ANTIARRHYTHMIC DRUGS AND CARDIAC ION CHANNELS - MECHANISMS OF ACTION

In this review a description and an analysis are given of the interact ion of antiarrhythmic drugs with their molecular target, i.e. ion chan nels and receptors. Our approach is based on the concept of vulnerable parameter i.e. the electrophysiological property which plays a crucia l role in the genesis of arrhythmias. To prevent or stop the arrhythmi a a drug should modify the vulnerable parameter by its action on chann el or receptor targets. In the first part, general aspects of the inte raction between drugs channel molecules are considered. Drug binding d epends on the state of the channel: rested, activated pre-open, activa ted open, or inactivated state. The change in channel behaviour with s tate is presented in the framework of the modulated-receptor hypothesi s. Not only inhibition but also stimulation can be the result of drug binding. In the second part a detailed and systematic description and an analysis are given of the interaction of drugs with specific channe ls (Na+, Ca2+, K+, ''pacemaker'') and non-channel receptors. Emphasis is given to the type of state-dependent block involved (rested, activa ted and inactivated state block) and the change in channel kinetics. T hese properties vary and determine the voltage- and frequency-dependen ce of the change in ionic current. Finally, the question is asked as t o whether the available drugs by their action on channels and receptor s modify the vulnerable parameter in the desired way to stop or preven t arrhythmias. (C) 1998 Elsevier Science Ltd. All rights reserved.