Br. J. clin. Pharmac. (1979), 8, 89S-93S
CLINICAL PHARMACOLOGY OF LABETALOL D.A. RICHARDS Glaxo Group Research Ltd, Ware, Hertfordshire SG12 ODS, UK
B.N.C. PRICHARD University College Hospital Medical School, University Street, London WC1 E 6JJ, UK
1 The clinical pharmacology of labetalol has been evaluated using pharmacological and physiological test methods. 2 Labetalol displaces the log dose-response curves to the right of isoprenaline-induced increases in heart rate, cardiac output and decreases in diastolic BP. The similarity in the displacements of these curves suggests labetalol has non-selective fl-adrenoceptor-blocking properties. 3 Labetalol inhibits exercise-induced increases in heart rate and systolic BP, inhibits tilt tachycardia and that associated with Valsalva's manoeuvre. 4 Direct comparison with propranolol using the methods above have shown that the fl-adrenoceptor-blocking effect of labetalol is qualitatively similar to that of propranolol but that propranolol is more potent weight for weight to the order of 4 to 6:1 propranolol:labetalol. In respect of their effects on respiratory function, labetalol and propranolol are qualitatively different; whereas propranolol increases airways resistance in equipotent fl-adrenoceptor-blocking doses, labetalol does not. 5 Labetalol displaces the log dose-response curves of phenylephrine and noradrenaline-induced increases in systolic and diastolic BPs to the right consistent with an oc-adrenoceptor-blocking action. 6 Labetalol inhibits increases in BP due to a cold stimulus, whereas propranolol does not. 7 The combined a- and fl-adrenoceptor-blocking effect of labetalol after acute and chronic administration leads to reductions in BP and peripheral resistance but little change in heart rate or cardiac output at rest. During exercise, increases in BP and heart rate are attenuated but cardiac output increases are only significantly diminished at high levels of exercise. 8 Labetalol is less lipophylic than propranolol, with a partition coefficient of 1.2. It is almost completely metabolized being extensively conjugated.
Introduction
Drugs that are specific antagonists at fiadrenoceptors have now been used in the treatment of hypertension for over 14 years. They have been used alone and in combination with other drugs (Prichard, 1978). The use of the non-competitive axadrenoceptor drug, phenoxybenzamine, with propranolol resulted in a marked fall in BP on assuming the erect posture (Beilin & Juel-Jensen, 1972). There have been reports of the use of phentolamine in conjunction with fl-adrenoceptor-blocking agents but the duration of action of phentolamine is probably too short to be of great value (Dawson et al., 1977), although some workers have found more encouraging results (Majid et al., 1974). Labetalol is a drug which competitively antagonizes both 1l- and a-adrenoceptors (Farmer et al., 1972). It has been shown in man that labetalol is a competitive antagonist at the a- and f-receptor sites (Boakes et al., 1971; Collier et al., 1972) and
0306-5251/79/170089-05 $01.00 1
numerous studies have confirmed this (Richards, 1976). Unlike previous experience with this combination of pharmacological effects in the treatment of hypertension (Beilin et al., 1972), significant postural or exercise hypotension is uncommon and tends to occur only with large doses.
fl-adrenoceptor-blocking activity Blockade of exogenous stimuli
Isoprenaline administered by intravenous infusion or bolus injection exerts both f1J- and fl2-adrenoceptor agonist effects, and its use has become established in the identification of drugs with f,-adrenoceptorblocking properties (McDevitt, 1977). Linear log dose-response curves of isoprenaline-induced increases in heart rate and reductions in diastolic BP ©) Macmillan Journals Ltd 1979
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D.A. RICHARDS & B.N.C. PRICHARD
are both shifted to the right after both oral and intravenous administration of labetalol. Shifts of the heart rate response curves are similar in magnitude to those of reductions in diastolic BP; labetalol thus has non-selective fi-adrenoceptor-blocking effects (Richards et al., 1976; Richards et al., 1977a). In studies in which the effects of labetalol were directly compared with those of propranolol, no qualitative differences were found, as both inhibited the effects of isoprenaline in a similar manner; but propranolol was found to be more potent weight for weight. Estimates of relative potency at both f1- and /2-adrenoceptor sites fell in the range 4 to 6:1 propranolol:labetalol (Richards et al., 1978a). It has also been demonstrated that the dose-response curve of increase in cardiac output produced by graded doses of isoprenaline is also shifted to the right by labetalol. This response is not influenced by the administration of phentolamine in sufficient doses to produce further a-adrenoceptor antagonism indicating that this is due to its fl-blocking action and that it is not influenced by the a-blocking activity of labetalol (Richards et al., 1978a).
Blockade of endogenous activity The increase in heart rate and systolic BP from vigorous physical exercise is inhibited by drugs with f,-adrenoceptor-blocking properties. Studies carried out with labetalol have shown that after oral administration there is a dose-related reduction in exercise heart rate and systolic BP (Richards et al., 1974). Similar effects have also been observed after intravenous labetalol (Richards et al., 1977a). In the same subjects comparing labetalol with propranolol similar qualitative affects were shown but propranolol was found to be more potent. The extent of the difference in potency was four- to sixfold and similar to that shown with isoprenaline responses (Richards et al., 1977c). The tachycardia induced by tilting was inhibited by labetalol, but again propranolol was more potent. This potency difference between labetalol and propranolol, however, was less marked when assessing the inhibition of the tachycardia induced by Valsalva's manoeuvre (Richards et al., 1977a). The relevance to asthma of the assessment of #-antagonist effects in the respiratory tract in normal healthy subjects is debatable. However, Kumana et al. (1974) have shown that propranolol administered to normal nonasthmatic men significantly reduces peak expiratory flow both at rest and following exercise. In another study these findings were confirmed for propranolol but in the same subjects who then received labetalol in equipotent fl-blocking doses, no significant reductions occurred (Richards et al., 1977c). After propranolol administration to another group of nonasthmatic normal subjects, resting FEV1 was reduced
and subsequently the fall in FEV1 induced by inhaled histamine was found to be enhanced; such an effect was not seen after labetalol (Maconochie et al., 1977). Thus, there seems to be a difference between labetalol and propranolol in respect of their effects on the respiratory tract. Such differences have also been shown in asthmatic patients (Skinner et al., 1975). In equipotent #-blocking doses, propranolol reduced FEV1 significantly but labetalol did not.
Blockade of a-adrenoceptors Exogenous stimuli Labetalol administered orally and intravenously inhibits the increases in BP induced by cxadrenoceptor stimulation with phenylephrine, and linear log dose-response curves of these increases were shifted to the right in a parallel manner (Richards et al., 1976; Richards et al., 1977a). Although exogenously infused noradrenaline in man exerts both cx- and fl-agonist effects, the predominating circulatory responses are those mediated through oa-adrenoceptors. Thus, dose-related increases in BP occur which are accompanied by reflexly induced reductions in heart rate and cardiac output. It has been shown that labetalol competitively antagonizes the systolic and diastolic pressor effects induced by noradrenaline (Richards et al., 1978a) but leaving the reflex reductions in heart rate and cardiac output unaffected (Richards et al., 1979). The modification by labetalol of noradrenaline-induced increases in BP is similar to that observed after the administration of phentolamine (Richards et al., 1978b). By contrast the cardioselective #-blocking drug atenolol had no effect on the increases in BP caused by noradrenaline. Although labetalol does not seem to elevate levels of endogenous catecholamines in the plasma, it does so when these are introduced exogenously (Richards et al., 1979). Although this latter effect does not seem to be of any clinical relevance, it might explain why labetalol was found to be less pharmacologically potent at inhibiting the effects of noradrenaline compared with those of phenylephrine (Richards et al., 1978a). When adrenaline is administered systemically to man it also exerts both oa- and f-agonist effects but its predominant effect within the circulation depends on the dose administered (Richards et al., 1979). Administration of adrenaline after previous administration of propranolol leads to marked increases in systolic and diastolic BPs accompanied by reductions in heart rate and probably cardiac output (Prichard & Ross, 1966). Administration of high doses of adrenaline after labetalol caused increases in diastolic BP but the increases in systolic BP were attenuated compared with those observed before labetalol
CLINICAL PHARMACOLOGY
administration. At high dose levels of adrenaline after labetalol, reductions in heart rate and cardiac output occurred and this pattern of change was similar to that occurring after noradrenaline. Blockade of endogenous sympathetic activity
Immersing a hand in ice-cold water for 60 s elevates BP in normal man but this is not accompanied by other major circulatory changes; thus, this procedure may be used to test a-adrenoceptor-blocking drugs (Maconochie et al., 1977). Administration of propranolol did not inhibit the cold-induced increase in BP but after a comparable f-adrenoceptorblocking dose of labetalol there was a significant inhibitory effect on mean arterial BP (Maconochie et al., 1977). In another study in which labetalol was administered intravenously an inhibitory effect was again observed. In contrast no similar effect occurred after administration of phentolamine and this was thought to be due to additional blocking effect of phentolamine on presynaptic a-adrenoceptors, which in turn modified its blocking effect on post-synaptic a-adrenoceptors. Presynaptic aadrenoceptor blockade does not seem to occur with labetalol (Blakeley & Summers, 1977) which might explain the difference between it and phentolamine. Relative a- and fl-blocking activity Apart from assessing the potency differences between labetalol and ,B-adrenoceptor-blocking drugs like propranolol and a-adrenoceptor-blocking drugs like phentolamine, the potency differences exerted by labetalol at the two sites have also been estimated. Richards et al. (1976) have found that a single dose of 400 mg labetalol orally produced a rightward shift in the isoprenaline dose-response curve to increases in heart rate and the fall in diastolic BP. At the same time, log dose-response curves of phenylephrineinduced increases in systolic BP also showed a rightward parallel displacement. Using these displacements it was found that the ratio of a :,B antagonism was approximately 1:3. When labetalol was given intravenously the ratio was 1:6.9 (Richards et al., 1977a). Haemodynamic effects The major haemodynamic effect of labetalol in man seems to be that of reducing BP without significantly altering either resting heart rate or cardiac output (Prichard et al., 1975; Koch, 1977; Richards et al., 1978a). This pattern of effects seems to be the result of its combined a- and fl-adrenoceptor-blocking properties.
91S
In contrast to the usual effects observed with drugs with f-adrenoceptor-blocking properties, after acute oral or intravenous administration of labetalol resting heart rate and cardiac output were not reduced. When cardiac output was measured serially after administration of labetalol no changes occurred but propranolol in the same subjects significantly reduced both heart rate and cardiac output. In particular propranolol did not reduce BP, whereas labetalol exerted a significant effect (Richards et al., 1978a). Similar findings to those observed with propranolol have also been observed after the cardioselective P-adrenoceptor-blocking drug atenolol but, again in contrast, labetalol with its combined a- and fl-adrenoceptor-blocking properties produces a totally different pattern of acute haemodynamic effects. On standing or on exercise, BP, heart rate, cardiac output and peripheral resistance were modestly reduced by labetalol (Koch, 1977). Pulmonary arterial pressures were reduced at rest, supine and standing, but were unchanged on exercise (Koch, 1977). Continuous oral administration was associated with a reduction in BP, heart rate and peripheral resistance, with no change in cardiac output, supine and standing (Edwards & Raftery, 1976; Mehta & Cohn, 1977). Heart rate and BP were reduced on exercise. At lower levels of exercise (350 kp/min) cardiac output was maintained and peripheral resistance fell, whereas at high levels of exercise (700 kp/min) there was some reduction in cardiac output (Edwards & Raftery, 1976). The pattern of haemodynamic response to intravenous labetalol at rest is similar to the combination of intravenous propranolol and hydrallazine (Prichard et al., 1975).
Phanmacokinetics
The pharmacokinetics and metabolism after oral doses of labetalol have been studied in mouse, rat, rabbit, dog and man. In these studies specially labelled tritium and [14C]-labelled labetalol have been used (Martin et al., 1976). Autoradiographic studies and radiochemical analysis of the tissues obtained from rats, rabbits and dogs given large oral doses of ["4C]-labetalol have shown that the radioactivity was quickly taken up into the tissues and then rapidly cleared from the body by way of the kidney and the bile. From measurements of plasma radioactivity and labetalol concentrations, it has been shown that labetalol is well absorbed but extensively metabolized during its passage through the gut and liver, that is, there is considerable first-pass metabolism. Labetalol is only about 50% bound to human plasma protein and therefore is rapidly cleared from protein.
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The lipophylicity of labetalol (partition coefficient 1.2 between chloroform and pH 7 buffer) is much less than that of propranolol (partition coefficient 9) or oxprenolol (partition coefficient 10). The profound lipophylic character of the latter two compounds is reflected in the high uptake of these drugs into the brain (Reiss et al., 1970; Baker & Foulkes, 1973). Thus, labetalol seems less likely to enter the brain of man, although this has not yet been confirmed. Autoradiography and radiochemical analysis of the brains from rats and rabbits given oral and intravenous doses of up to 200 mg ['4C]-labetalol have shown, as would be expected from the drug's partition coefficient, that the concentration of radioactivity in the brain was negligible. Studies carried out in pregnant rats and rabbits given oral and intravenous doses of up to 200 mg [14C]labetalol/kg have shown that there is negligible penetration of radioactivity into the foetus. There is a close relationship between pharmacodynamic and pharmacokinetic events with labetalol (Richards, 1976). Peak plasma concentrations of labetalol occurred 2 h after single oral doses (Richards et al., 1977b). Using logarithmic increases in oral dosing it was found that there was a linear correlation (r, = 0.84) between the plasma labetalol concentration 2 h after administration with the degree of inhibition of exercise tachycardia at that time (Richards et al., 1977b). A similar relationship existed between the plasma concentration and the inhibition of the exercise systolic BP. Relative to the oral dose administered only low levels of plasma labetalol are obtained and it has been shown that labetalol has a high 'first-pass' metabolism with a plasma half-life of 3.5-4.5 hours (Martin et al., 1976). Much higher plasma concentrations can therefore be
achieved with intravenous administration. Decline after oral administration is mono-exponential and the elimination of labetalol from the plasma is similar in patients with severely impaired renal function to that seen in normal subjects (Thompson et al., 1977). Studies on the inhibition of an exercise tachycardia have shown that about 75% of the maximum effect obtained was present 6 h after the oral administration of a single dose of 400 mg, with the suggestion that about 40-50% remained at 8 h (Richards et al., 1974). In both animals and man, labetalol is extensively conjugated. In every case, the major metabolites are glucuronides. The site of conjugation varies with the species. In the mouse, rat and rabbit the major metabolite is the O-phenyl glucuronide of labetalol. This metabolite is also present in dog and human urine. In the urine of these two species two other major glucuronides are also present. These metabolites have been isolated by chromatographic techniques and their structure determined. The major one of the two is formed by conjugation at the secondary alcohol group of labetalol. The other conjugate, which is present to a lesser extent, is labile and has been tentatively identified as the Nglucuronide (Martin et al., 1976). Labetalol is extensively metabolized, with no evidence of an active metabolite, and only 5% is excreted unchanged (Martin et al., 1976). From radiochemical analysis of the urine it has been shown that the rat excretes 48%, the mouse 72%, the rabbit 61%, the dog 66% and man 60% of the orally administered dose of radioactivity in the urine. Radiochemical analysis of the faeces showed that the remainder of the dose of radioactivity is excreted by this route (Martin et al., 1976).
References BAKER, S.B. & FOULKES, D.M. (1973). Blood concentration of compounds in animal toxicity tests. Biological effects of drugs in relation to their plasma concentrations. Ed. Davies, D.S. & Prichard, B.N.C. Pp. 41-50. London: Macmillan. BEILIN, L.J. & JUEL-JENSEN, B.E. (1972). Alpha and beta adrenergic blockade in hypertension. Lancet, i, 979-982. BLAKELEY, A.G.H. & SUMMERS, R.J. (1977). The effects of labetalol (AH 5158) on adrenergic transmission in the cat spleen. Br. J. Pharmac., 59, 643-660. BOAKES, A.J., KNIGHT, E.J. & PRICHARD, B.N.C. (1971). Preliminary studies of the pharmacological effects of 5(1-hydroxy -2-((1-methyl -3- phenylpropyl) amino) ethyl) -salicylamide (AH 5158) in man. Clin. Sci., 40, 18-19P. COLLIER, J.G., DAWNAY, N.A.H., NACHEV, C.H. & ROBINSON, B.F. (1972). Clinical investigation of an
antagonist at alpha and beta adrenoceptors-AH 5158A. Br. J. Pharmac., 44, 286-293.
DAWSON, A., SMITH, I. & JOHNSON, B.F. (1977). The transient antihypertensive effect of phentolamine in patients receiving beta blocker treatment. J. int. Med. Res., 5, 462-464. EDWARDS, R.C. & RAFTERY, E.B. (1976). Haemodynamic effects of long term oral labetalol. Br. J. clin. Pharmac., 3, (suppl.), 733-736. FARMER, J.B., KENNEDY, I., LEVY, G.P. & MARSHALL, R.J. (1972). Pharmacology of AH 5158: a drug which blocks both f,- and a-adrenoceptors. Br. J. Pharmnac., 45, 660-675. KOCH, G. (1977). Acute haemodynamic effects of an alpha and beta receptor blocking agent (AH 5158) on the systemic and pulmonary circulation at rest and during exercise in hypertensive patients. Am. Heart J., 93, 585-586. KUMANA, C.R., KAYE, C.M., MARLIN, G.E. & SMITH, D.M.
(1974). New approach to assessment of cardioselectivity of beta blocking drugs. Br. med. J., 4, 444 447.
CLINICAL PHARMACOLOGY MACONOCHIE, J.G., WOODINGS, E.P. & RICHARDS, D.A.
(1977). Effects of labetalol and propranolol on histamine induced bronchoconstriction in normal subjects. Br. J. clin. Pharmnac., 4, 157-162.
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RICHARDS, D.A., PRICHARD, B.N.C., BOAKES, A.J., TUCKMAN, J. & KNIGHT, E.J. (1977a). Pharmacological
basis for antihypertensive effects of intravenous labetalol. Br. Heart J., 39, 99-106.
MACONOCHIE, J.G., RICHARDS, D.A. & WOODINGS, E.P.
RICHARDS, D.A., PRICHARD, B.N.C. & DOBBS, R.J. (1978a).
(1977). Modification of pressor responses induced by 'cold'. Br. J. clin. Pharmac., 4, 389P.
Adrenoceptor blockade of the circulatory responses to intravenous isoproterenal. Clin. Pharmac. Therap., 24, 264-273.
MAJID, P.A., MEERAN, M.K., BENAIM, M.E., SHARMA, B. &
TAYLOR, S.H. (1974). Alpha and beta adrenergic receptor blockade in the treatment of hypertension. Br. Heart J., 36, 588-596. MARTIN, L.E., HOPKINS, R. & BLAND, R. (1976). Metabolism of labetalol by animals and man. Br. J. clin. Pharmac., 3, (suppl.), 695-710. McDEVITT, D.G. (1977). The assessment of f-adrenoceptor blocking drugs in man. Br. J. clin. Pharmac., 4,413-425. MEHTA, J.L. & COHN, J.N. (1977). Haemodynamic effects of labetalol on alpha and beta adrenergic blocking agent, in hypertensive subjects. Circulation, 55, 370-375. PRICHARD, B.N.C. (1978). ,B-adrenergic receptor blockade in hypertension past present and future. Br. J. clin. Pharmac., 5, 379-399. PRICHARD, B.N.C., THOMPSON, F.D., BOAKES, A.J. &
JOEKES, A.M. (1975). Some haemodynamic effects of compound AH 5158 compared with propranolol, propranolol plus hydrallazine and diazoxide; the use of AH 5158 in the treatment of hypertension. Clin. Sci. molec. Med., 48, 97s-lOls. PRICHARD, B.N.C. & ROSS, E.J. (1966). Use of propranolol in conjunction with alpha receptor blocking drugs in phaeochromocytoma. Am. J. Cardiol., 18, 394-398. REISS, W., RAJAGOPALAN, T.G., IMHOF, P., SCHMID, K. & KEVERLE, H. (1970). Metabolic studies on oxprenolol in
animals and man by means of radiotracer techniques and GLC analysis. Postgrad. med. J., 46, (suppl.), 32-43. RICHARDS, D.A. (1976). Pharmacological effects of labetalol in man. Br. J. clin. Pharmac., 3, (suppl.), 721-723.
RICHARDS, D.A., PRICHARD, B.N.C. & HERNANDEZ, R.
(1979). Circulatory effects of noradrenaline and adrenaline before and after labetalol. Br. J. clin. Pharmac., 7, 371-378. RICHARDS, D.A., TUCKMAN, J. & PRICHARD, B.N.C.
(1976). Assessment of a- and ,B-adrenoceptor-blocking actions of labetalol. Br. J. clin. Pharmac., 3, 849-855. RICHARDS, D.A., MACONOCHIE, J.G., BLAND, R.E., HOPKINS, R., WOODINGS, E.P. & MARTIN, L.E. (1977b).
Relationship between plasma concentrations and pharmacological effects of labetalol. Eur. J. clin. Pharmac., 11, 85-90. RICHARDS, D.A., WOODINGS, E.P. & MACONOCHIE, J.G.
(1977c). COmparison of the effects of labetalol and propranolol in healthy men at rest and during exercise. Br. J. clin. Pharmac., 4, 15-21. RICHARDS, D.A., WOODINGS, E.P. & PRICHARD, B.N.C.
(1978b). Circulatory and o-adrenoceptor-blocking effects of phentolamine. Br. J. clin. Pharmac., 5, 507-513. RICHARDS, D.A., WOODINGS, E.P., STEPHENS, M.D.B. &
MACONOCHIE, J.G. (1974). The effects of oral AH 5158, a combined a- and P-adrenoceptor antagonist, in healthy volunteers. Br. J. clin. Pharmac., 1, 505-510. SKINNER, C., GADDIE, J. & PALMER, K.N.V. (1975). Comparison of intravenous AH 5158 (labetalol) and propranolol in asthma. Br. med. J., 2, 59-61. THOMPSON, F.D., JOEKES, A.M. & HUSSEIN, M.M. (1977). Labetalol used as a hypotensive agent in the presence of renal disease. Kidney Int., 11, 287.
CLINICAL PHARMACOLOGY OF LABETALOL D.A. RICHARDS Glaxo Group Research Ltd, Ware, Hertfordshire SG12 ODS, UK
B.N.C. PRICHARD University College Hospital Medical School, University Street, London WC1 E 6JJ, UK
1 The clinical pharmacology of labetalol has been evaluated using pharmacological and physiological test methods. 2 Labetalol displaces the log dose-response curves to the right of isoprenaline-induced increases in heart rate, cardiac output and decreases in diastolic BP. The similarity in the displacements of these curves suggests labetalol has non-selective fl-adrenoceptor-blocking properties. 3 Labetalol inhibits exercise-induced increases in heart rate and systolic BP, inhibits tilt tachycardia and that associated with Valsalva's manoeuvre. 4 Direct comparison with propranolol using the methods above have shown that the fl-adrenoceptor-blocking effect of labetalol is qualitatively similar to that of propranolol but that propranolol is more potent weight for weight to the order of 4 to 6:1 propranolol:labetalol. In respect of their effects on respiratory function, labetalol and propranolol are qualitatively different; whereas propranolol increases airways resistance in equipotent fl-adrenoceptor-blocking doses, labetalol does not. 5 Labetalol displaces the log dose-response curves of phenylephrine and noradrenaline-induced increases in systolic and diastolic BPs to the right consistent with an oc-adrenoceptor-blocking action. 6 Labetalol inhibits increases in BP due to a cold stimulus, whereas propranolol does not. 7 The combined a- and fl-adrenoceptor-blocking effect of labetalol after acute and chronic administration leads to reductions in BP and peripheral resistance but little change in heart rate or cardiac output at rest. During exercise, increases in BP and heart rate are attenuated but cardiac output increases are only significantly diminished at high levels of exercise. 8 Labetalol is less lipophylic than propranolol, with a partition coefficient of 1.2. It is almost completely metabolized being extensively conjugated.
Introduction
Drugs that are specific antagonists at fiadrenoceptors have now been used in the treatment of hypertension for over 14 years. They have been used alone and in combination with other drugs (Prichard, 1978). The use of the non-competitive axadrenoceptor drug, phenoxybenzamine, with propranolol resulted in a marked fall in BP on assuming the erect posture (Beilin & Juel-Jensen, 1972). There have been reports of the use of phentolamine in conjunction with fl-adrenoceptor-blocking agents but the duration of action of phentolamine is probably too short to be of great value (Dawson et al., 1977), although some workers have found more encouraging results (Majid et al., 1974). Labetalol is a drug which competitively antagonizes both 1l- and a-adrenoceptors (Farmer et al., 1972). It has been shown in man that labetalol is a competitive antagonist at the a- and f-receptor sites (Boakes et al., 1971; Collier et al., 1972) and
0306-5251/79/170089-05 $01.00 1
numerous studies have confirmed this (Richards, 1976). Unlike previous experience with this combination of pharmacological effects in the treatment of hypertension (Beilin et al., 1972), significant postural or exercise hypotension is uncommon and tends to occur only with large doses.
fl-adrenoceptor-blocking activity Blockade of exogenous stimuli
Isoprenaline administered by intravenous infusion or bolus injection exerts both f1J- and fl2-adrenoceptor agonist effects, and its use has become established in the identification of drugs with f,-adrenoceptorblocking properties (McDevitt, 1977). Linear log dose-response curves of isoprenaline-induced increases in heart rate and reductions in diastolic BP ©) Macmillan Journals Ltd 1979
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D.A. RICHARDS & B.N.C. PRICHARD
are both shifted to the right after both oral and intravenous administration of labetalol. Shifts of the heart rate response curves are similar in magnitude to those of reductions in diastolic BP; labetalol thus has non-selective fi-adrenoceptor-blocking effects (Richards et al., 1976; Richards et al., 1977a). In studies in which the effects of labetalol were directly compared with those of propranolol, no qualitative differences were found, as both inhibited the effects of isoprenaline in a similar manner; but propranolol was found to be more potent weight for weight. Estimates of relative potency at both f1- and /2-adrenoceptor sites fell in the range 4 to 6:1 propranolol:labetalol (Richards et al., 1978a). It has also been demonstrated that the dose-response curve of increase in cardiac output produced by graded doses of isoprenaline is also shifted to the right by labetalol. This response is not influenced by the administration of phentolamine in sufficient doses to produce further a-adrenoceptor antagonism indicating that this is due to its fl-blocking action and that it is not influenced by the a-blocking activity of labetalol (Richards et al., 1978a).
Blockade of endogenous activity The increase in heart rate and systolic BP from vigorous physical exercise is inhibited by drugs with f,-adrenoceptor-blocking properties. Studies carried out with labetalol have shown that after oral administration there is a dose-related reduction in exercise heart rate and systolic BP (Richards et al., 1974). Similar effects have also been observed after intravenous labetalol (Richards et al., 1977a). In the same subjects comparing labetalol with propranolol similar qualitative affects were shown but propranolol was found to be more potent. The extent of the difference in potency was four- to sixfold and similar to that shown with isoprenaline responses (Richards et al., 1977c). The tachycardia induced by tilting was inhibited by labetalol, but again propranolol was more potent. This potency difference between labetalol and propranolol, however, was less marked when assessing the inhibition of the tachycardia induced by Valsalva's manoeuvre (Richards et al., 1977a). The relevance to asthma of the assessment of #-antagonist effects in the respiratory tract in normal healthy subjects is debatable. However, Kumana et al. (1974) have shown that propranolol administered to normal nonasthmatic men significantly reduces peak expiratory flow both at rest and following exercise. In another study these findings were confirmed for propranolol but in the same subjects who then received labetalol in equipotent fl-blocking doses, no significant reductions occurred (Richards et al., 1977c). After propranolol administration to another group of nonasthmatic normal subjects, resting FEV1 was reduced
and subsequently the fall in FEV1 induced by inhaled histamine was found to be enhanced; such an effect was not seen after labetalol (Maconochie et al., 1977). Thus, there seems to be a difference between labetalol and propranolol in respect of their effects on the respiratory tract. Such differences have also been shown in asthmatic patients (Skinner et al., 1975). In equipotent #-blocking doses, propranolol reduced FEV1 significantly but labetalol did not.
Blockade of a-adrenoceptors Exogenous stimuli Labetalol administered orally and intravenously inhibits the increases in BP induced by cxadrenoceptor stimulation with phenylephrine, and linear log dose-response curves of these increases were shifted to the right in a parallel manner (Richards et al., 1976; Richards et al., 1977a). Although exogenously infused noradrenaline in man exerts both cx- and fl-agonist effects, the predominating circulatory responses are those mediated through oa-adrenoceptors. Thus, dose-related increases in BP occur which are accompanied by reflexly induced reductions in heart rate and cardiac output. It has been shown that labetalol competitively antagonizes the systolic and diastolic pressor effects induced by noradrenaline (Richards et al., 1978a) but leaving the reflex reductions in heart rate and cardiac output unaffected (Richards et al., 1979). The modification by labetalol of noradrenaline-induced increases in BP is similar to that observed after the administration of phentolamine (Richards et al., 1978b). By contrast the cardioselective #-blocking drug atenolol had no effect on the increases in BP caused by noradrenaline. Although labetalol does not seem to elevate levels of endogenous catecholamines in the plasma, it does so when these are introduced exogenously (Richards et al., 1979). Although this latter effect does not seem to be of any clinical relevance, it might explain why labetalol was found to be less pharmacologically potent at inhibiting the effects of noradrenaline compared with those of phenylephrine (Richards et al., 1978a). When adrenaline is administered systemically to man it also exerts both oa- and f-agonist effects but its predominant effect within the circulation depends on the dose administered (Richards et al., 1979). Administration of adrenaline after previous administration of propranolol leads to marked increases in systolic and diastolic BPs accompanied by reductions in heart rate and probably cardiac output (Prichard & Ross, 1966). Administration of high doses of adrenaline after labetalol caused increases in diastolic BP but the increases in systolic BP were attenuated compared with those observed before labetalol
CLINICAL PHARMACOLOGY
administration. At high dose levels of adrenaline after labetalol, reductions in heart rate and cardiac output occurred and this pattern of change was similar to that occurring after noradrenaline. Blockade of endogenous sympathetic activity
Immersing a hand in ice-cold water for 60 s elevates BP in normal man but this is not accompanied by other major circulatory changes; thus, this procedure may be used to test a-adrenoceptor-blocking drugs (Maconochie et al., 1977). Administration of propranolol did not inhibit the cold-induced increase in BP but after a comparable f-adrenoceptorblocking dose of labetalol there was a significant inhibitory effect on mean arterial BP (Maconochie et al., 1977). In another study in which labetalol was administered intravenously an inhibitory effect was again observed. In contrast no similar effect occurred after administration of phentolamine and this was thought to be due to additional blocking effect of phentolamine on presynaptic a-adrenoceptors, which in turn modified its blocking effect on post-synaptic a-adrenoceptors. Presynaptic aadrenoceptor blockade does not seem to occur with labetalol (Blakeley & Summers, 1977) which might explain the difference between it and phentolamine. Relative a- and fl-blocking activity Apart from assessing the potency differences between labetalol and ,B-adrenoceptor-blocking drugs like propranolol and a-adrenoceptor-blocking drugs like phentolamine, the potency differences exerted by labetalol at the two sites have also been estimated. Richards et al. (1976) have found that a single dose of 400 mg labetalol orally produced a rightward shift in the isoprenaline dose-response curve to increases in heart rate and the fall in diastolic BP. At the same time, log dose-response curves of phenylephrineinduced increases in systolic BP also showed a rightward parallel displacement. Using these displacements it was found that the ratio of a :,B antagonism was approximately 1:3. When labetalol was given intravenously the ratio was 1:6.9 (Richards et al., 1977a). Haemodynamic effects The major haemodynamic effect of labetalol in man seems to be that of reducing BP without significantly altering either resting heart rate or cardiac output (Prichard et al., 1975; Koch, 1977; Richards et al., 1978a). This pattern of effects seems to be the result of its combined a- and fl-adrenoceptor-blocking properties.
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In contrast to the usual effects observed with drugs with f-adrenoceptor-blocking properties, after acute oral or intravenous administration of labetalol resting heart rate and cardiac output were not reduced. When cardiac output was measured serially after administration of labetalol no changes occurred but propranolol in the same subjects significantly reduced both heart rate and cardiac output. In particular propranolol did not reduce BP, whereas labetalol exerted a significant effect (Richards et al., 1978a). Similar findings to those observed with propranolol have also been observed after the cardioselective P-adrenoceptor-blocking drug atenolol but, again in contrast, labetalol with its combined a- and fl-adrenoceptor-blocking properties produces a totally different pattern of acute haemodynamic effects. On standing or on exercise, BP, heart rate, cardiac output and peripheral resistance were modestly reduced by labetalol (Koch, 1977). Pulmonary arterial pressures were reduced at rest, supine and standing, but were unchanged on exercise (Koch, 1977). Continuous oral administration was associated with a reduction in BP, heart rate and peripheral resistance, with no change in cardiac output, supine and standing (Edwards & Raftery, 1976; Mehta & Cohn, 1977). Heart rate and BP were reduced on exercise. At lower levels of exercise (350 kp/min) cardiac output was maintained and peripheral resistance fell, whereas at high levels of exercise (700 kp/min) there was some reduction in cardiac output (Edwards & Raftery, 1976). The pattern of haemodynamic response to intravenous labetalol at rest is similar to the combination of intravenous propranolol and hydrallazine (Prichard et al., 1975).
Phanmacokinetics
The pharmacokinetics and metabolism after oral doses of labetalol have been studied in mouse, rat, rabbit, dog and man. In these studies specially labelled tritium and [14C]-labelled labetalol have been used (Martin et al., 1976). Autoradiographic studies and radiochemical analysis of the tissues obtained from rats, rabbits and dogs given large oral doses of ["4C]-labetalol have shown that the radioactivity was quickly taken up into the tissues and then rapidly cleared from the body by way of the kidney and the bile. From measurements of plasma radioactivity and labetalol concentrations, it has been shown that labetalol is well absorbed but extensively metabolized during its passage through the gut and liver, that is, there is considerable first-pass metabolism. Labetalol is only about 50% bound to human plasma protein and therefore is rapidly cleared from protein.
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The lipophylicity of labetalol (partition coefficient 1.2 between chloroform and pH 7 buffer) is much less than that of propranolol (partition coefficient 9) or oxprenolol (partition coefficient 10). The profound lipophylic character of the latter two compounds is reflected in the high uptake of these drugs into the brain (Reiss et al., 1970; Baker & Foulkes, 1973). Thus, labetalol seems less likely to enter the brain of man, although this has not yet been confirmed. Autoradiography and radiochemical analysis of the brains from rats and rabbits given oral and intravenous doses of up to 200 mg ['4C]-labetalol have shown, as would be expected from the drug's partition coefficient, that the concentration of radioactivity in the brain was negligible. Studies carried out in pregnant rats and rabbits given oral and intravenous doses of up to 200 mg [14C]labetalol/kg have shown that there is negligible penetration of radioactivity into the foetus. There is a close relationship between pharmacodynamic and pharmacokinetic events with labetalol (Richards, 1976). Peak plasma concentrations of labetalol occurred 2 h after single oral doses (Richards et al., 1977b). Using logarithmic increases in oral dosing it was found that there was a linear correlation (r, = 0.84) between the plasma labetalol concentration 2 h after administration with the degree of inhibition of exercise tachycardia at that time (Richards et al., 1977b). A similar relationship existed between the plasma concentration and the inhibition of the exercise systolic BP. Relative to the oral dose administered only low levels of plasma labetalol are obtained and it has been shown that labetalol has a high 'first-pass' metabolism with a plasma half-life of 3.5-4.5 hours (Martin et al., 1976). Much higher plasma concentrations can therefore be
achieved with intravenous administration. Decline after oral administration is mono-exponential and the elimination of labetalol from the plasma is similar in patients with severely impaired renal function to that seen in normal subjects (Thompson et al., 1977). Studies on the inhibition of an exercise tachycardia have shown that about 75% of the maximum effect obtained was present 6 h after the oral administration of a single dose of 400 mg, with the suggestion that about 40-50% remained at 8 h (Richards et al., 1974). In both animals and man, labetalol is extensively conjugated. In every case, the major metabolites are glucuronides. The site of conjugation varies with the species. In the mouse, rat and rabbit the major metabolite is the O-phenyl glucuronide of labetalol. This metabolite is also present in dog and human urine. In the urine of these two species two other major glucuronides are also present. These metabolites have been isolated by chromatographic techniques and their structure determined. The major one of the two is formed by conjugation at the secondary alcohol group of labetalol. The other conjugate, which is present to a lesser extent, is labile and has been tentatively identified as the Nglucuronide (Martin et al., 1976). Labetalol is extensively metabolized, with no evidence of an active metabolite, and only 5% is excreted unchanged (Martin et al., 1976). From radiochemical analysis of the urine it has been shown that the rat excretes 48%, the mouse 72%, the rabbit 61%, the dog 66% and man 60% of the orally administered dose of radioactivity in the urine. Radiochemical analysis of the faeces showed that the remainder of the dose of radioactivity is excreted by this route (Martin et al., 1976).
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JOEKES, A.M. (1975). Some haemodynamic effects of compound AH 5158 compared with propranolol, propranolol plus hydrallazine and diazoxide; the use of AH 5158 in the treatment of hypertension. Clin. Sci. molec. Med., 48, 97s-lOls. PRICHARD, B.N.C. & ROSS, E.J. (1966). Use of propranolol in conjunction with alpha receptor blocking drugs in phaeochromocytoma. Am. J. Cardiol., 18, 394-398. REISS, W., RAJAGOPALAN, T.G., IMHOF, P., SCHMID, K. & KEVERLE, H. (1970). Metabolic studies on oxprenolol in
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