CURRENT DRUG THERAPY DONALD G. VIDT, MD, AND ALAN BAKST, PHARMD, EDITORS Labetalol and other agents that block both alpha* and beta-adrenergic receptors CAROLYN J. PEARCE, MD, AND J. DAVID WALLIN, MD HE IDEAL antihyper- BACKGROUND Labetalol, a compound that blocks both alpha- tensive agent has not yet and beta-adrenergic receptors, is the only drug of its class cur- been found. The 100 rently available in the United States. preparations currently Tavailable can all produce side ef- OBJECTIVE To review the pharmacology of labetalol and re- fects. lated compounds. The problem is that blood pres- sure is regulated by a number of SUMMARY Unlike "pure" beta blockers, labetalol maintains car- systems, and inhibiting one system diac output, reduces total peripheral resistance, and does not de- often produces a compensatory in- crease peripheral blood flow. It has been used to treat crease in the activity of another as hypertension of all degrees of severity and may be especially useful the body attempts to maintain its in black patients, elderly patients, patients with renal disease, and inappropriately high level of blood in pregnancy. It can be used in conditions that produce catecho- pressure. lamine crises, such as pheochromocytoma, clonidine withdrawal, For example, blockade of the and cocaine overdose. Its hemodynamic profile is attractive for beta-adrenergic system stimulates use in myocardial ischemia. The parenteral form is useful in situ- the alpha-adrenergic system and ations where blood pressure must be lowered quickly. The major results in peripheral vasoconstric- side effect is orthostatic hypotension, and hepatotoxicity has been tion. Conversely, blockade of the reported. alpha-adrenergic system produces tachycardia. In theory, a prepara- CONCLUSIONS Labetalol has several advantages over pure tion that inhibits both adrenocep- beta-blocking drugs and offers an alternative in managing hyper- tor subtypes would eliminate these tension that is difficult to control. problems and enable better blood • INDEX TERMS: LABETALOL; ADRENERGIC ALPHA RECEPTOR BLOCKADERS; pressure control than would an ADRENERGIC BETA RECEPTOR BLOCKADERS • CLEVE CLIN J MED 1994 61:59-69 agent that blocks only one subtype. Labetalol is the prototype com- From the Department of Medicine, Section of Nephrology, pound of the class of pharma- Louisiana State University School of Medicine, New Orleans. cologic agents that competitively Address reprint requests to C.J.P., Department of Medicine, block both alpha- and beta-adren- Section of Nephrology, 1542 Tulane Avenue, New Orleans, LA ergic receptors. Other agents in 70112. this class include arotinolol and amosulalol, which, like labetalol, are arylethanolamines (Figure 1) JANUARY • FEBRUARY 1994 CLEVELAND CLINIC JOURNAL OF MEDICINE 59 Downloaded from www.ccjm.org on October 1, 2021. For personal use only. All other uses require permission. LABETALOL • PEARCE AND WALLIN * Pharmacokinetics and metabolism The pharmacokinetics of labetalol have been de- R1 - CH - CH2 - NH - R2 termined in extensive studies performed in animals I and man.18"20 Following oral administration, ap- OH proximately 90% to 100% of labetalol is absorbed from the gastrointestinal tract, but only 25% of an * oral dose reaches the systemic circulation un- R1 - O - CH2 - CH - CH2 - NH - R2 changed due to extensive first-pass metabolism in the liver or the intestinal mucosa. Bioavailability I varies greatly among subjects, with a range reported OH from 11% to 86% (mean 33%).19 Food delays ab- sorption but increases bioavailability, possibly as a FIGURE 1. The arylethanolamines, (top) include labetalol, result of decreased first-pass metabolism or hepatic arotinolol, and amosulalol. The aryloxyisopropranolamines, blood flow. Increased bioavailability may also be (bottom) include celiprolol, nipradilol, bevantolol, and seen in the elderly21 or hepatically impaired. Conse- carvedilol. The asterisks show the position of the optic cen- quently, the dosage may need to be modified in ter of the compounds. Only labetalol is available in the United States. these groups. Renal failure does not appear to alter pharmacokinetics.22 Concomitant treatment with cimetidine increases bioavailability by as much as 23 and are available in Asia and Japan. Celiprolol, 30% to 54%. nipradilol, and bevantolol, available outside the Labetalol has a high volume of distribution: 567 to United States, are examples of aryloxyisoproprano- 805 L in healthy volunteers and 392 L in hyperten- lamines (Figure I); another, carvedilol, is undergo- sive patients.19 During long-term administration, ing clinical trials in the United States. These agents most of the drug is found in the peripheral tissue will be discussed later in this article. compartment. Low plasma binding (50%)18 as well as high plasma clearance (1500 mL/minute)19 further LABETALOL support this finding. Little placental transfer occurs, mainly due to labetalol's negligible lipid solubility. The bulk of the therapeutic information about The partition coefficient of labetalol between chlo- this family of agents comes from the study of labeta- roform and a buffer of pH 7.4 is 1.2, compared with lol, which has been marketed in Europe since 1975 9.0 for propranolol. Propranolol causes fetal beta-ad- and in the United States since 1982. Labetalol is renoceptor blockade in sheep when administered to effective in treating mild, moderate, and severe hy- the mother, but labetalol does not.24 Labetalol, but pertension,1"11 and the parenteral form is useful not its metabolites, has been shown to bind revers- when blood pressure needs to be lowered rapidly, as ibly to the melanin pigment of the eyes but has not in accelerated or malignant hypertension.12,13 It is been found to have long-term ocular toxicity.25 alpha-1-selective but beta-nonselective, and its ra- Peak plasma concentrations following oral doses tio of beta- to alpha-adrenergic blocking potency is are achieved within 1 to 2 hours.18,20 Excretion oc- 3:1 with oral administration and 7:1 with paren- curs over 8 to 12 hours, the majority of excreted teral administration14; these ratios may change with drug (about 75%) being in the form of an inactive dose or long-term therapy. Its alpha-blocking prop- glucuronide. The plasma elimination half-life fol- erties may be advantageous in attenuating the lowing oral administration is between 3 and 7.5 bradycardia commonly experienced with "pure" hours.19,20 The antihypertensive effect, which is ap- beta-adrenergic blockers. Its hemodynamic proper- parent within 20 minutes to 2 hours, reaches its ties are the result of its combined alpha- and beta- peak at 1 to 4 hours, and persists in a dose-depend- adrenergic blocking activity. Systemic vascular re- ent manner for about 8 to 12 hours after a single sistance and blood pressure are reduced in a 200-mg dose or 12 to 24 hours after a single 300-mg dose-dependent fashion, and there is little effect on dose.20 The maximal steady-state blood pressure re- cardiac output.15 Animal studies show evidence of a sponse with twice-a-day dosage occurs at 1 to 3 days, vasodilating property from a direct16 or beta-2- and the close correlation observed between daily agonist action.17 doses and mean steady-state plasma concentrations 60 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 61 • NUMBER 1 Downloaded from www.ccjm.org on October 1, 2021. For personal use only. All other uses require permission. LABETALOL • PEARCE AND WALLIN indicates that the kinetics vary in a linear fashion lamine concentrations.31 It is important to note that with dose. Other investigators have found large an unidentified metabolite or metabolites of labeta- variations in plasma concentrations during sus- lol may interfere with the fluorimetric method for tained therapy, probably due to individual differ- catecholamine determination and the spectrometric ences in clearance and bioavailability. assay for metanephrines, resulting in falsely high Following intravenous (IV) administration of 1.5 values for those substances. Using these methods to mg/kg, a rapid biexponential clearance of labetalol is screen labetalol-treated patients for pheochromocy- seen: its mean distribution half-life is 5.9 minutes toma may lead to a false-positive diagnosis. These and its elimination phase half-life is 4.9 hours. Labe- errors are prevented by measuring urinary excretion talol's hypotensive effect begins within 2 to 5 min- of 4-hydroxy-3-methoxy-mandelic acid; if this level utes after an IV dose, reaches its peak at 5 to 15 is high, urinary or plasma catecholamine concentra- minutes, and persists for about 2 to 4 hours or tions should be measured by high-performance liq- longer.18 uid chromatography (HPLC).32 The plasma concentration of free labetalol re- quired to produce a hypotensive effect in hyperten- Mechanism of action sive rats, dogs, and humans has been calculated to Receptor-binding studies have demonstrated that be about 5 x 10"8 to 10"7 M. A linear correlation labetalol interacts with alpha- and beta-adrenocep- between maximum inhibition of exercise-induced tors. Drug displacement studies indicate that the tachycardia and the logarithm of the plasma con- affinity of labetalol is about 10 times higher for the centration was found 2 hours after an oral dose of beta- than for the alpha-adrenoceptor. Its affinity for 100, 200, or 400 mg. Although IV administration the alpha-adrenoceptor is about 10 times less than produces an almost immediate effect on blood pres- phentolamine's, and its affinity for the beta-adreno- sures, a study of 12 hypertensive patients found no ceptor is about 10 times less than propranolol's.33 correlation between individual values for the area In vitro experiments using atrial strips, mesen- under the curve for plasma concentration vs time teric veins, and intact tracheal tubes from guinea and the area under the curve for blood pressure fall pigs demonstrated that labetalol is seven times less vs time.19 Mean plasma concentrations and mean potent than phentolamine mesylate in blocking al- hypotensive effects declined with time in hyperten- pha-adrenoceptors and 11 to 18 times less potent sive patients after oral doses, but wide interpatient than propranolol in blocking beta-adrenoceptors.