Labetalol combines both selective, competitive alpha1-adrenergic blocking and nonselective, competitive beta-adrenergic blocking activity in a single substance. In man, the ratios of alpha- to beta-blockade have been estimated to be approximately 1:3 and 1:7 following oral and intravenous administration, respectively. Beta2-agonist activity has been demonstrated in animals with minimal beta1-agonist (ISA) activity detected. In animals, at doses greater than those required for alpha- or beta-adrenergic blockade, a membrane-stabilizing effect has been demonstrated.
The capacity of labetalol to block alpha-receptors in man has been demonstrated by attenuation of the presser effect of phenylephrine and by a significant reduction of the presser response caused by immersing the hand in ice-cold water ("cold-presser test"). Labetalol's beta1-receptor blockade in man was demonstrated by a small decrease in the resting heart rate, attenuation of tachycardia produced by isoproterenol or exercise, and by attenuation of the reflex tachycardia to the hypotension produced by amyl nitrite. Beta2-receptor blockade was demonstrated by inhibition of the isoproterenol-induced fall in diastolic blood pressure. Both the alpha- and beta-blocking actions of orally administered labetalol contribute to a decrease in blood pressure in hypertensive patients. Labetalol consistently, in dose-related fashion, blunted increases in exercise-induced blood pressure and heart rate, and in their double product. The pulmonary circulation during exercise was not affected by labetalol dosing.
Single oral doses of labetalol administered in patients with coronary artery disease had no significant effect on sinus rate, intraventricular conduction, or QRS duration. The atrioventricular (AV) conduction time was modestly prolonged in 2 of 7 patients. In another study, intravenous labetalol slightly prolonged AV nodal conduction time and atrial effective refractory period with only small changes in heart rate. The effects on AV nodal refractoriness were inconsistent.
Labetalol produces dose-related falls in blood pressure without reflex tachycardia and without significant reduction in heart rate, presumably through a mixture of its alpha-blocking and beta-blocking effects. Hemodynamic effects are variable with small nonsignificant changes in cardiac output seen in some studies but not others, and small decreases in total peripheral resistance. Elevated plasma renins are reduced.
Doses of labetalol that controlled hypertension did not affect renal function in mild to severe hypertensive patients with normal renal function.
Due to the alpha1-receptor blocking activity of labetalol, blood pressure is lowered more in the standing than in the supine position, and symptoms of postural hypotension can occur. During dosing with intravenous labetalol, the contribution of the postural component should be considered when positioning patients for treatment, and patients should not be allowed to move to an erect position unmonitored until their ability to do so is established.
In a clinical pharmacologic study in severe hypertensives, an initial 0.25 mg/kg injection of labetalol, administered to patients in the supine position, decreased blood pressure by an average of 11/7 mmHg. Additional injections of 0.5 mg/kg at 15 minute intervals up to a total cumulative dose of 1.75 mg/kg of labetalol caused further dose-related decreases in blood pressure. Some patients required cumulative doses of up to 3.25 mg/kg. The maximal effect of each dose level occurred within 5 minutes. Following discontinuation of intravenous treatment with labetalol, the blood pressure rose gradually and progressively approaching pretreatment baseline values within an average of 16 to 18 hours in the majority of patients.
Similar results were obtained in the treatment of patients with severe hypertension requiring urgent blood pressure reduction with an initial dose of 20 mg (which corresponds to 0.25 mg/kg for an 80 kg patient) followed by additional doses of either 40 or 80 mg at 10 minute intervals to achieve the desired effect or up to a cumulative dose of 300 mg.
Labetalol administered as a continuous intravenous infusion, with a mean dose of 136 mg (27 to 300 mg) over a period of 2 to 3 hours (mean of 2 hours and 39 minutes) lowered the blood pressure by an average of 60/35 mmHg.
Exacerbation of angina and, in some cases, myocardial infarction and ventricular dysrhythmias have been reported after abrupt discontinuation of therapy with beta-adrenergic blocking agents in patients with coronary artery disease. Abrupt withdrawal of these agents in patients without coronary artery disease has resulted in transient symptoms, including tremulousness, sweating, palpitation, headache and malaise. Several mechanisms have been proposed to explain these phenomena, among them increased sensitivity to catecholamines because of increased numbers of beta-receptors.
Although beta-adrenergic receptor blockade is useful in the treatment of angina and hypertension, there are also situations in which sympathetic stimulation is vital. For example, in patients with severely damaged hearts, adequate ventricular function may depend on sympathetic drive. Beta-adrenergic blockade may worsen AV block by preventing the necessary facilitating effects of sympathetic activity on conduction. Beta2-adrenergic blockade results in passive bronchial constriction by interfering with endogenous adrenergic bronchodilator activity in patients subject to bronchospasm and may also interfere with exogenous bronchodilators in such patients.
Pharmacokinetics and Metabolism
Following intravenous infusion, the elimination half-life is about 5.5 hours and the total body clearance is approximately 33 mL/min/kg. The plasma half-life of labetalol following oral administration is about 6 to 8 hours. In patients with decreased hepatic or renal function, the elimination half-life of labetalol is not altered; however, the relative bioavailability in hepatically impaired patients is increased due to decreased "first-pass" metabolism.
The metabolism of labetalol is mainly through conjugation to glucuronide metabolites. These metabolites are present in plasma and are excreted in the urine and, via the bile, into the feces. Approximately 55% to 60% of a dose appears in the urine as conjugates or unchanged labetalol within the first 24 hours of dosing.
Labetalol has been shown to cross the placental barrier in humans. Only negligible amounts of the drug crossed the blood-brain barrier in animal studies. Labetalol is approximately 50% protein bound. Neither hemodialysis nor peritoneal dialysis removes a significant amount of labetalol from the general circulation (<1%).