Kurt Stoschitzky

Influence of beta-blockers on melatonin release.

AbstractObjective: Melatonin is a mediator in the establishment of the circadian rhythm of biological processes. It is produced in the pineal gland mainly during the night by stimulation of adrenergic beta1- and alpha1-receptors. Sleep disturbances are common side-effects of beta-blockers. The influence of specific beta-blockade as well as that of combined alpha-and beta-blockade on melatonin production has not been investigated in humans before. Methods: We performed a randomized, double-blind, placebo-controlled, cross-over study in 15 healthy volunteers. Subjects received single oral doses of 40 mg (R)-propranolol, 40 mg (S)-propranolol, 50 mg (R)-atenolol, 50 mg (S)-atenolol, 25 mg (R,S)-carvedilol, 120 mg (R,S)-verapamil or placebo at 1800 hours. Urine was collected between 2200 hours and 0600 hours, and 6-sulfatoxy-melatonin (aMT6s), the main metabolite of melatonin which is almost completely eliminated in urine, was determined by radioimmunoassay (RIA). Results: Mean nocturnal excretion of aMT6s in urine after intake of the drugs was as follows (in μg): placebo 26; (R)-propranolol 24 (−7%, NS); (S)-propranolol 5 (−80%, P < 0.001); (R)-atenolol 27 (+7%, NS); (S)-atenolol 4 (−86%, P < 0.01); (R,S)-carvedilol 23 (−10%, NS); (R,S)-verapamil 29 (+14%, NS). These data show that only the specifically beta-blocking (S)-enantiomers of propranolol and atenolol decrease the nocturnal production of melatonin whereas the non-beta-blocking (R)-enantiomers have no effect. Unexpectedly, (R,S)-carvedilol which inhibits both alpha- and beta-adrenoceptors does not decrease melatonin production. Conclusion: These findings indicate that beta-blockers decrease melatonin release via specific inhibition of adrenergic beta1-receptors. Since lower nocturnal melatonin levels might be the reason for sleep disturbances, further clinical studies should investigate whether or not oral administration of melatonin might avoid this well-known side-effect of beta-blockers. The reason why (R,S)-carvedilol does not influence melatonin production remains to be determined.

Enantioselective analysis of (R)- and (S)-atenolol in urine samples by a high-performance liquid chromatography column-switching setup.

An HPLC column-switching method for the enantioselective determination of (R,S)-atenolol in human urine was developed and validated. Diluted urine samples were injected onto a LiChrospher ADS restricted access column and atenolol was separated from most of the matrix components using 0.01 M Tris buffer. The atenolol peak was sharpened by a step gradient of 30% acetonitrile and the atenolol-containing fraction was switched onto an enantioselective column. Separation of the atenolol enantiomers was carried out on a Chirobiotic T (Teicoplanin) column using acetonitrile-methanol-acetic acid-triethylamine (55:45:0.3:0.2, v/v/v/v) as eluent. Detection of the effluent was performed by fluorescence measurement. Several experiments were carried out to suppress the high blank reading, which was efficiently achieved using Tris buffer in the first dimension. For the enantioselective analysis of (R)- and (S)-atenolol in plasma under the same conditions the sample capacity of the ADS column is considerably lower.

Comparing Beta-Blocking Effects of Bisoprolol, Carvedilol and Nebivolol

Objective: Bisoprolol, carvedilol and nebivolol have been shown to be effective in the treatment of heart failure. However, the beta-blocking effects of these drugs have never been compared directly. Methods: Therefore, we performed a randomized, double-blind, placebo-controlled, cross-over trial in 16 healthy males. Subjects received 10 mg bisoprolol, 50 mg carvedilol, 10 mg nebivolol and placebo on the first morning followed by 5 mg bisoprolol once daily, 25 mg carvedilol twice daily, 5 mg nebivolol once daily and placebo for 1 week. Heart rate and blood pressure were measured at rest and exercise 3 and 24 h following intake of the first dose, and immediately before and 3 hours following intake of the last dose of each drug. In addition, effects of the drugs on nocturnal melatonin release were determined, and quality of life (QOL) was evaluated. Results: Heart rate at exercise was decreased at 3 h following intake of the first single dose of each drug by bisoprolol (–24%), carvedilol (–17%) and nebivolol (–15%), and at 24 h following intake of the respective last dose of each drug following 1 week of chronic administration by bisoprolol (–14%), carvedilol (12 h; –15%) and nebivolol (–13%) (p < 0.05 in all cases). Thus, trough-to-peak-ratios at long-term were as follows: Bisoprolol, 58%; carvedilol (12 h), 85%; nebivolol, 91%. Nocturnal melatonin release was decreased by bisoprolol (–44%, p < 0.05) whereas nebivolol and carvedilol had no effect. QOL with carvedilol was slightly but significantly lower than with the other drugs, whereas bisoprolol and nebivolol did not alter QOL. Conclusions: These data show that peak beta-blocking effects of bisoprolol appear stronger than those of nebivolol and carvedilol. On the other hand, nebivolol exerts the highest trough-to-peak-ratio. However, beta-blocking effects of all the three drugs are similar at trough. Only bisoprolol but neither nebivolol nor carvedilol decreased nocturnal melatonin release, a feature which might cause sleep disturbances. Finally, only carvedilol slightly decreased QOL, whereas nebivolol and bisoprolol did not affect QOL. We conclude that different beta-blockers may exert clinically relevant different effects.

Racemic (R,S)‐propranolol versus half‐dosed optically pure (S)‐propranolol in humans at steady state: Hemodynamic effects, plasma concentrations, and influence on thyroid hormone levels

In a randomized, double‐blind, crossover study in 10 healthy volunteers the hemodynamic effects, drug plasma concentrations, and thyroid hormone profiles were compared after oral administration for 1 week of 40 mg t.i.d. racemic (R,S)‐propranolol versus 20 mg t.i.d. optically pure (S)‐propranolol. During exercise, both substances decreased heart rate (−14%, p < 0.01), as well as the overall rate pressure product (−19%, p < 0.01) to the same extent, indicating similar β‐blocking effects. After oral application of (R,S)‐propranolol the maximal plasma concentration (Cmax) and the area under the plasma concentration—time curve (AUC) of (S)‐propranolol were higher than those of (R)‐propranolol (eudismic ratios (S)‐ over (R)‐propranolol Cmax, 1.36 p < 0.01] and AUC, 1.42 p < 0.01]) despite dose‐equivalence of both enantiomers in the administered racemic (R,S)‐propranolol preparation indicating different pharmacokinetic properties. Mean values of Cmax and the AUC of (S)‐propranolol did not differ significantly after 1 week of oral administration of 40 mg (R,S)‐propranolol and 20 mg (S)‐propranolol t.i.d., respectively. The ratio of triiodothyronine to thyroxine was decreased by (R,S)‐propranolol (− 25%, p < 0.01) but not by (S)‐propranolol, suggesting that only the (R)‐enantiomer inhibits the conversion of thyroxine to triiodothyronine. Thus, half‐dosed optically pure (S)‐propranolol is an equally effective β‐adrenergic receptor antagonist compared with currently used racemic (R,S)‐propranolol. By contrast, the conversion of thyroxine to triiodothyronine is inhibited by (R)‐propranolol only. Because there is an efficient method available to separate the (R)‐ and (S)‐enantiomers of propranolol they should be used as optically pure drugs according to their specific indications rather than racemic (R,S)‐propranolol.

Different stereoselective effects of (R)- and (S)-propafenone : clinical pharmacologic, electrophysiologic, and radioligand binding studies

Propafenone is a class 1c antiarrhythmic agent with moderate β‐blocking activity as a result of a structural similarity to β‐adrenoceptor antagonists. In a randomized, double‐blind crossover exercise study, eight healthy volunteers were examined before and 2½ hours after oral administration of 300 mg (R,S)‐, 150 mg (R)‐, and 150 mg (S)‐propafenone hydrochloride. The mean rate pressure product was significantly reduced by (R,S)‐propafenone hydrochloride (− 5.2%; p = 0.045) and half‐dosed (S)‐propafenone hydrochloride (−5.9%; p = 0.013), whereas the (R)‐enantiomer caused no significant changes. There was a significant difference between the effects of (R)‐ and (S)‐propafenone (p = 0.033). In β‐adrenoceptor–binding inhibition experiments with (S)‐(125I)iodocyanopindolol in a sarcolemmaenriched cardiac membrane preparation, the eudismic ratio of (S)‐ over (R)‐propafenone was 54. On the spontaneously beating Langendorff‐perfused guinea pig heart, 3 · 10−6 mol/L of both (R)‐ and (S)‐propafenone resulted in significant changes (p < 0.01) on His bundle conduction (+ 79% ± 27% and + 69% ± 9%), as well as comparable decreases in the maximal rate of pacing with 1:1 conduction of the atrial (−54% ± 10% and −57% ± 8%) and ventricular myocardium (−42% ± 6% and −43% ± 6%), indicating equal effects in sodium channel–dependent antiarrhythmic class 1 activity. Thus (R)‐ and (S)‐propafenone exert different β‐blocking actions but equal effects on the sodium channel–dependent antiarrhythmic class 1 activity. More specific antiarrhythmic class 1 therapy with reduction of β‐blocking side effects may be attained with optically pure (R)‐propafenone hydrochloride instead of the currently used racemic mixture.

Enantioselective drug monitoring of (R)- and (S)-propranolol in human plasma via derivatization with optically active (R,R)-O,O-diacetyl tartaric acid anhydride

A sensitive high-performance liquid chromatographic method was developed for the stereoselective assay of (R)- and (S)-propranolol in human plasma. The method involves diethyl ether extraction of the drugs and a racemic internal standard, N-tert.-butylpropranolol, followed by derivatization of the compounds with the chiral reagent (R,R)-O,O-diacetyl tartaric acid anhydride. The resulting diastereomeric derivatives were separated isocratically on a reversed-phase column. Quantitation was achieved by the peak-height ratio method with reference to the internal standard. The assay was accurate and reproducible in the concentration range 1-100 ng of (R)- and (S)-propranolol per ml plasma, using fluorescence detection at lambda ex 290 nm and lambda em 335 nm. The applicability of this method was demonstrated for the determination of concentration-time profiles of propranolol enantiomers in the course of comparative pharmacokinetic studies.

Stereoselective increase of plasma concentrations of the enantiomers of propranolol and atenolol during exercise

In vitro studies have shown that, like catecholamines, both propranolol and atenolol are taken up by and released from adrenergic cells. We performed this study to investigate whether this may also play a role in humans and whether stereoselective aspects are important.

Stereoselective vascular effects of the (R)- and (S)-enantiomers of propranolol and atenolol.

Summary All β-adrenergic antagonists have an asymmetric carbon atom, and most commercially available β-blockers consist of (R)- and (S)-enantiomers in a fixed 1:1-ratio. The drugs are believed to be contraindicated when peripheral vascular disease exists, presumably due to unopposed adrenergic vasoconstriction. However, little is known about direct vascular effects of β-blockers or of Stereoselective effects on peripheral arteries. Therefore, we investigated the effects on forearm blood flow (FBF) of brachial artery infusions of the (R)- and (S)- enantiomers of propranolol and atenolol (2, 10, and 50 μg/min each) and their inhibitory effects on isoprenaline (Iso)-induced vasodilatation by forearm venous occlusion plethysmography in 12 healthy subjects. Only (R)-propranolol caused an increase in FBF (+ 21%, p < 0.05), whereas (S)-propranolol and (R)- and (S)-atenolol had no direct effect on peripheral arteries. Vasodilatation induced by Iso was abolished by (S)-propranolol and reduced by (R)-propranolol (-56%, p < 0.05) and (5)-atenolol (-68%, p < 0.05), whereas (R)-atenolol had no effect. Our results indicate that the optically pure (R)- and (S)-enantiomers of propranolol and atenolol do not exert direct vasoconstrictive effects. Furthermore, our results confirm that predominantly (S)-enantiomers have β-adre-noceptor blocking effects, but they also show that neither the non-β-blocking (R)-enantiomer of propranolol nor the (S)-enantiomer of the β1-selective agent atenolol is completely devoid of blocking effects on vascular β2-adrenoceptors.

Direct enantioselective determination of (R)- and (S)-propranolol in human plasma. Application to pharmacokinetic studies

In order to examine possible drug interactions of (R)- and (S)-propranolol a randomized, double blind, crossover study has been performed, administering orally single doses of 40 mg (R,S)- and of 20 mg (S)-propranolol. HCl three times daily over a week to reach steady state conditions. After the first single dose of 40 mg (R,S)-propranolol. HCl, the AUC0-infinity and Cmax values of the (S)-isomer were greater than those of the (R)-isomer: the ratio of AUC(S) over AUC(R) was 1.77 (P < 0.05) and that of Cmax 1.57 (P < 0.01). When (S)-propranolol.HCl was given as a single 20 mg dose, the AUC(S) value was a factor of 0.55 lower than that administration of 40 mg (R,S)-propranolol.HCl. At steady state, the AUC of (S)-propranolol was 1.52 times higher (P < 0.01) than that of the (R)-isomer after administration of 40 mg racemate, and comparing the (S)-isomer, the ratio was 1.21. Following administration of the first single dose of 40 mg of the racemate, the mean (SD) clearance of the (R)- and (S)-isomers was 110 (84) and 61 (37) ml min-1 kg-1, respectively; at steady state these values were 89 (55) and 57 (37) ml min-1 kg-1, respectively. Respective values for (S)-propranolol after single isomer administration (20 mg) were 86 (36) and 57 (25) ml min-1 kg-1 in single dose and steady state situations. The data are based on the quantitative analysis of (R)- and (S)-propranolol in plasma.(ABSTRACT TRUNCATED AT 250 WORDS)

Stereoselective release of (S)-atenolol from adrenergic nerve endings at exercise

In-vitro studies have shown that atenolol, a beta-blocking agent, is stereoselectively taken up by and released from adrenergic nerve endings by membrane depolarisation. To investigate the potential importance of these findings, blood samples were taken at rest and after exercise testing from 10 patients (mean [SE] age 60 [3] years) receiving long-term treatment with racemic atenolol. At rest, mean plasma concentration of (R)-atenolol was higher than that of (S)-atenolol (ratio 1.14, p less than 0.01), but after exercise there was a stereoselective increase in (S)-atenolol concentration, which changed the ratio to 0.66 (p less than 0.01). Since (S)-atenolol but not (R)-atenolol causes clinically relevant beta-blockade, our findings may have importance for the management of patients receiving beta-blocking drugs.