Chemical Properties
Off-White Powder
Originator
Dainippon (Japan)
Uses
anticonvulsant;carbonic anhydrase inhibitor, repetitive firing of voltage-gated sodium channels and reduction of T-type calcium channel currents blocker
Uses
For use as adjunctive treatment of partial seizures in adults with epilepsy.
Uses
muscarinic antagonist used as an antispasmodic
Uses
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.
Definition
ChEBI: A 1,2-benzoxazole compound having a sulfamoylmethyl substituent at the 3-position.
Manufacturing Process
To a solution of 8.0 of 3-bromomethyl-1,2-benzisoxazole (m.p. 64-66°) in 130
ml of methanol was added a solution of 8.1 g of sodium sulfite in 130 ml of
water. The mixture was heated with stirring at 50°C for 4 hours and
concentrated under reduced pressure. The crystalline residue was dissolved in
250 ml of methanol with warming and the insoluble material was filtered off.
The filtrate was concentrated under reduced pressure and the crystalline
residue of 1,2-benzisoxazole-3-methanesulfonyl chloride was washed with
diethyl ether to give crude sodium 1,2-benzisoxazole-3-methanesulfonate
(10.5 g).
To 100 ml of phosphorus oxychloride was added 10.5 g of the above-
mentioned sodium salt and the mixture was heated under reflux for 3 hours.
The excess of phosphorus oxychloride was distilled off under reduced
pressure. The residue was dissolved in 200 ml of ethyl acetate and the
removal of the insoluble material by filtration gave the solution of the 1,2-
benzisoxazole-3-methanesulfonyl chloride.
The solution of 1,2-benzisoxazole-3-methanesulfonyl chloride in ethyl acetate,
was cooled on an ice bath, saturated with dry ammonia gas, and allowed to
stand at room temperature for one hour. After the removal of the insoluble
material by filtration, the filtrate was concentrated to yield a crystalline solid,
which was washed with a small amount of ethyl acetate and recrystallized
from ethyl acetate to give the 3-sulfamoylmethyl-1,2-benzisoxazole (5.2 g),
m.p. 160-163°C.
Brand name
Zonegran (Dainippon Pharmaceutical Co., Japan);Exegran.
Therapeutic Function
Anticonvulsant; Antiepileptic
Biological Functions
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.
General Description
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.
Mechanism of action
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.
Pharmacokinetics
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.
Clinical Use
Antiepileptic
Side effects
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.
Safety Profile
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.
Veterinary Drugs and Treatments
Zonisamide may be useful as an “add-on” drug for refractory epilepsy
in dogs.
Drug interactions
Potentially hazardous interactions with other drugs
Antidepressants: anticonvulsant effect antagonised;
avoid with St John’s wort.
Antimalarials: anticonvulsant effect antagonised by
mefloquine.
Antipsychotics: anticonvulsant effect antagonised.
Orlistat: increased risk of convulsions.
Metabolism
Zonisamide is metabolised mainly by reductive cleavage
of the benzisoxazole ring of the parent drug by CYP3A4
to form 2-sulphamoylacetylphenol (SMAP) and also
by N-acetylation. Parent drug and SMAP can also be
glucuronidated.
The metabolites, which could not be detected in
plasma, are inactive. Excretion is mainly in the urine;
about 15 to 30
% appearing as unchanged drug, 15
%
as N-acetylzonisamide, and 50
% as the glucuronide of
SMAP.
