Astemizole

Structural formula
General
Non-proprietary name	Astemizole
other names	1- (4-fluorobenzyl) - N - {1- [2- (4-methoxyphenyl) ethyl] -4-piperidyl} -1 H -benzimidazol-2-ylamine ( IUPAC )
Molecular formula	C 28 H 31 FN 4 O
External identifiers / databases
CAS number 68844-77-9 EC number 272-441-9 ECHA InfoCard 100.065.837 PubChem 2247 ChemSpider 2160 DrugBank DB00637 Wikidata Q423437
Drug information
ATC code	R06 AX11
Drug class	Antiallergic
Mechanism of action	H 1 receptor antagonist
properties
Molar mass	458.57 g mol −1
Physical state	firmly
Melting point	149.1 ° 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 Caution H and P phrases H: 315-319-335 P: 261-305 + 351 + 338
Toxicological data	2560 mg kg −1 ( LD 50 ,  mouse ,  oral ) 35 mg kg −1 ( LD 50 ,  mouse ,  iv )
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Astemizole is a second generation antihistamine . It is one of the medicines that are used for the symptomatic treatment of allergies . Compared to the antihistamines of the first generation, it is said to have fewer side effects because it is unable to cross the blood-brain barrier into the central nervous system (CNS). Astemizole-containing drugs were first approved in 1984. Today it is no longer on the market in most countries because in rare cases there may be strong interactions with inhibitors of the enzyme CYP3A4 . In Germany and Austria it was available under the brand name Hismanal .

pharmacology

Mode of action and pharmacokinetics

Orally administered astemizole is a competitive antagonist of histamine at the H ₁ receptor and has an anticholinergic and antipruritic (itch-reducing) effect. It binds to H ₁ receptors in the gastrointestinal tract , in the uterus , in blood vessels and in the bronchial muscles . In addition, there may be interactions with H ₃ receptors, which can result in negative side effects. Astemizole also acts as a FIASMA (functional inhibitor of acid sphingomyelinase ).

Astemizole is rapidly absorbed from the gastrointestinal tract; it has a half-life of approximately 24 hours; its protein binding is about 96%. It is excreted with the faeces .

Side effects

The rare but all the more severe side effects that have led to a drastic reduction in the worldwide use of astemizole are primarily of a cardiotoxic nature. They are based on the same problems as with terfenadine : Since CYP3A4 plays an important role in the biotransformation of astemizole (as well as terfenadine), if this enzyme is inhibited - for example after appropriate drug administration - astemizole metabolism is disrupted . In such a case, its concentration increases and the potassium channels in the heart muscle can be blocked . This blockage can disrupt the repolarization of the heart cells, which in turn leads to a prolongation of the QT time in the ECG with the possible development of torsades de pointes tachycardia . This effect is all the more devastating in patients who already suffer from liver damage or QT prolongation. The German Medical Journal reported in a 1997 edition:

“ In the context of widespread, worldwide use of terfenadine and astemizole, individual suspected serious, life-threatening cardiotoxic side effects were reported from the end of the 1980s. Cardiac arrhythmias, QT prolongation, torsades de pointes, ventricular arrhythmias, ventricular fibrillation, syncope, cardiac arrest and deaths occurred. In these cases, there were predominantly clinically significant liver dysfunction, heart disease, simultaneous use of the above-mentioned macrolide antibiotics or antimycotics, or overdoses. Since 1986 until now, the BfArM from Germany has received five suspected cases of terfenadine and one suspected case of torsade de pointes for astemizole. In addition, one fatal outcome was reported in each case. "

research

At concentrations of 200 nM, astemizole blocks the voltage-gated potassium ion channel Eag1 (K _V 10.1), which is expressed by around 70% of known tumor types . Blocking this channel disrupts the proliferation of tumor cells, and astemizole could therefore be used for tumor therapy .

Individual evidence

1. ↑ Entry on Astemizole. In: Römpp Online . Georg Thieme Verlag, accessed on November 11, 2014.
2. ↑ ^{a b} Astemizole data sheet from Sigma-Aldrich , accessed on March 21, 2011 ( PDF ).
3. ↑ ^{a b} Entry on astemizole in the ChemIDplus database of the United States National Library of Medicine (NLM) .
4. ↑ ^{a b} Deutsches Ärzteblatt 94, issue 18 of May 2, 1997 .
5. ↑ 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 .
6. ↑ RE García-Ferreiro, D. Kerschensteiner, F. Major, F. Monje, W. Stühmer , LA Pardo: Mechanism of block of hEag1 K + channels by imipramine and astemizole. In: The Journal of general physiology. Volume 124, number 4, October 2004, pp. 301-317, doi : 10.1085 / jgp.200409041 , PMID 15365094 , PMC 2233905 (free full text).
7. ↑ AM Jiménez-Garduño, M. Mitkovski, IK Alexopoulos, A. Sánchez, W. Stühmer, LA Pardo, A. Ortega: KV10.1 K (+) - channel plasma membrane discrete domain partitioning and its functional correlation in neurons. In: Biochimica et Biophysica Acta . Volume 1838, number 3, March 2014, pp. 921-931, doi : 10.1016 / j.bbamem.2013.11.007 , PMID 24269539 .
8. ↑ J. García-Quiroz, J. Camacho: Astemizole: an old anti-histamine as a new promising anti-cancer drug. In: Anti-Cancer Agents in Medicinal Chemistry . Volume 11, Number 3, March 2011, pp. 307-314, PMID 21443504 .

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