VOLTAGE-DEPENDENT INTERACTIONS - THE INFLUENCE AND SIGNIFICANCE OF MEMBRANE-POTENTIAL ON DRUG-RECEPTOR INTERACTIONS

Some major drugs exert their therapeutic effect by inhibiting currents through voltage-gated ion channels. In particular, Na channels are bl ocked by local anesthetics, Class I antiarrhythmics, and some anticonv ulsants (phenytoin and carbamazepine) whereas Ca channels are blocked by dihydropyridines (nifedipine), phenylalkylamines (verapamil), and b enzothiazepines (diltiazem). Although their binding site is often pres ent in many different tissues, most of these compounds have a good the rapeutic index and are relatively tissue-specific in their action. Man y such drugs have been studied in considerable detail and their mechan isms of action were often found to be similar. In general, drug bindin g is strongly modulated by the pattern of electrical activity associat ed with the target channel and is most potent for patterns associated with pathological conditions. The most widely held hypothesis suggests that this happens because nearly all the therapeutically useful block ers of voltage-gated ion channels have an allosteric interaction with the gating mechanism oi the target channel, such that drug binding is greatly favored by specific conformations of the channel. In this revi ew, we describe the different models that have been proposed to accoun t for time- and voltage-dependent block of Na and Ca channels, with pa rticular emphasis on recent advances in our understanding of these phe nomena. We also discuss the use of similar principles to describe the action of channel activators and we suggest possible future directions . (C) 1994 Wiley-Liss, Inc.