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Home , Amosulalol, Arotinolol, Bevantolol, Celiprolol, Labetalol, Medroxalol

CURRENT DRUG THERAPY

DONALD G. VIDT, MD, AND ALAN BAKST, PHARMD, EDITORS

Labetalol and other agents that block both alpha* and beta- receptors

CAROLYN J. PEARCE, MD, AND J. DAVID WALLIN, MD

HE IDEAL antihyper- BACKGROUND , 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 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 . It can be used in conditions that produce catecho- pressure. lamine crises, such as , withdrawal, For example, blockade of the and 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 , and 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 and , which, like labetalol, are arylethanolamines (Figure 1)

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* 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 or the intestinal mucosa. 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 , , , and seen in the elderly21 or hepatically impaired. Conse- . 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 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 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 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- .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 action.17 doses and mean steady-state plasma concentrations

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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- 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- '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. variation occurred.20 Other investigators reported Both beta-1- and beta-2-adrenoceptors are blocked no correlation between plasma concentration and to a similar degree.34 Labetalol inhibits the contrac- blood pressure response, again likely due to the wide tile responses to alpha-receptor such as variation in individual sensitivity to labetalol's anti- in isolated aortic strips. It is four to hypertensive action.26 eight times less potent in blocking alpha-receptors than beta-receptors in isolated tissues. An intrinsic Effects on and the sympathomimetic activity of labetalol at beta-2-ad- renin-angiotensin-aldosterone system renoceptors has been suggested in studies of the In one study, labetalol decreased plasma isolated rat uterus and in human volunteers.17 angiotensin II and aldosterone concentrations 2 and In vivo experiments in animals and humans have 3 hours after IV administration. These effects hap- confirmed these alpha- and beta-blocking proper- pened much later than the effect on blood pressure, ties.14 The finding of nonselective beta blockade is and were most pronounced in patients who had supported by the effects of IV labetalol on phenyle- elevated levels of angiotensin II and aldosterone phrine-induced tachycardia and on initially.27 Other studies, however, have not demon- changes with the Valsalva maneuver. These experi- strated changes in the renin-angiotensin system.28 ments suggest that labetalol is about one fourth as Some investigators28,29 report a decrease in plasma potent as propranolol as a , and the ratio renin activity and plasma aldosterone levels during of alpha to beta blockade is about 1:7. long-term therapy, an effect that is attenuated by Labetalol's alpha-blocking properties have been diuretics, suggesting that this effect is mediated by demonstrated in human studies in which labetalol plasma volume expansion.30 Labetalol does not sub- inhibited the increase in blood pressure induced by stantially increase the plasma or urinary catecho- phenylephrine and while leaving

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TABLE 1 Systemic hemodynamic effects COMPARISON OF HEMODYNAMIC EFFECTS OF PROPRANOLOL, , AND LABETALOL* In a study comparing the effects of labetalol and propranolol in dogs that had undergone bilateral Beta- Alpha- Alpha-beta- vagotomies, labetalol reduced heart rate, cardiac adrenoceptor adrenoceptor adrenoceptor blockade blockade blockade contractility, and cardiac output, effects attributed 34 (propranolol) (prazosin) (labetalol) to beta blockade. Labetalol had no effect on total peripheral resistance at low doses and reduced it at i oT Heart rate higher doses, but propranolol increased total periph- Cardiac output I eral resistance over the range of doses tested. Conse- oT quently, labetalol caused larger decreases in blood Systemic vascular pressure than propranolol at equipotent cardiac resistance i i beta-adrenoceptor-blocking doses. The increased * T increase, 4- decrease, no change; data from reference 40 reduction in blood pressure observed in the labeta- lol-treated animals was apparently a result of periph- reflex reductions in heart rate and cardiac output eral due to vascular alpha-1-adreno- unaffected.35 Labetalol, unlike phentolamine, also ceptor blockade. blocks the cold pressor response in man, suggesting Intravenous administration of labetalol in that prejunctional alpha blockade does not occur healthy subjects and in hypertensive patients pro- with labetalol.36 Further support for alpha-1-selec- duces a rapid, substantial fall in systemic blood pres- tivity is found in the observation that labetalol is sure, primarily via reduction of total peripheral resis- ineffective in preventing clonidine-induced seda- tance. Heart rate is maintained or slightly reduced tion in rats, an effect mediated by alpha-2-adreno- due to blockade of reflex tachycardia. Unlike pure ceptors in the central nervous system.37 beta blockers (which decrease cardiac output), labe- Long-term studies suggest that labetalol's beta- talol maintains cardiac output, reduces total periph- blocking activity is constant, but there are differing eral resistance, and does not decrease peripheral reports about its sustained alpha-blocking activity. blood flow. In one study,39 in which labetalol was In one study, the disappearance of postural hypoten- administered IV, blood pressure reduction was found sion after 1 month's treatment with labetalol sug- to be due to small reductions in both cardiac output gested a decline in alpha-blocking activity. and systemic . After exercise, There is some evidence that labetalol exerts a blood pressure fell to a greater degree and cardiac direct vasodilative effect that contributes to its hypo- output decreased substantially, principally due to a tensive activity. Following elimination of sympa- reduction in heart rate, but there was an increase in thetic tone with hexamethonium, IV labetalol (0.01 stroke volume. occurred in to 0.1 mg/kg) significantly lowers blood pressure; this group of subjects. In patients treated with oral hydralazine also lowers blood pressure, but propra- labetalol for 12 months,40 blood pressure fell, but nolol has no effect. These observations are likely due increased stroke volume compensated for mild dec- to direct vasodilation by labetalol and hydralazine.16 rements in heart rate, and cardiac output was un- Like other beta blockers, labetalol has membrane- changed. The blood pressure decline was entirely stabilizing properties that produce local anesthesia due to changes in peripheral resistance, and no or- and antiarrhythmic effects. In experiments with hu- thostatic changes were noted (Table 1). man platelets, labetalol inhibits aggregation in vitro, In patients with mild-to-moderate hypertension completely preventing collagen-induced activation treated with labetalol for up to 6 years, a reduction and the secondary activation wave caused by in blood pressure of approximately 22% at rest and catecholamines and other aggregating stimuli. The during exercise was demonstrated.15 The total pe- release of beta-thromboglobulin and platelet factor 4 ripheral resistance index was reduced considerably, and the generation of thromboxane B2 from colla- while the cardiac index was found to have returned gen-stimulated platelets are inhibited by labetalol. to pretreatment levels with an increase in stroke Membrane-stabilizing properties may be responsible index. These observations suggest a possible regres- for some of these observations. Additionally, some sion of structural changes in the left ventricle and in aspects of the modulation of platelet function appear the resistance vessels. 38 to be related to effects on calcium availability. The effects of labetalol on renal function have

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been examined in three studies. No substantial al- lol with pure beta blockers; most found that in mild teration in glomerular filtration rate, renal plasma or moderate hypertension, there was no difference flow, filtration fraction, or free water clearance was in mean resting supine blood pressures, but that demonstrated after long-term labetalol therapy in sitting and standing blood pressures were decreased doses up to 2400 mg daily.41 One group of investiga- to a greater degree in labetalol-treated patients than tors reported that glomerular filtration rate actually in patients treated with other agents. Heart rate, increased during labetalol therapy, in contrast to the both at rest and during exercise, was decreased more effect of pure beta blockers, which lower renal in patients treated with pure beta blockers than in plasma flow and glomerular filtration rate. The con- labetalol-treated patients.6 comitant alpha blockade appears to be an important Several studies have documented the efficacy of factor in preventing alterations in renal hemody- labetalol in treating black hypertensive patients, namics. who historically have responded relatively poorly to pure beta-adrenoceptor blocking agents.7,8 Black pa- CLINICAL APPLICATIONS OF LABETALOL tients had a better response to labetalol than white patients did, and they required less diuretic added to Long-term treatment of hypertension their regimen to control their blood pressure in a Labetalol has been used successfully in Europe study comparing labetalol and propranolol.9 and the United States to manage mild, moderate, Labetalol has also been used successfully in eld- and severe hypertension and has proven to be an erly patients, in whom isolated systolic hypertension effective and safe agent with few side effects.1 Exten- accounts for a substantial portion of high blood pres- sive clinical trials confirm the hypotensive activity sure. In a prospective, randomized, multicenter, of labetalol compared with placebo or other antihy- double-blind study of 133 elderly patients with iso- pertensives. Tolerance did not develop in long-term lated systolic hypertension, labetalol decreased sys- trials, while a sustained lowering of blood pressure tolic blood pressure to an average of 144 mm Hg, a and systemic vascular resistance was maintained.15 mean reduction of 26 mm Hg compared with a In patients with severe and previously uncon- 9-mm Hg reduction with placebo, with which it trolled hypertension (supine diastolic blood pressure shared a similar safety profile.10 In a study using >125 mm Hg), labetalol has been found to be effec- 24-hour ambulatory blood pressure monitoring in tive when used alone compared with elderly patients, labetalol and enalapril were equally and furosemide used in combination. Daily doses of effective in lowering supine diastolic blood pressure up to 2400 mg of labetalol were used, with 500 to and were equally well tolerated. Labetalol, however, 1000 mg being the average daily dose. Other inves- was more effective in lowering ambulatory blood tigators have found labetalol to be effective when pressure and heart rate throughout the day.11 beta blockers or other antihypertensives have inade- Orthostatic hypotension induced by antihyper- quately controlled blood pressure.2 However, there tensives can be a serious problem in the elderly, who have been reports of decreasing efficacy over long have reduced baroreceptor sensitivity due to stiffen- periods of treatment when labetalol was used alone ing of the carotid arteries. Lower dosages (200 mg or to treat severe hypertension. less twice a day) have been found to produce little or Trials in patients with mild or moderate hyper- no orthostatic effect but still effectively lower blood tension have shown labetalol and methyldopa to pressure in this age group, possibly due to increased have equal efficacy.3 When was compared bioavailability in the elderly.10 with labetalol and then used in combination with it, both supine and standing blood pressures were de- Hypertensive emergencies and urgencies creased more by labetalol than by nifedipine, and Labetalol has been shown, in studies in Europe the combination was more effective than either and in the United States, to be effective and safe in agent alone.4 Labetalol (up to 600 mg daily) was the management of hypertensive emergencies. It can found to be more effective than hydrochlorothiazide be infused in dosages up to 2 mg/hour or given by in reducing standing blood pressure in mildly hyper- repeated IV bolus injections up to a total dose of 300 tensive patients, but the combination produced mg.1 However, large bolus injections of 1 to 2 mg/kg greater decreases in blood pressure than either agent have been reported to produce precipitous falls in alone.5 A number of studies have compared labeta- blood pressure. All patients receiving parenteral

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240 Patients presenting to o> Systolic the emergency department I 220 Diastolic or outpatient settings with E 200 E asymptomatic severe hy- 180 pertension (diastolic blood 3 160 pressure >120 mm Hg) are C/5 C/5 commonly treated with oral »0) 140 80 CL loading of antihypertensive 120 70 -O . Protocols us- o o 100 60 ing oral clonidine and m 80 Î 50 nifedipine have been Oral shown to be effective, but Intravenous 40 labetalol, side effects and some seri- labetalol (mg) 200 mg ous complications have _L _L _L been reported.42 In a recent 0 60 120 180 240 study,41 oral labetalol was Time (minutes) compared with oral clo- nidine in treating severe FIGURE 2. Responses of pulse and recumbent blood pressure to sequential bolus infusions but nonemergent hyperten- of labetalol (arrows). Smooth decline in blood pressure is seen with little alteration in pulse sion (mean baseline blood rate. From reference 1. pressures 199/132 mm Hg) without acute end-organ therapy should be closely and continuously moni- damage. Labetalol was administered as an initial dose tored, but intra-arterial blood pressure monitoring is of 200 mg followed by hourly 200-mg doses up to not necessary. In one multicenter study conducted in 1200 mg. Clonidine was administered as an initial the United States,12 59 patients (36 with sympto- oral dose of 0.2 mg, followed by hourly 0.1-mg doses matic accelerated hypertension) with supine blood up to 0.7 mg. Within 6 hours, 94% of the patients pressures averaging 211/134 mm Hg were given re- treated with labetalol had their diastolic blood pres- peated injections of labetalol beginning with a bolus sures reduced (mean reduction 54/37 mm Hg), com- of 20 mg in order to minimize hypotension and avoid pared with 83% of the clonidine-treated patients the possibility of sensitivity to the drug. Ten percent (mean reduction 52/32 mm Hg). Side effects were of the patients achieved the goal blood pressure with more common in the clonidine-treated group, with a single 20-mg bolus. The initial bolus was followed 66% of the patients reporting mild to severe seda- by repeated incremental doses of 20 to 80 mg given tion, , and dry mouth. Forty-four percent of at 10-minute intervals until the therapeutic goal was the labetalol-treated patients reported side effects, achieved (Figure 2). No significant adverse experi- which were generally mild and included dizziness, ences were reported, and 90% of the patients drowsiness, and . The authors concluded achieved the goal blood pressure. that labetalol was as effective as clonidine and had few side effects when used in the outpatient setting. The response to IV labetalol is comparable to that Single oral doses of 300 to 400 mg have been used, observed with , but unlike diazoxide,13 labe- but this route of administration does not allow for talol does not activate the renin-angiotensin system, adequate control of titration. induce increases in heart rate or cardiac output, or cause salt retention. Adverse reactions during IV administration are mostly mild and transient (nau- Renal impairment sea, vomiting, sweating, flushing, , faint- A number of studies7,41 have demonstrated that ness, excessive hypotension) and usually abate with patients with impaired renal function can achieve stopping the infusion, placing the patient in the effective blood pressure control with labetalol alone Trendelenburg position, and administering IV fluids. or in combination with diuretics or other antihyper- Due to possible orthostatic hypotension, IV admini- tensive agents. It has been concluded that labetalol stration should be performed with the patient in the has no deleterious effects on renal function at rest or supine position. during exercise.

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Ischemic heart disease cause it reduces myocardial oxygen consumption. and left ventricular dysfunction Labetalol has been compared as an The hemodynamic profile of labetalol is attrac- agent with the calcium antagonists and tive for use in patients with myocardial ischemia , which are potent vasodilators, and with with or without hypertension. Labetalol's efficacy as the pure beta blockers and propranolol.45 an antianginal agent is attributed to its alpha-ad- The calcium antagonists were found to improve left renoceptor blocking component, which minimizes ventricular pump function as reflected by the left the potential coronary spasm that may occur from ventricular end-diastolic pressure-cardiac output re- beta blockade alone, while its beta-blocking compo- lationship, while the beta blockers depressed func- nent may offset potential arrhythmias from vasodi- tion, and labetalol's effect was intermediate. The lation secondary to alpha blockade.44 calcium antagonists with peripheral vasodilating Normotensive patients with who were properties and labetalol can therefore be safely used treated with IV (0.5 mg/kg) or oral (200 mg fixed in patients without history of who have dose) labetalol were able to exercise longer before ischemic heart disease. angina or ischemic changes on electrocardiogram were recorded.45 Exercise-induced tachycardia and Hypertension during pregnancy increases in aortic pressures were blunted, and car- Several clinical trials have demonstrated labeta- diac output was unchanged or slightly lowered, but lol's efficacy and safety in pregnant patients with not significantly so. Coronary sinus flow was de- hypertension. In one trial of 176 pregnant women creased as heart rate and aortic pressure were low- with mild-to-moderate hypertension (diastolic ered. blood pressure >89 mm Hg) who received either Hypertensive patients with angina also benefited methyldopa 500 mg twice daily or labetalol 400 mg from labetalol therapy: their blood pressure was low- twice daily by random assignment, there were no ered and their exercise capacity improved with dos- differences in the percentage of babies who were ages in the range of 300 to 1600 mg/day.46 premature or small for their gestational age.50 Heart Labetalol, like , was found to improve rate, blood pressure, blood glucose level, respiratory diastolic filling indices and therefore may have an rate, and Silverman score of the babies did not differ impact on reversal of diastolic dysfunction in mild between the two treatment groups. Additional anti- hypertension, which is suggested to precede left hypertensive therapy was given to reach a target ventricular hypertrophy.47 The additional property blood pressure of <86 mm Hg in 13% of the patients of alpha blockade enhances ventricular relaxation receiving labetalol and 26% of those receiving by maintaining cardiac output at lower filling pres- methyldopa. There were four stillbirths in the sures. Myocardial alpha-adrenoceptors have been methyldopa group, three attributed to refractory hy- described; conceivably, blocking these receptors pertension and proteinuria. One patient in the labe- may improve ventricular compliance and filling. talol group who required additional hydralazine In a study of acute myocardial infarction with gave birth at the 29th week to a baby that died at 24 systemic hypertension,48 IV labetalol was adminis- hours of a bilateral pneumothorax. tered in incremental doses between 30 and 440 mg. Other studies comparing methyldopa with labeta- The blood pressure was safely and effectively lowered lol have found no significant differences in birth from 184/122 mm Hg to 118/84 mm Hg while heart weight, gestational age at birth, or Apgar scores. One rate, left ventricular filling pressure, cardiac index, group reported better blood pressure control and a and total peripheral resistance likewise decreased; lower frequency of proteinuria in women treated stroke volume remained essentially unchanged. with labetalol.51 Because the most significant peri- Other reports had similar findings, but in one study,49 natal prognostic factor in pregnancy-induced hyper- infusions of 0.5 mg/kg/hour reduced blood pressure tension is the presence or absence of proteinuria, the and cardiac output without changing the heart rate effect of labetalol on proteinuria was studied in a or left ventricular filling pressure in a group of pa- recent trial.52 One hundred and fourteen women tients in the early stages of uncomplicated myocar- with single and hypertension (diastolic dial infarction. The authors suggested that the com- blood pressure >90 mm Hg) without proteinuria bination of alpha and beta blockade may be were randomly assigned to receive labetalol or no hemodynamically advantageous in this situation be- antihypertensive therapy. Although labetalol

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TABLE 2 Third, the most recent use of labetalol in situ- ADVERSE EFFECTS OF LABETALOL* ations of catecholamine excess is in managing co- Symptom Prevalence (%) caine crises. "Crack" cocaine is responsible for ever- increasing numbers of admissions to emergency Tiredness 5.5 Dizziness 5.2 departments. Cocaine overdose results in systemic Headache 4.2 toxicity manifested by overwhelming sympathetic Gastrointestinal symptoms 3.0 stimulation of the central nervous system, respira- "Tingly" sensations in scalp 1.9 tory system, and cardiovascular system, which pro- Postural hypotension 1.4 gresses rapidly to death. After an adequate airway Dyspnea 1.2 Depression 0.8 has been secured, labetalol may be given in a 20-mg Sexual dysfunction 0.6 IV bolus with titrated doses and continuous infu- sion of up to 300 mg/24 hours until the patient's *Data from the British Committee on Safety of Medicines. condition stabilizes and the blood pressure returns Special report to the British Committee on Safety of 56 Medicines, incidence of side effects associated with labetalol, to normal. June 1978, British-monitored release trials of 6,638 patients Miscellaneous clinical uses Labetalol has been used to manage the hyperten- brought the blood pressure under control in 88% of sion associated with severe .57 In one series, the women receiving it, there was no difference in 15 patients were treated with a continuous infusion the frequency, quantity, or timing of subsequent pro- (1 to 10 mg/hour), incremental injections (95 to 75 teinuria between the treatment and control groups. mg), or oral doses of 200 to 800 mg, and 12 of the 15 As there is still debate over the usefulness of patients responded adequately. Labetalol is reported treating mild-to-moderate hypertension in preg- to be useful in conjunction with halothane anesthe- nancy, close attention should be paid to perinatal sia in producing controlled hypotension for various safety. Although trials comparing beta blockers surgical procedures including repair of coarctation with methyldopa report no differences in mortality of the aorta and ear surgery. An additional applica- between the two treatment groups, the beta block- tion has been in reducing intraocular tension in ers are placentally transferred24 and may affect fetal patients with glaucoma.58 heart rate, blood pressure, and possibly, glucose control. ADVERSE EFFECTS When rapid reductions in blood pressure are re- quired such as in severe preeclampsia, labetalol has The major adverse side effects are summarized in proven effective when administered IV.53 Table 2. Most symptoms are transient and do not require stopping treatment with the drug. Or- Pheochromocytoma, withdrawal thostatic hypotension does occur with IV treat- from alpha'2 agonists, and cocaine crisis ment as previously discussed, but appears to abate Three clinical situations, in which catecholamine with oral treatment after several weeks. excess is manifest with resultant uncontrolled hyper- Hepatotoxicity has been occasionally reported. tension and predisposition to cardiac arrhythmias, In one study,59 8% of 337 patients developed tran- may be amenable to treatment with labetalol. sient reversible transaminase elevations. Two thirds First is the preoperative management of pheo- of these patients experienced resolution, but five chromocytoma.54 Titrated dosages of up to 6400 mg patients were discontinued from the study and again daily have been used, and an IV dose of 50 mg prior developed transaminase elevations after restarting to surgical removal of these tumors gives adequate labetalol. In addition, 11 case reports have been coverage during the procedure. received by the Food and Drug Administration, in- Second, abrupt withdrawal of clonidine can pro- cluding one patient who died. It is recommended duce severe hypertension, which can be prevented or that labetalol be used with caution in patients with treated with labetalol.55 Labetalol may be adminis- a history of . tered prophylactically, but close monitoring of blood Ejaculatory failure has been reported in a small pressure is necessary so that adequate dosages are number of male patients. given. Most studies indicate that labetalol is neutral in

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its effect on plasma lipid levels. of hypoglycemia occurs either rarely, or not at all. Labetalol should be used with caution or avoided in clinical situations where beta blockade could be OTHER DRUGS WITH COMBINED ALPHA- AND harmful, although at therapeutic doses labetalol's BETA-BLOCKING PROPERTIES negative effect on cardiac contractility is less than that of pure beta blockers. Heart failure precipitated Figure I lists drugs of this category that are avail- by labetalol has been reported; heart failure should able for clinical use in various parts of the world. In be controlled with conventional agents before initi- general, their antihypertensive efficacy is similar to ating labetalol.44 Labetalol may cause heart block and that of labetalol. Celiprolol was demonstrated to be is contraindicated in patients with severe bradyar- well tolerated in a postmarketing surveillance study; rhythmias or greater than first-degree heart block. only 2.15% of 2311 patients discontinued Celiprolol in sensitive patients receiving la- because of adverse events. Carvedilol has been betalol has been reported; caution should be exer- shown to have a hemodynamic profile similar to cised in treating patients with . labetalol's61,62 and has been demonstrated to be an However, in a clinical study, labetalol was found effective antihypertensive agent. Other drugs of this to be well tolerated in patients with mild or moder- category such as prizidilol, , and dilevalol ate hypertension and chronic obstructive pulmo- have been withdrawn from clinical testing. nary disease with a mild reversible component.60 Dosages as high as 1200 mg daily had no deleterious SUMMARY effect on expiratory airflow over a 4-week period of administration. Both the forced expiratory flow, Pure beta-blocking drugs reduce heart rate and mid-expiratory phase and the forced expiratory vol- cardiac output, but produce reflex stimulation of ume in 1 second were monitored as indices of airway alpha-adrenoceptors, causing vasoconstriction; pure obstruction before and after exercise. No significant alpha blockers dilate peripheral arterioles but re- changes were noted at 2 hours after a maximal dose. flexively stimulate beta-adrenoceptors, causing Spirometric changes observed after exercise were tachycardia. Thus, blockade of either receptor type variable with no individual patient's forced expira- evokes stimulation of the other, limiting the antihy- tory volume in 1 second or forced expiratory flow, pertensive effect. mid-expiratory phase decreasing more than 15%. Labetalol, a weak blocker of both receptor types, Overall spirometric values were unchanged from acts synergistically to lower blood pressure with baseline and were not significantly different from minimal physiological disturbance. The parenteral those of the control group, who received hydrochlo- preparation is effective in hypertensive emergen- rothiazide for blood pressure control. cies, and the oral form is useful in long-term man- Only a few cases have been reported in which agement of hypertension of all degrees of severity, labetalol worsened symptoms of peripheral vascular particularly in the elderly, blacks, pregnant patients, disease, and it should be noted that a few patients and those with renal failure. It may be useful in who had circulatory disturbances while taking other ischemic heart disease with ventricular dysfunction, beta blockers experienced improvement or became and in catecholamine excess states. The major ad- symptom-free when they changed to labetalol. verse effect, orthostatic hypotension, is usually tran- There are no contraindications for the use of labe- sient and does not require stopping the drug. Hepa- talol in patients with diabetes mellitus, and masking totoxicity has been reported.

REFERENCES 4. Ohman KP, Weiner L, von Schenck H, Karlberg BE. Antihy- pertensive and metabolic effects of nifedipine and labetalol alone and in combination in primary hypertension. Eur ] Clin Pharma- 1. Wallin JD, O'Neil WM. Labetalol: current research and thera- col 1985; 29:149-154. peutic status. Arch Intern Med 1983; 143:485-490. 5. Bloomfield SS, Lucas CP, Gantt CI, Poland MP, Medakovic M. 2. Prichard BNC, Boakes AJ, Hernandes R. Long-term treat- Step II treatment with labetalol for essential hypertension. Am J ment of hypertension with labetalol. Br J Clin Pharmacol 1979; 8 Med 1983; 75(4A):81-86. Suppl 2: 171S-177S. 6. Frishman WH, Michelson EL, Johnson BF. Multiclinic com- 3. Sanders GL, Routledge PA, Rao JG, Gales GM, Davies DM, parison of labetalol to metoprolol in treatment of mild to moder- Rawlins MD. Labetalol, a cross-over double-blind controlled ate systemic hypertension. J Med 1983; 75(4A):54-67. trial. Eur ] Clin Pharmacol 1978; 14:301-304. Am

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7. Wallin JD. Antihypertensives and their impact on renal func- 30. Weidmann P, De Chatel R, Ziegler WH, Flammer J, Reubi F. tion. Am J Med 1983; 75(4A):103-108. Alpha- and beta-adrenergic blockade with oral administered labe- 8. Cubberly RB. Labetalol as monotherapy in hypertensive black talol in hypertension. Studies on blood volume, plasma renin and patients. J Clin Hypertens 1985; 4:304-314. aldosterone and catecholamine excretion. Am J Cardiol 1978; 9. Flamenbaum W, Weber MA, McMahon FG, Materson BJ, Carr 41:570-576. AA,Poland M. Monotherapy with labetalol compared with pro- 31. Kolloch R, Miano L, De Quattro V. Labetalol and urinary pranolol. Differential effects by race. J Clin Hypertens 1985; 1:59- catecholamines. Br Med J 1979; 1:268-269. 69. 32. Miano L, Kolloch R, De Quattro V. Increased catecholamine 10. Giles TD, Weber M, Bartels DW, silberman HM, Gilderman excretion after labetalol therapy: a spurious effect of drug metabo- LP, Burris JF. Treatment of isolated systolic hypertension with lites. Clin Chim Acta 1979; 95:211-217. labetalol in the elderly. Arch Intern Med 1990; 150:974-976. 33. Aggerbeck M, Guellaen G, Hanoune J. Biochemical evidence 11. Applegate WB, Borhani N, DeQuattro V, et al. Comparison of for the dual action of labetalol on alpha- and beta-adrenoceptors. labetalol versus enalapril as monotherapy in elderly patients with Br J Pharmacol 1978; 62:543-548. hypertension: results of 24 hour ambulatory blood pressure moni- 34. Farmer JB, Kennedy I, Levy GP, Marshall RJ. Pharmacology toring. Am J Med 1991; 90:198-205. of AH 5158: a drug which blocks both alpha and beta adrenocep- 12. Wilson DJ, Wallin JD, Vlachakis ND, et al. Intravenous labe- tors. Br J Pharmacol 1972; 45:660-675. talol in tbe treatment of severe hypertension and hypertensive 35. Richards DA, Prichard BNC, Hernandez R. Circulatory ef- emergencies. Am J Med 1983; 75(4A):95-102. fects of noradrenaline and before and after labetalol. Br 13. Rumboldt Z, Bagatin J, Vidovic A. Diazoxide vs labetalol: a J Clin Pharmacol, 1979; 7:371-378. crossover comparison of short-term effects in hypertension. Int J 36. Maconochie JG, Richards DA, Woodings EP. Modifications of Clin Pharmacol Res 1983; 3:47-54. pressor responses induced by "cold". Br J Clin Pharmacol 1977; 14. Richards DA, Maconochie JG, Bland RE, Hopkins R, Wood- 4:389. ings EP, Martin LE. Relationship between plasma concentra- 37. Drew GM, Gower AJ, Marriott AS. Pharmacological charac- tions and pharmacological effects of labetalol. Eur J Clin Pharma- terization of alpha-adrenoceptors which mediate clonidine-in- col 1977; 11:85-90. duced sedation [abstract]. Br J Pharmacol 1977; 61:468P. 15. Lund-Johansen P. Short- and long-term (six years) hemody- 38. Anfossi G, Trovati M, Lanzio M, Mularoni E, Massucco P, namic effects of labetalol in essential hypertension. Am J Med Emanuelli G. Effect of labetalol on human platelet function. 1983; 75(4A):24-31. Clin Exp Pharmacol Physiol 1988; 15:437-448. 16. Baum T, Sybertz EJ. Pharmacology of labetalol in experimental 39. Koch G. Haemodynamic effects of a combined alpha- and beta- animals. AmJ Med 1983; 75(4A):15-23. adrenoceptor blockade after intravenous labetalol in hypertensive 17. Riley AJ. Some further evidence for activity of patients at rest and during exercise. Br J Clin Pharmacol 1976; labetalol. Br J Clin Pharmacol 1980; 9:517-518. 3(4 Suppl 3):725-728. 18. Kanto J, Allonen H, Kleimola T, Mantyla R. Pharmacokinetics 40. Koch G. Haemodynamic adaptation at rest and during exercise of labetalol in healthy volunteers. Int J Clin Pharmacol Ther to long-term antihypertensive treatment with combined alpha- Toxicol 1981; 19:41-44. and beta-adrenoreceptor blockade by Labetalol. Br Heart J 1979; 19. McNeil JJ, Anderson AE, Louis WJ, Morgan DJ. Pharmacoki- 41:192-198. netics and pharmacodynamic studies of labetalol in hypertensive 41. Cruz F, O'Neill WM Jr, Clifton GG, Wallin JD. Effects of subjects. Br J Clin Pharmacol 1979; 8

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51. Lamming GD, Broughton Pipkin FB, Symonds EM. Compari- 57. Wesley AG, Hariparsad D, Pather M, Rocke DA. Labetalol in son of the alpha and beta blocking drug, labetalol and methyldopa tetanus. The treatment of sympathetic nervous system overactiv- in the treatment of moderate and severe pregnancy-induced hy- ity. Anaesthesia 1983; 38:243-249. pertension. Clin Exp Hypertens 1980; 2:865-895. 58. Bonomi L, Perietti S, Bellucci R, Massa F, Naya E.. Ocular 52. Cruickshank DJ, Robertson AA, Campbell DM. Does labeta- hypotensive actions of labetalol in rabbit and human eyes. Al- lol influence the development of proteinuria in pregnancy hyper- brecht Von Graefes Arch Klin Exp Ophthalmol 1981; 217:175- tension? A randomized controlled study. Eur J Obstet Gynecol 181. Reprod Biol 1992; 45:47-51. 59. Michelson EL, Frishman WH, Lewis JE, et al. Multicenter 53. Gardin A, Devey DA, Dommisse J. Intravenous labetalol and clinical evaluation of long-term efficacy and safety of labetalol in dihydralazine in severe hypertension in pregnancy. Clin Exp Hy- treatment of hypertension. Am J Med 1983; 75(4A):68-80. pertens 1982; 1:371-373. 60. George RB, Burford JG, Tinasewitz GT. Effects of abetalol in 54. Rosei EA, Brown JJ, Lever AF, Robertson AF, Robertson JI, hypertensive patients with chronic obstructive pulmonary disease. Trust PM. Treatment of pheochromocytoma and of Clonidine Chest 1983; 83:457-460. withdrawal hypertension with labetalol. Br J Clin Pharmacol 61. Hombach V, Kochs M, Hoher M, et al. Hemodynamic profile 1976; 3(4 Suppl 3):809-815. of Carvedilol. Eur] Clin Pharmacol 1990; 38:S101-S103. 55. Rosenthal T, Rabinowitz B, Boichis H, Elazar E, Brauner A, 62. Ollivier JP, Durier P, Bussiere JL, Gayet JL. Safety and efficacy Neufeld HN. Use of Labetalol in hypertensive patients during of once-daily Carvedilol vs twice-daily labetalol in mild to moder- discontinuation of Clonidine therapy. Eur] Clin Pharmacol 1981; ate hypertension. Eur J Clin Pharmacol 1990; 38(Suppl 2):S164- 20:237-240. S166. 56. Gay GR, Loper KA. The use of labetalol in the management of cocaine crisis. Ann Emerg Med 1988; 17:282-283.

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