Antihistamines: a review

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No. 5 H1 <strong>Antihistamines</strong>: a <strong>review</strong> 301 CHEMISTRY OF THE ANTIHISTAMINES The typical antihistamines have an ethylamine side chain (similar to that of histamine itself) which is united to one or more cyclic groups. The structural characteristics of the H1 receptor antagonists have been historically used for classifying them into six broad chemical families: ethanolamines, ethylenediamines, alkylamines, phenothiazines, piperazines and piperidines (Table I) 6 . Several of the new H1 receptor antagonists are chemically speaking piperidines, or at least they possess piperidine rings (Fig. 1). Many of them are direct derivatives of the parent compound or active metabolites of the primary molecules (such as cetirizine from hydroxyzine, or fexofenadine from terfenadine) 6 . Generally, the molecular nucleus of the H1 receptor antagonists is necessary for their H1 affinity and selectivity, while the side chains or radicals influence other properties of the molecules. As an example, the first-generation antihistamines contain aromatic rings and alkyl substituents which render them lipophyllic, thus explaining their ability to cross the haemato-encephalic barrier (HEB) 7 . Efforts have been directed at suppressing or preventing this property by adding or eliminating radicals in the molecular structure; thus, terfenadine requires its phenylbutanol structure in order not to cross the HEB 4,8 , and loratadine has a carboxyethyl ester radical which limits its distribution in the CNS 9 . The ethylamine group, which is common to all typical antihistamines, is also shared by many anticholinergic and adrenergic blocking compounds. For this reason, these compounds have antidopaminergic, antiserotoninergic and antimuscarinic effects, which in many patients become undesirable side effects. They have, however, also been taken advantage of for therapeutic purposes: the antiemetic and antikinetotic actions of many antihistamines (diphenhydramine, dimenhydrinate, phenothiazines) are predominantly due to their central sedative and anticholinergic properties 9 . Some antihistamines, such as cyproheptadine, ketotifen, astemizole and cetirizine also induce increased appetite, which has been ascribed to an antiserotoninergic action 9 . This undesired side effect, which is well documented particularly in the case of cyproheptadine, has been often taken advantage of in "reconstituents" and preparations for the treatment of hypo-orexia 10 . Table I. Chemical classification of the H1 antihistamines Chemical group Typical compounds Second-generation (first generation) compounds Alkylamines Bromphenyramine Acrivastine Chlorphenyramine Triprolidine Ethanolamines Diphenhydramine Dimenhydrinate Doxylamine Carbinoxamine Clemastine Ethylenediamines Pirylamine Tripelennamine Antazoline Phenothiazines Promethazine Mequitazine Piperazines Buclyzine, Ciclyzine Cinarizine, Flunarizine Oxatomide Hydroxyzine Cetirizine Piperidines Azatadine Loratadine Cyproheptadine Astemizole Ketotifen Levocabastine Mizolastine Ebastine Terfenadine Fexofenadine Miscellany Azelastine (ftalazinone derivative) MECHANISMS OF ACTION The antihistamines behave as competitive antagonists of histamine: they bind to the H1 receptor without activating it, and thus prevent histamine from binding to and activating this receptor. The binding of many antihistamines is readily reversible but some of them, such as terfenadine and astemizole, are not easily dissociated from their binding to the receptors 11 . Even though there are some specific molecules for which such effects have been documented, antihistamines as a group do not chemically inactivate histamine, nor do they antagonise it in a physiological sense, nor do they in any manner prevent its release 9 . Many recent studies suggest that some H1 receptor antagonists might also have antiinflammatory or antiallergic properties in the broadest sense of those concepts. Although the first publication in this context referred to azatadine 12 , this type of additional actions has been later attributed to many second-generation antihistamines.
302 I. J‡uregui Presa Volume 14 Cetirizine 13,14 reduces the attraction of inflammatory cells to the inflammatory focus after antigen challenge and inhibits the expression of the intercellular adhesion molecule 1 (ICAM-1) on the surface of epithelial cells. It also might be able to block the antigen-induced production of leukotrienes (LTC 4) 15 . Loratadine and its metabolite decarboethoxyloratadine inhibit the release of tryptase and amacroglobulin 16 , of interleukins (IL) 6 and 8 17 and of leukotrienes and prostaglandin D2 (PGD2) 18 , and also the expression of ICAM-1 and of HLA-II antigens on the surface of epithelial cells 19 . Terfenadine inhibits the inflammatory cellular infiltrate and the eosinophil activation products in nasal lavage fluid and also the expression of surface ICAM-1 20 . It may also inhibit the release of leukotrienes from basophils and eosinophils and of histamine from basophils, as well as inhibiting skin reactivity to the platelet activation factor (PAF) 15 . Topical azelastine, which was initially studied as a "dual action" antihistamine with a clinical profile similar to that of ketotifen or oxatomide 2 , also seems to inhibit the eosinophyllic infiltrate and the expression of surface ICAM-1 in nasal epithelial cells 21 . Ebastine might have an antagonist action on the IgE-induced release of PGD2 and LTC 4/D 4 22 . A recent study in a rat model ascribes to mizolastine an antiinflammatory effect on the skin reaction induced by arachidonic acid 23 . Finally, fexofenadine inhibits the spontaneous release of IL-6 in fibroblast cultures 24 and the eosinophil-induced release of IL-8 and GM-CSF, as well as the expression of surface ICAM-1 in cultures of nasal epithelial cells. These antiinflammatory effects of antihistamines are not considered to be linked to H 1 receptor blockage. As they have mostly been demonstrated in vitro and with experimental concentrations of the drugs that are much higher than those achieved in vivo with the usual pharmacological dosages, their relative importance within the overall spectrum of the clinical efficacy of these drugs is still unknown 15 . PHARMACOKINETICS AND PHARMACODYNAMICS Almost all the H1 receptor antagonists have adequate oral absorption and can achieve maximal plasma concentrations within the 24 hours follo- Cl HN N HISTAMINA HISTAMINE CH 2 CH 2 NH 2 CHLORPHENYRAMINE CLORFENIRAMINA N PRIMERA FIRST-GENERATION GENERACIîN DE ANTAGONISTAS H1 RECEPTOR ANTAGONISTS DE RECEPTORES H1 Cl CH CH 2 CH 2 CH O CH 2 CH 2 DIPHENHYDRAMINE DIFENHIDRAMINA Fig. 1a. Primary structure of histamine and of various H1 antihistamines. wing administration. Most of the second-generation antihistamines, with the exception of acrivastine, cetirizine, levocabastine, fexofenadine and perhaps some other active metabolites experience hepatic first-pass metabolism, so that the plasma concentrations of the parent drugs are usually indetectable a few hours after administration 26 . Nevertheless, the effects of the antihistamines, as documented in studies of inhibition of histamineinduced skin reactions, persist over a time that is variable for each compound (Table II). This might be due to a greater tissue concentration, or to active metabolites maintaining the effect 27 . Because all the H1 receptor antagonists inhibit the skin reactions induced by histamine, this test has become a standardised biologic test for the action of antihistamines 15 . However, as several authors have pointed out 28 , there is not always a N OH N N CH2CH2 O CH2CH2 O H N CH 3 CH 3 CH 3 CH 3 HIDROXICINA HYDROXYZINE
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Antihistamines: a review

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