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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 but has been withdrawn becauseoftoxic ity.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
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-
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).
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
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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'.
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.