Terfenadine

Last updated
Terfenadine
Terfenadine.svg
Clinical data
Trade names Seldane, Triludan, Teldane
AHFS/Drugs.com Multum Consumer Information
MedlinePlus a600034
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
  • Withdrawn
Pharmacokinetic data
Protein binding 70%
Metabolism Hepatic (CYP3A4)
Metabolites Fexofenadine
Elimination half-life 3.5 hours
Identifiers
  • (RS)-1-(4-tert-butylphenyl)-4-{4-[hydroxy(diphenyl)methyl]piperidin-1-yl}-butan-1-ol
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.051.537 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C32H41NO2
Molar mass 471.685 g·mol−1
3D model (JSmol)
Chirality Racemic mixture
  • OC(c1ccccc1)(c2ccccc2)C4CCN(CCCC(O)c3ccc(cc3)C(C)(C)C)CC4
  • InChI=1S/C32H41NO2/c1-31(2,3)26-18-16-25(17-19-26)30(34)15-10-22-33-23-20-29 (21-24-33)32(35,27-11-6-4-7-12-27)28-13-8-5-9-14-28/ h4-9,11-14,16-19,29-30,34-35H,10,15,20-24H2,1-3H3 X mark.svgN
  • Key:GUGOEEXESWIERI-UHFFFAOYSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Terfenadine is an antihistamine formerly used for the treatment of allergic conditions. It was brought to market by Hoechst Marion Roussel (now Sanofi) and was marketed under various brand names, including Seldane in the United States, Triludan in the United Kingdom, and Teldane in Australia. [1] It was superseded by fexofenadine in the 1990s due to the risk of a particular type of disruption of the electrical rhythms of the heart (specifically cardiac arrhythmia caused by QT interval prolongation) and has been withdrawn from markets worldwide. [2] : 53 

Contents

Pharmacology

Terfenadine acts as a peripherally-selective antihistamine, or antagonist of the histamine H1 receptor. [3] It is a prodrug, generally completely metabolized to the active form fexofenadine in the liver by the enzyme cytochrome P450 3A4. Due to its near complete metabolism by the liver immediately after leaving the gut, terfenadine normally is not measurable in the plasma. Terfenadine itself, however, is cardiotoxic at higher doses, while its major active metabolite is not. Terfenadine, in addition to its antihistamine effects, also acts as a potassium channel blocker (Kv11.1 encoded by the gene hERG ). Since its active metabolite is not a potassium channel blocker, no cardiotoxicity is associated with fexofenadine. [4] Sudden toxicity is possible even after years of use without problems as a result of an interaction with other medications such as erythromycin, or foods such as grapefruit. The addition of, or a dosage increase in, these CYP3A4 inhibitors makes it harder for the body to metabolize and remove terfenadine. In larger plasma concentrations, it may lead to toxic effects on the heart's rhythm (e.g. ventricular tachycardia and torsades de pointes ).

History

Terfenadine was synthesized by chemists at Richardson–Merrell in 1973 as a potential tranquilizer. [3] However, it was found to be inactive for such purposes as it did not cross the blood–brain barrier or enter the central nervous system. [3] Pharmacologist Richard Kinsolving noticed that terfenadine showed a structural resemblance to the antihistamine diphenhydramine, so terfenadine was tested as an antihistamine. [3] It was found to be a non-sedating antihistamine and was the first such drug to be discovered. [3]

In the United States, terfenadine as Seldane was brought to market in 1985 as the first non-sedating antihistamine for the treatment of allergic rhinitis. [1] [5] In June 1990, evidence of serious ventricular arrhythmias among those taking Seldane prompted the FDA to issue a report on the risk factors associated with concomitant use of the drug with macrolide antibiotics and ketoconazole. [1] Two months later, the FDA required the manufacturer to send a letter to all physicians, alerting them to the problem; in July 1992, the existing precautions were elevated to a black box warning [1] and the issue attracted mass media attention in reports that people with liver disease or who took ketoconazole, an antifungal agent, or the antibiotic erythromycin, could suffer cardiac arrhythmia if they also took Seldane. [5]

In January 1997, the same month when the U.S. Food and Drug Administration (FDA) had earlier approved a generic version of Seldane made by IVAX Corporation of Miami, the FDA recommended terfenadine-containing drugs be removed from the market and physicians consider alternative medications for their patients. [5] Seldane (and Seldane-D, terfenadine combined with the decongestant pseudoephedrine) were removed from the U.S. market by their manufacturer in late 1997 after the FDA approval of Allegra-D (fexofenadine/pseudoephedrine). [6] Terfenadine-containing drugs were subsequently removed from the Canadian market in 1999, [7] and are no longer available for prescription in the UK. [8]

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References

  1. 1 2 3 4 Thompson D, Oster G (May 1996). "Use of terfenadine and contraindicated drugs". JAMA. American Medical Association. 275 (17): 1339–41. doi:10.1001/jama.1996.03530410053033. PMID   8614120.
  2. ↑ Horak F (2010). "Antialergic and Vasoactive Drugs for Allergic Rhinitis Chapter 4". In Pawankar R, Holgate ST, Rosenwasser LJ (eds.). Allergy Frontiers:Therapy and Prevention. Vol. 5. Springer Science & Business Media. ISBN   978-4-431-99362-9.
  3. 1 2 3 4 5 Walter Sneader (31 October 2005). Drug Discovery: A History. John Wiley & Sons. pp. 406–. ISBN   978-0-470-01552-0.
  4. ↑ Roy M, Dumaine R, Brown AM (August 1996). "HERG, a primary human ventricular target of the nonsedating antihistamine terfenadine". Circulation. American Heart Association. 94 (4): 817–23. doi:10.1161/01.cir.94.4.817. PMID   8772706.
  5. 1 2 3 Rosenthal (January 14, 1997). "FDA May Pull Plug on Seldane". Los Angeles Daily News . TheFreeLibrary.com. Archived from the original on 2012-10-21. Retrieved 2010-11-11– via AP.
  6. ↑ "FDA Approves Allegra-D, Manufacturer To Withdraw Seldane From Marketplace". Food and Drug Administration. Archived from the original on 2008-02-23. Retrieved 2010-11-11.
  7. ↑ "Status of Terfenadine-Containing Drugs in Canada". Health Canada . 23 April 2004. Archived from the original on 13 July 2006.
  8. ↑ "Terfenadine - General Practice notebook". GPnotebook.co.uk. Oxbridge Solutions Lt.
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