Зонисамид

Описание

Zonisamide is a broad-spectrum antiepileptic effective in the treatment of refractory seizures. In cultured spinal cord neurons, zonisamide blocks the sustained firing of action potentials induced by depolarizing steps of current injected across the membrane.

Химические свойства

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Использование

Sulfonamide antiseizure agent; blocks repetitive firing of voltagesensitive sodium channels and reduces voltage-sensitive T-type calcium currents. Heterocyclic methanesulfonide with anticonvulsant pro perties. The compound is under investigation for potential therapeutic use as an antiepileptic drug. Anticonvulsant.

Определение

ChEBI: A 1,2-benzoxazole compound having a sulfamoylmethyl substituent at the 3-position.

Биологические функции

Zonisamide has only recently been approved for use in the United States, although it has been available in Japan for several years. It is effective in partial complex and generalized tonic–clonic seizures and also appears to be beneficial in certain myoclonic seizures. It has a long half-life (about 60 hours) and requires about 2 weeks to achieve steady-state levels. It causes cerebellovestibular side effects similar to those of most other AEDs sharing its mechanism of action. In addition, it appears to cause an increased incidence of kidney stones.

Общее описание

Zonisamide, a sulfonamide-type anticonvulsant was recentlyapproved for adjunctive therapy in the treatment ofpartial seizures in adults with epilepsy.Zonisamide isprimarily metabolized by reductive ring cleavage of the 1,2-benzisoxazole ring to 2-sulfamoyl-acetyl-phenol. This biotransformation is mainly carried out by theintestinal bacteria rather than the mammalian cytosolicaldehyde oxidase suggested earlier.Again, because ofthe presence of a sulfonamide moiety in zonisamide molecule,precaution should be given to patients who have ahistory of hypersensitivity reactions toward sulfonamidedrugs and concomitant use of zonisamide with other carbonicanhydrase inhibitors should also be avoided.

Механизм действия

Zonisamide is a sulfonamide derivative that is indicated as an adjunct for partial seizures in patients older than 16 years whose seizures are not controlled by first-line drugs. In Japan, it is used for myoclonic seizures as well. Apparently, it has more than one mechanism of action—all as yet unidentified. It is known to produce blockade of both sodium and T-type calcium channels. Because it also affects dopaminergic transmission, bipolar or schizoaffective disorder patients may improve.

Фармакокине?тика

The absorption for orally administered zonisamide is slow but nearly complete. Its pharmacokinetics are nonlinear, with a half life of 50 to 70 hours when administered alone or 27 to 46 hours when administered concurrently with enzyme-inducing AEDs. Protein binding is moderate (<50%). An oral dose of zonisamide is completely absorbed, with peak plasma concentration occurring in 2 to 6 hours. Although the presence of food will delay the attainment of its peak plasma concentration, oral bioavailability does not appear to be altered. More than one-third of each oral dose is excreted in the urine in an unchanged form. The routes of metabolism for zonisamide include acetylation to form its N-acetyl metabolite, reduction by CYP3A4/CYP2D6, and the formation of an open-ring metabolite, 2-sulfamoylacetyl phenol. These metabolites subsequently are eliminated unconjugated or glucuronidated in the urine, with an elimination half-life of 63 hours. Its coadministration with enzyme-inducing AEDs, such as phenytoin, CBZ, or phenobarbital, and with valproate will alter its pharmacokinetics by reducing its half-life and serum concentration. The half-life for zonisamide is decreased to 27 hours in the presence of phenytoin, to 38 hours in the presence of either CBZ or phenobarbital, and to 46 hours with valproate. Other drugs that inhibit or induce CYP3A4 could affect the metabolism of zonisamide.
Zonisamide should be used with caution in patients with hepatic or renal disease. It also has shown to be teratogenic in animal studies.

Побочные эффекты

Zonisamide is contraindicated in patients with a history of allergy to sulfonamides. The most frequent side effects include somnolence, anorexia, dizziness, agitation, confusion, headache, cognitive impairment, and memory loss. In addition, an incidence of drug-induced psychosis has been noted. Reports from both the United States and Europe have indicated that development of renal stones may occur with use of this drug. A family history of nephrolithiasis may be a contraindication, and urinary monitoring for hypercalciuria may be warranted in bedridden patients or those receiving multiple AEDs. Although the incidence of severe rashes attributable to zonisamide is low, sulfonamides are associated with Stevens-Johnson syndrome. Thus, it is recommended to discontinue the drug immediately should a rash occur.

Профиль безопасности

Moderately toxic by ingestion,intraperitoneal, subcutaneous, and intravenous routes. Anexperimental teratogen. Other experimental reproductiveeffects. When heated to decomposition it emits very toxicfumes of SOx and NOx. An anticonvulsant.