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European Journal of Heart Failure 2001 3(3):343-349; doi:10.1016/S1388-9842(01)00126-X
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© 2001 European Society of Cardiology

Differing beta-blocking effects of carvedilol and metoprolol

Kurt Stoschitzky*, Gergana Koshucharova, Robert Zweiker, Robert Maier, Norbert Watzinger, Friedrich M. Fruhwald and Werner Klein

Medizinische Universitätsklinik, Abteilung für Kardiologie Graz, Austria

* Corresponding author. Tel.: +43-3163852544; fax: +43-3163853733 E-mail address: kurt.stoschitzky{at}kfunigraz.ac.at (K. Stoschitzky).


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: Metoprolol is a beta1-selective beta-adrenergic antagonist while carvedilol is a non-selective beta-blocker with additional blockades of alpha1-adrenoceptors. Administration of metoprolol has been shown to cause up-regulation of beta-adrenoceptor density and to decrease nocturnal melatonin release, whereas carvedilol lacks these typical effects of beta-blocking drugs.

Aims: To compare beta-blocking effects of metoprolol and carvedilol when applied orally in healthy subjects.

Methods: We investigated the effects of single oral doses of clinically recommended amounts of metoprolol (50, 100 and 200 mg) and carvedilol (25, 50 and 100 mg) to those of a placebo in a randomised, double-blind, cross-over study in 12 healthy male volunteers. Two hours after oral administration of the drugs heart rate and blood pressure were measured at rest, after 10 min of exercise, and after 15 min of recovery.

Results: Metoprolol tended to decrease heart rate during exercise (–21%, –25% and –24%) to a greater extent than carvedilol (–16%, –16% and –18%). At rest, increasing doses of metoprolol caused decreasing heart rates (62, 60 and 58 beats/min) whereas increasing doses of carvedilol caused increasing heart rates (62, 66 and 69 beats/min), 50 and 100 mg carvedilol failed to differ significantly from the placebo (71 beats/min).

Conclusions: We conclude that clinically recommended doses of carvedilol cause a clinically relevant beta-blockade in humans predominantly during exercise where it appears to be slightly (although not significantly) less effective than metoprolol. On the other hand, the effects of carvedilol on heart rate at rest appear rather weak, particularly in subjects with a low sympathetic tone. This might be caused by a reflex increase on sympathetic drive secondary to peripheral vasodilation resulting from the alpha-blocking effects of the drug. These results might be helpful in explaining why carvedilol, in contrast to metoprolol, may fail to cause up-regulation of beta-adrenoceptor density and does not decrease nocturnal melatonin release. This, in turn, may be a reason for the weak side-effects of carvedilol resulting from the beta-blockade. In addition, our data might be of interest in the interpretation of the forthcoming results of the COMET trial, although it has to be emphasised that they were derived from healthy subjects and, therefore, cannot be directly extrapolated to patients with heart failure.

Key Words: Carvedilol • Metoprolol • Beta-blockers • Heart failure • Melatonin

Received August 10, 2000; Revised November 8, 2000; Accepted January 17, 2001


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
In recent years, beta-blockers have been shown to be highly effective in the treatment of congestive-heart-failure (CHF). Carvedilol decreased mortality in a large randomised placebo-controlled study by 65% [1], metoprolol did so by 34% [2]. However, it is not known whether carvedilol is more effective than metoprolol. Therefore, the Carvedilol-or-Metoprolol-European-Trial (COMET) was launched in order to directly compare the effects of carvedilol and metoprolol in patients with CHF [3]. In this context, it appears important to emphasise the pronounced differences between the pharmacological effects of carvedilol and metoprolol.

Metoprolol is a selective antagonist of adrenergic beta1-receptors [4] whereas carvedilol is a non-selective beta-blocker with additional alpha1-blocking and antioxidant effects [5]. Both drugs are used as racemates in research as well as in clinical practice, i.e. they consist of equal amounts of (R)- and (S)-enantiomers. For both drugs, beta-blockade has been shown to reside predominantly in the (S)-enantiomers, whereas the (R)-enantiomers do not contribute to this effect. However, both (R)- and (S)-carvedilol are equally effective alpha-blockers. Therefore, currently used racemic (R,S)-metoprolol consists of 50% of a beta1-blocker, (S)-metoprolol, and 50% of a compound that does not exert any effect on adrenergic receptors, (R)-metoprolol. On the other hand, racemic (R,S)-carvedilol consists of 50% of an antagonist of both alpha1- and beta-receptors, (S)-carvedilol, and 50% of a pure alpha1-blocker without beta-blocking effects, namely (R)-carvedilol [6–10].

Chronic administration of beta-blockers without additional effects produces reactive up-regulation of beta-receptor density [11]. In addition, beta-blockers reduce nocturnal melatonin production [12]. However, carvedilol has been shown neither to cause up-regulation of beta-receptor density in some cases [13] nor to influence nocturnal melatonin production [12]. The lack of these typical effects of beta-blockers in (R,S)-carvedilol is currently unexplained. However, there are several hypotheses as to which mechanisms might possibly account for these properties in carvedilol: Firstly, an insufficient beta-blockade by (R,S)-carvedilol in clinical practice; secondly, intrinsic sympathomimetic activity (ISA) of (R,S)-carvedilol; thirdly, reflex activation of sympathetic tone caused by vasodilation due to an alpha-blockade of both (R)- and (S)-carvedilol. However, ISA was not described with (R,S)-carvedilol [14]. On the other hand, in a recent study in healthy subjects who received single oral doses of (R)-, (S)- and (R,S)-carvedilol, the racemate failed to significantly decrease heart rate, whereas optically pure (R)-carvedilol slightly increased resting heart-rate [15], thus supporting the third hypothesis mentioned above.

In order to address these unsolved issues, we performed a randomised, double-blind, placebo-controlled, cross-over study in 12 healthy volunteers using three doses of (R,S)-metoprolol (50, 100 and 200 mg) and (R,S)-carvedilol (25, 50 and 100 mg). These dosages represent the upper range recommended for these drugs in clinical practice as well as those used in the US carvedilol trial [1] and in MERIT [2] in order to determine effective beta-blockade of (R,S)-metoprolol and (R,S)-carvedilol in humans.

Throughout the following text, whenever metoprolol and carvedilol are mentioned without specific reference to the (R)- and (S)-enantiomers, the commercially available racemic (R,S)-mixture was used.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Study protocol
Twelve healthy male volunteers, aged 19–45-years, received single oral doses of 50, 100 and 200 mg (R,S)-metoprolol, 25, 50 and 100 mg (R,S)-carvedilol and placebo at intervals between 3 and 7 days according to a randomised, double-blind, placebo-controlled, cross-over protocol. Prior to inclusion in the study subjects gave written informed consent and underwent a short physical examination, ECG, and determination of routine laboratory parameters to ensure current health. Subjects with obstructive pulmonary disease, diabetes mellitus, peripheral arterial disease, AV-block, bradycardia (resting heart rate <50/min) or hypotension (blood pressure <100/70 mmHg) were excluded.

On each day of the study, subjects entered the laboratory between 07.00 and 09.00 h following an overnight fast. The blinded study medication was swallowed with 50–100 ml of water. Two hours later, exercise was performed for 10 min on a bicycle ergometer at 70% of mean individual work load. Heart rate and blood pressure were measured at rest immediately before the onset of exercise, during the last minute of exercise, and at rest after 15 min of recovery. Continuous ECG monitoring and cuff sphygmomanometry were used to record heart rate and blood pressure. The investigations conformed with the principles outlined in the Declaration of Helsinki (Br Med J 1964; ii: 177).

2.2. Materials
(R,S)-metoprolol tartrate and (R,S)-carvedilol were taken from formulations commercially available in Austria (Beloc® and Dilatrend®, respectively). The blinded pharmaceutical formulations (hard gelatine capsules) containing 50 mg (R,S)-metoprolol, 100 mg (R,S)-metoprolol, 200 mg (R,S)-metoprolol, 25 mg (R,S)-carvedilol, 50 mg (R,S)-carvedilol, 100 mg (R,S)-carvedilol or placebo together with mannitol and carbosil as auxiliary materials, were prepared according to the specifications of the European Pharmacopoeia at the Institute of Pharmaceutical Technology, Karl Franzens University, Graz, Austria.

2.3. Statistical analysis
Results are given as arithmetic means ±1 S.D. unless otherwise indicated. Significant differences within groups were calculated using Repeated Measures ANOVA (Friedman's Repeated Measures ANOVA on Ranks when applicable), and the Student–Newman–Keuls test for post-hoc testing. A P-value <0.05 was considered statistically significant


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
Subjects were 33±7 years-of-age, were 178±4 cm in height and weighed 71±8 kg, and performed 151±17 W over 10 min on the bicycle ergometer.

Haemodynamic results are summarised in Table 1. At rest, increasing doses of metoprolol caused a progressive decrease in heart rate (62, 60 and 58 beats/min) which was significantly different from the placebo in all cases, whereas increasing doses of carvedilol caused increasing heart rates (62, 66 and 69 beats/min). Doses of 50 and 100 mg carvedilol failed to differ significantly from the placebo (Fig. 1), and 200 mg metoprolol were significantly more effective than 100 mg carvedilol (P<0.05). Similar trends were observed during recovery. Compared to the placebo, metoprolol significantly decreased heart rate during exercise (–21%, –22% and –24%), as did carvedilol (–16%, –17% and –18%) (Fig. 2). The effects of metoprolol appeared to be slightly (although not significantly) more pronounced than those of carvedilol.


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  		Table 1 Heart rate (beats/min) and systolic and diastolic blood pressure (mmHg) at rest, after 10 min of exercise, and after 15 min of recoverya

 


Figure 1
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  		Fig. 1 Effects of single oral doses of placebo, 25, 50 and 100 mg carvedilol, and 50, 100 and 200 mg metoprolol on resting heart rate: Increasing doses of metoprolol decrease heart rate, whereas increasing doses of carvedilol increase heart rate. Means ± S.E.M.; n =12; *, P<0.05 (compared to placebo).

 


Figure 2
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  		Fig. 2 Effects of single oral doses of placebo, 25, 50 and 100 mg carvedilol, and 50, 100 and 200 mg metoprolol on heart rate during exercise: Metoprolol appears to be slightly, although not significantly more effective than carvedilol. Means ± S.E.M.; n =12; *, P<0.05 (compared to placebo).

 
Systolic blood pressure was significantly decreased by 100 and 200 mg metoprolol during exercise and by 50, 100 and 200 mg metoprolol during recovery, whereas metoprolol had no significant effect on systolic blood pressure at rest. Fifty and 100 mg carvedilol decreased systolic blood pressure at rest, during exercise and during recovery, whereas 25 mg carvedilol had a significant effect on systolic blood pressure only during recovery. There were no significant differences between the effects of either of the drugs on systolic blood pressure.

There were no significant effects of any of the drugs on diastolic blood pressure in this study with oral single-dose administration. All baseline values of heart rates and blood pressures at rest were comparable to placebo values given in Table 1.


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
The present data show that clinically recommended doses of carvedilol and metoprolol exert different clinical consequences from beta-blockade: Heart rate during exercise, one of the most relevant parameters to determine clinically effective beta-blockade, was decreased by both carvedilol and metoprolol. The effects of 50, 100 and 200 mg metoprolol (–21%, –22% and –24%) appeared more pronounced than those of 25, 50 and 100 mg carvedilol (–16%, –17% and –18%) (Fig. 2), although there were no significant differences between carvedilol and metoprolol.

Both at rest before exercise as well as after 15 min of recovery metoprolol decreased heart rate, but to a lesser extent than during exercise. As expected, increasing doses of metoprolol caused decreasing heart rates (Fig. 1). On the other hand, carvedilol failed to exert significant effects on heart rate under these resting conditions except for 25 mg carvedilol which slightly decreased heart rate at rest before exercise but not during recovery. Unexpectedly, increasing doses of carvedilol caused increasing heart rates (62, 66 and 69 beats/min at rest, Fig. 1, and 69, 70 and 73 beats/min during recovery), a finding opposite to what would be expected with a beta-blocker.

These findings obtained with carvedilol might possibly be explained by a decrease in blood pressure caused by the alpha-blocking effects of the drug which may be expected to cause a compensatory increase in sympathetic tone. On the one hand, an increase in sympathetic tone might diminish the effects of the drug on both heart rate and blood pressure. In the present study, carvedilol did not show significant effects on diastolic blood pressure, and 25 mg carvedilol also failed to decrease systolic blood pressure at rest. On the other hand, the increase in sympathetic tone mentioned above might diminish or nearly abolish the clinical consequences of the beta-blocking effects of carvedilol: Indeed, under conditions with a physiologically low sympathetic tone, i.e. at rest and during recovery, carvedilol failed to significantly decrease heart rate (except for 25 mg carvedilol which slightly decreased heart rate at rest but not during recovery) whereas metoprolol, which lacks alpha-blocking effects, significantly decreased heart rate both at rest and during recovery. A further reason for these different effects of metoprolol and carvedilol on resting heart rate might be the fact that metoprolol, but not carvedilol, exhibits pronounced inverse agonist activity on beta1-adrenoceptors [16,17]. In addition, a very recent in vitro study concluded that carvedilol displays higher intrinsic sympathomimetic activity compared to metoprolol [17].

These data suggest that carvedilol exerts net clinical beta-blockade predominantly under conditions with an elevated sympathetic tone, i.e. during exercise in the present study, whereas its decreasing effects on heart rate are rather weak when sympathetic tone is low, i.e. at rest in healthy subjects. This might be one reason why carvedilol appears to exert less side-effects resulting from beta-blockade than other (‘pure’) beta-blockers [18]. In addition, the weak net clinical consequences of beta-blockade exhibited by carvedilol at rest might explain why — in contrast to other (‘pure’) beta-blockers — it does not decrease nocturnal melatonin release as shown in a previous study [12] since nocturnal sleep is doubtless one of the most distinct resting conditions. In addition to the guanine-nucleotide-modulatable binding property and the nearly complete lack of inverse agonist activity on beta1-receptors of carvedilol [16,17], this might be a further reason why long-term therapy with carvedilol may fail to cause up-regulation of beta-receptor density [13] which is a typical effect of beta-blocking drugs without additional effects [11].

The observed increase in heart rate with increasing doses of carvedilol at rest and during exercise might be explained by the fact that the affinity of carvedilol to beta1-receptors is approximately 2-fold higher than that to alpha1-receptors [19–21]. Therefore, beta-blockade obtained with 25 mg carvedilol might be more complete than alpha-blockade, resulting in a greater increase in alpha- than in beta-blockade with increasing doses of carvedilol producing a higher compensatory increase in sympathetic tone and thus decreasing the influence of the drug on resting heart rate at increasing doses. On the other hand, these data further emphasise that the effects of a beta-blocking drug on resting heart rate alone cannot be used as an index of its pharmacological beta-blocking potency, particularly when it possesses additional effects such as carvedilol.

It is important to note that the results of the present study, which was performed in healthy males who usually have a low sympathetic tone at rest, cannot be directly extrapolated to patients with heart failure, since the net clinical effects of beta-blockade of carvedilol may be markedly higher in patients with an increased sympathetic tone even under resting conditions such as those with CHF. Thus, it is not surprising that studies with carvedilol in patients with CHF yielded clear and significant decreasing effects of the drug on resting heart rate [22–27] which are in contrast to the results of the present single-dose study where carvedilol only had a slight/no effect on resting heart rate. However, this decrease in heart rate was obtained after long-term administration of carvedilol and active metabolites have been described which might increase the beta-blocking potency of the drug [18]. In four of these studies [24–27] carvedilol was also compared to metoprolol with the dosage of metoprolol approximately twice that of carvedilol in three studies [25–27] and equal doses of carvedilol and metoprolol in one study [24]. The net clinical beta-blocking effect at rest of carvedilol and metoprolol expressed by resting heart rate was similar [25–27] with the exception of one study where dosages of carvedilol were equal and the decrease of resting heart rate obtained with carvedilol was greater than that with metoprolol [24]. On the other hand, carvedilol was even shown to be able to increase heart rate in healthy volunteers, particularly when administered intravenously [28]. Therefore, the net clinical beta-blocking effects of carvedilol under resting conditions appear to depend strongly on the basal sympathetic tone of the subject receiving the drug, a behaviour that is supported by the results of the present study. In addition, our data support the results from previous studies [25–27] that clinically relevant beta-blockade obtained by metoprolol is as effective as that of half-dosed carvedilol, i.e. the dose relationship of carvedilol and metoprolol in COMET [3].

Our data further suggest that the potentially superior effects of carvedilol on clinical outcomes in patients with CHF cannot be explained by higher beta-blocking effects of carvedilol when clinically daily recommended doses of carvedilol (25–100 mg) or metoprolol (50–200 mg) are administered in a 1:2 ratio. Furthermore, the alpha-blocking effect of carvedilol is also unlikely to account for a potential benefit of carvedilol over ‘pure’ beta-blockers since the doxazosin arm of the ALLHAT trial had to be finished prematurely due to a doubling of the risk of CHF [29]. The antioxidant and anti-neutrophil effects [30] and/or the prevention of contractile dysfunction induced by hydroxyl radicals [31] could be the ultimate potential benefits of carvedilol over metoprolol known to date for patients with CHF.

There are two important limitations of the present study: Firstly, we studied healthy volunteers who usually have a lower sympathetic tone at rest and a higher density of adrenergic beta-receptors than patients suffering from congestive heart failure. Secondly, we examined the effects of single doses of the drugs which may differ from those during long-term therapy.

We conclude that recommended doses of carvedilol cause pronounced beta-blockade in humans mainly during exercise where it appears to be slightly (although not significantly) less effective than double-dosed metoprolol. On the other hand, the net clinical consequences of the beta-blocking effects of carvedilol, i.e., a decrease in heart rate under resting conditions, appear rather weak in subjects with a low sympathetic tone. This might be a result of compensatory sympathetic stimulation due to a decrease in blood pressure resulting from the alpha-blocking effect of the drug. In addition to the guanine-nucleotide-modulatable binding properties and the nearly complete lack of inverse agonist activity on beta1-receptors of carvedilol [16,17], these results might explain why carvedilol, in contrast to metoprolol, may fail to cause up-regulation of beta-adrenoceptor density and does not decrease nocturnal melatonin release, two typical effects of ‘pure’ beta-blockers. The weak net clinical consequences of its beta-blocking effects at rest might be the reason for the weak side-effects of carvedilol resulting from beta-blockade. However, irrespective of that, carvedilol appears at least as effective as metoprolol in reducing arterial blood pressure and morbidity and mortality resulting from congestive heart failure [1,2]. Taken together, our results might be of interest in the interpretation of the forthcoming results of COMET, although it has to be emphasised that they were derived from healthy subjects and cannot be directly extrapolated to patients with heart failure.


   Acknowledgements
 
The authors wish to thank Prof Werner Korsatko, Institute of Pharmaceutical Technology, Karl Franzens University, Graz, Austria, for the preparation of the blinded galenic formulations.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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