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  • US: Oral — withdrawn, was Rx-only; Eye drops — over-the-counter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
IUPAC name
  • 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)
SMILES
  • O=C3c1sccc1C(\c2c(cccc2)C3)=C4/CCN(C)CC4
InChI
  • 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 Y
  • Key:ZCVMWBYGMWKGHF-UHFFFAOYSA-N Y
  (verify)

It was patented in 1970 and came into medical use in 1976.[7]

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.[8] Besides its anti-histaminic activity, it is also a functional leukotriene antagonist[9] and a phosphodiesterase inhibitor.[10]

"[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.[11]

Side effects

Side effects of systemic (oral) use include drowsiness, weight gain (11-12lbs), dry mouth, irritability, and increased nosebleeds.[12]

Pharmacology

Ketotifen is a selective antihistamine – that is, an inverse agonist of the histamine H1 receptor (Ki = 0.166 nM)[13] – and mast cell stabilizer.[14] In addition, ketotifen has weak anticholinergic (Ki = 204 nM for mACh) and antiserotonergic (Ki = 38.9 nM for 5-HT2A) activity.[13][15] 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.[16]

Society and culture

Brand names

Ketotifen is marketed under many brand names worldwide.[17]

References
  1. "Zaditor- ketotifen fumarate solution". DailyMed. 13 February 2020. Retrieved 4 September 2020.
  2. Sokol, Kristin C.; Amar, Neil K.; Starkey, Jonathan; Grant, J. Andrew (2013). "Ketotifen in the management of chronic urticaria: Resurrection of an old drug". Annals of Allergy, Asthma & Immunology. 111 (6): 433–6. doi:10.1016/j.anai.2013.10.003. PMC 4309375. PMID 24267353.
  3. Shawky, Rabah M.; Seifeldin, Neveen S. (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, Torsten (2012). "A Summary of the New International EAACI/GA2LEN/EDF/ WAO Guidelines in Urticaria". World Allergy Organization Journal. 5 (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, M. K.; Giménez-Arnau, A. M.; Grattan, C. E. H.; Kapp, A.; Maurer, M.; Merk, H. F.; Rogala, B.; Saini, S.; Sánchez-Borges, M.; Schmid-Grendelmeier, P.; Schünemann, H.; Staubach, P.; Vena, G. A.; Wedi, B. (2009). "EAACI/GA²LEN/EDF/WAO guideline: Management of urticaria". Allergy. 64 (10): 1427–43. doi:10.1111/j.1398-9995.2009.02178.x. PMID 19772513. S2CID 14587946.
  6. Li, Zhenhong; Celestin, Jocelyn (February 23, 2015). Ketotifen: A Role in the Treatment of Idiopathic Anaphylaxis. American Academy of Allergy, Asthma & Immunology Annual Meeting. Houston.
  7. Fischer, Jnos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 548. ISBN 9783527607495.
  8. Grahnén, A.; Lönnebo, A.; Beck, O.; Eckernäs, S-Å; Dahlström, B.; Lindström, B. (1992). "Pharmacokinetics of ketotiffn after oral administration to healthy male subjects". Biopharmaceutics & Drug Disposition. 13 (4): 255–62. doi:10.1002/bdd.2510130404. PMID 1600111. S2CID 72293850.
  9. Fink, A.; Bibi, H.; Eliraz, A.; Schlesinger, M.; Bentwich, Z. (1986). "Ketotifen, disodium cromoglycate, and verapamil inhibit leukotriene activity: determination by tube leukocyte adherence inhibition assay". Annals of Allergy. 57 (2): 103–106. ISSN 0003-4738. PMID 3090908.
  10. Castillo, J. G.; Gamboa, P. M.; García, B. E.; Oehling, A. (1990). "Effect of ketotifen on phosphodiesterase activity from asthmatic individuals". Allergologia Et Immunopathologia. 18 (4): 197–201. ISSN 0301-0546. PMID 1702263.
  11. Klooker, T. K.; Braak, B.; Koopman, K. E.; Welting, O.; Wouters, M. M.; Van Der Heide, S.; Schemann, M.; Bischoff, S. C.; Van Den Wijngaard, R. M.; Boeckxstaens, G. E. (2010). "The mast cell stabiliser ketotifen decreases visceral hypersensitivity and improves intestinal symptoms in patients with irritable bowel syndrome" (PDF). Gut. 59 (9): 1213–21. doi:10.1136/gut.2010.213108. PMID 20650926. S2CID 18889707.
  12. "Zaditen - MIMS online". www.mims.co.uk.
  13. Kakiuchi M, Ohashi T, Musoh K, Kawamura K, Morikawa K, Kato H (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". Jpn. J. Pharmacol. 73 (4): 291–8. doi:10.1254/jjp.73.291. PMID 9165365.
  14. Thomas L. Lemke; David A. Williams (2008). Foye's Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. pp. 1019–. ISBN 978-0-7817-6879-5.
  15. V Alagarsamy (16 June 2012). Textbook of Medicinal Chemistry Vol II - E-Book. Elsevier Health Sciences. pp. 38–. ISBN 978-81-312-3259-0.
  16. Jürgen Drews (6 December 2012). Immunopharmacology: Principles and Perspectives. Springer Science & Business Media. pp. 282–. ISBN 978-3-642-75561-3.
  17. "Ketotifen International". Drugs.com. Retrieved 4 September 2020.
  • "Ketotifen". Drug Information Portal. U.S. National Library of Medicine.
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