Zonisamide - Anticonvulsant (Anti-Epileptic) Drug

Zonisamide

Zonisamide (a sulfonamide derivative) is a substituted 1,2-benzisoxazole anticonvulsant, and is indicated in the treatment of partial, generalised, and mixed seizures, espe-cially in those patients whose seizures are refractory to other anti-epileptics inhibition of the spread of seizure activity with zonisamide therapy may be explained by zonisamide’s reduc-tion of the T-type calcium current. The degree of current inhibi-tion is concentration-dependant and allows fewer channels to be open during depolarisation, thereby suppressing the inward current. These effects occur without evoking a change in inac-tivation kinetics or voltage-dependant action. Zonisamide also has a biphasic effect on dopamine function that is dependant on the dose.

Therapeutic doses of 20 to 50 mg/kg enhance dopamine function while supratherapeutic doses of 100 mg/kg inhibit dopamine function. This biphasic effect on dopamine function may explain the anticonvulsant and mood stabilising effects at therapeutic doses and the sedative side effects at suprathera-peutic doses.

Zonisamide is rapidly and almost completely absorbed from the gastrointestinal tract following oral administration. Zonisamide binds to erythrocytes extensively because of its affinity for binding to carbonic anhydrase and other red cell protein components. The peak plasma concentrations range from 2 to 5 mcg/ml after an oral zonisamide dose of 200 to 400 mg, and will generally occur within 2 to 6 hours. At concen-trations of 1.0 to 7.0 mcg/ml, zonisamide is approximately 40% bound to plasma proteins. Zonisamide is hepatically metabolised to acetyl and glucuronide conjugate metabolites The plasma elimination half-life is approximately 63 hours.

Therapeutic zonisamide plasma concentration ranges from 10 to 30 mg/L. Adverse effects have occurred with plasma concentrations of greater than 30 mg/L. Adverse effects include anorexia, nausea, vertigo, somnolence, ataxia, headache, tremor, and increased incidence of renal calculi. Hyperthermia and oligohidrosis, often resulting in heat stroke, have been reported among paediatric patients, following therapeutic administration of zonisamide. Seizures have been reported following abrupt withdrawal of zonisamide therapy. Psychosis, including auditory hallucinations, mania, delusions, paranoia, and violent behaviour, have been reported in adults and chil-dren following therapeutic administration of zonisamide. The patients’ psychiatric symptoms gradually disappeared following discontinuation of zonisamide therapy. Severe skin rashes, including Stevens-Johnson syndrome and toxic epidermal necrolysis, were also reported with a few fatalities.

following overdose. Multiple generalised tonic-clonic seizures and cardiac arresthave also occurred.Human overdose information is limited. Bradycardia, hypo-tension, respiratory depression, and coma have been reported

Treatment is symptomatic and supportive. Monitor for evidence of decreased sweating and increased temperature in paediatric patients following zonisamide ingestion. Paediatric patients appear to be at increased risk for zonisamide-associated oligohidrosis and hyperthermia.

Anencephaly and atrial septal defects occurred after first trimester exposure to zonisamide and other anticonvulsant agents, although it is not clear if zonisamide is the direct cause.