Clinical Pharmacokinetics of Labetalol

Abstract

Labetalol was the first of a new class of antihypertensive drugs with both alpha- and beta-adrenoceptor blocking properties present in the same molecule. Its efficacy has been confirmed by double-blind studies in the treatment of all grades of hypertension and in angina pectoris. The drug's major dose-related side effect is postural hypotension. The clinical formulation of labetalol consists of equal proportions of 4 optical isomers. One of these (the RR isomer) is probably responsible for the drug's beta-adrenoceptor blockade and another (the SR isomer) produces most of the alpha-blockade. Most of the presently available pharmacokinetic information concerning labetalol is from studies utilising a fluorimetric assay but this has recently been superseded by more specific high-pressure liquid chromatographic (HPLC) procedures. Labetalol is absorbed rapidly after oral administration with peak plasma concentrations generally being achieved within 2 hours. The bioavailability varies from 10% to over 80% in different subjects. Average bioavailability has been reported to correlate with age, with values of approximately 30% in the 30- to 40-year age group and approximately 65% at 80 years. There is also evidence that the bioavailability increases moderately when the drug is taken with food. About 50% of the drug is bound in the plasma. The apparent volume of distribution at equilibrium varies from approximately 200 to over 800L, suggesting that concentration of labetalol occurs in extravascular sites. Radiochemical analysis in animals has shown high levels of accumulation in the lung, liver and kidney with little present in brain tissue. This is in keeping with the relatively low lipid solubility of labetalol. The half-life of labetalol in plasma is 3 to 3.5 hours. The drug is eliminated mainly by hepatic metabolism with the production of several biologically inactive glucuronides which in turn are excreted in the urine and bile. Approximately 85% of labetalol in the blood is removed during a single passage through the liver; thus, like propranolol, labetalol's clearance is probably flow dependent (i.e. it is sensitive to alterations in hepatic blood flow). Small doses of the drug (i.e. 300mg daily) have been shown to reduce antipyrine clearance by approximately 15%, and further studies are necessary to determine whether high doses produce a greater, possibly clinically significant, inhibition of mixed-function oxidase activity. After both single doses and during long term treatment the plasma concentration-time profile of labetalol shows marked variation between different individuals.(ABSTRACT TRUNCATED AT 400 WORDS)

Single Dose of Labetalol in Normotensive Pregnancy: Effects on Maternal Hemodynamics and Uterine and Fetal Flow Velocity Waveforms

“…After a single dose of labetalol, the plasma concentration versus time profile shows marked variation between individuals and there is no uniform relationship between the plasma concentra tion and the fall in BP; it has been concluded that individual sensitivity to the drug plays a major role in determining the BP response [81-In this study, the antihypertensive effect of labetalol in the normotensive subjects was clear-cut. The mean drop in MAP was 16%, which agrees with previous studies with the same dose of intravenous labetalol [4,7], The antihypertensive effect remained mea surable for more than 1 h. Labetalol has one major side effect, postural hypotension [8], and 1 of our 10 subjects complained of slight dizziness during the study; the fall in BP in that case was 44%.…”

“…The pharmacodynamics of labetalol have been fairly well investigated in nonpregnant and pregnant women [6][7][8]. After a single dose of labetalol, the plasma concentration versus time profile shows marked variation between individuals and there is no uniform relationship between the plasma concentra tion and the fall in BP; it has been concluded that individual sensitivity to the drug plays a major role in determining the BP response [81-In this study, the antihypertensive effect of labetalol in the normotensive subjects was clear-cut.…”

Evaluation of Adherence Should Become an Integral Part of Assessment of Patients With Apparently Treatment-Resistant Hypertension

“…[80][81][82] Table 3 summarizes the pharmacokinetic characteristics of the most frequently used antihypertensive drugs belonging to the 5 main classes. [83][84][85][86][87][88][89][90][91][92][93] Drug monitoring may also be influenced by preanalytical errors. False-negative results might be because of nonspecific drug adsorption on the plastic tube or separator gel used or to drug instability at higher temperature or sensitivity to light as described for nifedipine.…”

Life-Threatening Hyperkalemia after Intravenous Labetolol Injection for Hypertensive Emergency in a Hemodialysis Patient

“…Labetolol was introduced to the market in 1984 and since then has been used extensively to treat severe hypertension. Some authors recommend it for patients with chronic renal failure [11,12].…”