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At least 19 recordsLinked to original sources
PubMed1985

Comparison of the effects of labetalol and SCH 19927, the R1R isomer of labetalol, on the rat isolated right ventricle and aorta.

The effects of labetalol and its R1R isomer, SCH 19927, on the accumulation of radioactivity from [3H]-noradrenaline, and on the subsequent spontaneous and nerve-evoked outflow of radioactivity have been investigated in the rat isolated right ventricle. In addition, the effect of these agents on the contractions of the electrically-driven rat right ventricle to isoprenaline and of the rat isolated aorta to phenylephrine and 5-hydroxytryptamine are reported. Labetalol and SCH 19927 (both at 10(-6)M) inhibited the accumulation of radioactivity from [3H]-noradrenaline by 26 and 37%, respectively. The spontaneous outflow of radioactivity, following loading of the ventricle with [3H]-noradrenaline, was increased by labetalol and SCH 19927 (both at 10(-6)M) by a cocaine and idazoxan-insensitive mechanism. The nerve-evoked outflow of radioactivity was increased by labetalol and SCH 19927 (both at 10(-6)M). The ability of labetalol and SCH 19927, to increase nerve-evoked outflow was maintained in the presence of cocaine (10(-5)M) or idazoxan (10(-7)M) but reversed in the presence of cocaine and idazoxan. It is suggested that labetalol and its R1R isomer act both to inhibit neuronal uptake of noradrenaline and as antagonists at prejunctional alpha 2-adrenoreceptors. Labetalol and SCH 19927 reduced the contractile responses associated with the nerve-evoked outflow of radioactivity probably mainly by acting as antagonists at postjunctional beta 1-adrenoreceptors. The contractile responses of the electrically-driven rat right ventricle to isoprenaline were inhibited by labetalol and SCH 19927. SCH 12297 (pA2 = 8.9) was 4 times more potent than labetalol (pA2 = 8.3) as a beta 1-adrenoreceptor antagonist. The ability of labetalol and SCH 19927 at greater than or equal to 10(-7)M to depress maximal responses to isoprenaline may represent membrane stabilizing activity. The contractile responses of rat aorta to phenylephrine were inhibited by labetalol and SCH 19927. Labetalol (pA2 = 7.5) was 4X more potent than SCH 19927 (pA2 = 6.9) as an alpha 1-adrenoreceptor antagonist. SCH 19927 and labetalol had no effect on contractile responses to 5-hydroxytryptamine.

Animals↗
PubMed1985

Pharmacodynamics of intravenous labetalol and follow-up therapy with oral labetalol.

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.

Administration, Oral↗
PubMed1983

Treatment of hypertension with labetalol in neurosurgical practice. Influence of labetalol on cerebral perfusion pressure in dogs without and with intracranial mass lesions.

In neurosurgical patients autoregulation of cerebral perfusion is often lost. Therefore, a sudden increase in blood pressure may lead to an increase in cerebral blood flow and cerebral oedema may follow. The influence of labetalol, a new alpha- and beta-adrenoceptor blocking agent, on intracranial pressure and cerebral perfusion pressure was investigated in dogs without and with mass lesions. During hypotension with labetalol the intracranial pressure remained unchanged and the cerebral perfusion pressure decreased to the same extent as mean arterial pressure (30%). Labetalol seems to be suitable to treat hypertension perioperatively in neurosurgical patients but it is not a suitable drug for induced hypotension.

Animals↗
PubMed1979

Labetalol in controlled hypotension: administration of labetalol when adequate hypotension is difficult to achieve.

A study of controlled hypotension was undertaken in 50 major surgical patients using labetalol, a drug with both alpha- and beta-adrenoceptor blocking activity. The patients were such that difficulty in achieving controlled hypotension could be anticipated: the young, the anxious and those for whom halothane was contraindicated. The administration of labetalol quickly induced hypotension which was controlled easily and was rapidly antagonized.

Adolescent↗
PubMedDate not supplied

Glucuronidation of labetalol at the two hydroxy positions by bovine liver microsomes. Isolation, purification, and structure elucidation of the glucuronides of labetalol.

Glucuronidation is known to be a major metabolic pathway for labetalol. As the drug contains a phenolic and an alcoholic hydroxy group, in principle two regio isomeric glucuronides can be formed. By incubating the substrate labetalol with bovine liver microsomes, in the presence of the co-substrate UDP-glucuronic acid, both hydroxy positions were glucuronidated. The different glucuronides were isolated from the incubation mixture using Bond-Elut extraction cartridges and separated by means of high performance liquid chromatography. The formation of glucuronides was confirmed by performing reference incubations using radiolabeled UDP-glucuronic acid. Structure elucidation of the various glucuronides was done by nuclear magnetic resonance, ultraviolet spectroscopy, and mass spectrometry.

Animals↗
PubMed1976

A review of the animal pharmacology of labetalol, a combined alpha- and beta-adrenoceptor-blocking drug.

1 The animal pharmacology of labetalol, a drug that blocks both alpha- and beta-adrenoreceptors, is reviewed. 2 In isolated tissues the blockade by labetalol of both alpha- and beta-adrenoreceptors satisfied accepted critera for competitive antagonism. In contrast phentolamine was a competitive antagonist at alpha-adrenoreceptors only, and propranolol a competitive antagonist at beta-adrenoreceptors only. Labetalol was 6-10 times less potent than phentolamine in blocking alpha-adrenoreceptors and 1.5-3 times less potent than propranolol in blocking beta-adrenoreceptors. Labetalol itself was 4-8 times more potent at beta- than at alpha-adrenoreceptors. 3 In anaesthetized dogs labetalol given intravenously blocked vasopressor responses to phenylephrine positive chronotropic, vasodepressor and bronchodilator response to isoprenaline. Phentolamine blocked the effect of phenylephrine only, and propranolol the effects of isoprenaline only. Labetalol was about 7 times less potent than phentolamine in blocking alpha-adrenoreceptors, about 4 times less potent than propranolol in blocking cardiac beta1-adrenoreceptors, and 11-17 times less potent than propranolol in blocking vascular and bronchial beta2-adrenoceptors. This difference in the relative potency of labetalol arises because propranolol is a slightly more potent antagonist at beta2- than at beta1-adrenoreceptors. Labetaol itself was about 16 times more potent at cardiac beta1- than at vascular alpha-adrenoreceptors. In conscious dogs labetaol given orally blocked vasopressor responses to phenylephrine and positive chonotropic responses to isoprenaline. 4 In anesthetized dogs and pithed rats labetaol blocked alpha- or beta-adrenoreceptor-mediated responses to sympathetic nerve stimulation and intravenously administered phenylephrine or isoprenaline to approximately the same extent. 5 Labetalol does not possess partial agonist (intrinsic sympathomimetic) activity at cardiac beta1-adrenoreceptors. 6 The blocking action of labetalol both in vivo was shown to be specific for alpha- and beta-adrenoreceptors. 7 The haemodynamic effects of labetalol are attributable to its adrenoreceptor-blocking actions. The observed responses vary from one experiment situation to another depending on the balance of autonomic influences. For example, in barbitone-anaesthetized dogs, in which sympathetic tone predominates, both labetalol and propranolol reduced heart rate, contractility, output and work--effects which are attributable to beta-adrenoreceptor blockade. Labetalol differed from propranolol in decreasing rather than increasing total peripheral resistance and in causing larger falls in blood pressure at equipotent beta-adrenoreceptor-blocking doses. These differences are probably attributable to peripheral vasodilatation resulting from the vascular alpha-adrenoreceptor-blocking action of labetalol...

Adrenergic alpha-Antagonists↗
PubMed1990

Labetalol for the control of elevated blood pressure following coronary artery bypass grafting.

In a multicenter study, the efficacy and safety of intravenous (IV) labetalol for the control of elevated blood pressure were studied in the intensive care unit (ICU) in 65 patients within 4 hours following coronary artery bypass grafting (CABG). Patients with pre-existing ventricular dysfunction, bradycardia, bronchospastic disease, or postoperative complications were excluded. All patients were monitored with a thermodilution pulmonary artery catheter. Entry criteria were a systolic blood pressure (SBP) greater than 140 mm Hg or diastolic blood pressure (DBP) greater than 90 mm Hg for at least five minutes. Intravenous labetalol was loaded incrementally (5, 10, 20, and 40 mg at 10-minute intervals) to a maximum cumulative dose of 75 mg, until either SBP decreased 10% or DBP decreased 10% and was less than 90 mm Hg. Responders were entered into a 6-hour maintenance period, and received 5 to 40 mg of IV labetalol every 10 minutes as needed for blood pressure control. Hemodynamic data and temperature were recorded at baseline, just before each dose of labetalol during the loading period, and at the end of the maintenance period. Alternative therapy was given in the case of nonresponse or adverse events. Intravenous labetalol successfully controlled post-CABG hypertension in 55 of 65 patients (85%); of these, 46 responded to 35 mg or less. Although 28 patients required no further labetalol in the maintenance period, in the others dosage varied from 5 to 400 mg. Reductions in SBP and DBP were associated with moderate reductions in pulse pressure (SBP-DBP) and heart rate (HR). Cardiac index decreased by 18.5%, with a 12.5% decrease in stroke index and 8.1% decrease in HR. Systemic vascular resistance did not increase significantly. Four patients (6%) developed hypotension related to IV labetalol. There was one death due to perioperative myocardial infarction, which was unrelated to labetalol use. The mechanism of action of IV labetalol in controlling hypertension after CABG surgery seems to be moderate negative inotropy and chronotropy. Its alpha-blocking effects seem to be important in preventing reflex vasoconstriction. This is directly opposite to the primary vasodilator effect found when IV labetalol is used to control nonsurgical hypertension. Because of these actions, labetalol should be avoided or used with caution in patients with preoperative and postoperative cardiac dysfunction. In patients with normal left ventricular function, IV labetalol appears to be a safe, effective agent in controlling post-CABG hypertension, with the added potential benefit of enhanced myocardial oxygen balance.

Analysis of Variance↗
PubMed2000

Gender differences in labetalol kinetics: importance of determining stereoisomer kinetics for racemic drugs.

STUDY OBJECTIVE: To evaluate the impact of gender on labetalol kinetics. DESIGN: Part of a randomized, crossover study. SETTING: Academic medical center. PATIENTS: Nineteen hypertensive patients (14 men, 5 women; 6 blacks, 13 whites). INTERVENTIONS: Participants had labetalol dosages titrated to a specific antihypertensive response, then underwent ambulatory blood pressure monitoring (ABPM) and a pharmacokinetic study. Labetalol plasma concentrations were measured by high-performance liquid chromatography (HPLC) and labetalol stereoisomer ratios were determined in a single plasma sample by chiral HPLC, both with fluorescence detection. MEASUREMENTS AND MAIN RESULTS: Labetalol concentrations were 80% higher in women (area under the concentration-time curve [AUC]/dose x 1000: 6.79 +/- 2.11 in women vs 3.82 +/- 1.37 hr/L in men, p<0.05), yet both genders had a similar antihypertensive response by 24-hour ABPM. Dose-corrected AUC (AUC/dose x 1000) for labetalol's stereoisomers in women and men, respectively, were S,R-labetalol 7.55 +/- 1.47 and 4.83 +/- 1.54 hr/L (p<0.05), S,S-labetalol 8.23 +/- 2.93 and 4.65 +/- 1.78 hr/L (p<0.05), R,S-labetalol 6.99 +/- 3.30 and 4.25 +/- 2.35 hr/L (p=0.11), and R,R-labetalol 3.91 +/- 2.57 and 3.55 +/- 3.08 hr/L (NS). CONCLUSION: The higher labetalol concentration in women than in men was explained largely by differences in inactive and alpha1-blocking stereoisomers. However, concentrations were similar between genders for the beta-blocking stereoisomer (R,R-labetalol), possibly explaining the similarity in antihypertensive response to the drug. This study highlights the importance of determining stereoisomer kinetics for agents administered as racemates, particularly when relating concentrations to pharmacologic response.

Adult↗
PubMed1976

Pharmacological effects of labetalol in man.

1 The pharmacological effects of labetalol have been studied in normal healthy subjects. The results of these studies are reviewed. 2 In the evaluation of the beta-adrenoreceptor-blocking effects of labetalol various indices of beta-adrenoceptor blockade in man were used. Labetalol administered orally and intravenously competitively antagonized the effects of isoprenaline on heart rate and diastolic blood pressure. The beta-adrenoceptor blockade induced was regarded as 'non-selective'. In addition, labetalol produced dose-related inhibitory effects on exercise-induced increases in heart rate any systolic blood pressure and similar dose-related inhibitory effects on the tachycardia induced by valsalva's manoeuvre. Labetalol had only a modest inhibitory effect on the tachycardia induced by tilting since blood pressure was reduced on a dose-related basis. 3 Labetalol was a specific competitive antagonist of the alpha-adrenoceptor agonist effects of systemically administered phenylephrine and locally infused noradrenaline. In addition, oral and intravenous administration of labetalol reduced systolic and diastolic blood pressure in the supine, standing and sitting positions. 4 The onset and duration of the alpha- and beta-antagonist effects of oral labetalol did not seem to be dissociated in time and there was a close correlation between the change in plasma concentration and pharmacological effects. 5 In comparative studies with propranolol, similar beta-antagonist effects were observed but propranolol was 4-6 times more potent weight for weight. Precise comparison, however, was complicated by the combined alpha- and beta -effects of labetalol, especially as the predominant effect of labetalol in normotensive subjects was to reduce blood pressure; whereas the predominant effect of propranolol was to reduce heart rate. In addition propranolol had inhibitory effects on ventilatory function in normal subjects, whereas labetalol in equivalent beta-adrenoreceptor-blocking doses did not. 6 From the details of the studies reviewed it was concluded that in man labetalol possesses combined alpha- and beta-adrenoreceptor antagonist properties.

Adrenergic alpha-Antagonists↗
PubMed1976

Metabolism of labetalol by animals and man.

1 The disposition and metabolism of labetalol and either 14C- or 3H-labetalol has been studied in mouse, rat, rabbit, dog and man. 2 Radiolabelled labetalol was administered orally at doses of 100 mg/kg to the mouse, up to 50 mg/kg to the rat and rabbit, 20 mg/kg to the dog and 200 mg to man. From measurements of the total plasma radioactivity it was shown that labetalol was well absorbed by all the species. When the measurements of plasma radioactivity and labetalol concentrations were compared, it was found labetaol had been extensively metabolized by the first-pass effect in rat, rabbit and man. Metabolism by this route occurred to a lesser extent in the dog. 3 Radiochemical analysis of the tissues from rats, rabbits and dogs showed that the highest concentrations of radioactivity were found in the lung, liver and kidney. Very little radioactivity was present in the brain. Over 99% of the radioactivity was cleared from the tissues by 7 d. When doses of up to 200 mg 14C-labetalol/kg were given to pregnant rats and 50 mg 14C-labetalol/kg to pregnant rabbits, autoradiographic and radiochemical analysis of the full-term foetuses showed that only small amounts of radioactivity were present in the foetus. 4 The mouse excreted 72%, the rate 48%, the rabbit 61%, the dog 66% and man 60% of the oral dose of radioactivity in the urine. Analysis of themouse and rat faeces showed that the remainder of the dose of radioactivity was excreted in the faeces. 5 Radiochemical analysis of the urine and faeces collected from rats and dogs after an intravenous dose of 1 mg 14C- and 3H-labetalol/kg showed that excretion of radioactivity occurred via both the kidney and bile. 6 An intravenous dose of 1 mg 3H-labetalol/kg to dog and 1 mg 'cold' labetalol/kg to man was not as extensively metabolized as a similar oral dose. 7 The percentage of the dose excreted in the urine as unchanged drug was 2% in the rabbit, 11% in the rat, 19% in the dog and up to 5% in man. The O-phenyl glucuronide was the major metabolite present in the mouse, rat, and rabbit urine. Dog and man also formed this metabolite, but to a lesser extent. A second glucuronide was the major metabolite present in dog urine. This was probably formed through conjugation of glucuronic acid was the secondary alcohol group of labetalol. The major metabolite present in human urine was an unidentified conjugate of labetalol. Minor metabolites of labetalol present in rat, rabbit and dog urine were hydroxylabetalol and its glucuronyl conjugate.

Administration, Oral↗
PubMedDate not supplied

Labetalol: a review of its pharmacology, pharmacokinetics, clinical uses and adverse effects.

Labetalol is a combined alpha- and beta-adrenoceptor blocking agent for oral and intravenous use in the treatment of hypertension. It is a nonselective antagonist at beta-adrenoceptors and a competitive antagonist of postsynaptic alpha 1-adrenoceptors. Labetalol is more potent at beta that at alpha 1 adrenoceptors in man; the ratio of beta-alpha antagonism is 3:1 after oral and 6.9:1 after intravenous administration. Labetalol is readily absorbed in man after oral administration, but the drug, which is lipid soluble, undergoes considerable hepatic first-pass metabolism and has an absolute bioavailability of approximately 25%. There are no active metabolites, and the elimination half-life of the drug is approximately 6 hours. Unlike conventional beta-adrenoceptor blocking drugs without intrinsic sympathomimetic activity, labetalol, when given acutely, produces a decrease in peripheral vascular resistance and blood pressure with little alteration in heart rate or cardiac output. However, like conventional beta-blockers, labetalol may influence the renin-angiotensin-aldosterone system and respiratory function. Clinical studies have shown that the antihypertensive efficacy of labetalol is superior to placebo and to diuretic therapy and is at least comparable to that of conventional beta-blockers, methyldopa, clonidine and various adrenergic neuronal blockers. Labetalol administered alone or with a diuretic is often effective when other antihypertensive regimens have failed. Studies have shown that labetalol is effective in the treatment of essential hypertension, renal hypertension, pheochromocytoma, pregnancy hypertension and hypertensive emergencies. In addition, preliminary studies indicate that labetalol may be of value in the management of ischemic heart disease. The most troublesome side effect of labetalol therapy is posture-related dizziness. Other reported side effects of the drug include gastrointestinal disturbances, tiredness, headache, scalp tingling, skin rashes, urinary retention and impotence. Side effects related to the beta-adrenoceptor blocking effect of labetalol, including asthma, heart failure and Raynaud's phenomenon, have been reported in rare instances.

Animals↗
PubMed1988

Role of vasodilation in the antihypertensive and antianginal effects of labetalol: implications for therapy of combined hypertension and angina.

Beta-adrenergic blockade is established therapy in the management of both hypertension and angina pectoris. This review evaluates the use of combined alpha-adrenergic and beta-adrenergic blockade for these conditions, with reference to labetalol. There are three major differences between labetalol and propranolol or similar conventional beta-blockers. First, in the mechanism of the antihypertensive effect, peripheral vasodilation plays a prominent role during the use of labetalol. In particular, acute therapy with labetalol rapidly reduces the blood pressure because of this reduction in the systemic vascular resistance. During prolonged therapy with labetalol over many years, blood pressure remains reduced with a sustained fall in the systemic vascular resistance. Second, in patients with combined hypertension and angina pectoris, fixed doses of labetalol (200 mg twice daily) gave the same blood pressure values, effort tolerance, and nitrate usage as did atenolol 100 mg once daily in a double-blind, double-dummy, crossover study. Labetalol gave higher heart rates at rest and during exercise (both p less than 0.01). The higher heart rate with labetalol could be an advantage in some patients with effort angina and a disadvantage in others. Third, in hypertensive asthmatics, labetalol appears to have a relative bronchosparing effect, when compared with propranolol. The possession by labetalol of beta2-stimulating qualities (intrinsic sympathomimetic activity) may explain part of the dilating effect and the bronchosparing quality. Thus labetalol 1) lowers blood pressure by a mechanism involving vasodilation, 2) has an equiantianginal effect to atenolol yet a higher heart rate, and 3) may be bronchosparing. Differences among various beta-blockers may be important in matching the properties of the beta-blocker chosen to the requirements of the individual patient.

Angina Pectoris↗
PubMed1983

Monotherapy with labetalol in the treatment of mild hypertension: a double-blind study.

The antihypertensive effects of oral labetalol compared with placebo were evaluated in 74 mildly hypertensive patients (standing diastolic blood pressure 95 to 110 mm Hg) in a bicentric double-blind parallel group study. Following a four-week placebo phase, 36 patients were randomly assigned to receive labetalol and 38 to receive placebo. A five-week titration phase followed during which the dose of labetalol was increased weekly from 100 mg twice a day to 600 mg twice a day to achieve a standing diastolic blood pressure of less than 90 mm Hg and decreased 10 mm Hg or more from baseline. A matching number of placebo capsules for each dose of labetalol was dispensed for blinding purposes. Patients then entered a two-month maintenance phase. A thiazide diuretic could be added when the standing diastolic blood pressure was 100 mm Hg or greater at the highest dose of the study drug. At the end of this phase, the administration of labetalol (or placebo) was abruptly discontinued and patients were given the same number of placebo capsules twice a day taken during maintenance. Blood pressure and heart rate in the supine and standing position were measured eight to 10 hours after a dose at each visit. This study demonstrated that labetalol (median daily doses of 600 mg) was significantly more effective than placebo (p less than 0.05) in lowering the supine and standing blood pressures. Significantly more (p less than 0.001) placebo-treated patients than labetalol-treated patients (six versus 20) required the addition of a thiazide diuretic. Control of hypertension (that is, standing diastolic blood pressure less than 90 mm Hg) was achieved in significantly (p less than 0.001) more labetalol-treated patients than placebo-treated patients at the monotherapy endpoint (26 of 36; 72 percent versus six of 38; 16 percent). Blood pressure overshoot did not occur when labetalol was abruptly discontinued. Not one labetalol-treated patient discontinued the study because of adverse experiences. Labetalol is a safe and effective treatment for patients with mild hypertension.

Adult↗
PubMed1983

Step II treatment with labetalol for essential hypertension.

Labetalol, a new alpha- and beta-adrenergic blocking agent, was administered to 57 patients with essential hypertension whose standing diastolic blood pressure was 105 to 120 mm Hg after three and four weeks of placebo therapy and greater than 90 mm Hg after three to four weeks of therapy with hydrochlorothiazide, 25 mg twice a day. Patients were then randomly assigned on a double-blind basis to receive either labetalol, 100 mg twice a day, or placebo combined with hydrochlorothiazide. Thereafter, the dose of labetalol was titrated weekly in both groups to a maximum of 400 mg twice a day to achieve a standing diastolic blood pressure of less than 90 mm Hg that was also decreased from the hydrochlorothiazide baseline by 10 mm Hg or more (therapeutic goal). Labetalol was abruptly discontinued after four weeks of treatment and patients were given hydrochlorothiazide alone for two additional weeks. After one week of labetalol therapy, 100 mg twice a day (added to hydrochlorothiazide), there was a significantly greater reduction in supine systolic/diastolic blood pressure (6/5 mm Hg, p less than 0.04/less than 0.03) and standing blood pressure (9/7 mm Hg, p less than 0.01/less than 0.01) than with placebo therapy (3/0.5 and 3/1 mm Hg, respectively). The blood pressure reduction in the labetalol-treated group was associated with a 4 and 5 beats per minute reduction in the supine and standing heart rates, respectively. The median labetalol dose required to achieve the standing diastolic blood pressure goal was 400 mg twice a day. After four weeks of labetalol treatment, the mean reduction in blood pressure from the hydrochlorothiazide baseline was 12/13 mm Hg (p less than 0.01/0.01) in the standing position and 8/8 mm Hg (p less than 0.01/0.01) in the supine position. These blood pressure reductions were accompanied by a mean reduction in heart rate of 7 beats per minute. The most frequently reported complaints other than thiazide-induced nocturia included dizziness, fatigue, nausea, rash, and/or pruritus. Most of these complaints were reported at a similar incidence while patients were receiving placebo or hydrochlorothiazide alone as when receiving labetalol with hydrochlorothiazide. After abrupt withdrawal of labetalol, no evidence of rebound hypertension was observed. Labetalol is a safe and effective step II drug when added to hydrochlorothiazide for the treatment of patients with moderate to moderately severe hypertension.

Adult↗
PubMed1990

Labetalol pharmacokinetics and pharmacodynamics: evidence of stereoselective disposition.

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.

Administration, Oral↗
PubMed1993

The dose dependency of the alpha-adrenoceptor antagonist and beta-adrenoceptor partial agonist activity of dilevalol and labetalol in man.

1. The alpha-adrenoceptor antagonist, beta 1-adrenoceptor antagonist and beta 2-partial agonist activity of dilevalol, a beta-adrenoceptor antagonist with vasodilating properties and labetalol were investigated in two studies. 2. In the first study, six healthy male subjects received serially increasing concentrations phenylephrine after single oral doses of dilevalol 200 mg, labetalol 400 mg and placebo at weekly intervals in a randomised double-blind manner. An exercise step test was performed at the end of the infusions. 3. The doses of phenylephrine required to increase systolic and diastolic blood pressures by 20 mmHg (PS20 and PD20 respectively) were increased by labetalol 400 mg (P < 0.05) but unchanged by dilevalol 200 mg. The dose ratios for PS20 (means +/- s.d.) were: dilevalol 200 mg 1.1 +/- 0.1, labetalol 400 mg 2.2 +/- 0.1. There was no difference in the percentage reduction in exercise tachycardia between dilevalol and labetalol. 4. In the second study, 10 healthy male subjects received infusions with serially increasing concentrations of phenylephrine and angiotensin II before and after single oral doses of dilevalol 200, 400 and 800 mg, labetalol 200 mg and placebo at weekly intervals in a double-blind randomised manner. Finger tremor was measured (piezoelectric accelerometer) with each infusion. An exercise step test was performed at the end of the infusions. 5. The PS20 and PD20 of phenylephrine were increased by labetalol 200 mg and unchanged by dilevalol. The dose ratios for PS20 were: dilevalol 200 mg 1.1 +/- 0.2. dilevalol 400 mg 1.1 +/- 0.4, dilevalol 800 mg 1.4 +/- 0.4 and labetalol 200 mg 2.5 +/- 0.7. The dose ratios for PD20 were: dilevalol 200 mg 1.1 +/- 0.4, dilevalol 400 mg 0.9 +/- 0.3. dilevalol 800 mg 1.3 +/- 0.4 and labetalol 200 mg 2.3 +/- 0.9. 6. The PS20 and PD20 of angiotensin II were unchanged by any of the drugs. 7. Exercise heart rate was reduced by dilevalol 200 mg (130 +/- 13 beats min-1), 400 mg (123 +/- 12 beats min-1), 800 mg (125 +/- 9 beats min) and labetalol 200 mg (143 +/- 12 beats min-1) vs placebo (161 +/- 17 beats min-1). 8. Finger tremor was significantly increased by dilevalol 800 mg (13.17 +/- 10.51 vs 6.62 +/- 4.51 centivolts for placebo: P < 0.01). Neither phenylephrine nor angiotensin II had an effect on finger tremor. 9. In conclusion, dilevalol 200, 400 and 800 mg demonstrated beta 1-adrenoceptor antagonist activity with no evidence of alpha 1-adrenoceptor antagonist activity. Labetalol 200 and 400 mg showed both beta 1- and alpha 1-antagonist activity. Dilevalol 800 mg demonstrated significant partial beta 2-adrenoceptor agonist activity by increasing finger tremor.

Adrenergic alpha-Antagonists↗
PubMed1990

Usefulness of labetalol in chronic atrial fibrillation.

Beta-adrenergic blocking agents are useful in controlling excessive ventricular rate in chronic atrial fibrillation (AF) but often reduce exercise capacity. To investigate the advantage of labetalol--a unique beta blocker with alpha-blocking property--in chronic AF, 10 patients without underlying structural heart disease were studied with treadmill test, 12-minute walk and 24-hour ambulatory electrocardiographic monitoring. Patients were randomized and crossed over to receive 4 phases of treatment (placebo, digoxin, digoxin with half-dose labetalol, and full-dose labetalol). Exercise durations were 14.1 +/- 1.5, 14.2 +/- 1.5, 16.1 +/- 1.1 and 15.6 +/- 1.1 minutes, respectively, indicating that labetalol did not reduce exercise tolerance. Although digoxin had no advantage over placebo in controlling maximal heart rate (177 +/- 2 vs 175 +/- 3 beats/min), labetalol, both as monotherapy or as an adjunct to digoxin, was advantageous (156 +/- 4 vs 177 +/- 2 beats/min, p less than 0.01, and 154 +/- 4 vs 177 +/- 2 beats/min, p less than 0.01, respectively). The rate-pressure product was consistently lowered by labetalol at rest and during exercise. At peak exercise, the addition of labetalol to digoxin reduced the maximal rate-pressure product achieved from 30,900 +/- 1300 to 24,100 +/- 2,000 mm Hg/min (p less than 0.01) and the maximal rate-pressure product was lowest with full-dose labetalol (22,300 +/- 1,600 mm Hg/min). During submaximal exercise on treadmill or during the 12-minute walk, the combination of labetalol and digoxin produced the best heart rate control, whereas labetalol monotherapy was comparable to digoxin therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Atrial Fibrillation↗