Stereoselective effects of (R)- and (S)-carvedilol in humans

Area of Science:

• Pharmacology
• Cardiovascular Physiology

Background:

• Carvedilol is used as a racemic mixture ((R,S)-carvedilol).
• The individual enantiomers, (R)-carvedilol (alpha-blocker) and (S)-carvedilol (alpha- and beta-blocker), have not been tested in humans.
• Understanding enantiomer-specific effects is crucial for optimizing drug therapy.

Purpose of the Study:

• To investigate the distinct cardiovascular and endocrine effects of (R)-carvedilol, (S)-carvedilol, and racemic (R,S)-carvedilol in healthy volunteers.
• To determine the impact of individual carvedilol enantiomers on heart rate, blood pressure, and melatonin secretion.

Main Methods:

• A randomized, double-blind, placebo-controlled, crossover study involving 12 healthy male volunteers.
• Administration of single oral doses of (R,S)-carvedilol, (R)-carvedilol, (S)-carvedilol, and placebo.
• Measurement of heart rate and blood pressure at rest and during exercise, and determination of urinary 6-hydroxy-melatonin sulfate (aMT6s) levels.

Main Results:

• (S)-carvedilol significantly decreased heart rate and systolic blood pressure during exercise and recovery.
• (R)-carvedilol increased heart rate during exercise and recovery, suggesting increased sympathetic tone.
• (R,S)-carvedilol decreased heart rate and systolic blood pressure, but neither enantiomer nor the racemic mixture affected melatonin release (aMT6s).

Conclusions:

• (S)-carvedilol is responsible for the beta-blocking activity of carvedilol.
• (R)-carvedilol may exert a sympathomimetic effect, potentially as a compensatory response to alpha-blockade.
• The lack of effect on melatonin release by carvedilol enantiomers may contribute to its favorable side-effect profile compared to other beta-blockers.