Labetalol: A Review of its Pharmacology and Therapeutic Use in Hypertension

Summary

Synopsis: Labetalol¹ is an orally active adrenoceptor blocking drug which is a competitive antagonist at both α- and β-adrenoceptor sites. Its β-blocking effects resemble those of propranolol, but its overall haemodynamic effects are akin to those of a comination of propranolol and an α-adrenoceptor blocking drug such as phenoxybenzamine. Unlike with conventional β -adrenoceptor blocking drugs, acute administration of labetalol reduces peripheral vascular resistance and blood pressure and has little effect on cardiac output.

Theoretically, labetalol has advantages over β -adrenoceptor blocking drugs alone in the treatment of hypertension, but any real advantage, particularly in mild or moderate hypertension, has yet to be conclusively demonstrated in therapeutic trials. Labetalol may be particularly useful in some patients whose blood pressure is not adequately controlled by β-adrenoceptor blocking drugs alone or combined with a diuretic, but possibly at the expense of a postural hypotensive effect. Postural hypotension is the most troublesome side-effect, occasionally necessitating withdrawal of therapy, but severe side-effects such as are seen with effective antihypertensive dosages of phenoxybenzamine do not occur with labetalol.

Pharmacology: In isolated tissues and in intact animals labetalol is a competitive antagonist at α-adrenoceptors and is a non-selective antagonist at β-adrenoceptors. Labetalol has no intrinsic agonist activity but has some direct myocardial depressant activity at high dosages. Thus at β₁-adrenoceptors labetalol resembles propranolol but is less potent on a weight for weight basis than propranolol. In cat spleen, labetalol is an antagonist of postsynaptic α-adrenoceptors and thus may resemble prazosin in its action at α-adrenoceptors.

In man, labetalol given orally or intravenously, inhibits the effects of an infusion of isoprenaline (β-blockade) and of phenylephrine and noradrenaline (α-blockade). As in animals, labetalol is more potent at β-than at α-adrenoceptors in man, the ratio being 3: 1 after oral and 6.9: 1 after intravenous labetalol.

Unlike propranolol and the β-adrenoceptor blocking drugs generally, acutely administered labetalol results in a decrease in peripheral vascular resistance and a fall in blood pressure in hypertensive animals. In man, acutely administered labetalol reduces peripheral vascular resistance and blood pressure and generally does not lower cardiac output or stroke volume in the supine position. Heart rate is not usually altered in supine resting subjects, but is generally decreased compared with basal values on standing and during exercise. Heart rate is consistently decreased during continuous oral administration in hypertensive patients. A significant fall in blood pressure occurs within a few minutes of intravenous labetalol in untreated hypertensive patients and also in those concurrently receiving β-adrenoceptor blocking drugs. A hypotensive effect is evident within 2 hours of an oral dose of labetalol.

In a study comparing the haemodynamic effects of intravenous labetalol with those of propranolol alone or in combination with hydrallazine, the pattern of haemodynamic effects was most akin to that of a combination of propranolol and hydrallazine. Cardiac output has been reported in some studies to be reduced in the upright position and during exercise as a result of a fall in heart rate, stroke volume being unaltered.

As with conventional β-adrenoceptor blocking drugs, the mode of action of labetalol is not clear. The reduction in blood pressure after intravenous administration of labetalol to hypertensive patients whose blood pressure was inadequately controlled by β-adrenoceptor blocking agents may indicate that the antagonism of α-adrenoceptors predominates after acute administration. It is not clear whether a or β effects are of greater importance in reducing blood pressure during continuous oral administration.

Pharmacokinetics: Labetalol is readily absorbed in man after oral administration, but plasma concentrations of unchanged drug are low due to considerable first-pass metabolism. Bioavailability is about 40%. Labetalol is about 50% bound to human plasma protein. There is a clear relationship between plasma concentration and the effects of labetalol on exercise heart rate and blood pressure. As with metoprolol and tolamolol, the decline in plasma concentration is more rapid than the decline in pharmacological effects.

Labetalol is extensively metabolised after oral administration, the major metabolite being an unidentified conjugate accounting for 45% of an oral dose. About 15% of the dose is present as the o-phenylglucuronide of labetalol and 5% or less as the unchanged drug. The principle metabolites are pharmacologically inactive. About 55 to 60% of an oral dose of labetalol is recovered in the urine over a 24-hour period. The half-life of elimination is 3.5 to 4.5 hours and is not altered in the presence of impaired renal function.

Therapeutic trials: Placebo-controlled studies have shown labetalol to be superior to placebo when given orally in fixed or individually titrated doses to patients with mild, moderate or severe hypertension. Open studies, largely in patients whose blood pressure was not satisfactorily controlled by previous antihypertensive therapy, suggests that labetalol may be particularly useful in some such patients. An open 3-year study suggests that the efficacy of labetalol is comparable with that of α-methyldopa in patients who had been treated for periods of up to almost 5 years.

As might be expected, titrated doses of labetalol and propranolol produced a closely similar reduction in supine blood pressure, but labetalol produced a greater fall in the upright position. Labetalol 400 and 600mg daily was a more effective antihypertensive treatment than oxprenolol 480mg plus phentolamine 60mg daily, but, at the dosage used in this study phentolamine would exert little hypotensive effect. However, the fall in blood pressure achieved with pindolol plus hydrallazine at usual therapeutic dosages, was almost identical with that achieved with labetalol alone. Initial results with intravenous labetalol in the treatment of severe hypertension including that associated with phaeochromocytoma and clonidine withdrawal are promising.

As labetalol has α-adrenoceptor blocking properties in addition to its β-adrenoceptor blocking effect, it theoretically offers some advantages over ‘pure’ β-adrenoceptor blocking drugs, but any real advantage over β-blockers alone in the routine treatment of mild to moderate hypertension has yet to be conclusively demonstrated.

Side-effects: The most troublesome side-effect reported during oral labetalol treatment of hypertension is posture-related dizziness, which in some instances has been associated with documented postural hypotension, and has occasionally necessitated withdrawal of labetalol. Postural effects tend to occur more with higher dosages than with low dosages, and early in the course of treatment.

Other side-effects which may occur occasionally include tiredness and weakness, muscle cramps, mild constipation, headache, failure of ejaculation and scalp tingling. Positive anti-nuclear factor has been reported, but its significance and relationship to labetalol therapy are not clear and the effect is not positively associated with labetalol.

As with conventional β-adrenoceptor blocking drugs, heart failure should be controlled with digitalis and diuretic therapy before labetalol is given. Until further information on the effects of labetalol on respiratory function is available, labetalol is best avoided where possible in asthmatic patients.

Dosage: The usual starting oral dose is 100mg three times daily preferably after food. When a diuretic is given concomitantly this dosage may be sufficient in some patients with mild hypertension, but higher dosages are usually necessary for optimum response. If control is less than optimum after 1 or 2 weeks, the dose should be increased to 200mg three or four times daily. The effective daily dosage of labetalol is usually 300 to 800mg in mild to moderate hypertension, 600 to l,200mg in moderately severe disease and 1,200 to 2,400mg in severe hypertension. Dosages lower than these may be adequate in patients also receiving a diuretic.

Intravenous labetalol is indicated for use in hospitalised patients in whom rapid control of severe hypertension is necessary. It may be given by bolus injection of 50mg over a 1-minute period, repeated if necessary at 5 minute intervals until response is satisfactory; or by intravenous infusion, 200mg in 200ml of sodium chloride and dextrose solution, at the rate of 2mg per minute. The total dose should not exceed 200mg by bolus injection or 300mg by infusion. A satisfactory response may be obtained less often in patients receiving concomitant therapy with β-adrenoceptor blocking and other antihypertensive drugs. Dosages of 300mg or greater may be needed in patients with phaeochromocytoma. Once blood pressure has been controlled by intravenous labetalol, maintenance oral therpay should be initiated.