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Astemizole

Astemizole
Systematic (IUPAC) name
1-[(4-fluorophenyl)methyl]- N-[1-[2-(4-methoxyphenyl)ethyl]- 4-piperidyl]benzoimidazol-2-amine
Clinical data
AHFS/Drugs.com
MedlinePlus
Pregnancy
category
Legal status
  • Unscheduled
Routes of
administration
Oral
Pharmacokinetic data
Bioavailability ?
Metabolism Hepatic
Biological half-life 24 hours
Excretion Fecal
Identifiers
CAS Registry Number  Y
ATC code R06
PubChem CID:
IUPHAR/BPS
DrugBank  Y
ChemSpider  Y
UNII  Y
KEGG  Y
ChEBI  Y
ChEMBL  Y
Chemical data
Formula C28H31FN4O
Molecular mass 458.571 g/mol
 Y   

Astemizole (R43512, marketed under the brand name Hismanal) was a second-generation antihistamine drug that has a long duration of action. Astemizole was discovered by Janssen Pharmaceutica in 1977. It has been withdrawn from the market in most countries because of rare but potentially fatal side effects (QTc interval prolongation and related arrhythmias due to hERG channel blockade).[1]

Contents

  • Metabolism 1
  • Pharmacology 2
  • Toxicity 3
  • References 4
  • External links 5

Metabolism

It is metabolized by CYP3A4.[2]

Pharmacology

Astemizole is a histamine H1-receptor antagonist. It is structurally similar to terfenadine and haloperidol (a butyrophenone antipsychotic). It has anticholinergic and antipruritic effects.

Astemizole competitively binds to histamine H1-receptor sites in the gastrointestinal tract, uterus, blood vessels, and bronchial muscle. This suppresses the formation of edema and pruritus (caused by histamine).

Despite some earlier reports that Astemizole does not cross the blood–brain barrier, several studies[3][4] have shown high permeability and high binding to protein folds associated with Alzheimer's.

Astemizole may also act on histamine H3 receptors, thereby producing adverse effects.

Astemizole does also act as FIASMA (functional inhibitor of acid sphingomyelinase).[5]

Astemizole is rapidly absorbed from the gastrointestinal tract; protein binding is around 96 percent.

Astemizole may cause life-threatening arrhythmia.

Toxicity

Astemizole has an oral LD50 of approximately 2052 mg/kg (in mice).

References

  1. ^ Zhou Z, Vorperian VR, Gong Q, Zhang S, January CT (June 1999). "Block of HERG potassium channels by the antihistamine astemizole and its metabolites desmethylastemizole and norastemizole". J. Cardiovasc. Electrophysiol. 10 (6): 836–43.  
  2. ^ Matsumoto S, Yamazoe Y (February 2001). "Involvement of multiple human cytochromes P450 in the liver microsomal metabolism of astemizole and a comparison with terfenadine". British Journal of Clinical Pharmacology 51 (2): 133–42.  
  3. ^ Rojo, Leonel E.; Alzate-Morales, Jans; Saavedra, Iván N.; Davies, Peter; Maccioni, Ricardo B. (2010). "Selective Interaction of Lansoprazole and Astemizole with Tau Polymers: Potential New Clinical Use in Diagnosis of Alzheimer's Disease". Journal of Alzheimer's Disease (IOS Press) 19 (2): 573–589.  
  4. ^ Di, Li; Kerns, Edward H; Fan, Kristi; McConnell, Oliver J; Carter, Guy T (7 March 2003). "High throughput artificial membrane permeability assay for blood–brain barrier". European Journal of Medicinal Chemistry 38 (3): 223–232.  
  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 (2011). "Identification of novel functional inhibitors of acid sphingomyelinase". PLoS ONE 6 (8): e23852.  

External links

  • Statement on Astemizole from Health Canada
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