What is the role of zonisamide (ZNS) in the treatment of epilepsy?

Updated: Jan 28, 2020
  • Author: Juan G Ochoa, MD; Chief Editor: Selim R Benbadis, MD  more...
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Answer

Answer

Zonisamide (ZNS) was synthesized as a benzisoxazole in 1974. It is chemically unrelated to any of the other AEDs; it is a small-ringed structure related to sulfonamide antibiotics with pH-dependent solubility in water. [17, 18, 19, 20, 21, 22, 23, 24]

The major mechanism of action of ZNS is reduction of neuronal repetitive firing by blocking sodium channels and preventing neurotransmitter release. It also exerts influence on T-type calcium channels and prevents influx of calcium. In addition, ZNS exhibits neuroprotective effects through free radical scavenging.

When administered orally, ZNS is absorbed quickly and completely, reaching peak levels in 2-4 hours. It has a relatively long half-life of 60 hours. It has a high affinity for binding to red blood cells (RBCs) and a 40% protein-binding capacity, exhibiting a linear dose/plasma concentration at doses of 100-400 mg.

Partially metabolized by the liver (70%), ZNS uses the cytochrome P-450 system, which is followed by glucuronidation. Although it uses the cytochrome P-450 system, it is not an inducer of the system. Metabolites of ZNS are not biologically active, and 35% of the drug is excreted unchanged in the urine.

ZNS has been approved by the US Food and Drug Administration (FDA) as adjunctive therapy for patients with partial seizures who are 12 years or older. It is preferred clinically because of the ease of patient tolerance, degree of seizure reduction, long half-life, and lack of drug interactions with other AEDs. ZNS provides dose-dependent, effective, and generally well-tolerated adjunctive therapy in patients with partial seizures.

Retrospective studies have shown that ZNS is a very effective treatment for myoclonus, especially in juvenile myoclonic epilepsy. In small series of women of childbearing years, spontaneous abortions and congenital abnormalities in human fetuses have been reported at a rate of 7%, which is more than twice the rate in the general population (2-3%). However, many of these women were treated with polytherapy.

The most commonly reported adverse reactions to ZNS are dizziness, anorexia, headache, ataxia, confusion, speech abnormalities, mental slowing, irritability, tremor, and weight gain. Gradual titration of the drug appears to reduce the manifestations of adverse reactions. Somnolence and fatigue have been reported frequently. ZNS is associated with renal stones in 1.5% of patients; therefore, the risk in patients with a history of renal stones must be weighed against the therapeutic benefits of the medication.

Oligohidrosis has been reported in children, mainly as a result of the effect on carbonic anhydrase. Idiosyncratic skin reactions (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis) have been reported in Japan at a rate of 46 per million patient-years of exposure. ZNS should not be used in patients who are allergic to sulfonamides.

PHT, CBZ, PHB, and VPA decrease the half-life from 63 hours to 27-46 hours, thereby reducing levels of ZNS; however, ZNS does not affect the levels of these drugs.

ZNS is a good alternative for patients with compliance problems because of its long half-life; it can be used once daily without significant fluctuation of blood levels. In addition, it does not have the cosmetic and pharmacokinetic problems of PHT. Its mechanism of action, inhibiting thalamic T-calcium currents, may make it effective in absence epilepsy and juvenile myoclonic epilepsy.


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