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Department of Physiology, Carbamazepine and phenytoin, two of the most commonly prescribed
antiepileptic drugs, have been proposed to share a similar mechanism of
action by use-dependent inhibition of Na+ channels. The
proposed similar mechanism of action, however, cannot explain the
common clinical experiences that the two drugs are different; in some
patients, one drug may be more effective than the other. This may occur
even when optimal therapeutic concentrations are reached with both
medications in plasma or the cerebrospinal fluid. In this study, we
show that the action of the two drugs on Na+ channels are
quantitatively very different. The affinity between inactivated
Na+ channels and carbamazepine (apparent dissociation
constant ~25 µM) is ~3 times lower than that of
phenytoin, yet the binding rate constant of carbamazepine onto the
inactivated Na+ channels is ~38,000
M
1/sec1, or ~5
times faster than that of phenytoin. It is speculated that
carbamazepine may be more effective than phenytoin in treating seizures
whose ictal depolarization shift is relatively short, whereas a better
response to phenytoin may imply abnormal discharges characterized by
more prolonged depolarization.
Copyright © by The American Society for Pharmacology and Experimental Therapeutics
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