Zonisamide

Nobody knows exactly how zonisamide controls seizures. It showed anticonvulsant activity in several experimental models. In animals, it worked against tonic extension seizures induced by maximal electroshock, but it didn't work against clonic seizures induced by subcutaneous pentylenetetrazol. Zonisamide raised the threshold for generalized seizures in the kindled rat model, and it shortened cortical focal seizures induced by electrical stimulation of the visual cortex in cats. It also suppressed both interictal spikes and the secondarily generalized seizures produced by cortical application of tungstic acid gel in rats or by cortical freezing in cats. How far these models apply to human epilepsy is unknown.

Zonisamide may produce these effects through action at sodium and calcium channels. In vitro pharmacological studies suggest that it blocks sodium channels and reduces voltage-dependent, transient inward currents (T-type Ca2+ currents). This stabilizes neuronal membranes and suppresses neuronal hypersynchronization. In vitro binding studies have shown that zonisamide binds to the GABA/benzodiazepine receptor ionophore complex in an allosteric fashion, and this does not change chloride flux. Other in vitro studies have shown that zonisamide (10 to 30 μg/mL) suppresses synaptically-driven electrical activity without affecting postsynaptic GABA or glutamate responses (cultured mouse spinal cord neurons). Neuronal or glial uptake of [3H]-GABA (rat hippocampal slices) was not affected either. So zonisamide does not appear to potentiate the synaptic activity of GABA. In vivo microdialysis studies showed that it facilitates both dopaminergic and serotonergic neurotransmission.

Zonisamide is a carbonic anhydrase inhibitor. What this action contributes to its therapeutic effects is unknown. But because it inhibits carbonic anhydrase, zonisamide may cause metabolic acidosis