Quantitative structure/activity relations based on use-dependent block and repriming kinetics in myocardium.

Area of Science:

• Pharmacology
• Cardiac Electrophysiology
• Medicinal Chemistry

Background:

• Class 1 antiarrhythmic drugs modulate cardiac excitability through sodium channel interactions.
• Drug properties, including size and lipid solubility, influence channel blocking and recovery kinetics.

Purpose of the Study:

• To review studies on class 1 antiarrhythmic drugs to test structural hypotheses of their actions.
• To investigate the relationship between drug properties, sodium channel block, and cardiac excitability.

Main Methods:

• Analysis of maximum upstroke velocities from intracellularly recorded action potentials (APs).
• Evaluation of drug molecular weights, lipid distribution coefficients, and repriming kinetics.
• Modeling of drug recovery times using a cylindrical pore model.

Main Results:

• The size/solubility hypothesis is supported for drugs with molecular weights up to 350, showing smaller, more lipid-soluble drugs have faster repriming.
• Lipid distribution coefficients correlate with blocking ability within drug classes.
• Slower drug kinetics may be associated with increased cardiotoxicity.

Conclusions:

• Drug size and lipid distribution are critical factors in antiarrhythmic drug potency and cardiotoxicity.
• Repriming kinetics significantly contribute to the overall efficacy and safety profile of these drugs.
• Hydrophilic and hydrophobic pathways influence drug recovery kinetics, highlighting the role of lipid distribution.