versus + 5 mm Hg, -23 versus + 4 mm Hg), diastolic blood pressure (-9 versus + 2 mm Hg, -12 versus + 5 mm Hg), and total systemic resistance (-259 versus + 42 dynes-sec cm-5, -390 versus + 74 dynes-sec cm-5) in young and older hypertensive subjects, respectively. There was no significant changes in heart rate, stroke volume index, or cardiac index in either age group. These data indicate that labetalol lowers blood pressure in young an older hypertensives primarily by reducing peripheral resistance and that the antihypertensive effect may be somewhat greater in older patients.

The effects of prazosin, labetalol, and medroxalol were studied in the rabbit sino-atrial node, Purkinje cells and papillary muscles. At concentrations producing similar bradycardia, labetalol and medroxalol reduced the maximum rate of depolarization (Vmax) and overshoot potential in the sinus node. Prazosin had no such effects. These large and highly significant reductions in Vmax and overshoot in sinus node cells were observed at concentrations of medroxalol and labetalol which had no negative inotropic effect. If depolarization in the sinus node was due to the second inward current, this would imply that such currents in the sinus node and contracting cardiac muscle are pharmacologically distinct. All three drugs prolonged action potential duration in the sinus node, Purkinje cells and papillary muscles in a dose-related manner. Recovery after 1 h in drug-free solution from the effects of medroxalol and labetalol was only partial in the sinus node, but almost complete in Purkinje cells and papillary muscle. Recovery from prazosin was complete in all tissues. All three drugs depressed Vmax in Purkinje cells and papillary muscles in a dose-related manner, and recovery was complete. It is concluded that all three drugs had class 1 and class 3 antiarrhythmic actions, which could contribute to their protective effects in ischaemia and reperfusion independently of blockade of myocardial alpha-adrenoceptors.

1 The antagonist potencies of labetalol and each of its four stereoisomers have been compared at alpha 1-, beta 1- and beta 2-adrenoceptors in anaesthetized dogs and in isolated tissues. 2 The RR stereoisomer is a potent, non-selective antagonist at beta-adrenoceptors but has only weak alpha 1-adrenoceptor blocking activity. 3 The SR stereoisomer was the most potent antagonist at alpha 1-adrenoceptors, and it also had similar potency as an antagonist at beta-adrenoceptors. 4 The alpha- and beta-adrenoceptor blocking profile of the RS stereoisomer is intermediate between that of the RR and SR, but the SS stereoisomer is a relatively weak antagonist at both alpha- and beta-adrenoceptors. 5 It is concluded that, although most of the alpha 1-adrenoceptor blocking activity of labetalol is attributable to the SR stereoisomer and nearly all of its beta-adrenoceptor blocking activity resides in the RR stereoisomer, each of the stereoisomers contributes to the overall pharmacological profile of labetalol.

The mechanism of the vasodilatory action of carvedilol (BM 14190), a new antihypertensive agent, was investigated in normal volunteers. Intra-arterial blood pressure and ECG were monitored continuously. Carvedilol (1 mg/min for 15 minutes) produced a rapid reduction in blood pressure and a transient increase in heart rate. At the end of infusion, systolic and diastolic blood pressure were reduced by 23% (-32.3 mm Hg) and 18% (-13.6 mm Hg), respectively, whereas heart rate was not different from baseline. At the doses used, the hypotensive effect of carvedilol was greater than that of labetalol (36 and 72 mg in 15 minutes). Carvedilol and labetalol antagonized isoproterenol-induced hypotension and tachycardia, at serum levels greater than or equal to 8 and 20 mg/ml, respectively. Both drugs antagonized phenylephrine pressor effects. A similar degree of inhibition (25% of control) of pressor effects was observed for carvedilol and labetalol when their respective serum concentrations were 23 ng/ml and 80 ng/ml. Neither carvedilol nor labetalol had any effect on AII pressor responses. Carvedilol serum levels as high as 150 ng/ml failed to inhibit AII-induced pressor responses. Our results suggest that at the doses used in this study, carvedilol has both alpha 1-and nonselective beta-receptor blocking properties. Moreover, carvedilol is approximately three to five times more potent than labetalol in blocking alpha 1-and beta-receptors and in reducing blood pressure.

1. The competitive alpha- and beta-adrenoceptor blocking agent labetalol, in concentrations up to 10(-4) M, produced dose-dependent increases in transmitter overflow from the isolated blood perfused spleen of the cat following nerve stimulation at 10 and 30 Hz. 2. At concentrations above 10(-4) M labetol produced a pronounced decrease in transmitter overflow. 3. Labetalol (1.5 X 10(-4) M) increased the recovery of 3H label in the venous blood following the close-arterial infusion of [3H]-(-)-noradrenaline indicating that the drug inhibits uptake of the amine. 4. Both labetalol (3.8 X 10(-5) M) and piperoxan (7.4 X 10(-6) M) produced parallel shifts to the right of the dose-response curves to noradrenaline and oxymetazoline in isolated strips of cat splenic capsule. In this preparation both drugs acted as competitive postsynaptic alpha-adrenoceptor blocking agents. 5. Labetalol (3.3 X 10(-5) M) increased the transmitter overflow following stimulation of the splenic nerves with 200 impulses at 10 Hz. The overflow could be further increased by subsequent addition of piperoxan (7.2 X 10(-6 M). Piperoxan (5.7 X 10(-6) M) alone produced a marked increase in transmitter overflow which could be further increased by subsequent addition of desmethylimipramine (DMI; 3.2 X 10(-5) M). Cocaine (1.5 X 10(-5) M) or DMI (5.4 X 10(-5 M) produced a small increase in transmitter overflow which was not further increased by addition of labetalol (2.8 X 10(-5) M). 6. Labetalol produced a biphasic effect on the responses of the isolated blood perfused spleen of the cat to nerve stimulation. With low doses (up to 10(-4) M) vascular responses were potentiated and with high doses (greater than 10(-4) M) inhibited. The potentiation was related to uptake blockade and the inhibition to decreased transmitter overflow and postsynaptic alpha-adrenoceptor blockade. 7. Labetalol appears to act as a postsynaptic alpha-adrenoceptor antagonist in the isolated blood perfused spleen of the cat with little effect on presynaptic alpha-adrenoceptors. The moderate elevation of transmitter overflow by the drug is related to the inhibitory effect of the drug on neuronal uptake rather than on presynaptic alpha-adrenoceptors.

Renal function studies were performed in subjects with mild hypertension treated with labetalol (n = 5) and moderate to moderately severe hypertension treated in a random double-blind fashion with either labetalol (n = 6) or methyldopa (n = 6). Drugs were given in doses sufficient to reduce standing diastolic blood pressure to less than 90 mm Hg. This was achieved in all subjects without significant side effects. Inulin clearance, para-aminohippurate clearance, filtration fraction, free-water clearance, and maximal concentrating ability was assessed before and after 15 days of drug. No alterations in any parameter were noted with labetalol. Inulin clearance fell by 13% (p less than 0.05), and filtration fraction fell from 0.23 to 0.18 (p less than 0.02), but other parameters of renal function did not change with methyldopa.

The effect of labetalol on histamine-induced bronchoconstriction was studied in anaesthetized guinea-pigs. Unlike propranolol (1 mg kg-1), the same dose of labetalol did not enhance histamine-induced bronchoconstriction. To determine whether the absence of enhancement of the respiratory effects of histamine by labetalol was due to its alpha 1-blocking properties or to its partial agonist activity at beta 2-adrenoceptors, the effects of propranolol plus prazosin and of propranolol plus labetalol on histamine-induced bronchoconstriction were examined. In both cases, the bronchoconstrictor effects of histamine were enhanced to the same extent as with propranolol alone. These data support the hypothesis that the non impairment of respiratory mechanics by labetalol is not due to antagonism at alpha-adrenoceptors and may be mediated by its partial agonist activity at beta 2-adrenoceptors.

Dilevalol is the R-R' optical isomer of labetalol and differs pharmacologically from the racemic mixture in the following ways: it is seven-fold more potent as a selective beta-2 agonist; it is four times more potent as a nonselective beta antagonist; it has no clinically significant alpha antagonist property. Dilevalol is a vasodilator and reduces blood pressure by reducing systemic vascular resistance. It has a half-life of 15-18 hours, and is demonstrated to be effective as an antihypertensive agent for 24-30 hours. Hemodynamic studies in humans show that following administration of dilevalol either orally or intravenously, blood pressure falls as a consequence of a decrease in systemic vascular resistance. Cardiac index is unchanged and heart rate decreases slightly. Dilevalol is shown to cause regression of left ventricular hypertrophy in younger individuals, to improve left ventricular performance and to have no effect on parameters of renal function. Prospective double-blinded clinical trials in comparison with placebo, propranolol, metoprolol and atenolol were conducted and demonstrate dilevalol to be an effective antihypertensive agent with a favorable side effect profile with a particularly low incidence of central nervous system side effects.

The effects of labetalol, diltiazem and verapamil on antipyrine and indocyanine green clearance were evaluated in a placebo-controlled, repeated measures evaluation. Twelve healthy subjects received either labetalol (200 mg every 12 hours), diltiazem (90 mg. every 8 hours), verapamil (80 mg every 8 hours), or placebo (every 12 hours) for 4 days. On the morning of Day 3 immediately following their dose, the subjects assumed the supine position for 90 minutes, after which time a 0.5 mg/kg dose of indocyanine green was administered. Blood samples were obtained serially over a 20 minutes period for indocyanine green plasma concentration determinations by HPLC. Ten minutes later, subjects ingested a 1.2 Gm. dose of antipyrine and blood samples were obtained over a 48 hour period for antipyrine plasma concentration determinations by HPLC. A 2 week washout period separated treatment sequences. Mean (SD) antipyrine clearance (L/hr/kg) following diltiazem [0.028 (0.010)] and verapamil [0.030 (0.012)] treatment was significantly lower than that observed following placebo [0.039 (0.012)]. Antipyrine clearance following labetalol administration [0.033 (0.010)] was not significantly different from that observed following placebo, diltiazem or verapamil administration. No effects of these drugs on indocyanine green clearance could be detected.

Changes in mean arterial pressure (MAP), heart rate (HR), and plasma concentrations of norepinephrine (NE) and epinephrine were measured in eight hypertensive patients in a supine position after stepwise infusion of incremental sodium nitroprusside doses and intravenous injection of cumulative labetalol doses. Both drugs induced rises in plasma NE concentration that were linearly related to reductions in MAP. For any reduction in blood pressure (BP), however, the rise in plasma NE concentration induced by labetalol was approximately four times that induced by sodium nitroprusside. The difference can be explained by two effects of labetalol: impairment of neuronal NE uptake and beta-adrenergic-receptor blockade, which are known to reduce NE clearance from plasma. After both drugs there was a correlation between changes in HR and changes in BP and a correlation between changes in HR and changes in plasma NE concentration. Slopes of the regression lines for both relationships were less after labetalol than after sodium nitroprusside, presumably because of the beta-adrenergic-blocking properties of labetalol. Multiple-regression analysis indicated that the plasma NE rise was an important determinant of the vasodepressor response to each drug. The greater plasma NE elevation after labetalol may limit its antihypertensive effect.

1. Using conventional microelectrode techniques for the intracellular recordings of the membrane potential, the effects of labetalol were studied on cardiac Purkinje, atrial and ventricular muscle fibres of the dog. 2. Labetalol (1-10 microM) reduced, in a concentration-dependent manner, the action potential amplitude (APA) and the maximum rate of rise of the action potential (Vmax) in Purkinje fibres. 3. The action potential duration (APD) was decreased in Purkinje fibres but significantly increased in ventricular fibres after small concentrations of labetalol (1-3 microM). The atrial fibres were not very sensitive to labetalol. 4. Depolarization of the cardiac Purkinje fibres by increasing the external potassium concentration (8-12 mM), potentiated the labetalol effects on APA and Vmax but blocked its effects on the APD. 5. The effects of labetalol on Vmax of Purkinje fibres were dependent on the frequency of stimulation. 6. The ratio of the effective refractory period to the APD was increased both in normally polarized and depolarized Purkinje fibres after treatment with labetalol (10 microM). 7. Labetalol (10 microM) shifted the membrane responsiveness curve of Purkinje fibres by about 10 mV in the hyperpolarizing direction. 8. The slow response obtained in K-depolarized, Ba-treated Purkinje fibres was not significantly affected by labetalol (10-100 microM). 9. It is suggested that labetalol can exert Class I and Class III antiarrhythmic actions in cardiac muscle of the dog in vitro.

1 Labetalol (AH 5158A) inhibited the adrenaline-stimulated adenylate cyclase activity of rat liver and heart. This drug had no effect on basal or guanosine triphosphate (GTP)-activated adenylate cyclase activities. 2 Labetalol displaced the binding of the specific ligands [3H]-dihydroergocryptine and (-)-[3H]-dihydroalprenolol from their respective alpha and beta-adrenoceptors in rat heart and liver. The affinity of labetalol was 10 fold higher for the beta- than for the alpha-adrenoceptor. It appeared to be 10 to 100 times less potent than phentolamine in blocking alpha-adrenoceptors and 5 to 10 times less potent than propranolol in blocking beta-receptors. 3 It is concluded that labetalol exerts its dual alpha- and beta-antagonism by acting directly on the plasma membranes, where it binds competitively to alpha- and beta-adrenoceptors.

A single oral dose of 300 mg labetalol was given to 10 subjects with uncomplicated primary hypertension; its effects on blood pressure, heart rate (HR), plasma renin activity (PRA), and plasma concentration of catecholamines and of their major metabolites, octopamine ( OTP ), and dopamine-beta hydroxylase (DbH) were investigated. Although HR did not change after dosing, both systolic and diastolic blood pressure decreased in 2 hr and remained below control up to 12 hr. There was symptomatic orthostatic hypotension in two subjects in the first 2 hr after dosing. PRA decreased in the first 2 hr and followed a gradual rise that became significant at 24 hr. Although DbH did not change, plasma concentrations of norepinephrine (NE) and its major metabolites and of OTP increased between 2 and 4 hr after dosing and remained elevated up to 12 hr. There was no correlation between change in blood pressure and control levels or changes of PRA or NE concentrations.

Labetalol inhibits alpha- and beta-adrenergic receptors. Systemic and regional hemodynamic alterations after intravenous labetalol and its cardiovascular reflexive and metabolic effects were evaluated in 12 subjects with mild to moderately severe essential hypertension. Supine systolic, diastolic, and mean pressures were reduced (from 180/101 and 125 to 149/86 and 109 mm Hg; P less than 0.001). The fall was accentuated during head-up tilt and was accompanied by decreased cardiac output and central blood volume in subjects in both the supine and tilted positions. Neither heart rate nor total peripheral resistance was changed by labetalol, suggesting that venodilation resulting from alpha-adrenergic-receptor inhibition played an important role in arterial pressure reduction.

The effectiveness, safety, and pharmacodynamics of repeated doses of intravenous labetalol for rapid reduction of severe hypertension and of subsequent oral labetalol dosing were studied. Twelve patients with severe hypertension were admitted to the hospital after the withholding of antihypertensive therapy for 2 to 14 days. Thirty minutes after an injection of vehicle only, labetalol, 0.25 mg/kg body weight, was injected and followed by repeat injections of 0.5 mg/kg every 15 minutes until the supine diastolic blood pressure (BP) was reduced to less than 90 mm Hg or a total of 3.25 mg/kg had been administered. Twenty-four hours after the last injection, oral labetalol was started at an initial dosage of 100 or 200 mg b.i.d., then increased every 2 days until the standing diastolic BP was less than 90 mm Hg or a maximum daily dosage of 2400 mg was reached. The initial injection achieved mean falls in supine systolic/diastolic BPs of 11/7 mm Hg. Subsequent injections produced additional falls in a dose-related fashion; the mean falls after the last injection (total cumulative dose 2.7 mg/kg) were 40/20 mm Hg. The effect lasted for 12 hours or more in most patients and tended to be biphasic, with one peak at approximately 5 minutes and another much less pronounced peak at about 4 hours. There was no evidence of precipitous falls in BP. All patients were able to ambulate 6 hours after the last injection without symptoms of postural hypotension. Oral labetalol effectively and safely restored and maintained the BP reductions achieved with intravenous labetalol.

1 The effects of the combined alpha- and beta-adrenoceptor blocking drug, labetalol, on the uptake of [3H]-(-)-noradrenaline into the isolated vas deferens of the rat have been determined and compared with those of some other alpha-adrenoceptor blocking drugs and cocaine. 2 Labetalol, like cocaine, produced a simple competitive inhibition of [3H]-(-)-noradrenaline uptake and was about 4 times less potent than cocaine. It is concluded that labetalol is a potent inhibitor of uptake1. Phentolamine and thymoxamine also inhibited [3H]-(-)-noradrenaline uptake, and were respectively 8 and 14 times less potent than cocaine. Tolazoline, piperoxan and yohimbine were inactive in concentrations up to 30 microgram/ml. 3 The uptake1 blocking action of labetalol could explain, at least in part, the previously reported difference in its ability to block noradrenaline and phenylephrine vasopressor responses in the anaesthetized dog. 4 The possibility that uptake1 inhibitory concentrations of labetalol could be present in the blood of subjects receiving normal antihypertensive doses of the drug is discussed.

1 The effects of several doses of labetalol (0.03 to 1 mg/kg) given intravenously and into the vertebral artery were examined in anaesthetized dogs. Labetalol produced to immediate (5 min) change in blood pressure or heart rate when given by either route, with one exception. Heart rate increased after the first dose (0.03 mg/kg i.v.) of labetalol. By contrast, clonidine (1 micrograms/kg) elicited an immediate and prolonged fall in blood pressure and heart rate when given into the vertebral artery, but not intravenously. 2 In the isolated perfused gracilis muscle of the dog, following alpha- and beta-adrenoceptor blockade, intra-arterial injections of labetalol (0.3 to 10 mg) or diazoxide (0.3 to 1 mg) produced decreases in perfusion pressure that were dose-related in both magnitude and duration. The doses of labetalol and diazoxide required to produce a half-maximal vasodilatation were 1.5 mg and 0.7 mg respectively. 3 In adrenalectomized, vagotomized spinal dogs, both labetalol (0.1 to 1 mg/kg i.v.) and hydralazine (1 mg/kg i.v.) elicited a fall in blood pressure without changing heart rate or cardiac output. 4. These results suggest that the hypotension produced by systemically administered labetalol does not involve an action in the brain. It may involve instead a direct vasodilatation of resistance blood vessels, since labetalol in sufficient amounts, directly dilates resistance vessels and lowers blood pressure in dogs devoid of adrenergic tone. Direct vasodilatation may be a component of the hypotensive action of labetalol.

The hypotensive effect of short-term labetalol, the alpha- and beta-adrenoceptor blocker, is greater in subjects in the orthostatic position, possibly because of the alpha-adrenoceptor blockade. During prolonged use the orthostatic blood pressure fall disappears. To verify whether or not this is due to reduction in alpha-blocking activity, phenylephrine-induced increase in blood pressure was studied in six subjects with mild essential hypertension before and after 3 and 6 days and 1 and 6 mo of continuous treatment with 200 mg labetalol three times a day by mouth. At the same intervals, isoproterenol-induced tachycardia was followed to assess beta-blockade. After 3 days on labetalol, the log dose-response curve of phenylephrine-induced increase in blood pressure shifted to the right and the dose of agonist required to elicit a 20% increase in systolic pressure was 1.7 times that before treatment. There was a progressive decline in the dose of agonist that induced the same increase in pressure so that after 6 mo of continuous labetalol it was the same as control. In contrast, the amount of isoproterenol needed to induce a 20% increase in heart rate was two to three times that before labetalol and did not change throughout 6 mo of therapy. These data indicate a decline in the alpha-adrenoceptor-blocking effect of oral labetalol without concomitant change in the degree of beta-adrenoceptor blockade. This might account for the disappearance of orthostatic hypotension early in the course of treatment and for some decrease in the antihypertensive efficacy of labetalol.

To evaluate the role of beta-adrenoceptor blockade on lower limb circulation in patients with peripheral arterial disease, heart rate, blood pressure, calf blood flow and vascular resistance were measured at rest and during reactive hyperemia in seven patients with hypertension and intermittent claudication. The study was performed as a placebo-controlled, double-blind, crossover trial of 10 days with doses of propranolol, 80 mg twice a day, pindolol, 5 mg twice a day, labetalol, 200 mg twice a day, and labetalol, 400 mg twice a day as active drug. Heart rate was lowest during propranolol dosing and blood pressure was lowest during labetalol dosing irrespective of the labetalol dose used. The degree of peripheral arterial disease modulated the effect of beta-blockade on limb circulation. In the less symptomatic limbs, reactive hyperemic flow was greater after pindolol than after the other drugs and did not differ from the level recorded after placebo. These differences were inconsistent and small in the more symptomatic limbs. Thus as the peripheral arterial disease became more severe and extensive, beta-blockade, irrespective of its type, lost its hemodynamic effect on lower limb circulation.

Isoprenaline produced dose-dependent reductions of responses of the isolated uterus of the rat produced by an EC(80) of acetylcholine. Propranolol acted as a competitive antagonist to isoprenaline. Labetolol also reduced the acetylcholine-induced contractions but was much less potent than isoprenaline. The greatest reduction was smaller than that produced by isoprenaline. Propranolol antagonized the lower doses of labetolol. It is suggested that labetolol possesses partial agonist activity at the beta-adrenoceptors of the rat isolated uterus.

Cardiac electrophysiologic effects of a single oral dose of labetalol were determined in seven patients 4 to 9 days after a coronary artery bypass graft. Surface ECG and bipolar electrograms recorded from temporary pacing wires affixed to the normal right ventricle and abnormal left ventricle at the time of surgery were used to determine conduction intervals. Electrophysiologic parameters were recorded during fixed-rate atrial pacing. Sinus heart rate and blood pressure were monitored. Three patients received 100 mg and four patients received 200 mg labetalol. The drug had no significant effect on intraventricular conduction intervals or QRS duration. It did not significantly influence sinus heart rate or AV conduction time, but in two patients there was prolongation in AV conduction that may have been drug-induced. Labetalol induced a modest but significant decrease in systolic and diastolic blood pressure. In another study propranolol, unlike labetalol, had prolonged AV and intraventricular conduction in the abnormal left ventricle, but not in the normal right ventricle. The absence of these effects with labetalol may reflect lesser local anesthetic effect on intraventricular conduction and an alpha-adrenergic blocking effect that interferes with beta-blockade-induced prolongation of AV conduction.

Labetalol reduces blood pressure in normotensive and hypertensive subjects. The effects of a therapeutic dose of intravenous labetalol upon the cardiovascular responses to intravenous isoproterenol and norepinephrine in 6 normotensive subjects were studied in order to investigate the drug's mode of action. Before labetalol, intravenous isoproterenol increased heart rate and reduced diastolic blood pressure in a dose-dependant manner; likewise, intravenous norepinephrine increased both systolic and diastolic pressure. The order of administration of these agonists was randomized between the subjects before and after labetalol. Following labetalol (1.5 mg/kg intravenously) the effects of isoproterenol were antagonized such that cumulative log-dose response curves of mean isoproterenol-induced increases in heart rate and reductions in diastolic pressure were shifted to the right in a parallel manner to approximately the same extent. At the same time, the mean norepinephrine-induced increases in systolic and diastolic blood pressure were also antagonized in a competitive manner. These responses were compared with others in the same subjects under the same conditions and it was concluded that the antihypertensive effect of labetalol is explained by concurrent blockade of alpha-and beta-adrenoceptors.

Dilevalol (50 mg) was given orally twice daily for eight days in six healthy subjects. All parameters were obtained following 1st (on day 1) and 15th (on day 8) dosages. Blood samples for plasma drug concentrations were taken for a 12-hour (after 1st dosage) or a 24-hour (after 15th dosage) post-drug period. Blood pressure (BP) as well as heart rate (HR) at supine position, during 50 degrees tilting and during a submaximal exercise were measured after each dosage. The mean time to maximum concentration (tmax) was faster, and the mean area under the plasma concentration-time curve (AUC) was greater after 15th dosage than following 1st dosage. No significant differences were observed in the maximum plasma concentration (Cmax), the distribution half-life (t 1/2 alpha) or the elimination half-life (t 1/2 beta) between the two dosages. BP at supine position as well as during 50 degrees tilting decreased significantly after each dosage, and did not differ between 1st and 15th dosages. Postural changes in BP or HR during 50 degrees tilting were not induced following 1st or 15th dosage. The suppressing effects (%R) on an increase in HR during a submaximal exercise were significantly larger after 15th dosage than after 1st dosage. A significant correlation was observed between plasma dilevalol concentration and %R in HR. These data indicate that the hypotensive effect of dilevalol is not altered during the repeated administration of the drug for 8 days. However, the beta-blocking activity of dilevalol might be enhanced during the repeated dosages, which is, in part, attributed to dosage-dependent elevation in plasma drug concentrations.

(1) When incremental infusions of drugs that increase blood pressure are given to human subjects to assess "pressor responsiveness," only the lower part of the sigmoid dose-response curve can be obtained. (2) Fitting a quadratic function does not involve discarding data points, which is usually the case with a linear fit, and it provides a more satisfactory fit to the lower part of a sigmoid dose-response curve. (3) In the presence of a competitive antagonist, a pressor dose-response curve will be shifted to the right. In this situation the dose-response curves obtained before and after treatment with antagonist should be fitted simultaneously to a quadratic model in which the parallel shift is one of the parameters. (4) The use of quadratic fitting is illustrated by reference to clinical experiments to obtain the following three curves for drugs that modify peripheral alpha adrenoceptors: norepinephrine pressor response curves after placebo and doxazosin, an alpha 1 antagonist; norepinephrine pressor response curves after placebo, labetalol, and medroxalol (drugs with combined alpha 1 and beta blocking properties); and phenylephrine pressor response curves before and after prazosin. (5) Fitting a quadratic function is the appropriate initial step in the analysis of pressor dose-response curves in man.

Dilevalol (25 mg----50 mg----100 mg) or labetalol (100 mg) was given orally in six healthy subjects. The study was carried out on four occasions with a week interval. Blood samples for plasma drug concentrations were taken for a 24-hour post-drug period. Blood pressure (BP) as well as heart rate (HR) at supine position, during 50 degrees tilting and during a submaximal exercise were measured after each treatment. The mean maximum plasma concentration (Cmax) as well as the mean area under the plasma concentration-time curve (AUC) increased in a dose-dependent manner after dilevalol. These parameters after dilevalol 100 mg were significantly lower than after labetalol 100 mg. No significant differences were observed in the time to maximum concentration (tmax), the distribution half-life (t1/2 alpha) or the elimination half-life (t1/2 beta) between dilevalol and labetalol. There were no significant differences in BP at supine position or during 50 degrees tilting among the dosages. Postural changes in HR during 50 degrees tilting was significantly smaller after dilevalol 100 mg than following labetalol 100 mg. The suppressing effect of dilevalol 100 mg on an increase in HR during a submaximal exercise was significantly greater than during labetalol 100 mg. These data indicate that although plasma drug concentrations are lower after dilevalol than following labetalol, the beta-blocking activity of dilevalol is more potent than labetalol.