Why do some drugs preferentially block open sodium channels?

It has been known for some time now that many antiarrhythmics and local anesthetics block sodium channels especially when they are depolarized. Two major phases of channel blocking occur, one "transient" and one "maintained" during the depolarization. Open channel blocking is thought to occur when intracellular forms of drug access the open channel via an aqueous pathway. This early phase of drug access is transient in the sense that opening of channels occurs for only a brief period of time (a few ms) after a depolarizing stimulus. There is also drug access to the receptor during maintained depolarizations, such as during the plateau phase of cardiac action potentials. New results provided by Kodama et al. regarding these two phases of drug blocking, transient and maintained, have prompted the structural analysis presented here. A surprisingly simple size criterion is developed that explains why certain drugs cannot use the pathway that is available during maintained depolarizations.