Antihistamines: a review

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No. 5 H1 <strong>Antihistamines</strong>: a <strong>review</strong> 303 HO N CH 3 N CH CH N C CH CH 2 ACRIVASTINE ACRIVASTINA CH 2 CH 2 CH 2 CH C TERFENADINA TERFENADINE O LORATADINA LORATADINE SEGUNDA SECOND-GENERATION GENERACIîN DE ANTAGONISTAS H1 RECEPTOR ANTAGONISTS DE RECEPTORES H1 Fig. 1b. Primary structure of histamine and of various H1 antihistamines. correlation between the degree of inhibition of the skin response and the clinical efficacy of the various drugs. All the "classical" antihistamines and also many of the second-generation ones (terfenadine 29 , ebastine 30 , astemizole 31 , loratadine 26 , mizolastine 32 ) are metabolised to a greater or lesser extent by the hepatic cytochrome p-450 system (CYP), a fact of utmost importance in the development of drug interactions and drug toxicity. The CYP is an enzymatic system responsible for drug metabolism and detoxification present in the liver and in other tissues, and its constituent isoenzymes are classified into "families" according to the similarity of their aminoacid sequences 33 . As a result of genetic variability, the number of p-450 isoenzymes varies, and each drug is metabolised in a different manner 15 . Astemizole or terfenadine are metabolised by the 3A4 family (CYP3A4). Within this same family, some substances can behave as enzymatic inhibitors while others act as enzyme substrates, and this OH N C O CH2CH2 O C OH HO N CH 2 CH 2 CH 2 C Q Q HCl N OH FEXOFENADINE FEXOFENADINA CH 3 C CH 3 CH 3 CH 3 CH 3 COOH CH 2 O AZELASTINE AZELASTINA N N N Cl CH N N CH2 CH2 O CH2 C OH CH 3 ASTEMIZOLE ASTEMIZOL LEVOCABASTINE LEVOCABASTINA HC O N CH2 CH2 CH2 C C HC O EBASTINE EBASTINA N CH 2 CH 2 CH 2 C C CAREBASTINE CAREBASTINA F NC gives rise to multiple interactions 33 . Table III summarises some inhibitors and substrates of the CYP3A4. It should be noted that natural flavonoids present in grape juice may also inhibit the 3A4 family 33,34 and that erythromycin is at the same time inhibitor and substrate for the CYP3A4 33 . On the other hand, erythromycin is by itself able to block some potassium channels in the myocardium 35 . This might be fundamental, as will be explained later, in its interactions with some antihistamines. SIDE EFFECTS ON THE CARDIOVASCULAR SYSTEM The potential cardiotoxicity of antihistamines was first reported in relation with astemizole 36 and later with terfenadine 37 . Considerable attention was focused on the latter drug, however, possibly because it was the most widely used one in the USA 38 . O N H O H CH 3 CH 3 CH 3 CH 3 CH 3 O O C OH CH 3 COOH
304 I. J‡uregui Presa Volume 14 Table II. Chemical classification of the H1 antihistamines 15,24,26 Drug Dose Plasma elimination Skin test Protein binding Clearance (mg/day) half-life suppression (%) (ml á min -1 á kg -1 ) Acrivastine 16 - 24 ~2 hours 8 hours 50 4.41 Astemizole 10 - 20 12 - 20 days 6 - 8 weeks 97 11.0 Azelastine (oral) 4 - 8 22 - 42 hours 1 week 77 - 88 8.45 Bromphenyramine 9 - 18 24.9 hours 3 - 9 hours Chlorphenyramine 6 - 12 24.2 hours 24 hours Clemastine 2 - 3 7 - 12 hours 10 - 24 hours Cetirizine 10 7 - 10 hours 24 - 72 hours 93 - 98 0.8 Hydroxyzine 75 20 hours 2 - 36 hours Ebastine 10 15 hours 28 hours 97.7 1.3 - 2.0 Levocabastine Nasal spray 0.6 35 - 40 hours 10 - 12 hours 55 0.43 Eye drops 0.2 35 - 40 hours 4 hours Loratadine 10 8 - 24 hours 12 - 14 hours 97 - 99 ? Mizolastine 10 14.5 hours 24 hours 1.15 Noberastine 10 15 hours 32 - 72 hours Terfenadine 120 17 hours 24 - 72 hours 97 8.8 Fexofenadine 120 - 180 14.4 hours 24 - 72 hours The reported arrhythmia associated to astemizole and terfenadine is a polymorphic ventricular tachycardia known by the name of torsades de pointes because of its changing electrical axis in the ECG, with waves of alternating amplitudes and directions (Figure 2). Torsades de pointes may appear as acute episodes with haemodynamic compromise and even sudden cardiac death 39 and are associated to a lengthening of the QT interval in the sinus rhythm ECG. The QT interval itself depends on the duration of the cardiac action potential, which is in its turn dependent on the ionic currents and fluxes in the myocardium and most particularly on the socalled potassium rectifier channel 40 . As already pointed out, terfenadine is a prodrug acting through its acid metabolite (terfenadine carboxylate, or fexofenadine), and this conversion occurs through a CYP3A4-dependent hepatic first-pass metabolism. Terfenadine is a potent blocker of the potassium rectifier channel 41 . Its accumulation in the organism because of overdosage or of the concomitant administration of other substrate drugs or CYP3A4 inhibitors may lengthen the heart rate-corrected QT interval (QTc). If the concomitant drug is erythromycin, which is at the same time a CYP3A4 substrate and a CYP3A4 inhibitor 33 and also a potassium rectifier channel blocker 35 , the heart repolarisation derangements will be even more marked. This effect might perhaps be shared by all the piperidine antihistamines 42 , but it has been demonstrated mainly with astemizole, terfenadine and ebastine 43 at a dosage one- to fourfold the respective peripheral antihistamine one although not with the active metabolites fexofenadine and carebastine, in experimental models 44,45 . Nevertheless, an isolated clinical observation has been published of torsades de pointes and lengthened QT interval in a patient with indetectable levels of astemizole and "therapeutic" concentrations of its major metabolite demethyl-astemizole 46 . Cetirizine, an active metabolite of hydroxyzine, does not prolong the QTc interval at dosages up to sixfold the indicated therapeutic ones 47 . Loratadine has the same interactions with macrolides and imidazoles as the other piperidines, yet this does not induce clinically significant changes in the QTc interval 48,49 . It has been reported that loratadine, contrary to astemizole, terfenadine and ebastine, does not block the potassium channels even at concentrations 100-fold its normal plasma level 50 . Even so, and according to WHO drug surveillance data, loratadine and cetirizine have also been associated, though much less frequently than terfenadine or astemizole, to reports of sudden or cardiac death 51 . There are also recent experimental studies suggesting that loratadine might be able to block certain potassium channels 52 .
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Antihistamines: a review

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