Astemizole antihistaminic activity

Astemizole undergoes extensive first-pass hepatic metabolism via cytochrome P450 (CYP 450) enzymes (primarily 3A4) to three primary, active, metabolites, desmethylastemizole, norastemizole, and 6-hydroxydesmethylastemizole. The major metabolites of astemizole, desmethylastemizole and norastemizole, possess antihistaminic activity approaching that of the parent compound. The of astemizole... 

One important analogue of morphine is fentanyl, a clinically used narcotic that is about 100 times more potent than morphine. Several analogues have been synthesised such as sufentanil, alfentanil, lofentanil and, even more interestingly, structurally related compounds with different activities such as astemizole (antihistaminic), droperidol (tranquillizing), loperamide (antidiarrheal) and lorcainide (antiarrhythmic) [50]. 

Iatrogenic Reactions broadly refer to any adverse reactions that are unintentionally produced by physicians in their patients. For example, one of the side effects of many antihistaminic preparations (Hj antagonists) such as ethanolamine derivatives (prototype diphenhydramine) is heavy sedation. Although sedation may be desirable for some patients, it may interfere with daytime activities, and this needs to be considered when prescribing such medications. Other antihistaminic preparations (also 11 antagonists) such as piperidine derivatives (prototypes terfenadine or astemizole) have no sedative properties (Figure 3.2). 

The second-generation antihistamines include acrivastine, astemizole, azelastine, carebastine, cetirizine, ebastine, loratadine, mizolastine, and terfenadine. They are used orally and some of them can be given by local application to the nose and eyes (2,16). They are relatively free from anticholinergic, antiserotonergic, and alpha-adrenergic activity. They cause markedly less sedation, perhaps because they penetrate the central nervous system less well than the first-generation antihistamines, being relatively hydrophilic (17-19). 

CYP2J subfamily. CYP2J2 is the only gene of this subfamily. It is known to be expressed in many extrahepatic tissues and may play a role in the oxidative bioactivation of arachidonic acid to form epoxyeicosatrienoic acids, which modulate bronchial smooth muscle tone and airway transepithelial ion transport [53], CYP2J2 is also active toward other compounds such as linoleic acid and testosterone. Recently, it has been reported that CYP2J2 is involved in the intestinal first-pass metabolism of an antihistamine drug, astemizole [54],... 

The toxicity of astemizole also appears to be remarkably low. An acute toxicity study in rats found that at 25,000 times the antihistaminic dose (2,560 mg/kg) the drug produced some transient sedation but no lethality up to 2 weeks after administration—an extreme safety margin. This raises the possibility that antihistamines may have intrinsic antiasthmatic activity, but at such doses that the toxicity of the first-generation drugs precluded such a use at safe doses. 

It is a long-acting, nonsedating tricyclic antihistaminic drug. It possesses praetieally little anticholinergic activity. It shows potency that is fairly comparable to astemizole and signifieantly greater than terfenadine. ... 

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