Zonisamide, sold under the brand name Zonegran among others, is a

medication Medication (also called medicament, medicine, pharmaceutical drug, medicinal product, medicinal drug or simply drug) is a drug used to medical diagnosis, diagnose, cure, treat, or preventive medicine, prevent disease. Drug therapy (pharmaco ...

used to treat the symptoms of

epilepsy Epilepsy is a group of Non-communicable disease, non-communicable Neurological disorder, neurological disorders characterized by a tendency for recurrent, unprovoked Seizure, seizures. A seizure is a sudden burst of abnormal electrical activit ...

and

Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...

. Chemically it is a

sulfonamide In organic chemistry, the sulfonamide functional group (also spelled sulphonamide) is an organosulfur group with the Chemical structure, structure . It consists of a sulfonyl group () connected to an amine group (). Relatively speaking this gro ...

. It serves as an

anticonvulsant Anticonvulsants (also known as antiepileptic drugs, antiseizure drugs, or anti-seizure medications (ASM)) are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also used in the treatme ...

used primarily as an adjunctive therapy in adults with Parkinson's disease, partial-onset seizures; infantile spasm, mixed seizure types of Lennox–Gastaut syndrome, myoclonic and generalized tonic clonic seizure. Despite this it is also sometimes used as a monotherapy for partial-onset seizures. In 2020, it was the 276th most commonly prescribed medication in the United States, with more than 1million prescriptions.

Medical uses

Epilepsy

Zonisamide is approved in the United States, and United Kingdom for adjunctive treatment of partial seizures in adults and Japan for both adjunctive and monotherapy for partial seizures (simple, complex, secondarily generalized), generalized (tonic, tonic-clonic (grand mal), and atypical absence) and combined seizures. In Australia it is marketed as both an adjunctive therapy and monotherapy for partial seizures only.

Parkinson's disease

It has been approved for the treatment of the motor symptoms of Parkinson's disease (PD), as an adjunct to levodopa, in a few countries such as Japan. In Japan, zonisamide has been used as an adjunct to levodopa treatment since 2009. In addition, there is clinical evidence that zonisamide in combination with levodopa control of motor symptoms of PD but evidence for the treatment of the non motor symptoms of PD lacking.

Adverse effects

Adverse effects by incidence: Very common (>10% incidence) adverse effects include: * Anorexia *

Somnolence Somnolence (alternatively sleepiness or drowsiness) is a state of strong desire for sleep, or sleeping for unusually long periods (compare hypersomnia). It has distinct meanings and causes. It can refer to the usual state preceding falling aslee ...

* Dizziness * Agitation * Irritability * Confusional state * Depression * Diplopia * Memory impairment * Decreased bicarbonate Common (1–10% incidence) adverse effects include: * Ecchymosis * Hypersensitivity * Affect lability * Anxiety *

Insomnia Insomnia, also known as sleeplessness, is a sleep disorder where people have difficulty sleeping. They may have difficulty falling asleep, or staying asleep for as long as desired. Insomnia is typically followed by daytime sleepiness, low ene ...

* Psychotic disorder * Bradyphrenia * Disturbance in attention * Nystagmus * Paraesthesia * Speech disorder *

Tremor A tremor is an involuntary, somewhat rhythmic muscle contraction and relaxation involving neural oscillations, oscillations or twitching movements of one or more body parts. It is the most common of all involuntary movements and can affect the h ...

* Abdominal pain *

Constipation Constipation is a bowel dysfunction that makes bowel movements infrequent or hard to pass. The Human feces, stool is often hard and dry. Other symptoms may include abdominal pain, bloating, and feeling as if one has not completely passed the ...

* Diarrhoea * Dyspepsia * Nausea * Rash * Pruritus * Alopecia * Nephrolithiasis *

Fatigue Fatigue is a state of tiredness (which is not sleepiness), exhaustion or loss of energy. It is a signs and symptoms, symptom of any of various diseases; it is not a disease in itself. Fatigue (in the medical sense) is sometimes associated wit ...

* Influenza-like illness * Pyrexia * Oedema peripheral * Weight loss Incidence unknown * Reproductive toxic effects

Interactions

Zonisamide and other carbonic anhydrase inhibitors such as topiramate, furosemide, and hydrochlorothiazide have been known to interfere with amobarbital, which has led to inadequate anesthetization during the Wada test. Zonisamide may also interact with other carbonic anhydrase inhibitors to increase the potential for metabolic acidosis. Additionally, the metabolism of zonisamide is inhibited by

ketoconazole Ketoconazole, sold under the brand name Nizoral, among others, is an antiandrogen, antifungal drug, antifungal, and antiglucocorticoid medication used to treat a number of fungal infections. Applied to the skin it is used for fungal skin inf ...

ciclosporin Ciclosporin, also spelled cyclosporine and cyclosporin, is a calcineurin inhibitor, used as an immunosuppressant medication. It is taken Oral administration, orally or intravenously for rheumatoid arthritis, psoriasis, Crohn's disease, nephr ...

, miconazole, fluconazole and carbamazepine (in descending order of inhibition) due to their effects on the

CYP3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine, which in humans is encoded by ''CYP3A4'' gene. It organic redox reaction, oxidizes small foreign organic molecules ( ...

enzyme. Zonisamide is not known to inhibit cytochrome P450 enzymes when present at therapeutic concentrations.

Mechanism of action

Zonisamide is an antiseizure drug chemically classified as a sulfonamide and unrelated to other antiseizure agents. The precise mechanism by which zonisamide exerts its antiseizure effect is unknown, although it is believed that the drug blocks

sodium Sodium is a chemical element; it has Symbol (chemistry), symbol Na (from Neo-Latin ) and atomic number 11. It is a soft, silvery-white, highly reactive metal. Sodium is an alkali metal, being in group 1 element, group 1 of the peri ...

and T-type calcium channels, which leads to the suppression of neuronal hypersynchronization (that is, seizure-form activity). It is also known to be a weak carbonic anhydrase inhibitor (similarly to the anticonvulsant topiramate). It is also known to modulate GABAergic and

glutamate Glutamic acid (symbol Glu or E; known as glutamate in its anionic form) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a Essential amino acid, non-essential nutrient for humans, meaning that ...

rgic neurotransmission.

Pharmacokinetics

Absorption

Variable, yet relatively rapid rate of absorption with a time to peak concentration of 2.8–3.9 hours. Bioavailability is close to 100% and food has no effect on the bioavailability of zonisamide but may affect the rate of absorption.

Metabolism

Zonisamide is metabolized mostly by the

isoenzyme, but also CYP3A7 and CYP3A5, to 2-(sulphamoylacetyl)-phenol via reductive cleavage of the 1,2- benzisoxazole ring.

History

Zonisamide was discovered by Uno and colleagues in 1972 and launched by Dainippon Sumitomo Pharma (formerly Dainippon Pharmaceutical) in 1989 as Excegran in Japan. It was marketed by Élan in the United States starting in 2000 as Zonegran, before Élan transferred their interests in zonisamide to Eisai Co., Ltd. in 2004. Eisai also markets Zonegran in Asia (China, Taiwan, and fourteen others) and Europe (starting in Germany and the United Kingdom).

Research

Tardive dyskinesia

In an open-label trial zonisamide attenuated the symptoms of tardive dyskinesia.

Obesity

It has also been studied for

obesity Obesity is a medical condition, considered by multiple organizations to be a disease, in which excess Adipose tissue, body fat has accumulated to such an extent that it can potentially have negative effects on health. People are classifi ...

with significant positive effects on body weight loss and there are three ongoing clinical trials for this indication. It was to be sold, when combined with bupropion, under the brand name Empatic, until its development was discontinued.

Migraine

Zonisamide has been studied for and used as a migraine preventative medication, when topiramate is either ineffective or cannot be continued due to side effects.

Bipolar depression

It has also been used

off-label Off-label use is the use of pharmaceutical drugs for an unapproved indication (medicine), indication or in an unapproved age group, dose (biochemistry), dosage, or route of administration. Both prescription drugs and over-the-counter drugs (OTCs) ca ...

by psychiatrists as a mood stabilizer to treat bipolar depression.

References

{{Portal bar , Medicine Anticonvulsants Benzisoxazoles Calcium channel blockers Carbonic anhydrase inhibitors Sodium channel blockers Sulfonamides