Zonisamide

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Zonisamide
Zonisamide structure.svg
Ball-and-stick model of the zonisamide molecule
Systematic (IUPAC) name
benzo[d]isoxazol-3-ylmethanesulfonamide
Clinical data
Trade names Zonegran
AHFS/Drugs.com monograph
MedlinePlus a603008
Pregnancy
category
  • AU: D
  • US: C (Risk not ruled out)
Legal status
Routes of
administration		 Oral
Pharmacokinetic data
Bioavailability ~100%[1]
Protein binding 40%[1]
Metabolism Hepatic through CYP3A4[1]
Biological half-life 63 hours in plasma[1]
Excretion Renal (62%); Faeces (3%)[1]
Identifiers
CAS Number 68291-97-4 YesY
ATC code N03AX15 (WHO)
PubChem CID: 5734
IUPHAR/BPS 7047
DrugBank DB00909 YesY
ChemSpider 5532 YesY
UNII 459384H98V YesY
KEGG D00538 YesY
ChEBI CHEBI:10127 YesY
ChEMBL CHEMBL750 YesY
PDB ligand ID ZON (PDBe, RCSB PDB)
Chemical data
Formula C8H8N2O3S
Molecular mass 212.227 g/mol
  • O=S(=O)(N)Cc2noc1ccccc12
  • InChI=1S/C8H8N2O3S/c9-14(11,12)5-7-6-3-1-2-4-8(6)13-10-7/h1-4H,5H2,(H2,9,11,12) YesY
  • Key:UBQNRHZMVUUOMG-UHFFFAOYSA-N YesY
Physical data
Melting point 162 °C (324 °F)
  (verify)

Zonisamide is a sulfonamide anticonvulsant approved for use as an adjunctive therapy in adults with partial-onset seizures; infantile spasm, mixed seizure types of Lennox–Gastaut syndrome, myoclonic, and generalized tonic clonic seizure.[2]

Medical uses

Epilepsy

Zonisamide is approved in the United States,[3] United Kingdom,[4] and Australia[5] for adjunctive treatment of partial seizures in adults and in 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.[6] For epilepsy, most studies have used oral zonisamide in daily doses ranging from 200 to 600 milligrams/day, divided in 2 daily doses, adjusted to maintain serum levels of 15 to 40 micrograms/milliliter[7][8][9][10]

Parkinson's disease

An open trial on zonisamide in seven Parkinson's disease patients had positive results, according to this 2001 report.[11] Since then, it has been reported to treat the resting tremor that other therapies may leave behind.[12] By early November 2005, Dainippon Sumitomo had filed a NDA for the use of zonisamide in Parkinson's disease; it is to be marketed as Tremode.[13]

Tardive dyskinesia

In an open-label trial zonisamide attenuated the symptoms of tardive dyskinesia.[14]

Obesity

It has also been studied for obesity[15] with significant positive effects on body weight and there are three ongoing clinical trials for this indication.[16][17][18] It is to be sold, when combined with bupropion, under the brand name Empatic.

Migraine

Zonisamide has been studied for and used as a migraine preventative medication, and has also been shown to be effective in some cases of neuropathic pain.

Bipolar depression

It has also been used off-label by psychiatrists as a mood stabilizer to treat bipolar depression.[19][20]

Adverse effects

Adverse effects by incidence:[1][21][22]

Very common (>10% incidence) adverse effects include:

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  • Anorexia
  • Somnolence
  • Dizziness
  • Agitation
  • Irritability
  • Confusional state
  • Depression
  • Diplopia
  • Memory impairment
  • Decreased bicarbonate

Common (1-10% incidence) adverse effects include:

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  • Ecchymosis
  • Hypersensitivity
  • Affect lability
  • Anxiety
  • Insomnia
  • Psychotic disorder
  • Bradyphrenia
  • Disturbance in attention
  • Nystagmus
  • Paraesthesia
  • Speech disorder
  • Tremor
  • Abdominal pain
  • Constipation
  • Diarrhoea
  • Dyspepsia
  • Nausea
  • Rash
  • Pruritis
  • Alopecia
  • Nephrolithiasis
  • Fatigue
  • Influenza-like illness
  • Pyrexia
  • Oedema peripheral
  • Weight loss

Uncommon (0.1-1% incidence) adverse effects include:

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Rare/Very rare (<0.1% incidence) adverse effects include:

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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.[23] Zonisamide may also interact with other carbonic anhydrase inhibitors to increase the potential for metabolic acidosis.[1]

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.[24]

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).[5] It is also known to be a weak carbonic anhydrase inhibitor (similarly to the anticonvulsant, acetazolamide). It is also known to modulate GABAergic and glutamatergic neurotransmission.[5][25][26][27][28]

Pharmacokinetics

Absorption

Variable, yet relatively rapid rate of absorption with a time to peak concentration of 2.8-3.9 hours. Food has no effect on the bioavailability of zonisamide[29]

Metabolism

Zonisamide is metabolized mostly by the CYP3A4 isoenzyme, but also CYP3A7 and CYP3A5,[30] to 2-(sulphamoylacetyl)-phenol via reductive cleavage of the 1,2-benzisoxazole ring.[31]

History

Zonisamide was discovered by Uno and colleagues in 1972[32] and launched by Dainippon Sumitomo Pharma (formerly Dainippon Pharmaceutical) in 1989 as Excegran in Japan.[33] 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.[34] Eisai also markets Zonegran in Asia (China, Taiwan, and fourteen others)[35] and Europe (starting in Germany and the United Kingdom).[36]

References

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External links

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 Lua error in package.lua at line 80: module 'strict' not found.
  2. ↑ Comprehensive Pharmacy Review, Leon Shargel, 6th edition, p988
  3. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  4. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  5. ↑ 5.0 5.1 5.2 Lua error in package.lua at line 80: module 'strict' not found.
  6. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  7. ↑ Shimizu A, Ikoma R, & Shimizu T: Effects and side effects of zonisamide during long-term medication. Curr Ther Res 1990; 47:696-706
  8. ↑ Iinuma K, Handa I, Fueki N, et al: Effects of zonisamide (AD-810) on refractory epilepsy in children: special reference to temporal lobe abnormalities. Curr Ther Res 1988; 43:281-282
  9. ↑ Sakamoto K, Kurokawa T, Tomita S, et al: Effects of zonisamide in children with epilepsy. Curr Ther Res 1988; 43:378-383
  10. ↑ Shimizu A, Yamamoto J, Yamada Y, et al: The antiepileptic effect of zonisamide in patients with refractory seizures. Curr Ther Res 1987; 42:147-155
  11. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  12. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  13. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  14. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  15. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  16. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  17. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  18. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  19. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  20. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  21. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  22. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  23. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  24. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  25. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  26. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  27. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  28. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  29. ↑ http://www.drugbank.ca/drugs/DB00909
  30. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  31. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  32. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  33. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  34. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  35. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  36. ↑ Lua error in package.lua at line 80: module 'strict' not found.
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