Clinical pharmacology and mechanism of action of zonisamide.
Antiepileptic drugs (AEDs) suppress seizures by selectively modifying the excitability of neurons and blocking seizure firing with minimal disturbance of nonepileptic activity. All AEDs have been shown to work by at least one of 3 main mechanisms of action: through modulation of voltage-gated ion channels, enhancement of synaptic inhibition, and inhibition of synaptic excitation. Zonisamide is a novel AED that has a broad combination of complementary mechanisms of action, which may offer a clinical advantage over other antiepileptic agents. By altering the fast inactivation threshold of voltage-dependent sodium channels, zonisamide reduces sustained high-frequency repetitive firing of action potentials. Zonisamide also inhibits low-threshold T-type calcium channels in neurons, which may prevent the spread of seizure discharge across cells. In addition, zonisamide is a weak inhibitor of carbonic anhydrase. However, this mechanism is not believed to contribute to the antiepileptic activity of zonisamide. Although zonisamide also seems to alter dopamine, serotonin, and acetylcholine metabolism, it is not clear to what extent these effects on neurotransmitters are involved in the clinical actions of the drug. In addition to these actions, recent evidence suggests that zonisamide may exert neuroprotective actions, independent of its antiepileptic activity. These potential effects may be important in preventing neuronal damage caused by recurrent seizures. Therefore, it seems that the multiple pharmacological actions of zonisamide may contribute to the seizure reductions observed in a wide range of epilepsies and may help to preserve efficacy in individual patients despite possible changes in electrophysiological status.
Biton
Victor
V
Arkansas Epilepsy Program, Little Rock, AR, USA. vbiton@alltel.net
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology* / Q000627:therapeutic use*; D004827:Epilepsy / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D007473:Ion Channels / Q000187:drug effects / Q000502:physiology; D007555:Isoxazoles / Q000494:pharmacology* / Q000652:urine*; D009474:Neurons / Q000187:drug effects; D018377:Neurotransmitter Agents / Q000378:metabolism; D000078305:Zonisamide
D000927:Anticonvulsants; D007473:Ion Channels; D007555:Isoxazoles; D018377:Neurotransmitter Agents; D000078305:Zonisamide