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 blocked by local anesthetics, Class I antiarrhythmics, and some anticonvulsants (phenytoin and carbamazepine) whereas Ca channels are blocked by dihydropyridines (nifedipine), phenylalkylamines (verapamil), and benzothiazepines (diltiazem). Although their binding site is often present in many different tissues, most of these compounds have a good therapeutic index and are relatively tissue‐specific in their action. Many such drugs have been studied in considerable detail and their mechanisms of action were often found to be similar. In general, drug binding is strongly modulated by the pattern of electrical activity associated 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 blockers of voltage‐gated ion channels have an allosteric interaction with the gating mechanism of the target channel, such that drug binding is greatly favored by specific conformations of the channel. In this review, we describe the different models that have been proposed to account for time‐ and voltage‐dependent block of Na and Ca channels, with particular emphasis on recent advances in our understanding of these phenomena. We also discuss the use of similar principles to describe the action of channel activators and we suggest possible future directions. © 1994 Wiley‐Liss, Inc.