Introduction
Zonisamide is a sulfonamide anticonvulsant approved for use as an adjunctive therapy in adults with partial-onset seizures. Zonisamide may be a carbonic anhydrase inhibitor although this is not one of the primary mechanisms of action. Zonisamide may act by blocking repetitive firing of voltage-gated sodium channels leading to a reduction of T-type calcium channel currents, or by binding allosterically to GABA receptors. This latter action may inhibit the uptake of the inhibitory neurotransmitter GABA while enhancing the uptake of the excitatory neurotransmitter glutamate.
Uses
Zonisamide is a sulfonamide anticonvulsant used to treat partial seizures.
For use as adjunctive treatment of partial seizures in adults with epilepsy.
Associated Conditions
Pharmacodynamics
Zonisamide is a sulfonamide and therefore unrelated to other seizure medications. The mechanism is not know but it may block sodium and calcium channels. Blocking of these channels may prevent neuronal hypersynchronization. Sonisamide has also been found to potentiate dopaminergic and serotonergic neurotransmission but does not appear to potentiate syanptic activity by GABA (gamma amino butyric acid).
Mechanism of Action
Zonisamide binds to sodium channels and voltage sensitive calcium channels, which suppresses neuronal depolarization and hypersynchronization. Zonisamide also inhibits carbonic anhydrase to a weaker extent, but such an effect is not thought to contribute substantially to the drug's anticonvulsant activity.
Absorption
The absorption is rapid with a time to peak concentration of 2.8-3.9 hours. Food has not effect on bioavailability.
Volume of Distribution
- 1.45 L/kg
Protein Binding
40% (at concentrations of 1.0-7.0 µg/mL)
Route of Elimination
Zonisamide is excreted primarily in urine as parent drug and as the glucuronide of a metabolite.
Half Life
63 hours
Clearance
- 0.30 - 0.35 mL/min/kg [patients not receiving enzyme-inducing antiepilepsy drugs (AEDs)]
- 0.35 - 0.5 mL/min/kg [Concomitant administration of phenytoin and carbamazepine]
Toxicity
Symptoms of overdose include diminished breathing, loss of consciousness, low blood pressure, and slow heartbeat.
Food Interactions
- Avoid alcohol. Ingesting alcohol may increase drowsiness and dizziness.
- Take with or without food.
Dosage
Adults Over Age 16: The prescriber should be aware that, because of the long half-life of zonisamide, up to two weeks may be required to achieve steady state levels upon reaching a stable dose or following dosage adjustment. Although the regimen described below is one that has been shown to be tolerated, the prescriber may wish to prolong the duration of treatment at the lower doses in order to fully assess the effects of zonisamide at steady state, noting that many of the side effects of zonisamide are more frequent at doses of 300 mg per day and above. Although there is some evidence of greater response at doses above 100-200 mg/day, the increase appears small and formal dose-response studies have not been conducted.
The initial dose of Zonisamide should be 100 mg daily. After two weeks, the dose may be increased to 200 mg/day for at least two weeks. It can be increased to 300 mg/day and 400 mg/day, with the dose stable for at least two weeks to achieve steady state at each level. Evidence from controlled trials suggests that Zonisamide doses of 100-600 mg/day are effective, but there is no suggestion of increasing response above 400 mg/day. There is little experience with doses greater than 600 mg/day.
