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Summary Drugs 36 (Suppl. 6): 20-25 (1988) 0012-6667/ 88/060 0-0020/$3 .00/0 © ADIS Press Limited All rights reserved. Progress in Antihypertensive Therapy with a Multiple-Action Drug B.N.e. Prichard and B. Tomlinson Department of Clinical Pharmacology, The Rayne Institute, University College and Middl esex School of Medicine, London, United Kingdom The ;3-blockers in clinical use have been classified into 2 major divisions, nonselective or selective agents, and those with or without intrinsic sympathomimetic activity (ISA). These properties confer diff ering pharmacological properties with some relevance to the treatment of hypertension. A !J-blocker with significant !J:r ISA can be regarded as a mul- tiple-action drug. A third division of !J-blockers is a newer development; these agents. be- sides blocking the s-receptor. possess imp ortant peripheral vasodilator activity. Labetalol was the first drug of this group and prizidolol followed. but has been withdrawn because of toxic ity. Several other agents now under evaluation include bucindolol and medroxolol, and carvedilol and dilevalol (I ofthe isomers of'labetalol), which have been the most widely studied in hypertension. Combined action results in important haemodynamicdiff erences compared with pure !J-blockade. Notably. peripheral resistance is reduced. and there is less reduction in. or no effect on. cardiac output. The 3 following mechanism s have been described as responsible for peripheral vasodilatation: a-receptor blockade. !J:ragonism. and a dilator action in- dependent of either the a- or ;3-receptors. Evidence for these various mechanism s is mo re readily obtainable from animal experiments, but some confirmatory evidence has been obtained in man . Inh ibition of a-stim ulation has been fo und with labetalol and to a small degree with medroxalol and carvedilol. !JrMediated vasodilatation has been shown by dilevalol and medroxol ol, and evidence of vasodilatation independent of a- or s-receptors has been obtained with carvedilol. More evidence is required to confirm the exact contri- bution of each of these mechanisms. The mode of antihypertensive action of !J-blockade remains unclear. as does the exact contribution of the 3 m echanism s of peripheral vasodilatation. However, the combination of pharma cological effects represents an additional means of lowering blood pressure. Haemodynamics are more favourably modified. and it is hoped that the advantages of !J-blockade will be retained. in clinical use have been classified into 2 major divisions, according to whether they possess selectivity for and the pres- ence or absence of intrinsic sympathomimetic ac- tivity (ISA). These properties result in a number of pharmacological differences (Cruickshank & Prichard 1988; Prichard & Tomlinson 1986). There is evidence that results in a slightly greater antihypertensive effect than that seen with nonselective agents (Cruickshank & Prichard 1988). A significant degree of ISA (partial agonism) at the as seen with pindolol, represents an

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Summary

Drugs 36 (Suppl. 6): 20-25 (1988)0012-6667/88/0600-0020/$3 .00/0© ADIS Press LimitedAll rights reserved.

Progress in Antihypertensive Therapy with aMultiple-Action Drug

B.N.e. Prichard and B. TomlinsonDepartment of Clin ical Pharmacology, The Rayne Inst itute, University College andMiddl esex School of Medicine, London, United Kingdom

The ;3-blockers in clinical use have been classified into 2 major divisions, nonselectiveor selective agents, and those with or without intrinsic sympathomimetic activity (ISA).These properties confer differing pharmacological properties with some relevance to thetreatment ofhypertension. A !J-blocker with significant !J:rISA can be regarded as a mul­tiple-action drug. A third division of!J-blockers is a newer development; these agents. be­sides blocking the s-receptor. possess important peripheral vasodilator activity. Labetalolwas the first drug of this group and prizidolol fo llowed. but has been withdrawn becauseoftoxic ity. Several other agents now under evaluation include bucindolol and medroxolol,and carvedilol and dilevalol (I ofthe isomers of' labetalol), which have been the most widelystudied in hypertension.

Combined action results in important haemodynamic differences compared with pure!J-blockade. Notably. peripheral resistance is reduced. and there is less reduction in. or noeffect on. cardiac output. The 3 fo llowing mechanisms have been described as responsiblefor peripheral vasodilatation: a-receptor blockade. !J:ragonism. and a dilator action in­dependent of either the a- or ;3-receptors. Evidence for these various mechanism s is morereadily obtainable from animal experiments, but some confirmatory evidence has beenobtained in man . Inh ibition ofa-stim ulation has been fo und with labetalol and to a smalldegree with medroxalol and carvedilol. !JrMediated vasodilatation has been shown bydilevalol and medroxolol, and evidence of vasodilatation independent of a- or s-receptorshas been obtained with carvedilol. More evidence is required to confirm the exact contri­bution of each of these mechanisms.

The mode ofantihypertensive action of!J-blockade remains unclear. as does the exa ctcontribution ofthe 3 mechanism s ofperipheral vasodilatation. However, the combinationof pharma cological effects represents an additional means of lowering blood pressure.Haemodynamics are more favourably modified. and it is hoped that the advantages of!J-blockade will be retained.

~-Blockers in clinical use have been classifiedinto 2 major divisions, according to whether theypossess selectivity for ~J-receptors, and the pres­ence or absence of intrinsic sympathomimetic ac­tivity (ISA). These properties result in a numberof pharmacological differences (Cruickshank &

Prichard 1988; Prichard & Tomlinson 1986). Thereis evidence that ~J-selectivity results in a slightlygreater antihypertensive effect than that seen withnonselective agents (Cruickshank & Prichard 1988).A significant degree of ISA (partial agonism) at the~2"receptor, as seen with pindolol, represents an

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Progress in Antihypertensive Therapy with a Multiple-Action Drug 21

additional mechanism for lowering blood pressure.As a result of {jrstimulation, peripheral resistanceis lower than with {j-blockerswithout this property(Man in't Veld & Schalekamp 1982). However,since the {j-blockade of pindoloI is nonselective, thispossibly offsets to some extent the vasodilatationmediated by {jragonism and attenuates its anti­hypertensive effect. It may be that selective {j,­

antagonism plus {j2-ISA, which may be present inceliprolol , represents a useful combination inhypertension. However, this remains to be proven,as some studies have not shown that this impartsa greater antihypertensive effect than that of a{jl-selective drug without ISA (Silke et al. 1986;Stumpe et al. 1985). It should be noted that pro­gressive increases in ~,-ISA result in a reductionin antihypertensive effect (Leonetti et al. 1985).

A newer group of ~-blockers possesses, in ad­dition to ~-blockade, significant peripheral vaso­dilator activity.

1. Multiple-Action {j-Blockers

Labetalol was the first drug of this group, withreports of its activity appearing in the early 1970s(Louis et al. 1984; Prichard 1984). Prizidolol fol­lowed and its pharmacological properties and usein hypertension were widely studied, but it waswithdrawn because of toxicity. A number of othermultiple-action {j-blockers have been described(Cruickshank & Prichard 1988); these include bu­cindolol and medroxolol, and carvedilol and dile­valol, which have been the most widely evaluatedin hypertension.

2. Haemodynamlc Effects

The haemodynamic effect of a drug with ~­

blocking effects plus peripheral vasodilator actionshows features that might be expected from a com­bination of these 2 properties (Lund-Johansen1979). Acute oral administration of a {j-blockerwithout ISA reduces heart rate and cardiac outputand increases peripheral resistance at rest or withexercise. Vasodilatation produced by an ai-blockersuch as prazosin results in reduced peripheral re-

sistance at rest or with exercise, whereas cardiacoutput may increase. Haemodynamic changes afterthe combination of a {j-blocker plus prazosin , orafter labetalol, were similar and there was less ofa fall in heart rate or cardiac output than after pure{j-blockade. In addition, there was a reduction , inconstrast to an increase, in peripheral resistance(Lund-Johansen 1979, 1984).

Although there will be variation according to thedosage used, the physiological conditions underwhich measurements are made and the ratio of the~-blockade to vasodilator properties of the drug,there is direct and indirect evidence that thehaemodynamic effects of ~-blockers with vasodi­lator properties follow a similar pattern.

The fall in blood pressure after administrationof prizidolol for 6 to 8 months in hypertensivepatients was associated with a fall in peripheral re­sistance and heart rate, both at rest and with ex­ercise, while cardiac output did not change (Lund­Johansen & Omvik 1982).

In animals, carvedilol reduced blood pressurethrough a fall in peripheral resistance, with cardiacoutput little affected, in contrast to propranololwhich increased peripheral resistance and reducedcardiac output (Tanaka et al. 1987). Administra­tion of carvedilol in patients with hypertension hasbeen associated with a fall in forearm vascular re­sistance, whereas propranolol increased peripheralresistance and reduced cardiac output (Eggertsenetal. 1984). In contrast to {j-blockers without vaso­dilator properties, carvedilol does not reduce renalblood flow, as the fall in renal vascular resistancecompensates for the fall in blood pressure (Dupontet al. 1987). Haemodynamic studies comparingtreatment with carvedilol and propranolol in an­gina patients revealed a tendency for vascular re­sistance to fall at rest and to be little affected onexercise with carvedilol, whereas propranolol in­creased vascular resistance at rest and on exercise.Cardiac output is reduced at rest and on exercisewith propranolol and is little affected in either stateby carvedilol (Wendt et al. 1987).

In conscious dogs, dilevalol also reduced peri­pheral resistance and had a marginal effect on heartrate. At intermediate doses it caused a small in-

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Progress in Antih ypertensive Therapy with a Multiple-Action Drug 22

crease in cardiac output, whereas larger doses hadno effect (Baum et al. 1981). Studies of patientswith mild hypertension have shown a fall in vas­cular resistance at rest with no change in heart rateor cardiac output after single oral doses of dilevalol400mg, or 400mg twice daily for 2 weeks. Withexercise the drug's ,s-blocking component becamemore apparent. Vascular resistance fell but not tothe same level as before dilevalol, and exercisingheart rate and cardiac output were reduced (Bugni1988). Another study of hypertensive patients after6 weeks of dilevalol administration has also showna reduced peripheral resistance similar to that withthe a-blockers urapidil and doxazosin and in con­trast to that with 2 ,s-blockers studied (Tsukiyamaet al.). Similar to carvedilol, glomerular filtrationrate is maintained after dilevalol treatment, whichis unlike the pattern after 'simple' ,s-blockade(Wallin et al. 1988).

Other multiple-action antihypertensive drugshave been less extensively evaluated, but investi­gations indicate that the haemodynamic changesafter medroxalol in animals (Dage et al. 1981) orbucindolol in hypertensive patients (Kimura et al.1987) are similar to these described for carvediloland dilevalol.

So far no comparative haemodynamic studiesof the multiple-action antihypertensive drugs havebeen performed in man, but evidence suggests thatthe effects of these drugs are broadly similar.

3. Mechanism of Peripheral ResistanceReduction

The 3 following mechanisms have been re­ported as responsible for the peripheral vasodila­tation: an a I-receptor blocking action, which in­terferes with vasoconstrictor tone; a ,s2-agonism,which leads to a ,srmediated vasodilatation; and adilator action independent of either the a- or ,s­receptors. Evidence for the mechanism of dilata­tion of the various agents has been obtained fromanimal investigations and in many cases confir­matory evidence has been obtained from humanstudies.

3.1 a-Blocking Activity

Carvedilol has been shown to relax rat aorticstrip precontracted by noradrenaline, but this ac­tion appears nonspecific as it is similar only to thatwith glyceryl trinitrate and less than occurs withprazosin (Strein et al. 1987). Relaxation of aorticstrips precontracted by noradrenaline or potassiumchloride is achieved by similar concentrations ofcarvedilol, whereas there is a separation of the dose­response curves with labetalol, as lower doses arerequired for noradrenaline contracted strips com­pared with potassium chloride contracted strips(Sponer et al. 1987).Although there was some shiftin the blood pressure dose-response curve to a­

adrenoceptor stimulation with methoxamine in thepithed rat after carvedilol, this was much less thanthat seen after doses of phentolamine, which hadan equivalent antihypertensive effect (Sponer et al.1987). In an assessment of endogenous sympath­etic activity in conscious rabbits, Bartsch et al.(1987) found that equivalent antihypertensive dosesof intravenous prazosin or labetalol (al inhibition),or guanethidine (inhibition of neuronal noradren­aline release), resulted in a greater postural hypo­tensive effect than seen with carvedilol. There issome evidence of a-receptor inhibition in man.Cubeddu et al. (1987) showed that intravenous car­vedilol inhibited pressor responses to single dosesof phenylephrine in normal volunteers, whereas re­sponses to single doses of angiotensin were not af­fected. Tomlinson et al. (1988) performed dose-re­sponse studies and found that oral carvedilolinhibited responses to phenylephrine but not re­sponses to angiotensin.

Although the effect was much less than that oflabetalol, Sybertz et al. (1981) have shown that di­levalol causes the dose-response curve to phenyl­ephrine in anaesthetised dogs to shift to the right,whereas pressor responses to angiotensin are notaffected. a-Blockade, assessed by inhibition ofpressor responses to phenylephrine, has also beendemonstrated after administration of medroxalolin animals (Dage et al. 1981) and man (Elliott etal. 1984; Jaillon et al. 1982).

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Progress in Antihypertensive Therapy with a Multiple-Action Drug 23

3.2 {j2-Agonism

{j2-Agonism is not thought to be part of thevasodilating mechanism of carvedilol, as preincu­bation of rat aortic strips with the {jz-blocker ICI118551 did not influence the vasorelaxing actionof carvedilol (Sponer et al. 1987). There is, how­ever, evidence suggesting that {jz-agonism contrib­utes to the antihypertensive effect of dilevalol, la­betalol and medroxalol.

Propranolol has been shown to inhibit the re­laxant effect of dilevalol and labetalol in isolatedguinea pig trachea (Matsunaga et al. 1985). Baum& Sybertz (1983) showed that pretreatment withpropranolol in anaesthetised ganglion-blocked dogsinhibited the antihypertensive action of pindololand dilevalol, which confirmed a {j2-mediated di­lator component. However, propranolol did not af­fect the fall in blood pressure caused by hydrala­zine or prizidilol. Propranolol also blocked theantihypertensive action of pindolol in spontan­eously hypertensive rats and partly inhibited theeffect of labetalol or dilevalol (Baum & Sybertz1983). Dilevalol has been found to increase aorticcompliance, and this was inhibited to a significantdegree by propranolol (Watkins et al. 1987). Theantihypertensive effect of medroxalol in animals isalso partly inhibited by propranolol, with its {j, ­

plus {j2-blocking activity, whereas {j,-blockade bypractolol was without effect (Dage et al. 1983).

3.3 Vasodilatation Independent of a-Blockadeor {jz-Stimulation

Although investigation of multiple-action drugsmay reveal evidence of an a-blocking or (j2-medi­ated vasodilator action in animals or man, it doesnot necessarily follow that this property fully ex­plains the reduction in peripheral resistance causedby these drugs.

Sponer et at. (1987) showed that, for equallyantihypertensive doses in the pithed rat, prazosin(0.15 rug/kg) caused a 23.3-fold shift of the a,­agonist methoxamine dose-response curve and a9.9-fold shift of the noradrenaline dose-responsecurve. After phentolamine (2.8 mg/kg) the shifts

were 30.6 and 44.8, respectively. However, aftercarvedilol (0.37 rug/kg) the corresponding shiftswere 4.27 and 2.78, which were similar to the 2.85and 2.81 shifts seen after dihydralazine (1.1 mg/kg).Dihydralazine produced a 1O.2-fold shift with aflattening of the angiotensin II dose-responsecurve,whereas the other agents had no effect. Other in­vestigations in animals discussed above (Bartsch etal. 1987; Strein et al. 1987) confirm the dissocia­tion of the antihypertensive activity of carvediloland a-blockade .

Animal investigations with dilevalol, however,might be interpreted as suggesting that the reduc­tion in peripheral resistance is to a considerabledegree mediated by the {j2-mediated vasodilatormechanism , as the drug's dilator action in the fem­oral vascular bed of the dog is completely blockedby propranolol (Baum & Sybertz 1983). There wassome residual antihypertensive effect after largerdoses of dilevalol in ganglion-blocked anaesthet­ised dogs given propranolol (0.3 rug/kg, IV) [Baum& Sybertz 1983], although a larger dose of pro­pranolol might result in a greater blockade, andsimilar results to those obtained in the dog wereobtained in spontaneously hypertensive rats (Baum& Sybertz 1983).

4. Conclusion

Although the mode of antihypertensive effectfrom {j-adrenergic blockade remains a matter ofdebate, {j-blockers without any additional proper­ties are highly effective in the treatment of hyper­tension (Cruickshank & Prichard 1988;Prichard &Owens 1984). Multiple-action drugs are potent in­hibitors at the {j-receptor and possession of peri­pheral vasodilator activity represents an additionalpharmacological property for lowering blood pres­sure. Haemodynamics are more favourably mod­ified and it is hoped that the advantages of {j-block­ade will be retained .

References

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Progress in Antihypertensive Th erapy with a Mult iple-Action Drug 24

betalol and guanethidine. Journal of Cardiovascular Pharma­cology 10 (Suppl. II ): S49-S51, 1987

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Baum T, Sabin C, Moran RM. Compariso n of orthostat ic andsympathetic inhibitory action of ant i-hypertensive drugs in rats.Clinical and Experimental Hypertension 3: 219-243, 1981

Bugni WJ. The hemodynam ic effects of dilevalol in patient s withmild hypertension. Journal of Cardiovascular PharmacologyII (Suppl. 2): 36, 1988

Cruickshank JM, Prichard BNC. Beta-blockers in clinical prac­tice, pp. 1-1003, Churchill Livingstone, Edinburgh, 1988

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Dage RC, Cheng HC, Woodward JK. Cardio vascular propertiesof medroxalol, a new ant i-hypertensive drug. Journal of Car­diovascular Pharmacology 3: 299-315, 1981

Dage RC, Hsieh CP, Spedding M. Vasodilation by medroxalolmediated by beta-2 adrenergic receptor stimulation. Journal ofCardiovascular Pharmacology 5: 143-150, 1983

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Author's address: Prof. B.N.C. Prichard, Departm ent of ClinicalPharm acology, The Rayne Institute, University College and Mid­dlesex School of Medicine, 5 University Street, London, WCIE6JJ (United Kingdom).

Discussion

Prof T. Takeda (Japan): You propose 3 mech­anisms for the vasodilating effect of carvedilol, thatis a I-blocking, .B2-agonism and some 'other effect'.

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Progress in Antihypertensive Therapy with a Multiple-Action Drug 25

Is this 'other effect' a direct action on vascularsmooth muscle, or some nitrate-like effect?

Prof B. Prichard (United Kingdom): There are3 possible mechanisms for the vasodilating effect.Carvedilol possesses these: a-antagonism, a directvasodilating effect, and .a-blockingactivity . Whichmechanism is more important is subject to con­siderable debate and speculation. Acutely, the drug'speripheral vasodilatory effect is probably a directaction . However, with time the .a-blocking prop­erties would assume significance.

Dr G. Belz (Federal Republic of Germany):Should we try to lower total peripheral resistanceas the prime target of hypertension?

Prof Prichard: We focus on blood pressure itselfbecause it is probably the blood pressure that isresponsible for the complications in hypertension.However, there is no reason why we shouldn't havethe best of both worlds, i.e. lower blood pressureand focus on specific haemodynamic changes at thesame time. Hopefully this will occur with com­bined action drugs.