Beta-blocking effects of timolol at low plasma concentrations.

Area of Science:

• Pharmacology
• Cardiovascular Physiology

Background:

• Timolol is a beta-adrenergic receptor antagonist used clinically.
• Understanding the concentration-effect relationship of timolol is crucial for its therapeutic application and managing side effects.

Purpose of the Study:

• To investigate the concentration-effect relationship of intravenous timolol.
• To assess the influence of quinidine pretreatment on timolol's effects.
• To correlate plasma timolol concentrations with cardiac beta-blockade.

Main Methods:

• A randomized, double-blind, crossover study involving six healthy volunteers.
• Assessment of cardiac beta-adrenoceptor blockade by measuring isoproterenol dose ratios.
• Quantification of plasma timolol concentrations and cyclic adenosine monophosphate (cAMP) and norepinephrine levels.

Main Results:

• A linear relationship was observed between logarithm of plasma timolol concentration and logarithm of isoproterenol dose ratio (r=0.89) at concentrations below 1 ng/ml.
• Timolol attenuated isoproterenol-induced increases in heart rate, cAMP, and norepinephrine.
• Quinidine pretreatment increased timolol plasma levels and enhanced its cardiac beta-blocking effects by 10-40%.

Conclusions:

• Timolol competitively antagonizes isoproterenol effects at low plasma concentrations (<1 ng/ml).
• Quinidine administration augments timolol's plasma levels and beta-blockade.
• Low plasma levels of timolol can explain its systemic side effects and actions when applied ocularly.