Glinical Investigator
Clin Investig (1992) 70 : S 27-S 36
© Springer-Verlag 1992
Clinical pharmacology of carvedilol B. Tomlinson, B.N.C. Prichard, B.R. Graham, and R.J. Walden Department of Clinical Pharmacology, University College, London
Summary. Animal work has shown that carvedilol is a nonselective/%blocking drug. It has a vasodilatot action from a-receptor blockade, but there is evidence that it has further action to relax smooth muscle, possibly from calcium channel antagonism. Carvedilol is lipid soluble and 25% bioavailable, and it has a half-life of about 7 h. It lowers blood pressure at rest and reduces the tachycardia and the rise of blood pressure on exercise. It reduces the level of blood pressure reached during isometric exercise or the cold pressor test. Cardiac output at rest is maintained, and the haemodynamics in the compromised heart is improved. It has an important peripheral vasodilator action, peripheral flow being maintained to important organs, e.g. kidneys, despite the fall in blood pressure. Exercising renin and noradrenaline levels are increased, as are the latter at rest. Carvedilol is lipid neutral. Carvedilol shifts the dose-response curve to isoprenaline to the right, as well as to e-stimulants such as phenylephrine. Responses to angiotensin are little affected. The ratio of fl- to a-blockade has been found to be 7.6 for 50 mg and 12.5 for 100 mg of carvedilol. There is no evidence of a decline in a-blockade after 1 week of continuous administration. Key words" Carvedilol - Clinical p h a r m a c o l o g y Review - Haemodynamics
Animal in vitro and in vivo experiments, including those in conscious animals, have demonstrated that carvedilol is a non-selective, /?-adrenoceptor blocking drug. It is slightly more potent than propranolol in the conscious rabbit, less in the rat, and very similar in the dog, with labetalol being
relatively weak in all three species. Carvedilol does not have any intrinsic sympathomimetic activity [35], but it has membrane stabilising activity at a similar level to propranolol [36]. Carvedilol has in addition to its/~-blocking activity a direct vasodilator effect. In the rat aortic strip preparation contracted by noradrenaline, potassium chloride or a thromboxane agonist, the relaxation produced by carvedilol is more like glyceryl trinitrate and less like the el-blocker prazosin [36]. Bartsch et al. [1] assessed the inhibition of endogenous sympathetic activity in the conscious rabbit. They employed equivalent antihypertensive doses and measured the postural hypotension of el-inhibition from prazosin or labetalol or inhibition of neurone release of noradrenaline by guanethidine, all of which gave a greater postural effect than carvedilol. There is, however, evidence that a-blockade contributes to the blood pressure lowering action in animals. Sponer et al. [35] studied doses of phentolamine, prazosin, carvedilol and dihydralazinc that produced a similar fall in blood pressure in the pithed spontaneously hypertensive rats (SHR). The dose-response curve to methoxamine (el-stimulation) was shifted by a factor of 30.6 by phentolamine (el +e2-blockade), 23.3 by prazosin (cq-blockade), 4.27 by carvedilol and 2.85 by dihydralazine. The responses to clonidine (e2-stimulation) are shifted by a factor of 53.1 by phentolamine and 4.56 by carvedilol, and those to noradrenaline (el >e2 stimulation) by 44.8 by phentolamine, 9.9 by prazosin, 2.78 by carvedilol and 2.81 by dihydralazine. Angiotensin II was not affected by the administration of phentolamine with a shift of 1.11 (range 0.77-1.51) or prazosin, 1.0 (0.28-1.24). The effect of carvedilol was marginal with a shift of 1.33 (1.05-1.65), with dihydralazine showing a 10.2 (4.86-17.4) shift.
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Another explanation of the vasodilator action of carvedilol may be that of calcium channel blockade; although the concentrations required are high, this action may be relevant at the top of the hypotensive dose range [13]. Overall, it has been concluded that the c~l-blockade is mainly responsible for the antihypertensive effect of carvedilol, but calcium antagonism may play a part in certain peripheral vascular beds [31]. The haemodynamic changes responsible for the antihypertensive effect involve a reduction of peripheral resistance without reflex tachycardia as a result of the/?-blockade. Renal blood flow is not reduced, and sodium excretion is maintained [31]. The stereoisomers of carvedilol have been examined. Only the S isomer possesses /?-blocking activity similar to findings with other /?-blocking drugs, while the R and S isomers were similar in e-blocking activity. The S isomer possessing both c~- and /?-effects had the greater antihypertensive action [2]. Clinical pharmacological investigations have confirmed these findings in animals.
Pharmacokinetics Studies with oral carvedilol (25 and 50 rag) in normal volunteers have revealed a time to maximum concentration of 1.2-1.5 h with a linear relationship between the areas under the curve (AUC) at each oral dose increment. Comparison with intravenous administration indicates a bioavailability of about 25% [24]. Carvedilol is lipid soluble; it has a large volume of distribution (132 1) indicating extensive tissue binding, and plasma protein binding is about 95%. The total body clearance is 590 ml/min via liver metabolism. After oral administration carvedilol has a terminal half-life of about 7 h [19, 20, 24]. Pharmacokinetic parameters, Cmax,AUC, half-life, are not affected by the co-administration of hydrochlorothiazide [29]. In cirrhosis of the liver there is a substantial increase in the C~a x of carvedilol. Systemic clearance is reduced, half-life is prolonged, and bioavailability was increased to 80%. Although it is difficult to explain, there was about a threefold increase in the apparent volume of distribution [25]. Renal failure does not affect the handling of carvedilol [12]. Studies of the stereoisomers of carvedilol have revealed that the R ( + ) isomer is cleared at a slower rate than the S ( - ) isomer, although the difference was not enough to make a significant difference in the half-life after intravenous administration. The bioavailability of the R ( + ) isomer
is twice that of the S ( - ) isomer, with a higher AUC. However, the elimination half-life after oral administration was reported as longer with the S ( - ) isomer, which is difficult to explain [26].
Haemodynamies Effect on supine and tilt blood pressure
Intravenous carvedilol reduces the supine blood pressure. In the study of Cubeddu et al. [4, 5] in normal volunteers, blood pressure fell after 15 mg i.v. from 138/64 to 105/50, the heart rate (HR) rising insignificantly from 54 to 60. Tomlinson et al. [40] studied the effect of 12.5, 25, 50, 100 and 200 mg in a randomised, double-blind study. The systolic blood pressure was 117 m m H g on placebo, and the fall was significant at 50 mg and above: 1 0 7 m m H g at 50rag, 1 0 6 m m H g after 200 mg. The fall in standing systolic pressure is greater than in the supine position, and it was also significant at 50 mg and above, compared with placebo (116 mmHg) the levels were 100 m m H g systolic pressure after both 100 and 200 mg. An extension from 6 to 12 subjects (Fig. 1) shows a fall in systolic blood pressure on tilting after 200 mg (P
Clin Investig (1992) 70 : S 27-S 36
© Springer-Verlag 1992
Clinical pharmacology of carvedilol B. Tomlinson, B.N.C. Prichard, B.R. Graham, and R.J. Walden Department of Clinical Pharmacology, University College, London
Summary. Animal work has shown that carvedilol is a nonselective/%blocking drug. It has a vasodilatot action from a-receptor blockade, but there is evidence that it has further action to relax smooth muscle, possibly from calcium channel antagonism. Carvedilol is lipid soluble and 25% bioavailable, and it has a half-life of about 7 h. It lowers blood pressure at rest and reduces the tachycardia and the rise of blood pressure on exercise. It reduces the level of blood pressure reached during isometric exercise or the cold pressor test. Cardiac output at rest is maintained, and the haemodynamics in the compromised heart is improved. It has an important peripheral vasodilator action, peripheral flow being maintained to important organs, e.g. kidneys, despite the fall in blood pressure. Exercising renin and noradrenaline levels are increased, as are the latter at rest. Carvedilol is lipid neutral. Carvedilol shifts the dose-response curve to isoprenaline to the right, as well as to e-stimulants such as phenylephrine. Responses to angiotensin are little affected. The ratio of fl- to a-blockade has been found to be 7.6 for 50 mg and 12.5 for 100 mg of carvedilol. There is no evidence of a decline in a-blockade after 1 week of continuous administration. Key words" Carvedilol - Clinical p h a r m a c o l o g y Review - Haemodynamics
Animal in vitro and in vivo experiments, including those in conscious animals, have demonstrated that carvedilol is a non-selective, /?-adrenoceptor blocking drug. It is slightly more potent than propranolol in the conscious rabbit, less in the rat, and very similar in the dog, with labetalol being
relatively weak in all three species. Carvedilol does not have any intrinsic sympathomimetic activity [35], but it has membrane stabilising activity at a similar level to propranolol [36]. Carvedilol has in addition to its/~-blocking activity a direct vasodilator effect. In the rat aortic strip preparation contracted by noradrenaline, potassium chloride or a thromboxane agonist, the relaxation produced by carvedilol is more like glyceryl trinitrate and less like the el-blocker prazosin [36]. Bartsch et al. [1] assessed the inhibition of endogenous sympathetic activity in the conscious rabbit. They employed equivalent antihypertensive doses and measured the postural hypotension of el-inhibition from prazosin or labetalol or inhibition of neurone release of noradrenaline by guanethidine, all of which gave a greater postural effect than carvedilol. There is, however, evidence that a-blockade contributes to the blood pressure lowering action in animals. Sponer et al. [35] studied doses of phentolamine, prazosin, carvedilol and dihydralazinc that produced a similar fall in blood pressure in the pithed spontaneously hypertensive rats (SHR). The dose-response curve to methoxamine (el-stimulation) was shifted by a factor of 30.6 by phentolamine (el +e2-blockade), 23.3 by prazosin (cq-blockade), 4.27 by carvedilol and 2.85 by dihydralazine. The responses to clonidine (e2-stimulation) are shifted by a factor of 53.1 by phentolamine and 4.56 by carvedilol, and those to noradrenaline (el >e2 stimulation) by 44.8 by phentolamine, 9.9 by prazosin, 2.78 by carvedilol and 2.81 by dihydralazine. Angiotensin II was not affected by the administration of phentolamine with a shift of 1.11 (range 0.77-1.51) or prazosin, 1.0 (0.28-1.24). The effect of carvedilol was marginal with a shift of 1.33 (1.05-1.65), with dihydralazine showing a 10.2 (4.86-17.4) shift.
$28
Another explanation of the vasodilator action of carvedilol may be that of calcium channel blockade; although the concentrations required are high, this action may be relevant at the top of the hypotensive dose range [13]. Overall, it has been concluded that the c~l-blockade is mainly responsible for the antihypertensive effect of carvedilol, but calcium antagonism may play a part in certain peripheral vascular beds [31]. The haemodynamic changes responsible for the antihypertensive effect involve a reduction of peripheral resistance without reflex tachycardia as a result of the/?-blockade. Renal blood flow is not reduced, and sodium excretion is maintained [31]. The stereoisomers of carvedilol have been examined. Only the S isomer possesses /?-blocking activity similar to findings with other /?-blocking drugs, while the R and S isomers were similar in e-blocking activity. The S isomer possessing both c~- and /?-effects had the greater antihypertensive action [2]. Clinical pharmacological investigations have confirmed these findings in animals.
Pharmacokinetics Studies with oral carvedilol (25 and 50 rag) in normal volunteers have revealed a time to maximum concentration of 1.2-1.5 h with a linear relationship between the areas under the curve (AUC) at each oral dose increment. Comparison with intravenous administration indicates a bioavailability of about 25% [24]. Carvedilol is lipid soluble; it has a large volume of distribution (132 1) indicating extensive tissue binding, and plasma protein binding is about 95%. The total body clearance is 590 ml/min via liver metabolism. After oral administration carvedilol has a terminal half-life of about 7 h [19, 20, 24]. Pharmacokinetic parameters, Cmax,AUC, half-life, are not affected by the co-administration of hydrochlorothiazide [29]. In cirrhosis of the liver there is a substantial increase in the C~a x of carvedilol. Systemic clearance is reduced, half-life is prolonged, and bioavailability was increased to 80%. Although it is difficult to explain, there was about a threefold increase in the apparent volume of distribution [25]. Renal failure does not affect the handling of carvedilol [12]. Studies of the stereoisomers of carvedilol have revealed that the R ( + ) isomer is cleared at a slower rate than the S ( - ) isomer, although the difference was not enough to make a significant difference in the half-life after intravenous administration. The bioavailability of the R ( + ) isomer
is twice that of the S ( - ) isomer, with a higher AUC. However, the elimination half-life after oral administration was reported as longer with the S ( - ) isomer, which is difficult to explain [26].
Haemodynamies Effect on supine and tilt blood pressure
Intravenous carvedilol reduces the supine blood pressure. In the study of Cubeddu et al. [4, 5] in normal volunteers, blood pressure fell after 15 mg i.v. from 138/64 to 105/50, the heart rate (HR) rising insignificantly from 54 to 60. Tomlinson et al. [40] studied the effect of 12.5, 25, 50, 100 and 200 mg in a randomised, double-blind study. The systolic blood pressure was 117 m m H g on placebo, and the fall was significant at 50 mg and above: 1 0 7 m m H g at 50rag, 1 0 6 m m H g after 200 mg. The fall in standing systolic pressure is greater than in the supine position, and it was also significant at 50 mg and above, compared with placebo (116 mmHg) the levels were 100 m m H g systolic pressure after both 100 and 200 mg. An extension from 6 to 12 subjects (Fig. 1) shows a fall in systolic blood pressure on tilting after 200 mg (P
