Zonisamide, sold under the brand name Zonegran among others, is a medication used to treat the symptoms of epilepsy and Parkinson's disease.[5][6] Chemically it is a sulfonamide. It serves as an anticonvulsant 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.[7] Despite this it is also sometimes used as a monotherapy for partial-onset seizures.[6][8]
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| Trade names | Zonegran, Zonisade |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a603008 |
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| Routes of administration | By mouth |
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| Pharmacokinetic data | |
| Bioavailability | ~100%[4] |
| Protein binding | 40%[4] |
| Metabolism | Liver through CYP3A4[4] |
| Elimination half-life | 63 hours in plasma[4] |
| Excretion | Kidney (62%); Faeces (3%)[4] |
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| ECHA InfoCard | 100.118.526 |
| Chemical and physical data | |
| Formula | C8H8N2O3S |
| Molar mass | 212.22 g·mol−1 |
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| Melting point | 162 °C (324 °F) |
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In 2020, it was the 276th most commonly prescribed medication in the United States, with more than 1 million prescriptions.[9][10]
Medical uses
Epilepsy
Zonisamide is approved in the United States,[2][11] and United Kingdom[12] 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.[13] In Australia it is marketed as both an adjunctive therapy and monotherapy for partial seizures only.[8]
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.[5][6] In Japan, zonisamide has been used as an adjunct to levodopa treatment since 2009.[14] 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.[15][16]
Adverse effects
Adverse effects by incidence:[4][17][18]
Very common (>10% incidence) adverse effects include:
- Anorexia
- Somnolence
- Dizziness
- Agitation
- Irritability
- Confusional state
- Depression
- Diplopia
- Memory impairment
- Decreased bicarbonate
Common (1–10% incidence) adverse effects include:
- Ecchymosis
- Hypersensitivity
- Affect lability
- Anxiety
- Insomnia
- Psychotic disorder
- Bradyphrenia
- Disturbance in attention
- Nystagmus
- Paraesthesia
- Speech disorder
- Tremor
- Abdominal pain
- Constipation
- Diarrhoea
- Dyspepsia
- Nausea
- Rash
- Pruritus
- Alopecia
- Nephrolithiasis
- Fatigue
- Influenza-like illness
- Pyrexia
- Oedema peripheral
- Weight loss
Incidence unknown
- Reproductive toxic effects[19]
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.[20] Zonisamide may also interact with other carbonic anhydrase inhibitors to increase the potential for metabolic acidosis.[4]
Additionally, the metabolism of zonisamide is inhibited by ketoconazole, ciclosporin, miconazole, fluconazole and carbamazepine (in descending order of inhibition) due to their effects on the CYP3A4 enzyme.[21]
Zonisamide is not known to inhibit cytochrome P450 enzymes when present at therapeutic concentrations.[22]
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 and T-type calcium channels, which leads to the suppression of neuronal hypersynchronization (that is, seizure-form activity).[8] It is also known to be a weak carbonic anhydrase inhibitor (similarly to the anticonvulsant topiramate). It is also known to modulate GABAergic and glutamatergic neurotransmission.[8][23][24][25][26]
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.[27][22]
Metabolism
Zonisamide is metabolized mostly by the CYP3A4 isoenzyme, but also CYP3A7 and CYP3A5,[28] to 2-(sulphamoylacetyl)-phenol via reductive cleavage of the 1,2-benzisoxazole ring.[29]
History
Zonisamide was discovered by Uno and colleagues in 1972[30] and launched by Dainippon Sumitomo Pharma (formerly Dainippon Pharmaceutical) in 1989 as Excegran in Japan.[31] 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.[32] Eisai also markets Zonegran in Asia (China, Taiwan, and fourteen others)[33] and Europe (starting in Germany and the United Kingdom).[34]
Research
Tardive dyskinesia
In an open-label trial zonisamide attenuated the symptoms of tardive dyskinesia.[35]
Obesity
It has also been studied for obesity[36] with significant positive effects on body weight loss and there are three ongoing clinical trials for this indication.[37][38][39] It was to be sold, when combined with bupropion, under the brand name Empatic, until its development was discontinued.[40]
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.[6]
Bipolar depression
It has also been used off-label by psychiatrists as a mood stabilizer to treat bipolar depression.[41][42]
