Sodium Channel Blocking Agents

Drugs sharing this mechanism include phenytoin (Dilantin), carbamazepine (Tegretol), oxcarbazepine (Tri-leptal), topiramate (Topamax), valproic acid (Depakene), zonisamide (Zonegran), and lamotrigine (Lamictal). All of these agents have the capacity to block sustained high-frequency repetitive firing (SRF) of action potentials. This is accomplished by reducing the amplitude of sodium-dependent action potentials through an enhancement of steady-state inactivation. The sodium channel exists in three main conformations: a resting (R) or activatable state, an open (0) or conducting state, and an inactive (I) or nonactivatable state. The anticonvul-sant drugs bind preferentially to the inactive form of the channel. Because it takes time for the bound drug to dissociate from the inactive channel, there is time dependence to the block. Since the fraction of inactive channels is increased by membrane depolarization as well as by repetitive firing, the binding to the I state by antiepileptic drugs can produce voltage-, use-, and time-dependent block of sodium-dependent action potentials. This effect is similar to that of local anesthetic drugs (see Chapter 27) and is shown in Figure 32.1.

These agents are discussed together because their pharmacological properties, clinical indications for the treatment of epilepsy, and presumed mechanisms of action are similar. They differ from each other in several ways, however, and one drug cannot routinely be substituted for another. They differ primarily in their phar-macokinetic properties, their adverse reactions, and their interactions with other drugs. In addition to blocking sodium channels, some possess other therapeutically relevant mechanisms of action as well.

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