Clin Investig (1992) 70:$39 $42
Glinical Investigator © Springer-Verlag 1992
Clinical experience with dual-acting drugs in hypertension K.H. Rahn Department of Medicine D, Universit/it Mfinster
Summary. There are now several antihypertensive agents with dual actions. Among these, labetalol has been studied most extensively. The drug has a place in the chronic treatment of hypertension and in the therapy of hypertensive emergencies. Carvedilol, now available in Germany, has been shown to be effective in different forms of hypertension. Celiprolol binds to beta 1- and beta 2receptors. This drug also binds to alpha 2-receptors. It is not clear, at present, whether or not this binding property contributes to its antihypertensive effect.
Key words: Carvedilol - Celiprolol - Labetalol Dual-acting drugs - Hypertension
In the treatment of patients with hypertension, drugs with different mechanisms of action are frequently combined. The reason for this combination of drugs is that decreasing blood pressure by one mechanism often leads to activation of compensatory mechanisms working against this blood pressure reduction. Thus, during antihypertensive treatment with vasodilating agents, reflex stimulation of the heart occurs, which causes cardiac output to rise. In turn, the blood-pressure-lowering effect of the vasodilator is antagonized. Combination of several drugs may complicate therapy because of differences in the onset and duration of action. Combining several blood-pressure-lowering mechanisms in one drug molecule could prevent these difficulties. There are now several drugs with dual mode of action available for the treatment of hypertension. Labetalol has been extensively studied and is now available worldwide for the treatment of hypertensive patients. Celiprolol is broadly available in Europe. Carvedilol has recently become
available in Germany and is a drug that combines alpha- and beta-adrenergic blocking activities. It has been demonstrated to be effective in different forms of hypertension. Celiprolol is a beta-blocker that binds with a higher affinity to the beta lthan to the beta 2-receptors [17]. Celiprolol also binds to alpha 2-receptors. However, it remains to be proven that binding to alpha 2-receptors contributes to the antihypertensive action of this drug. The effects of carvedilol in patients with hypertension will be discussed in subsequent papers. Therefore, here I shall concentrate on the actions of labetalol. Labetalol combines alpha 1- and beta-receptorblocking activities. The drug contains two asymmetric carbon atoms and the clinical formulation of the drug consists of equal proportions of the four resulting optical isomers. These isomers have been shown to differ widely in their pharmacological profile. Most of the betareceptor blockade can be attributed to the RR isomer [8]. In contrast, most of the alpha l-blocking activity is due to the SR isomer. The betablocking activity of the other two isomers is negligible. It has now been clearly demonstrated that the four optical isomers of labetalol differ in their pharmacokinetic properties. For this reason, the contribution of the individual isomers to the total concentration of labetalol in plasma and tissues changes during long-term treatment with the drug. There are data suggesting that this results in alterations of the pharmacodynamic profile. In this respect, we should pay particular attention to a study by Semplicini et al. [16]. The authors determined the effect of isoprenaline on heart rate and the influence of phenylephrine on blood pressure in subjects with essential hypertension before and repeatedly during 6-month treatment with 200 mg oral doses of labetalol 3 times a day. Treat-
$40 Table 1. Pharmacokinetic data of labetalol Bioavailability of oral doses Plasma protein binding Elimination half-life Whole blood clearance
40% 50% 8h 1000 ml/min
ment with labetalol caused a parallel shift of the isoprenaline dose-response curve to the right, indicating beta-receptor blockade. This beta-blocking activity of labetalol was maintained throughout the whole treatment period, although the effect was less pronounced after 6 months. During treatment days 3 and 6, labetalol also antagonized the effect of phenylephrine on systolic blood pressure, suggesting alpha-receptor blockade. This labetalol action had, however, disappeared after 1 and 6 months of treatment with the drug. The data published by Semplicini et al. [16] suggest that the alpha-receptor blocking activity of labetalol decreases during chronic treatment with the drug. This decrease in alpha-receptor blocking activity with no change in beta-receptor blockade could result from the stereoselective metabolism of labetalol. There is, however, one problem with these authors' study. Whereas labetalol lowered the patients' blood pressure 3 and 6 days as well as 1 month after the start of treatment, the blood pressure had returned to the control levels after 6 months. This could be caused by the decline of alpha-receptor blocking activity. Together with some decrease of beta-receptor blocking action, it could, however, also be due to poor patient compliance. Unfortunately, this was not tested in the study. When given in oral doses, the bioavailability of labetalol averages about 40% (Table 1) with considerable interindividual variation [10]. This rather low bioavailability is due to the extensive first-pass metabolism of the drug. The bioavailability of oral labetalol increases somewhat when the drug is taken together with food. Furthermore, there is some increase in the bioavailability with increasing age. In patients with chronic liver disease, the bioavailability of labetalol may be considerably enhanced. Treatment with cimetidine strongly increases the oral bioavailability of labetalol [6]. In this study, the four isomers of labetalol were determined separately. This determination revealed that cimetidine did not increase the plasma concentrations of the RR isomer, whereas the plasma levels of the other three isomers rose significantly. This study thus provides evidence of a stereoselective disposition of labetalol in man.
Plasma protein binding in labetalol amounts to approximately 50%. In man, labetalol is extensively metabolized. Less than 5% of a dose is excreted unchanged in the urine [10]. The terminal phase half-life of the drug averages to 8 h [6]. The whole blood clearance is approximately 1000 ml/ min. Half-life and clearance of the drug are not altered in patients with severe renal failure [10]. No significant amounts of the drug are removed by hemodialysis and by continuous ambulatory peritoneal dialysis [4]. In hypertensive patients, intravenous application of labetalol causes blood pressure to decrease within minutes, as shown in a study by [7]. With intravenous doses ranging from 0.5-3 mg/kg, the effect on systolic and diastolic blood pressure is clearly dose-dependent and lasts about 12 h [19]. Because of the rapid onset of action, intravenous doses of labetalol can be used for the treatment of hypertensive emergencies. Numerous studies have demonstrated that oral labetalol given in the form of monotherapy can decrease blood pressure in patients with hypertension [13]. Patients with mild hypertension may be controlled with drug doses as low as 200 rag/day. In general, oral doses not exceeding 1600 mg/day are used for the chronic treatment of hypertension, although some patients with more severe disease forms may be successfully treated with higher doses. Usually, the blood-pressure-lowering effect of oral labetalol starts after about 2 h and lasts for 8-12 h. Therefore, it is advisable to give labetalol in the form of 2-3 oral doses per day. In some studies, oral treatment with labetalol was continued for many years, and the drug maintained its blood-pressure effect without the development of tolerance [13]. The hemodynamic effects of long-term treatment with oral doses of labetalol have been studied by Lund-Johansen [9]. During 1-year oral treatment, the drug reduced mean arterial blood pressure both at rest in the sitting position and during exercise on a bicycle ergometer. Cardiac output and heart rate were decreased. Total peripheral resistance was reduced by labetalol at all exercise levels studied. The decrease of this parameter at rest in the sitting position failed to reach statistical significance. However, during rest in a supine position labetalol significantly diminished total peripheral resistance. This hemodynamic pattern is atypical for a pure beta-blocker without intrinsic sympathomimetic activity and suggests the contribution of alpha-blockade. Blood volume and body weight may increase in some hypertensive patients during long-term
$41 Table 2. Side effects of labetalol Heart failure Bronchial constriction Disturbed peripheral circulation Postural hypotension Hepatotoxicity
treatment with labetalol (Weidmann et al. 1978). In a study by Rasmussen and Nielsen [15], the effect of labetalol on plasma volume and extracellular volume did not reach statistical significance in the whole group of hypertensive patients studied. However, in some patients both parameters were about 20% higher during treatment with the drug than during the placebo period. Labetalol has been shown to have variable effects on kidney hemodynamics. Whereas Rasmussen and Nielsen [15] found the glomerular filtration rate to be unchanged during labetalol therapy, the drug decreased both glomerular filtration rate and renal plasma flow by about 20% in a study by Keusch et al. [5]. This rather small rate of decline has apparently no consequences for hypertensive patients treated with the drug. During longterm administration of labetalol, there is in general some decrease of plasma renin activity and often also of plasma aldosterone concentration [8]. In view of the increase of plasma volume, which occurs in some hypertensive patients during treatment with labetalol, a combination of this drug with a diuretic seems to be a logical approach. The additive antihypertensive effect of labetalol and diuretics has been confirmed in several studies
[13]. The frequency of side effects caused by labetalol seems to be comparable to the frequency of unwanted reactions to beta-blockers and diuretics. In long-term studies, labetalol had to be withdrawn in about 10% of the patients because of the side effects [13]. Most adverse reactions to labetalol are apparently due to the beta-receptor blocking activity of the drug. These are heart failure, bronchial constriction and disturbed peripheral circulation (Table 2). In addition, labetalol sometimes causes postural hypotension, which could be the result of alpha-receptor blockade. Recently, there has been concern about the hepatotoxic effects of labetalol. A patient with fatal labetalol-induced hepatic injury has been reported by Douglas et al. [2]. In 1990, the Food and Drug Administration of the USA conducted an analysis of all post-marketing reports of hepatotoxicity in which exposure to labetalol was mentioned [1]. A total of 11 case reports strongly implicated labetalol as the offending
agent. In 3 of the patients, the hepatotoxicity was fatal. In view of the wide use of labetalol, the incidence of hepatotoxicity is apparently low and may be compared with the frequency of hepatic damage caused by methyldopa. Nevertheless, it seems advisable to receive baseline liver function tests before starting therapy with labetalol and to retest liver function periodically during treatment with the drug. If laboratory evidence of liver injury is noted, labetalol therapy should be stopped and never restarted. Beta-receptor blocking agents not rarely cause muscular fatigue. It has been shown that long-term treatment with propranolol decreases endurance time during submaximal exercise in hypertensives [11]. In contrast, labetalol had no influence on exercise tolerance (Feit et al. 1985). Labetalol given in the form of monotherapy seems to be approximately as effective as an antihypertensive agent as other potent hypotensive drugs, for instance methyldopa (Prichard 1984). In a study by Prichard and Boakes [14], bloodpressure control was improved in hypertensive subjects when labetalol was substituted for fl-blockers. Recently, labetalol in daily oral doses ranging from 200-1600 mg/day was compared with ateno1ol in doses from 50-100 mg/day in patients with essential hypertension (Townsend et al. 1990). In this multicenter study, labetalol was shown to be more effective as a blood-pressure-lowering agent than the fl-blocker. Little is known about the efficacy of labetalol as an antihypertensive agent in hypertensive patients resistant to other blood-pressure-lowering drugs. Morgan et al. [12] found that labetalol was satisfactorily effective in some patients resistant to other antihypertensive agents. In an open study, we substituted labetalol in combination with hydrochlorothiazide and amiloride for a therapy consisting of propranolol, hydralazine, hydrochlorothiazide and amiloride. The combination of beta-blocker, vasodilator and diuretics had been unsatisfactorily effective in lowering blood pressure in 12 patients with moderate-tosevere hypertension. In these subjects, labetalol, too, was insufficiently effective when combined with the diuretics. In contrast, captopril combined with the diuretics led to acceptable blood-pressure levels. Taken together, labetalol can be used as an antihypertensive agent in patients with different degrees of severity. In mild hypertension, labetalol will be sufficiently effective when given in the form of monotherapy. In view of the reported side ef-
$42
fects of labetalol, beta-blockers, calcium antagonists, ACE-inhibitors and diuretics would, however, be preferable in this situation. In patients resistant to other antihypertensive agents, labetalol, too, will frequently not be satisfactorily effective. The place of labetalol seems to be mainly in those patients in whom one intends to combine a betablocker with a vasodilating drug. Labetalol can be given intravenously in hypertensive emergencies. The drug clearly has a place in situations where blood pressure elevation is due to activation of both alpha- and beta-receptors, such as pheochromocytoma and clonidine withdrawal. References 1. Clark JA, Zimmermann HJ, Tanner LA (1990) Labetalol hepatotoxicity. Ann Int Med 113:210-213 2. Douglas DD, Yang RD, Jensen P, Thiele DL (1989) Fatal labetalol-induced hepatic injury. Am J Med 87 : 235-236 3. Feit A, Holtzman R, Cohen M, E1-Sherif N (1985) Effect of labetalol on exercise tolerance and double product in mild to moderate essential hypertension. Am J Med 78: 937-941 4. Halstenson CE, Opsahl JA, Pence TV, Luke DR, Sirgo MA, Plachetka JR, Abraham PA, Matzke GR (1986) The disposition and dynamics of labetalol in patients on dialysis. Clin Pharmacol Ther 40:462-468 5. Keusch G, Weidmann P, Ziegler WH, Chatel R de, Reubi FC (1980) Effects of chronic alpha and beta adrenoceptor blockade with labetalol on plasma catecholamines and renal function in hypertension. Klin Wochenschr 58 : 25-29 6. Lalonde RL, O'Rear TL, Wainer IW, Drda KD, Herring VL, Bottorff MB (1990) Labetalol pharmacokinetics and pharmacodynamics: evidence of stereoselective disposition. Clin Pharmacol Ther 48:509-519 7. Lebel M, Langlois S, Belleau LJ, Grose JH (1985) Labetalol infusion in hypertensive emergencies. Clin Pharmacol Ther 37:615-618 8. Louis WJ, McNeill JJ, Drummer OH (1984) The pharmacology of combined alpha-beta-blockade I. Drugs 28 : 16-34 9. Lund-Johansen P (1984) The pharmacology of combined alpha-beta-blockade II. Drugs 28:35 50
10. McNeill, Louis WJ (1984) Clinical pharmacokinetics of labetalol. Clin Pharmacokin 9:157-168 11. Mooy J, Baak M van, B6hm R, Does R, Petri H, Kemenade J van, Rahm KH (1987) The effects of verapamil and propranolol on exercise tolerance in hypertensive patients. Clin Pharmacol Ther 41:490-495 12. Morgan T, Gillies A, Morgan G, Adam W (1978) The effect of labetalol in the treatment of severe drug-resistant hypertension. Med J Aust 1 : 393-396 13. Prichard BNC (1984) Combined alpha- and beta-receptor inhibition in the treatment of hypertension. Drugs 28:51-68 14. Prichard BNC, Boakes AJ (1976) Labetalol in long-term treatment of hypertension. Br J Clin Pharmacol 3 : 743-750 15. Rasmussen S, Nielsen PE (1981) Blood pressure, body fluid volumes and glomerular filtration rate during treatment with labetalol in essential hypertension. Br J Clin Pharmacol 12 : 349-353 16. Semplicini A, Pessina AC, Rossie GP, Hlede M, Morandin F (1983) Alpha-adrenoceptor blockade by labetalol during long-term dosing. Clin Pharmacol Ther 33:278-283 17. Sponer G, Bartsch W, Hooper RG (1990) Drugs acting on multiple receptors :/~-blockers with additional properties. In: Ganten D, Mulrow PJ (eds) Pharmacology of antihypertensive therapeutics. Springer, Berlin Heidelberg New York, pp 131-226 18. Townsend RR, DiPette DJ, Goodman R, Blumfield D, Cronin R, Gradman A, Katz LA, McCarthy EP, Sopko G (1990) Combined alpha/beta-blockade versus//1-selective btockade in essential hypertension in black and white patients. Clin Pharmacol Ther 48 : 665-675 19. Vlachakis ND, Maronde RF, Maloy JW, Medakovic M, Kassem N (1985) Pharmacodynamics of intravenous labeta1ol and follow-up therapy with oral labetalol. Clin Pharmacol Ther 38 : 503-508 20. Weidmann P, Chatel R de, Ziegler WH, Flammer J, Reubi F (1978) Alpha and beta adrenergic blockade with oraliy administered labetalol in hypertension. Studies on blood volume, plasma renin and aldosterone and catecholamine excretion. Am J Cardiol 41 : 570-576
Prof. Dr. K.H. Rahn Department of Medicine D Universitfit Mfinster Albert Schweitzer Strasse 33 W-4400 Miinster, FRG
Glinical Investigator © Springer-Verlag 1992
Clinical experience with dual-acting drugs in hypertension K.H. Rahn Department of Medicine D, Universit/it Mfinster
Summary. There are now several antihypertensive agents with dual actions. Among these, labetalol has been studied most extensively. The drug has a place in the chronic treatment of hypertension and in the therapy of hypertensive emergencies. Carvedilol, now available in Germany, has been shown to be effective in different forms of hypertension. Celiprolol binds to beta 1- and beta 2receptors. This drug also binds to alpha 2-receptors. It is not clear, at present, whether or not this binding property contributes to its antihypertensive effect.
Key words: Carvedilol - Celiprolol - Labetalol Dual-acting drugs - Hypertension
In the treatment of patients with hypertension, drugs with different mechanisms of action are frequently combined. The reason for this combination of drugs is that decreasing blood pressure by one mechanism often leads to activation of compensatory mechanisms working against this blood pressure reduction. Thus, during antihypertensive treatment with vasodilating agents, reflex stimulation of the heart occurs, which causes cardiac output to rise. In turn, the blood-pressure-lowering effect of the vasodilator is antagonized. Combination of several drugs may complicate therapy because of differences in the onset and duration of action. Combining several blood-pressure-lowering mechanisms in one drug molecule could prevent these difficulties. There are now several drugs with dual mode of action available for the treatment of hypertension. Labetalol has been extensively studied and is now available worldwide for the treatment of hypertensive patients. Celiprolol is broadly available in Europe. Carvedilol has recently become
available in Germany and is a drug that combines alpha- and beta-adrenergic blocking activities. It has been demonstrated to be effective in different forms of hypertension. Celiprolol is a beta-blocker that binds with a higher affinity to the beta lthan to the beta 2-receptors [17]. Celiprolol also binds to alpha 2-receptors. However, it remains to be proven that binding to alpha 2-receptors contributes to the antihypertensive action of this drug. The effects of carvedilol in patients with hypertension will be discussed in subsequent papers. Therefore, here I shall concentrate on the actions of labetalol. Labetalol combines alpha 1- and beta-receptorblocking activities. The drug contains two asymmetric carbon atoms and the clinical formulation of the drug consists of equal proportions of the four resulting optical isomers. These isomers have been shown to differ widely in their pharmacological profile. Most of the betareceptor blockade can be attributed to the RR isomer [8]. In contrast, most of the alpha l-blocking activity is due to the SR isomer. The betablocking activity of the other two isomers is negligible. It has now been clearly demonstrated that the four optical isomers of labetalol differ in their pharmacokinetic properties. For this reason, the contribution of the individual isomers to the total concentration of labetalol in plasma and tissues changes during long-term treatment with the drug. There are data suggesting that this results in alterations of the pharmacodynamic profile. In this respect, we should pay particular attention to a study by Semplicini et al. [16]. The authors determined the effect of isoprenaline on heart rate and the influence of phenylephrine on blood pressure in subjects with essential hypertension before and repeatedly during 6-month treatment with 200 mg oral doses of labetalol 3 times a day. Treat-
$40 Table 1. Pharmacokinetic data of labetalol Bioavailability of oral doses Plasma protein binding Elimination half-life Whole blood clearance
40% 50% 8h 1000 ml/min
ment with labetalol caused a parallel shift of the isoprenaline dose-response curve to the right, indicating beta-receptor blockade. This beta-blocking activity of labetalol was maintained throughout the whole treatment period, although the effect was less pronounced after 6 months. During treatment days 3 and 6, labetalol also antagonized the effect of phenylephrine on systolic blood pressure, suggesting alpha-receptor blockade. This labetalol action had, however, disappeared after 1 and 6 months of treatment with the drug. The data published by Semplicini et al. [16] suggest that the alpha-receptor blocking activity of labetalol decreases during chronic treatment with the drug. This decrease in alpha-receptor blocking activity with no change in beta-receptor blockade could result from the stereoselective metabolism of labetalol. There is, however, one problem with these authors' study. Whereas labetalol lowered the patients' blood pressure 3 and 6 days as well as 1 month after the start of treatment, the blood pressure had returned to the control levels after 6 months. This could be caused by the decline of alpha-receptor blocking activity. Together with some decrease of beta-receptor blocking action, it could, however, also be due to poor patient compliance. Unfortunately, this was not tested in the study. When given in oral doses, the bioavailability of labetalol averages about 40% (Table 1) with considerable interindividual variation [10]. This rather low bioavailability is due to the extensive first-pass metabolism of the drug. The bioavailability of oral labetalol increases somewhat when the drug is taken together with food. Furthermore, there is some increase in the bioavailability with increasing age. In patients with chronic liver disease, the bioavailability of labetalol may be considerably enhanced. Treatment with cimetidine strongly increases the oral bioavailability of labetalol [6]. In this study, the four isomers of labetalol were determined separately. This determination revealed that cimetidine did not increase the plasma concentrations of the RR isomer, whereas the plasma levels of the other three isomers rose significantly. This study thus provides evidence of a stereoselective disposition of labetalol in man.
Plasma protein binding in labetalol amounts to approximately 50%. In man, labetalol is extensively metabolized. Less than 5% of a dose is excreted unchanged in the urine [10]. The terminal phase half-life of the drug averages to 8 h [6]. The whole blood clearance is approximately 1000 ml/ min. Half-life and clearance of the drug are not altered in patients with severe renal failure [10]. No significant amounts of the drug are removed by hemodialysis and by continuous ambulatory peritoneal dialysis [4]. In hypertensive patients, intravenous application of labetalol causes blood pressure to decrease within minutes, as shown in a study by [7]. With intravenous doses ranging from 0.5-3 mg/kg, the effect on systolic and diastolic blood pressure is clearly dose-dependent and lasts about 12 h [19]. Because of the rapid onset of action, intravenous doses of labetalol can be used for the treatment of hypertensive emergencies. Numerous studies have demonstrated that oral labetalol given in the form of monotherapy can decrease blood pressure in patients with hypertension [13]. Patients with mild hypertension may be controlled with drug doses as low as 200 rag/day. In general, oral doses not exceeding 1600 mg/day are used for the chronic treatment of hypertension, although some patients with more severe disease forms may be successfully treated with higher doses. Usually, the blood-pressure-lowering effect of oral labetalol starts after about 2 h and lasts for 8-12 h. Therefore, it is advisable to give labetalol in the form of 2-3 oral doses per day. In some studies, oral treatment with labetalol was continued for many years, and the drug maintained its blood-pressure effect without the development of tolerance [13]. The hemodynamic effects of long-term treatment with oral doses of labetalol have been studied by Lund-Johansen [9]. During 1-year oral treatment, the drug reduced mean arterial blood pressure both at rest in the sitting position and during exercise on a bicycle ergometer. Cardiac output and heart rate were decreased. Total peripheral resistance was reduced by labetalol at all exercise levels studied. The decrease of this parameter at rest in the sitting position failed to reach statistical significance. However, during rest in a supine position labetalol significantly diminished total peripheral resistance. This hemodynamic pattern is atypical for a pure beta-blocker without intrinsic sympathomimetic activity and suggests the contribution of alpha-blockade. Blood volume and body weight may increase in some hypertensive patients during long-term
$41 Table 2. Side effects of labetalol Heart failure Bronchial constriction Disturbed peripheral circulation Postural hypotension Hepatotoxicity
treatment with labetalol (Weidmann et al. 1978). In a study by Rasmussen and Nielsen [15], the effect of labetalol on plasma volume and extracellular volume did not reach statistical significance in the whole group of hypertensive patients studied. However, in some patients both parameters were about 20% higher during treatment with the drug than during the placebo period. Labetalol has been shown to have variable effects on kidney hemodynamics. Whereas Rasmussen and Nielsen [15] found the glomerular filtration rate to be unchanged during labetalol therapy, the drug decreased both glomerular filtration rate and renal plasma flow by about 20% in a study by Keusch et al. [5]. This rather small rate of decline has apparently no consequences for hypertensive patients treated with the drug. During longterm administration of labetalol, there is in general some decrease of plasma renin activity and often also of plasma aldosterone concentration [8]. In view of the increase of plasma volume, which occurs in some hypertensive patients during treatment with labetalol, a combination of this drug with a diuretic seems to be a logical approach. The additive antihypertensive effect of labetalol and diuretics has been confirmed in several studies
[13]. The frequency of side effects caused by labetalol seems to be comparable to the frequency of unwanted reactions to beta-blockers and diuretics. In long-term studies, labetalol had to be withdrawn in about 10% of the patients because of the side effects [13]. Most adverse reactions to labetalol are apparently due to the beta-receptor blocking activity of the drug. These are heart failure, bronchial constriction and disturbed peripheral circulation (Table 2). In addition, labetalol sometimes causes postural hypotension, which could be the result of alpha-receptor blockade. Recently, there has been concern about the hepatotoxic effects of labetalol. A patient with fatal labetalol-induced hepatic injury has been reported by Douglas et al. [2]. In 1990, the Food and Drug Administration of the USA conducted an analysis of all post-marketing reports of hepatotoxicity in which exposure to labetalol was mentioned [1]. A total of 11 case reports strongly implicated labetalol as the offending
agent. In 3 of the patients, the hepatotoxicity was fatal. In view of the wide use of labetalol, the incidence of hepatotoxicity is apparently low and may be compared with the frequency of hepatic damage caused by methyldopa. Nevertheless, it seems advisable to receive baseline liver function tests before starting therapy with labetalol and to retest liver function periodically during treatment with the drug. If laboratory evidence of liver injury is noted, labetalol therapy should be stopped and never restarted. Beta-receptor blocking agents not rarely cause muscular fatigue. It has been shown that long-term treatment with propranolol decreases endurance time during submaximal exercise in hypertensives [11]. In contrast, labetalol had no influence on exercise tolerance (Feit et al. 1985). Labetalol given in the form of monotherapy seems to be approximately as effective as an antihypertensive agent as other potent hypotensive drugs, for instance methyldopa (Prichard 1984). In a study by Prichard and Boakes [14], bloodpressure control was improved in hypertensive subjects when labetalol was substituted for fl-blockers. Recently, labetalol in daily oral doses ranging from 200-1600 mg/day was compared with ateno1ol in doses from 50-100 mg/day in patients with essential hypertension (Townsend et al. 1990). In this multicenter study, labetalol was shown to be more effective as a blood-pressure-lowering agent than the fl-blocker. Little is known about the efficacy of labetalol as an antihypertensive agent in hypertensive patients resistant to other blood-pressure-lowering drugs. Morgan et al. [12] found that labetalol was satisfactorily effective in some patients resistant to other antihypertensive agents. In an open study, we substituted labetalol in combination with hydrochlorothiazide and amiloride for a therapy consisting of propranolol, hydralazine, hydrochlorothiazide and amiloride. The combination of beta-blocker, vasodilator and diuretics had been unsatisfactorily effective in lowering blood pressure in 12 patients with moderate-tosevere hypertension. In these subjects, labetalol, too, was insufficiently effective when combined with the diuretics. In contrast, captopril combined with the diuretics led to acceptable blood-pressure levels. Taken together, labetalol can be used as an antihypertensive agent in patients with different degrees of severity. In mild hypertension, labetalol will be sufficiently effective when given in the form of monotherapy. In view of the reported side ef-
$42
fects of labetalol, beta-blockers, calcium antagonists, ACE-inhibitors and diuretics would, however, be preferable in this situation. In patients resistant to other antihypertensive agents, labetalol, too, will frequently not be satisfactorily effective. The place of labetalol seems to be mainly in those patients in whom one intends to combine a betablocker with a vasodilating drug. Labetalol can be given intravenously in hypertensive emergencies. The drug clearly has a place in situations where blood pressure elevation is due to activation of both alpha- and beta-receptors, such as pheochromocytoma and clonidine withdrawal. References 1. Clark JA, Zimmermann HJ, Tanner LA (1990) Labetalol hepatotoxicity. Ann Int Med 113:210-213 2. Douglas DD, Yang RD, Jensen P, Thiele DL (1989) Fatal labetalol-induced hepatic injury. Am J Med 87 : 235-236 3. Feit A, Holtzman R, Cohen M, E1-Sherif N (1985) Effect of labetalol on exercise tolerance and double product in mild to moderate essential hypertension. Am J Med 78: 937-941 4. Halstenson CE, Opsahl JA, Pence TV, Luke DR, Sirgo MA, Plachetka JR, Abraham PA, Matzke GR (1986) The disposition and dynamics of labetalol in patients on dialysis. Clin Pharmacol Ther 40:462-468 5. Keusch G, Weidmann P, Ziegler WH, Chatel R de, Reubi FC (1980) Effects of chronic alpha and beta adrenoceptor blockade with labetalol on plasma catecholamines and renal function in hypertension. Klin Wochenschr 58 : 25-29 6. Lalonde RL, O'Rear TL, Wainer IW, Drda KD, Herring VL, Bottorff MB (1990) Labetalol pharmacokinetics and pharmacodynamics: evidence of stereoselective disposition. Clin Pharmacol Ther 48:509-519 7. Lebel M, Langlois S, Belleau LJ, Grose JH (1985) Labetalol infusion in hypertensive emergencies. Clin Pharmacol Ther 37:615-618 8. Louis WJ, McNeill JJ, Drummer OH (1984) The pharmacology of combined alpha-beta-blockade I. Drugs 28 : 16-34 9. Lund-Johansen P (1984) The pharmacology of combined alpha-beta-blockade II. Drugs 28:35 50
10. McNeill, Louis WJ (1984) Clinical pharmacokinetics of labetalol. Clin Pharmacokin 9:157-168 11. Mooy J, Baak M van, B6hm R, Does R, Petri H, Kemenade J van, Rahm KH (1987) The effects of verapamil and propranolol on exercise tolerance in hypertensive patients. Clin Pharmacol Ther 41:490-495 12. Morgan T, Gillies A, Morgan G, Adam W (1978) The effect of labetalol in the treatment of severe drug-resistant hypertension. Med J Aust 1 : 393-396 13. Prichard BNC (1984) Combined alpha- and beta-receptor inhibition in the treatment of hypertension. Drugs 28:51-68 14. Prichard BNC, Boakes AJ (1976) Labetalol in long-term treatment of hypertension. Br J Clin Pharmacol 3 : 743-750 15. Rasmussen S, Nielsen PE (1981) Blood pressure, body fluid volumes and glomerular filtration rate during treatment with labetalol in essential hypertension. Br J Clin Pharmacol 12 : 349-353 16. Semplicini A, Pessina AC, Rossie GP, Hlede M, Morandin F (1983) Alpha-adrenoceptor blockade by labetalol during long-term dosing. Clin Pharmacol Ther 33:278-283 17. Sponer G, Bartsch W, Hooper RG (1990) Drugs acting on multiple receptors :/~-blockers with additional properties. In: Ganten D, Mulrow PJ (eds) Pharmacology of antihypertensive therapeutics. Springer, Berlin Heidelberg New York, pp 131-226 18. Townsend RR, DiPette DJ, Goodman R, Blumfield D, Cronin R, Gradman A, Katz LA, McCarthy EP, Sopko G (1990) Combined alpha/beta-blockade versus//1-selective btockade in essential hypertension in black and white patients. Clin Pharmacol Ther 48 : 665-675 19. Vlachakis ND, Maronde RF, Maloy JW, Medakovic M, Kassem N (1985) Pharmacodynamics of intravenous labeta1ol and follow-up therapy with oral labetalol. Clin Pharmacol Ther 38 : 503-508 20. Weidmann P, Chatel R de, Ziegler WH, Flammer J, Reubi F (1978) Alpha and beta adrenergic blockade with oraliy administered labetalol in hypertension. Studies on blood volume, plasma renin and aldosterone and catecholamine excretion. Am J Cardiol 41 : 570-576
Prof. Dr. K.H. Rahn Department of Medicine D Universitfit Mfinster Albert Schweitzer Strasse 33 W-4400 Miinster, FRG
