Ketotifen

Ketotifen, sold under the brand name Zaditor among others, is a second-generation noncompetitive H1-antihistamine and mast cell stabilizer. It is most commonly sold as a salt with fumaric acid, ketotifen fumarate, and is available in two forms. In its ophthalmic form, it is used to treat allergic conjunctivitis.[1] In its oral form, it is used to prevent asthma attacks or anaphylaxis, as well as various mast cell, allergic-type disorders.[2][3][4][5][6]

Ketotifen
Clinical data
Trade namesZaditor[1]
AHFS/Drugs.comMonograph
MedlinePlusa604033
Pregnancy
category
  • AU: B1
Routes of
administration		By mouth (tablets), topical eye drops
ATC code
Legal status
Legal status
  • US: Oral — withdrawn, was Rx-only; Eye drops — over-the-counter
Pharmacokinetic data
Bioavailability60%
Protein binding75%
MetabolismHepatic
Elimination half-life12 hours
Identifiers
  • 4-(1-Methylpiperidin-4-ylidene)-4,9-dihydro-10H-benzo[4,5]cyclohepta[1,2-b]thiophen-10-one
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.047.348
Chemical and physical data
FormulaC19H19NOS
Molar mass309.43 g·mol−1
3D model (JSmol)
  • O=C3c1sccc1C(\c2c(cccc2)C3)=C4/CCN(C)CC4
  • InChI=1S/C19H19NOS/c1-20-9-6-13(7-10-20)18-15-5-3-2-4-14(15)12-17(21)19-16(18)8-11-22-19/h2-5,8,11H,6-7,9-10,12H2,1H3 checkY
  • Key:ZCVMWBYGMWKGHF-UHFFFAOYSA-N checkY
  (verify)

It was patented in 1970 and came into medical use in 1976.[7] In 2020, it was the 289th most commonly prescribed medication in the United States, with more than 1 million prescriptions.[8][9]

Medical uses

Ketotifen relieves and prevents eye itchiness and/or irritation associated with most seasonal allergies. It starts working within minutes after administering the drops. The drug has not been studied in children under three.[1] The mean elimination half life is 12 hours.[10] Besides its anti-histaminic activity, it is also a functional leukotriene antagonist[11] and a phosphodiesterase inhibitor.[12]

"[O]ral ketotifen has been used in patients with asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, chronic urticaria, cold-induced urticaria, cholinergic urticaria, exercise-induced urticaria, [systemic mast cell disease including mastocytosis, Mast Cell Activation Syndrome (MCAS), allergic and nonallergic anaphylaxis, angioedema], and food allergy in Canada, Europe, and Mexico." Now available via prescription at US compounding pharmacies: "For adults and older children with asthma or allergic disease, the recommended dose of ketotifen is 1 mg twice daily." "FDA staff did recommend more extensive evaluations for management of urticaria."[4][5]

The drug may also help relieve irritable bowel syndrome.[13]

Side effects

Side effects of systemic (oral) use include drowsiness, weight gain (11–12 lb (5.0–5.4 kg)), dry mouth, irritability, and increased nosebleeds.[14]

Pharmacology

Ketotifen is a selective antihistamine – that is, an inverse agonist of the histamine H1 receptor (Ki = 0.166 nM)[15] – and mast cell stabilizer.[16][17] In addition, ketotifen has weak anticholinergic (Ki = 204 nM for mAChTooltip muscarinic acetylcholine receptor) and antiserotonergic (Ki = 38.9 nM for 5-HT2A) activity.[15][18] However, at the dosages in which it is typically used clinically, both the anticholinergic and antiserotonergic activity of ketotifen are said not to be appreciable.[19]

Society and culture

Brand names

Ketotifen is marketed under many brand names worldwide.[20]

References
  1. "Zaditor- ketotifen fumarate solution". DailyMed. 13 February 2020. Retrieved 4 September 2020.
  2. Sokol KC, Amar NK, Starkey J, Grant JA (December 2013). "Ketotifen in the management of chronic urticaria: resurrection of an old drug". Annals of Allergy, Asthma & Immunology. 111 (6): 433–436. doi:10.1016/j.anai.2013.10.003. PMC 4309375. PMID 24267353.
  3. Shawky RM, Seifeldin NS (2015). "The relation between antihistamine medication during early pregnancy & birth defects". Egyptian Journal of Medical Human Genetics. 16 (4): 287–90. doi:10.1016/j.ejmhg.2015.04.003.
  4. Zuberbier T (January 2012). "A Summary of the New International EAACI/GA(2)LEN/EDF/WAO Guidelines in Urticaria". The World Allergy Organization Journal. 5 (Suppl 1): S1–S5. doi:10.1186/1939-4551-5-S1-S1. PMC 3488932. PMID 23268477.
  5. Zuberbier T, Asero R, Bindslev-Jensen C, Walter Canonica G, Church MK, Giménez-Arnau AM, et al. (October 2009). "EAACI/GA(2)LEN/EDF/WAO guideline: management of urticaria". Allergy. 64 (10): 1427–1443. doi:10.1111/j.1398-9995.2009.02178.x. PMID 19772513. S2CID 14587946.
  6. Li Z, Celestin J (February 23, 2015). Ketotifen: A Role in the Treatment of Idiopathic Anaphylaxis. American Academy of Allergy, Asthma & Immunology Annual Meeting. Houston. Archived from the original on June 11, 2021. Retrieved March 3, 2017.
  7. Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 548. ISBN 9783527607495.
  8. "The Top 300 of 2020". ClinCalc. Retrieved 7 October 2022.
  9. "Ketotifen - Drug Usage Statistics". ClinCalc. Retrieved 7 October 2022.
  10. Grahnén A, Lönnebo A, Beck O, Eckernäs SA, Dahlström B, Lindström B (May 1992). "Pharmacokinetics of ketotifen after oral administration to healthy male subjects". Biopharmaceutics & Drug Disposition. 13 (4): 255–262. doi:10.1002/bdd.2510130404. PMID 1600111. S2CID 72293850.
  11. Fink A, Bibi H, Eliraz A, Schlesinger M, Bentwich Z (August 1986). "Ketotifen, disodium cromoglycate, and verapamil inhibit leukotriene activity: determination by tube leukocyte adherence inhibition assay". Annals of Allergy. 57 (2): 103–106. PMID 3090908.
  12. Castillo JG, Gamboa PM, García BE, Oehling A (1990). "Effect of ketotifen on phosphodiesterase activity from asthmatic individuals". Allergologia et Immunopathologia. 18 (4): 197–201. PMID 1702263.
  13. Klooker TK, Braak B, Koopman KE, Welting O, Wouters MM, van der Heide S, et al. (September 2010). "The mast cell stabiliser ketotifen decreases visceral hypersensitivity and improves intestinal symptoms in patients with irritable bowel syndrome". Gut. 59 (9): 1213–1221. doi:10.1136/gut.2010.213108. PMID 20650926. S2CID 18889707.
  14. "Zaditen - MIMS online". www.mims.co.uk.
  15. Kakiuchi M, Ohashi T, Musoh K, Kawamura K, Morikawa K, Kato H (April 1997). "Studies on the novel antiallergic agent HSR-609: its penetration into the central nervous system in mice and guinea pigs and its selectivity for the histamine H1-receptor". Japanese Journal of Pharmacology. 73 (4): 291–298. doi:10.1254/jjp.73.291. PMID 9165365.
  16. Thomas L. Lemke; David A. Williams (2008). Foye's Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. pp. 1019–. ISBN 978-0-7817-6879-5.
  17. Ang DC, Hilligoss J, Stump T (September 2015). "Mast Cell Stabilizer (Ketotifen) in Fibromyalgia: Phase 1 Randomized Controlled Clinical Trial". Clin J Pain. 31 (9): 836–842. doi:10.1097/AJP.0000000000000169. PMC 4417653. PMID 25370135.
  18. V Alagarsamy (16 June 2012). Textbook of Medicinal Chemistry Vol II - E-Book. Elsevier Health Sciences. pp. 38–. ISBN 978-81-312-3259-0.
  19. Jürgen Drews (6 December 2012). Immunopharmacology: Principles and Perspectives. Springer Science & Business Media. pp. 282–. ISBN 978-3-642-75561-3.
  20. "Ketotifen International". Drugs.com. Retrieved 4 September 2020.
  • "Ketotifen". Drug Information Portal. U.S. National Library of Medicine.
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