G c n Pharma(.. t ol 9 pp. 399 to 402 Pt'r!lamon Prc~x Ltd 1978 prultcd In Great BrJfum

MINIREVIEW THE P H A R M A C O L O G Y OF LABETALOL, AN ~- A N D f l - A D R E N O C E P T O R B L O C K I N G A G E N T A. G. H. BLAKELEYand R. J. SUMMERS Department of Pharmacology, Glasgow University, Glasgow G l2 8QQ. Scotland, UK. (Received 10 February 1978)

In the first detailed description of the pharmacology of labetalol (AH 5158) Fig. I the drug was shown to be a competitive antagonist at both ~t- and fl-adrenoceptors. It also had membrane stabilizing CONH~ L__ OH CH3 I I HO/~CH.CHz. NH.~H CH2- C H 2 ~ Fig. 1. properties, and inhibited a cocaine sensitive uptake process for catecholamines (Farmer et al., 1972). The suggestion made in this paper, that the drug might be useful in the treatment of hypertension has been followed up with some success (see papers in Proceedings o f a S y m p o s i u m on L a b e t a l o I - - A p r i l , 1976, edited by Richards & Turner in Br. J. clin. Pharmac. 3(4)). Our aim is to review the information that has been obtained concerning the pharmacology of this interesting compound. ACTIONS ON &ADRENOCEPTORS Labetalol competitively inhibits the response of fl-adrenoceptors both to exogenously applied catecholamines in animals and man and to sympathetic nerve stimulation in animals. In man labetalol competitively inhibits the dilatation of forearm veins (Collier et al., 1972) and the positive inotropic and vasodepressor effects of isoprenaline given by intravenous infusion (Richards et al,, 1976; Richards et al., 1977a). Labetalol also antagonizes in a dose dependent manner, the sympathetically mediated reflex increase in heart rate associated with exercise (Richards et al., 1974: Richards et al., 1977b). These results indicate that labetalol competitively inhibits in a non specific manner both the fll-adrenoceptors of the heart and fl2-adrenoceptors of the blood vessels in man. In animals labetalol competitively inhibits the positive inotropic response to isoprenaline in guinea-pig left atrium (Farmer et al., 1972) and the positive chronotropic response to isoprenaline in the spinal dog (Farmer et al., 1972), anaesthetized dog and pithed rat (Brittain & Levy, 1976). The drug also inhibits positive chronotropic responses to cardiac sympathetic nerve stimulation in the anaesthetized dog and to stimulation of the entire 399

spinal preganglionic sympathetic outflow in the pithed rat (Brittain & Levy, 1976). It can be safely concluded that labetalol competitively antagonizes responses to isoprenaline in both man and animals. Both f i r and fl2-adrenoceptors are blocked to a similar extent and the pA 2 values obtained vary from 7.05 to 8.31 (for table of values see Farmer et al., 1972 and Brittain & Levy, 1976). Labetalol would appear to possess little intrinsic activity on fl-adrenoceptors as judged from experiments with spinal dogs (Farmer et al., 1972) and anaesthetized dogs (Brittain & Levy, 1976) depleted of endogenous catecholamines by pretreatment with syrosingopine and from experiments with guinea-pig atria (Farmer et al,, 1972). In man labetolol also has little effect on heart rate following intravenous infusion (Collier et al., 1972). ACTIONS

ON

a-ADRENOCEPTORS

Labetalol competitively inhibits the response of :t-adrenoceptors to exogenously applied catecholamines and sympathetic nerve stimulation. In man labetalol competitively antagonizes the vasoconstrictor response of forearm veins to noradrenaline (Collier et al., 1972) and the pressor response to phenylephrine (Richards et al., 1976). The contractile response to noradrenaline in the rat vas deferens and aorta, guinea-pig mesenteric vein, rabbit aorta (Farmer et al., 1972: Brittain & Levy, 1976) and cat spleen (Blakeley & Summers, 1977), are antagonized competitively. The pressor response to noradrenaline in the dog (Kennedy & Levy, 1975) and the pressor response to phenylephrine in the spinal dog, anaesthetized dog and pithed rat (Farmer et al., 1972; Brittain & Levy, 1976) and the contractile response to oxymetazoline in the cat spleen (Blakeley & Summers, 1977) are also antagonized in a competitive manner. In the dog the blockade is self limiting unless uptake of catecholamines has been blocked by cocaine (Farmer et al., 1972) or an ~t-agonist which is not a substrate for uptake has been used, indicating that labetalol has uptake blocking properties. The pressor response to nerve stimulation in the anaesthetized dog and pithed rat is also antagonized (Brittain & Levy, 1976). In the cat spleen however low doses of labetalol potentiate the response indicating that in this tissue the uptake blocking action of labetalol may be more important (Blakeley & Summers, 1977).

400

A.G.H.

BLAKELt:Y anti R. J. St_'MM~!~S

in contrast to its lack of ~lectivity against //-adrenoccptors labetalol appears to bc a selective blocker of postsynaptic 7-adrenoceptors, having little or no effect on the prejunctional ~-adrenoceptors which are believed to govern transmitter release (Kirpekar & Puig, 1971 ; Starke, 1972; Enero et al., 1972: Langer, 1974). The effect on presynaptic 7-adrenoceptors has been studied by measurement of overflow of the adrenergic transmitter from the isolated cat spleen following stimulation of the splenic nerves (Blakeley & Summcrs, 1977). It was found that in concentrations between 10 ¢' and 10 4 M labetalol produced a dosedependent increase in transmitter overflow. This effect was not ,seen in the presence of DMI or cocaine in concentrations that block uptaket. (Iversen, 1976), but was still present in the pre~ncc of piperoxan in concentrations known to block presynaptic :c-adrenoceptors (Blakclcy & Summers, 1975). It was concluded that labetalol elevated transmitter overflow by blocking uptakca, and had no detectable antagonist action in the concentration used at presynaptic :¢-adrenoceptors. It is therefore selective for postsynaptic z~-adrcnoceptors. Additional evidence for the selective blocking action of labetalol at postsynaptic :~-adrenoceptors has been obtained in the rat vas deferens. In this preparation labetalol acts as a competitive antagonist of the preferential postsynaptic ~-agonist phenylephrine (Starke et al., 1975). In the same preparation the twitch response to nerve stimulation is antagonized in a dose-dependent manner b.~ presynaptic z~-agonists such as oxymetazoline. This inhibitory effect is antagonized by presynaptic ~-adrenoceptor blocking agents such as yohimbine but labetalol has no effect indicating no presynaptic ~ adrenoceptor blocking effect (Brown, McGrath & Summers, in preparation). Labetalol is also ineffective in reversing the effects presynaptic ~2-agonist clonidine's action in both inducing sedation in the C N S (Drew et al., 1977) and in reducing acetyl choline release in guinea pig ileum (Drew, 1977). There is some evidence in man, but not from animal studies, that labetalol may possess some intrinsic ~-adrenoceptor stimulating activity. It has been reported (Collier et al., 1972: Frick & Porsti, 1976) that labetalol can cause scalp tingling in a proportion of patients and this effect has been suggested to bc a sensitivity index of zc-adrenoceptor stimulation. Labetalol is less potent as an antagonist of ~-adrenoceptors than ,B-adrenoceptors the pA, values ranging from 6.0 to 7.45. Using phenylephrinc as an :~-adrenoeeptor agonist and isoprenaline as a /Ladrenoceptor agonist the ratio of potency /,¢:z¢ blockade ranges from 3.1 (Richards et al., 1976) to 16:1 (Brittain & Levy, 1976)indicating that there may be species and/or tissue variation in the affinity of labetalol for the adrenoceptors. INHIBITION O F N O R A D R E N A L I N E UPTAKE

The action of labetalol as an a-adrenoceptor antagonist of noradrenaline in anaesthetized dogs was de,scribed as "'self limiting" in that shifts to the right only occurred with doses of labetalol up to 1 mg/kg (Farmer et al., 1972). The self limiting nature of the

blockade was abolished by pretrcatmcnt v, ith cocaine or if the agonist used was oxymetazoline which is not a substrate for uptakc~ {Birmingham et al.. 19701. It was concluded that labctalol was an inhibitor of uptake1. Subsequently, Kennedy & Lc~v (1975} pointed out that the cocaine sensitive uptake process in lung which is not associated with nerve endings and distinct from uptakc~ {Alabaster & Bahklc, 1973) might also account for the effects that they had seen. This is unlikely to bc the case since in the isolated blood perfused cat spleen labetalol ( 1.5 x 10 "~M) inhibited uptake of noradrenalinc infused intra-artcrially and at lower concentrations (2 x 10 ~ MI prolonged and potentiated the response of the spleen to nerve stimulation (Blakeley & Summers, 1977l in a manner resembling that c,f DMI and cocaine. Labcta1ol therefore blocks the cocaine sensitive uptake process, uptakes, in the periphery. The possible contribution of the cocaine sensitive process in lung is still in question. EFFECTS ON N O R A D R E N A I . I N E METABOLISM

The effects of labetalol on the metabolism of [3H]noradrenaline released from adrenergic nerve terminals has been examined in the cat spleen (Summers & Tillman, 1977). Labetalol was found to produce a dose-dependent increase in the proportion of -~H recovered as [3H]noradrenalinc and a decrease in the proportion recovered as the intraneuronal deaminated product [3H]dihydroxyphenylethyleneglycol ( D O P E G ) following nerve stimulation. This type of behaviour is typical of drugs which inhibit neuronal uptake (Cubeddu et al., 1974). Production of other metabolites was not affected indicating that labetaloi does not inhibit either extra neuronal uptake or the degradative enzymes monoamine oxidase or catechol-O-methyl transferase. Its effects on noradrenaline metabolism are therefore duc to inhibition of neuronal uptake. METABOLISM O F LABETALOL

This has been studied in mouse, rat, rabbit, dog and man (Martin et al.. 1976). Following oral administration labetalol is well absorbed but undergoes extensive first pass metabolism in all species. Some 50°~,', of the drug is bound to plasma proteins. There are species differences in the major routes of metabolism. In mouse and rat the O-phenyl glucuronide is the major urinary metabolite but in dog another glucuronide predominates. In man labetalol is excreted in the form of an unidentified conjugate. The rat, rabbit and human conjugates of labetalol and hydroxylabetalol have been tested for pharmacological activity and found to be weaker ~- and fl-adrenoceptor antagonists than iabetalol. The half-life of the elimination of an intravenous dose of labetalol estimated from the terminal portion of the clearance curve was 3.5-4.5 hr in man (Martin et al., 1976j. The relationship between plasma concentration and the effects of labetalol has been studied in man (Richards et al., 1977a). Two hours after an oral dose of labetalol there is good correlation (r = 0.84) between the plasma concentration of the drug and

The pharmacology of labetalol its effect in reducing the increase in heart rate after exercise. When the drug was given intravenously there was a prompt effect on the cardiovascular system. Within 2 min the heart rate and blood pressure had fallen to a level that was maintained for the next 10rain. Between 2 and 10~min the drug concentration in the plasma fell by a factor of 10. With orally administered labetalol the cardiovascular effect over a 5-hr period was generally better maintained than the plasma concentration of the drug. These observations raise the question whether the plasma concentration of labetalol is the principal factor responsible for the effect or whether the effective moiety is some untested metabolite of the drug. EFFECTS ON RESPONSES T O AGONISTS O T H E R T H A N T H O S E ACTING O N ADRENOCEPTORS

The adrenoceptor blockade produced by labetalol is specific. In man the responses of forearm veins to 5-HT and angiotensin II are not antagonized by labetalol (Collier et al., 1972) neither are responses to histamine, 5-HT, acetylcholine or barium chloride in the rabbit aortic strip (Brittain & Levy, 1976). In guineapig left atria and in the anaesthetised dog the positive inotropic effect of calcium chloride is not attenuated neither is the effect of barium chloride on the guinea pig mesenter-ic vein nor the anaesthetized dog blood pressure (Farmer et al.. 1972). M e m b r a n e stabilizinq effect

Labetaiol in high doses (> 10 -4 M) produces negative inotropic effects in isolated driven guinea-pig left atria, spinal dogs. In anaesthetized dogs the heart is protected against arrhythmias induced by noradrenaline or ouabaine (Farmer et aL, 1972). In the cat spleen labetalol in concentrations greater than 10 -4 M reduces the responses of the spleen to nerve stimulation and the overflow of transmitter from the spleen (Blakeley & Summers, 1977). These effects are consistent with a membrane stabilizing effect of the drug. Effects on plasma renin levels in hypertension

Labetalol produces a drastic reduction in plasma renin concentration in hypertensive patients (Koch, 1977). Since catecholamines are known to stimulate renin secretion by an action on E-adrenoceptors (Vandongen et al., 1973: Vandongen & Peart, 1974) tt may be that labetalol lowers plasma renin levels by E-adrenoceptor blockade. Effects on coronary blood f l o w

It has been reported that unlike some other E-adrenoceptor blockers labetalol has a mild coronary vaso dilator effect (Maxwell, 1973). T H E USE O F L A B E T A L O L IN T H E TREATMENT OF HYPERTENSION

Labetalol has been used with some effect in the treatment of hypertension (see Richards & Turner. 1976).

401

One explanation for its antihypertensive effect is that it reduces the effectiveness of the sympathetic division of the autonomic nervous system (ANS) by blocking both cardiac fl- and peripheral vascular :t-adrenooeptors (Majid et al., 1974). The effects of blocking either type of receptor separately would be effectively to stimulate the other as the ANS compensates for the interference. This compensation would reduce the effectiveness of the treatment. The effectiveness of the antihypertensive action of combined :~- and fl-adrenoceptor blockade would also be reduced if the :t-blockade was not only of postsynaptic :t-adrenoceptor but also on those on the adrenergic nerve endings. Presynaptic :t-adrenoceptors are important in the negative feedback control of transmitter release (see Starke, 1977; Langer, 1977). A presynaptic ~t-antagonist, like phentolamine, would by increasing transmitter release minimize not only its own sympatholytic effectiveness postsynaptically but also that of a simultaneously administered fl-antagonist even though the ~t- and fl-blockade as estimated by exogenous agonists may be good. The effects of labetalol have been compared with those of oxpreno1ol and phentolamine (Johnson et al., 1976). It would be more interesting to compare it with say the E-antagonist oxprenolol and the :t-antagonist prazosin which has little effect on presynaptic :t-receptors (Cambridge et al., 1977; Doxey et al., 1977). It is quite possible that the antihypertensive effect of labetalol may be adequately explained by selective blockade of post synaptic :t-adrenoceptors and non selective blockade of Ell- and E2-adrenoceptors. However explanations for the antihypertensive of actions of other fl-blockers (Amer, 1977) based on their peripheral actions have not proved adequate and actions on the CNS have been found to be important. Since the antihypertcnsive action of labetalol does not correlate totally with its concentration in the circulating blood (Richards et al., 1977b) perhaps more attention should be paid to the possible central hypotensive effects of labetalol or its metabolites (Dargie et al., 1976). However labetalol with its combined actions as a selective presynaptic ~- and non selective i-antagonist would seem to be well suited for the role of an antihypertensive drug except for its ability to potentiate adrenergic transmission and the effects of noradrenaline by its block of amine uptake. REFERENCES ALABASTERV. A. & BAHKLEY. S. (1973) The removal of noradrenaline in the pulmonary circulation of rat isolated lungs. Br. J. Pharmac. 47, 325-331. AMER M. S. (1977) Mechanisms of action of fl-blockers in hypertension. Biochem. Pharmac. 26, 171-176. BIRMINGHAMA. T., PATERSON G . 8£ WOJCICKI J. (1970) A comparison of the sensitivities of innervated and dennervated rat vasa deferentia to agonist drugs. Br. J. Pharmac. 39, 748-754. BLAKELEYA. G. H. & SUMMERSR. J. (1975). The effects of piperoxan (933F) on uptake of noradrenaline and overflow of transmitter in the isolated blood perfused cat spleen. Proceedings of the 6th International Congress of Pharmacology July 20-25, 1975, Helsinki, Finland. BLAKELEY A. G. H. & SUMMERSR. J. (1977) The effects of labetalol (AH 5158) on adrenergic transmission in the cat spleen. Br. J. Pharmac. 59, 643-650.

402

A.G.H.

BLAKF[.I!~ and R. J. SI'MME,RS

BRIrrAIN R. T. & LFvV G. P. (1976) A review of the animal pharmacology of labetalol, a combined alpha and beta adrenoceptor blocking drug. Br. J. olin. Pharmac. 3, 681-694. CAMBRll)GE D., DAVEY M. J. & MASSINGHAMR. 11977) Prazosin, a selective antagonist of post-synaptic ~-adrenoceptors. Br. J. Pharmac. 59, 514P. COLI.II:R J. G., DAWNAY N. A. H., NACHEV Cll. & ROFIIN.'a)N B. F. 11972)Clinical investigation of an antagonist at alpha and beta adrenoceptors-AH 515~. Br. J. Pharmac. 44, 286 293. Ct:l~vi)[)t: X. L., BARNES E. M., LANGFR S. Z. & Wl!lNIR N (19741 Release of norepinephrine and dopamine fl hydroxylase by nerve stimulation. I. role of neuronal and cxtrancuronal uptake and presynaptic alpha receptors. J. Pharmac. exp. Ther. 190, 431 450. DAR(;It: H. J., DOt.LEar C. T. & DANIrL J. 11976) Labetalol in resistant hypertension. Br. J. olin. Pharmac. 3, 751 755. DoxY J. C., SMITH C. F. C & Walker J. M. 11977) Selectivity of blocking agents for pre and post synaptic ¢x-adrenoceptors. Br. J. Pharmac. 60, 91-96. DREW G. M. (1977) Pharmacological characterisation of presynaptic :( adrenoceptors which regulate cholinergic activity in the guinea-pig ileum. Br. J. Pharmac. 59, 513P. DRfiW (i. M.. GOWFR A. J. & MARRIO'lq A. S. (1977) Pharmacological characterisation of ~-adrenceptors which mediate elonidine-induced sedation. Br. 3. Pharmac. 61, 486P. ENI~RO M. A., LANGER S. Z., ROTHLIS R. O. & DE STEFANO F. J. E. 11972) Role of the :~ adrenoceptor in regulating noradrenalinc overflow by nerve stimulation. Br. J. Pharmac. 44, 672-688. FARMER J. B., KENNEDY I., LEVy G. P., MARSllALL R. J. (1972) Pharmacology of AH 5158, a drug which blocks both ~- and fl-adrenoceptors. Br. J. Pharmac. 45, 660-675. FRWK M. H. & PORS'n P. (1976) Combined alpha and beta adrcnoceptor blockade with labetalol in hypertension. Br. reed. J. I, 1046 1048. IVI~RSEN L. L. 11976) The Uptake and Storage of Noradrenaline in Sympathetic Nerves. Cambridge University Press. London. JOHNSON B. F., LA BROOY, J. & MUNRO-FAt:RF: A. D. 11976) The antihypertensive efficacy of combined alpha and beta adrcnoceptor blockade with phentolamineoxprenolol or with labetalol. Clin. Sci. molec. Med. 51, 505- 507. KI!NNEt)Y I. & L~vY G. P. (1975) Combined alpha and beta adrenoceptor blocking drug AH 5158: further studies on alpha adrenoceptor blockade in anaesthetised animals. Br. J. Pharmac. 53, 585-592. KIRPEKAR S. M. & PUIG M. (1971) Effect of flow stop

on noradrenaline release from normal spleens and spleens treated with c(~:aine, phentolamine or phenox.,,benzamine. Br. J. Pharmac. 43, 359 369 KtX'H G. 11977) Acute haemodynamic cffects 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, 585 591. LANGIiR S. Z 11974) Presynaptic regulation of catecholamine release. Bio('hcm. Pharmac. 23. 1793-18f~). MAre) P. A.. M~JRA,". M. K., BANAIM M. E. S|IARMA B. & TA', I.OR S. H. (1974~ Alpha and beta adrenergic blockade in the treatment of hypertension. Br. tteart J. 36. 588- 596. MARTfN L. E., HOVKL',,SR. & BLANI) R. (19761 Metabolism of labetalol b) animals and man. Br. J. elm. Phar,nac. 3, 695 710. MAXWrI.L G. M. 11973) The effects of a new alpha and beta adrcnoceptor antagonist (AH 5158) upon the general and coronary haemodynamics of intact dogs. B,-. J. Phtlrmac. 49. 370- 372. RI('HARDS D. A.. WOf)DINGS E. P.. STIPHI:NS M. D. B. & MAeON(WIHr J. G. (1974) The effects of oral AH 5158. a combined alpha and beta adrcnoceptor antagonist, in healthy volunteers. Br. J. clin. Pharmac. I, 505 510. RICHARDS D. A.. TU('KMAN J. & PRI'ICHARD B. N. C (1976) Assessment of alpha and beta adrenoceptor blocking actions of labetalol. Br. J. elm. Pharmac. 3, 849-855. RICttARI)S D. A.. MAf'ON(X'HIt- J. G.. BI.ANI) R. E., HOPKINS R., WOOD/N(.;S E. P. & MARTIN L. E. [1977a1 Relationship betv, cen plasma concentrations and pharmacological effects of labetalol. Eur. ,I. clin. P/tarmac. II, 85-90. RN'HARDS D. A.. PRlr('tt,~Rt) B. N. C.. BOAKt:SA. J.. Tt:CKStar', J. & KNIGIIT E. J. (1977b) Pharmacological basis of antihypertensive effects of intravenotts labetalol. Br. Heart J. 39, 99 106. SrARKI: K. 11972) x-Sympathomimetic inhibition of adrenergic and cholinergic transmission in the rabbit heart. Naunyn-Schmiedeherq's Arch. exp. PAth. Pharmak. 274, 18.45. STARKt K.. ENI×) T & TAt:hi H. D. (1975) Relative pre and post synaptic potencies of :~-adrenoceptor agonists in the rabbit pulmonary artery. Naut,yn-Schmiedeberg's Arch. exp. Path. Pharmak. 291, 55 78. SUMMERS R. J. & TILLMAN JANET (1977) The effect of AH 5158 on metabolism of 3H 1 - ) noradrenaline released from the cat spleen b~ nerve stimulation. Biochem. Pharmac. 26. 2137-2143. VANFX)NGEN R., PI!ART V~' S. 8~ BOI)Y G. W. (1973) Adrenergic stimulation of renin secretion in the isolated pcrfuscd rat kidney. Circulation Res. 32, 290-296. VAN'I~)NGEN R. & P~:ART W. S. 11974) The inhibition of renin ,~cretion by alpha-adrencrgic stimulation in the isolated rat kidney. CIm. Sci. Molec. Meal 47, 471-479.

The pharmacology of labetalol, an alpha- and beta-adrenoceptor blocking agent.

G c n Pharma(.. t ol 9 pp. 399 to 402 Pt'r!lamon Prc~x Ltd 1978 prultcd In Great BrJfum MINIREVIEW THE P H A R M A C O L O G Y OF LABETALOL, AN ~- A...
370KB Sizes 0 Downloads 0 Views