Terfenadine

Structural formula
Terfenadine structural formula without stereochemistry 1: 1 mixture of enantiomers (racemate)
General
Non-proprietary name	Terfenadine
other names	( RS ) -4- [4- (Hydroxy-diphenyl-methyl) -1-piperidyl] -1- (4- tert -butylphenyl) -butan-1-ol ( IUPAC ) (±) -4- [4- (Hydroxy-diphenyl-methyl) -1-piperidyl] -1- (4- tert -butylphenyl) -butan-1-ol DL -4- [4- (Hydroxy-diphenyl-methyl) -1-piperidyl] -1- (4- tert -butylphenyl) -butan-1-ol
Molecular formula	C 32 H 41 NO 2
Brief description	white solid
External identifiers / databases
CAS number 50679-08-8 EC number 256-710-8 ECHA InfoCard 100.051.537 PubChem 5405 DrugBank DB00342 Wikidata Q417909
Drug information
ATC code	R06 AX12
Drug class	Antihistamine
properties
Molar mass	471.67 g · mol -1
Melting point	149–152 ° C (morphological form I) 146–148 ° C (morphological form II) 146–148 ° C (morphological form III)
solubility	practically insoluble in water (10 mg l −1 at 30 ° C)
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed GHS labeling of hazardous substances no GHS pictograms H and P phrases H: 413 P: no P-phrases
Toxicological data	5000 mg kg −1 ( LD 50 ,  mouse ,  oral )
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Terfenadine is a drug and one of the H ₁ - antihistamines of the second generation. It is used to treat allergies . Terfenadine reduces allergic reactions by displacing histamine from the H ₁ receptor .

Terfenadine was first marketed as a component of a drug in 1982 by Marion Merrell Dow (now Sanofi-Aventis ) under the name Teldane . Terfenadine has since been withdrawn from the market in many countries, including Germany, due to deaths from cardiac arrhythmias .

Clinical information

Approved areas of application

Terfenadine was approved in Germany for the relief of allergic rhinitis , allergic conjunctivitis and allergic skin reactions.

According to expert circles, terfenadine is an outdated therapy principle, as there are safer and better tolerated alternatives.

Contraindications

Terfenadine must not be taken if:

• clearly impaired liver function
• Pre-existing heart diseases
• Disorders of the electrolyte balance , particularly a lack of potassium or magnesium
• Anorexia , vomiting, or diarrhea
• simultaneous treatment with numerous antibiotics or antifungal drugs
• simultaneous treatment with other medicinal products that inhibit the breakdown of terfenadine in the liver
• simultaneous treatment with class I or III antiarrhythmics
• simultaneous treatment with other drugs that delay electrical repolarization in the heart muscle

unwanted effects

Terfenadine is usually well tolerated. Confusion, insomnia, tiredness, dizziness, headache, depression, drowsiness, muscle tremors and gastrointestinal discomfort may occur. The drug affects the driving ability.

The use of terfenadine is not safe despite its good tolerability, since in rare cases cardiac arrhythmias (with QTc time lengthening ) can occur, which can lead to death via ventricular fibrillation and cardiac arrest .

Interactions with other substances

Interactions occur with drugs that are also broken down by or inhibit CYP3A4 - an isoenzyme of the cytochrome P450 system. These include miconazole , ketoconazole , itraconazole , erythromycin , clarithromycin , serotonin reuptake inhibitors, and grapefruit juice .

Special patient groups

The product must not be used in pregnant women, patients with heart disease and liver damage, or children.

Pharmacological properties

Mechanism of action

Terfenadine competes in the digestive tract , in the uterus , in blood vessel walls and in the bronchial muscles with the tissue hormone histamine for binding to the H ₁ receptor. This reversible binding to the H ₁ receptor reduces the consequences of an allergic histamine release such as B. Edema or itching.

Terfenadine also binds to a potassium channel in heart muscle cells ( hERG channel ). This bond delays the electrical repolarization in the heart muscle and is considered to be the cause of cardiac arrhythmias. Terfenadine also acts as a FIASMA (functional inhibitor of acid sphingomyelinase ).

Path of the drug through the body

Terfenadine is approximately 70% absorbed after oral administration . The substance is converted into the active metabolite fexofenadine in the liver by the enzyme CYP3A4 . The plasma half-life is 3.5 hours and protein binding is 70%.

Chemical information

Terfenadine has a similar structure to the antihistamine astemizole or the neuroleptic haloperidol . It contains a stereocenter and is therefore a chiral substance. There are two enantiomers of terfenadine, the ( R ) form and the ( S ) form. The drug is a 1: 1 mixture of enantiomers ( racemate ).

Terfenadine enantiomers

history

Terfenadine was synthesized in the early 1970s by a forerunner company of what would later become Marion Merrell Dow and first launched in 1982. Terfenadine was available over the counter for many years.

In 1993, Ray Woosley described a number of patients with arrhythmias taking terfenadine. In the years that followed, terfenadine was first made available again on prescription in many countries and then gradually withdrawn from the market (e.g. USA 1997). In the European Committee for Medicinal Products for Human Use , France was unable to prevail in 1998 with an initiative to withdraw all approvals for Terfenadine. In Germany only one high-dose form was withdrawn from the market by the competent authority . The manufacturer of the original preparation (then Hoechst ) voluntarily withdrew its terfenadine-containing drug from the market in the German-speaking area as well. The availability of terfenadine-containing generics in Germany to this day is viewed critically in specialist circles. In the course of the elimination of the reimbursement of non-prescription antihistamines, the Drugs Commission of the German medical profession recently observed an increase in the prescription of prescription-only and therefore reimbursable terfenadine.

The adverse effects of the drug terfenadine are also significant in the history of drug safety . The serious cardiac arrhythmias under terfenadine drew the attention of the specialist public to the phenomenon of " QT prolongation " caused by drugs, which had been neglected until then, and led to the recall of other drugs. Today all drugs are systematically examined for such effects before they are launched on the market.

Trade names and dosage forms

Terfenadine is the active component of the drugs Hisfedine , Terfedura , Terfemundine and others with purely generic names. These finished medicinal products are only sold in Germany within the German-speaking area.

Earlier trade names were u. a. Aldaban , Allerplus , Cyater , Nebralin , Seldane , Teldane , Teldanex , Terdin , Terfex , Ternadin , Triludan and other purely generic names.

Individual evidence

1. ↑ ^{a b} Terfenadine data sheet at Acros, accessed on February 21, 2010.
2. ↑ ^{a b c} The Merck Index . An Encyclopaedia of Chemicals, Drugs and Biologicals. 14th edition, 2006, ISBN 978-0-911910-00-1 , p. 1576.
3. ↑ ^{a b c} Datasheet Terfenadine from Sigma-Aldrich , accessed on October 23, 2016 ( PDF ).
4. ↑ ^{a b} Heinz Lüllmann u. a .: pharmacology and toxicology. 16th edition. Thieme, Stuttgart 2006, ISBN 978-3-13-368516-0 , pp. 112–114, ( limited preview in the Google book search).
5. ↑ ^{a b} drug telegram. Drug database: terfenadine. ( Memento of the original from January 2, 2015 in the Internet Archive ) Info: The  archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. Accessed November 30, 2008.
6. ↑ Torsten Kratz, Albert Diefenbacher: Psychopharmacotherapy in old age. Avoidance of drug interactions and polypharmacy. In: Deutsches Ärzteblatt. Volume 116, Issue 29 f. (July 22) 2019, pp. 508-517, p. 512.
7. ^ ^{A b} Woosley RL, Chen Y, Freiman JP, Gillis RA. Mechanism of the cardiotoxic actions of terfenadine. J Am Med Ass. 1993; 269 : pp. 1532-1536. PMID 8445816 .
8. ↑ H. Suessbrich, S. Waldegger, F. Lang, AE Busch | title = Blockade of HERG channels expressed in Xenopus oocytes by the histamine receptor antagonists terfenadine and astemizole. FEBS Letters Vol. 385, Issue 1, pp. 77-80.
9. ↑ Kornhuber J, Muehlbacher M, Trapp S, Pechmann S, Friedl A, Reichel M, Mühle C, Terfloth L, Groemer T, Spitzer G, Liedl K, Gulbins E, Tripal P: Identification of Novel Functional Inhibitors of Acid Sphingomyelinase . In: PLoS ONE . 6, No. 8, 2011, p. E23852. doi : 10.1371 / journal.pone.0023852 .
10. ^ Carr AA, Kinsolving R (1975). US Patent 3878217. Alpha-aryl-4-substituted piperidinoalkanol derivatives. Accessed November 30, 2008.
11. ↑ European Medicines Agency: CPMP / 257/98 – Final Opinion of the Medicinal Products Committee for Terfenadine . Accessed September 16, 2009.
12. ↑ Drugs Commission of the German Medical Association: “Innovations” instead of non-prescription drugs? Alleged back door leads to the pitfall. Medication prescription in practice. 2004; 31 : 88–89 ( PDF ( memento of July 15, 2014 in the Internet Archive )).
13. ↑ International Conference on Harmonization (2005). Guideline E14: The Clinical Evaluation of QT / QTc Interval Prolongation and Proarrhythmic Potential. Accessed November 30, 2008.

This article is about a health issue. It is not used for self-diagnosis and does not replace a diagnosis by a doctor. Please note the information on health issues !