Zonisamide

Description

Zonisamide is a new generation of sulfonamide anticonvulsant that is primarily used as supplemental therapy in treatment of partial seizures in combination with other antiepileptic medications. Besides, it is approved to be applied as an adjunctive therapy in adults suffering from infantile spasm, mixed seizure types of Lennox–Gastaut syndrome, myoclonic, and generalized tonic clonic seizure. Recent studies have proved that zonisamide can acts as a migraine preventative medication and is effective in several cases of neuropathic pain. In an open-label trial, zonisamide shows positive effects on attenuating the symptoms of tardive dyskinesia.
Zonisamide is a second-generation antiepileptic drug (AED) known with the proprietary brand name of Zonegran® (Eisai) in the UK and USA. It is assumed that zonisamide functions on the sodium and calcium channels in the brain cells, in which it controls electric-currents that are responsible for seizure activity. The FDA approved zonisamide in March 2000.

Indications

Epilepsy
Monotherapy of focal seizures with or without secondary generalization and adjunctive therapy of refractory focal seizures with or without secondary generalization.

Recommendations summarized from NICE (2012)

• Seizure types: on referral to tertiary care (absence seizures, focal seizures, myoclonic seizures).
• Epilepsy types: on referral to tertiary care (absence syndromes, juvenile myoclonic epilepsy, idiopathic generalized epilepsy, benign epilepsy with centrotemporal spikes, panayiotopoulos syndrome, late- onset childhood occipital epilepsy).

Dose titration

Epilepsy

Monotherapy
100 mg od for 14 days, then increased by 100 mg every 14 days; usual maintenance 300 mg od (max. 500 mg daily).

Adjunctive therapy
25 mg bd for 7 days, 50 mg bd for 7 days, then increased by 100 mg every 7 days; usual maintenance 300– 500 mg daily, divided into 1 or 2 doses (dose to be increased every 14 days in patients who are not on carbamazepine, phenobarbital, phenytoin, or other potent inducers of cytochrome P450 enzyme CYP3A4).

Plasma levels monitoring

Although plasma levels can be measured, and a therapeutic range has been postulated (10– 40 mg/ L), there is little evidence base for recommending routine measurement of plasma levels in clinical practice.

Cautions

• Patients with metabolic acidosis (consider dose reduction or discontinuation if metabolic acidosis develops).
• Patients with low body weight or poor appetite (monitor weight throughout treatment).
• Patients with risk factors or predisposition to nephrolithiasis.
• Elderly patients.

Interactions

With AEDs

• Exposure to zonisamide is lower in epileptic patients receiving CYP3A4- inducing agents such as phenytoin, carbamazepine, and phenobarbital. These effects are unlikely to be of clinical significance when zonisamide is added to existing therapy; however, changes in zonisamide concentrations may occur if concomitant CYP3A4- inducing antiepileptic or other medicinal products are withdrawn, dose adjusted or introduced, an adjustment of the zonisamide dose may be required.
• Zonisamide should be used with caution in adult patients treated concomitantly with carbonic anhydrase inhibitors such as topiramate and acetazolamide, as there are insufficient data to rule out a possible pharmacodynamic interaction.

• Caution is advised when starting or stopping zonisamide treatment or changing the zonisamide dose in patients who are also receiving P- gp substrates such as digoxin and quinidine.
• If co- administration with rifampicin (a potent CYP3A4 inducer) is necessary, the patient should be closely monitored and the dose of zonisamide and other CYP3A4 substrates adjusted as needed.

Special populations

Hepatic impairment

• Initially increase dose every 14 days in moderate impairment.
• Avoid in severe impairment.

• Initially increase dose every 14 days in moderate impairment. • Discontinue if renal function deteriorates.

• There are limited data from the use of zonegran in pregnant women and the potential risk in terms of reproductive toxicity for humans is unknown.
• Zonisamide must not be used during pregnancy unless it is required based on the clinical condition of the patient. In such cases, the dose of zonisamide should be monitored carefully during pregnancy and after birth, and adjustments made on a clinical basis.
• Zonisamide is excreted in human milk; the concentration in breastmilk is similar to maternal plasma. A decision must be made whether to discontinue breastfeeding or to discontinue/ abstain from zonisamide therapy.
  Due to the long retention time of zonisamide in the body, breastfeeding must not be resumed until 1 month after zonisamide therapy is completed.

Behavioural and cognitive effects in patients with epilepsy

The behavioural profile of zonisamide in patients with epilepsy features specific problems, which can occur with high doses. The most commonly reported behavioural symptoms are depression, irritability, agitation, and psychosis. Cognitive deficits reported by patients treated with zonisamide mainly involve attention, concentration, and language domains (most effects occur at high doses).

Psychiatric use

Zonisamide does not have any approved indications in psychiatry. Initial findings from uncontrolled studies suggesting that zonisamide may be effective in the treatment of bipolar disorder did not find confirmation. There is preliminary evidence for possible usefulness of zonisamide in the treatment of obesity and psychotropicassociated weight gain, as well as alcohol dependence and withdrawal.

References

https://en.wikipedia.org/wiki/Zonisamide
http://www.medicinenet.com/zonisamide-oral/article.htm
https://pubchem.ncbi.nlm.nih.gov/compound/5734#section=Top

Description

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.

Chemical Properties

Off-White Powder

Originator

Dainippon (Japan)

Uses

For use as adjunctive treatment of partial seizures in adults with epilepsy.

Uses

muscarinic antagonist used as an antispasmodic

Uses

anticonvulsant;carbonic anhydrase inhibitor, repetitive firing of voltage-gated sodium channels and reduction of T-type calcium channel currents blocker

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.

storage

Store at +4°C