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Additional features of beta-blockers

An article from the e-journal of the ESC Council for Cardiology Practice

The predominant action of beta-blockers, i.e., their inhibition of the stimulation of sympathetic beta-adrenoceptors by adrenaline and noradrenaline, is well known all around. However, some “special” beta-blockers, particularly Nebivolol, Carvedilol, Sotalol and Propranolol, exert a number of specific further effects completely independent from beta-blockade.

Cardiovascular Pharmacology and Pharmacotherapy

Beta-blockers derive their names from their main pharmacodynamic action, i.e., their inhibition of the stimulating effects of katecholamines on sympathetic beta-adrenoceptors.
However, there are some “special” beta-blockers that exert additional effects completely independent from their affinity to beta-receptors. Those are particularly Nebivolol, Carvedilol, Sotalol and Propranolol (Table).

Nebivolol is one of the “youngest members” in the family of beta-blockers widely used in clinical practice. Actually, Nebivolol is the drug with the highest beta1-selectivity (1). In addition, Nebivolol causes
NO-derived vasodilation which has been shown in humans by a marked increase in forearm blood flow that is completely abolished by coinfusion of L-NMMA, a specific inhibitor of NO-synthase (2). This vasodilating effect has clear clinical relevance since it has been shown that the beta-blocking potency of 5 mg Nebivolol is comparable to that of 25 mg Atenolol, whereas the blood pressure lowering effect of 5 mg Nebivolol is comparable to that of 100 mg Atenolol (3).

As a further feature, it was shown that Nebivolol does not decrease nocturnal melatonin release (4) which is a common side effect of most other beta-blockers as shown with Propranolol and Atenolol (5) (Figure). Since a decrease in nocturnal release of melatonin may be one reason of sleep disturbances, a common side effect of beta-blockers of the first and second generation, this finding observed with Nebivolol (and Carvedilol, see below) might be of practical importance in order to avoid this adverse effect.

In addition, plasma concentrations of Nebivolol do not increase during exercise (6), thus indicating that Nebivolol is not taken up into, stored in and released from adrenergic cells during exercise together with adrenaline and noradrenaline, a common feature of most other beta-blockers such as Propranolol and Atenolol (7) which might explain why these beta-blockers may still be effective after withdrawal of therapy even when they are no longer detectable in plasma.

Carvedilol is a non-specific antagonist of adrenergic beta1- and beta2-receptors with additional blocking effects on adrenergic alpha1-receptors (8). Thus, this drug exerts an additional effect independent of beta-blockade that, on the one hand, increases its blood pressure lowering effect and, on the other hand, may decrease potential side effects resulting from beta-blockade since the decrease of blood pressure caused by alpha-blockade may cause a reflectory increase of sympathetic tone thus reducing beta-blocking (side) effects such as bradycardia, bronchial constriction, impotence, etc.

Furthermore, Carvedilol does not reduce nocturnal melatonin release (5), a finding unique to Carvedilol and Nebivolol among all beta-blockers so far investigated on this issue (4) (Figure).
In addition, plasma concentrations of Carvedilol do not increase during exercise (9,10), thus one more finding unique to Carvedilol and Nebivolol among all beta-blockers so far investigated.

Sotalol is a non-selective, hydrophilic beta-blocker which prolongs cardiac repolarisation independent of its antiadrenergic action, thus representing class III antiarrhythmic properties (11).

Just like all other beta-blockers currently used in cardiovascular medicine, Sotalol is a racemic mixture consisting of equal amounts of d-Sotalol and l-Sotalol, with the d-enantiomer showing solely antiarrhythmic class III effects and the l-enantiomer exerting both antiarrhythmic class III and beta-blocking effects (12,13). Thus, racemic Sotalol is a combined beta-blocking and antiarrhythmic class III agent that may be useful in the treatment of both ventricular and supraventricular arrhythmias (11,14). The importance of this finding has been emphasised in the SWORD study (15) that was terminated prematurely because d-sotalol – the optically pure d-enantiomer that only exerts antiarrhythmic class III effects but no beta-blockade increased all-cause mortality compared to placebo by 65 % (p = 0.006), mainly due to arrhythmic deaths. Thus, antiarrhythmic class III properties may be useful in order to increase the antiarrhythmic efficacy of Sotalol. However, beta-blockade (effected exclusively by the l-enantiomer) appears to play a major role in the efficacy and safety of Sotalol.

Propranolol is a non-selective, lipophilic beta-blocker with two additional features: On the one hand, only the non-beta-blocking d-enantiomer inhibits the conversion of thyroxin to triiodothyronin, whereas only the l-enantiomer shows beta-blocking effects (16,17). Thus, a major part of the efficacy of Propranolol in patients suffering from hyperthyroidism resides exclusively in the non-beta-blocking d-enantiomer. This effect on thyroid hormones is well achieved with generally recommended doses of Propranolol in humans.

On the other hand, Propranolol has been shown to exert antiarrhythmic class I effects residing equally in both the d- and l enantiomers (18). However, only slight antiarrhythmic class I effects can be achieved even with the highest recommended doses of Propranolol in humans.

Regarding these additional effects of “special” beta-blockers such as Nebivolol, Carvedilol, Sotalol and Propranolol, one should always bear in mind that beta-blockers may exert a number of interesting features in addition to their well known effects on cardiac beta-adrenoceptors.

Table: Particular features of “special” beta-blockers

Beta-blocker  Particular feature(s)

High beta1-selectivity
NO-derived vasodilation
No effect on nocturnal melatonin release
No release from adrenergic cells

Inhibition of sympathetic alpha1-receptors
No effect on nocturnal melatonin release
No release from adrenergic cells

Antiarrhythmic class III effects

Propranolol   Inhibition of the conversion of T4 to T3
Slight antiarrhythmic class I effects

Effects of oral doses of 40 mg (R)-Propranolol, 40 mg (S)-Propranolol, 50 mg (R)-Atenolol, 50 mg (S)-Atenolol, 25 mg Carvedilol racemate and 5 mg Nebivolol racemate on nocturnal excretion of 6-Sulfatoxy-Melatonin (a6MTS, the main metabolite of melatonin that is almost completely released in urine): The beta-blocking (S)-enatiomers of Propranolol and Atenolol decreased aMT6s by more than 80 %, whereas the non-beta-blocking (R)-enantiomers of Propranolol and Atenolol as well as the racemic mixtures of Carvedilol and Nebivolol had no effect.
**, p < 0.01
***, p < 0.001; n.s., not significant (compared to placebo)

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.


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2. Dawes M, Brett SE, Chowienczyk PJ et al. The vasodilator action of nebivolol in forearm vasculature of subjects with essential hypertension. Br J Clin Pharmacol 1999; 48: 460-463

3. Cockroft JR et al. Nebivolol vasodilates human forearm vasculature: Evidence for an L-arginine/NO-dependent mechanism. J Pharmacol Exp Ther 1995; 274: 1067-1071

4. Stoschitzky K, Stoschitzky G. Beta-blocking effects of nebivolol, carvedilol and bisoprolol. Data on file 2004

5. Stoschitzky K, Sakotnik A, Lercher P, Zweiker R, Maier R, Liebmann P, Lindner W. Influence of beta-blockers on melatonin release. Eur J Clin Pharmacol 1999; 55: 111-115

6. Stoschitzky K, Stoschitzky G, Klein W, Müller F, Bühring K, Lamprecht G, Lindner W. Different effects of exercise on plasma concentrations of nebivolol, bisoprolol and carvedilol. Cardiovasc Drugs Ther 2004; 18: 135-138

7. Stoschitzky K, Kahr S, Donnerer J, Schumacher M, Luha O, Maier R, Klein W, Lindner W. Stereoselective increase of plasma concentrations of the enantiomers of propranolol and atenolol during exercise. Clin Pharmacol Ther 1995; 57: 543-551

8. Frishman WH. Carvedilol. New Engl J Med 1998; 339: 1759-1765

9. Stoschitzky K, Zweiker R, Klein W, Zitta S, Gruber L, Lamprecht G, Lindner W. Unpredicted lack of effect of exercise on plasma concentrations of carvedilol. J Cardiovasc Pharmacol 2002; 39: 58-60

10. Stoschitzky K, Koshucharova G, Zweiker R, Lercher P, Maier R, Klein W, Zitta S, Gruber L, Lamprecht G, Lindner W. Exercise does not affect plasma concentrations of (R)- and (S)-carvedilol. Cardiovasc Drugs Ther 2002; 16: 133-140

11. Fitton A, Sorkin EM. Sotalol – an updated review of its pharmacological properties and therapeutic use in cardiac arrhythmias. Drugs 1993; 46: 678-719

12. Gomoll AW, Bartek MJ. Comparative beta-blocking activities and electrophysiologic actions of racemic sotalol and its optical isomers in anesthetized dogs. Eur J Pharmacol 1986; 132: 123-135

13. Johnston GD, Finch MB, McNeill JA, Shanks RG. A comparison of the cardiovascular effects of (+)-sotalol and (±)-sotalol following intravenous administration in normal volunteers. Br J Clin Pharmacol 1985; 20: 507-510

14. Anderson JL, Prystowsky EN. Sotalol, an important new antiarrhythmic. Am Heart J 1999; 137: 388-409

15. Waldo AL, Camm AJ, de Ruyter H, Friedman PL, MacNeill DJ, Pauls JF, Pitt B, Pratt CM, Schwartz PJ, Veltri EP, for the SWORD investigators. Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction. Lancet 1996; 348: 7-12

16. Buchinger W, Lindner W, Lind P, Rath M, Langsteger W, Klima G, Költringer P, Eber O. Effect of R- versus S-propranolol on the peripheral thyroid hormone metabolism of hyperthyroid patients. Acta Med Austriaca 1988; 15 (Suppl 1): 62-63

17. Eber O, Buchinger W, Lindner W, Lind P, Rath M, Klima G, Langsteger W, Költringer P. The effect of D- versus L-propranolol in the treatment of hyperthyroidism. Clin Endocrinol 1990; 32: 363-372

18. Stark G, Stark U, Lueger A, Bertuch H, Pilger E, Pietsch B, Tritthart HA, Lindner W. The effects of the propranolol enantiomers on the intracardiac electrophysiological activities of Langendorff perfused hearts. Basic Res Cardiol 1989; 84: 461-468


Vol3 N°23

Notes to editor

Abteilung für Kardiologie
Auenbruggerplatz 15
A-8036 Graz, Austria
Phone: +43-316-385-80261
Fax: +43-316-385-3733

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.