ACTIONS AND PHARMACOLOGY This antihypertensive agent is a competitive, selective a1 blocker and a competitive, nonselective b blocker, with the b-blocking action being 4 to 8 times the a-blocking action. It can be given either orally or intravenously. It lowers blood pressure by blocking a 1 adrenoreceptors in vascular smooth muscle but, because of the simultaneous b blockade, causes no reflex tachycardia.
When given intravenously, the distribution to peripheral tissues is rapid, with a large volume of distribution (15.7 L/kg). Onset of action is 5 to 10 min, and the duration of action is 8 h. The elimination half-life is 5.5 h. When taken orally, it is rapidly absorbed, with an absorption half-life of about 12 min and peak plasma concentrations at about 50 min. Labetalol is safe for use in patients with renal insufficiency, because it is predominantly (95 percent) hepatically metabolized; however, oral dosing may need to be reduced in patients with hepatic disease, because of significant first-pass hepatic metabolism. Oral bioavailability is only 25 percent but increases in the elderly or when taken with food or cimetidine. The elimination half-life after an oral dose is 8 h.
Labetalol reduces systolic arterial pressure and total peripheral vascular resistance. Cardiac output may be slightly decreased or unchanged, pulmonary artery and wedge pressures decrease, and angiotensin II activity decreases, while cerebral blood flow, renal blood flow, and glomerular filtration rates are unchanged. With prolonged use, fluid retention may occur. Labetalol should be used with caution in patients with asthma and COPD, because of its nonselective b-blocking activity, which decreases the forced expiratory volume in 1 s (FEV-,) by causing bronchospasm. The use of labetalol should also be avoided in patients with bradycardia and second- or third-degree heart block.
INDICATIONS Labetalol can be used intravenously for hypertensive emergencies and be easily converted to the oral formulation as the first-line agent for hypertensive urgencies. It offers the advantages of providing a steady, consistent drop in blood pressure without decreasing cerebral blood flow or producing reflex tachycardia. It can be safely used in patients with cerebral vascular disease and coronary artery disease. Labetalol is ideal for use in syndromes associated with excessive catecholamine stimulation, such as from pheochromocytoma, MAO inhibitor-induced emergencies, and abrupt clonidine withdrawal. It has also been used in pregnancy-induced hypertension. It is a class C drug in pregnancy.
USE Labetalol can be given for hypertensive emergencies with repeated, incremental boluses starting with 20 to 40 mg IV, until the target blood pressure is achieved or a total dose of 300 mg is reached. After an intravenous bolus, the blood pressure falls in 5 min, with a maximum response in 10 min, and antihypertensive effect lasting for up to 6 h. After a 20-mg loading dose, labetalol may also be given as a continuous infusion by mixing 200 mg in 200 mL of D 5W and running this at 2 mg/min (2 mL/min). The infusion should be stopped when the target pressure has been achieved.
The initial oral dose in hypertensive urgencies is 200 mg. Patients can experience the onset of effects within 1 to 3 h. 16
SIDE EFFECTS AND CONTRAINDICATIONS Labetalol has a prolonged action because of its large volume of distribution and long elimination half-life. In 5 percent of patients, orthostatic hypotension is a complication of therapy. The nonselective b-blocking action can exacerbate heart failure and induce bronchospasm. A paradoxical hypertensive effect may occur when the drug is used in low doses in catecholamine-induced crisis, because of the predominant b blockade, leaving relatively unblocked a receptors for the circulating catecholamines. 17 In addition, patients with ischemic heart disease may experience exacerbation of angina and, in some cases, myocardial infarction after abrupt discontinuation of oral therapy.
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