Ethylenediamine antihistamine

Although the hydroxyzine ethylenediamines, Atarax and Vistaril, are not usually classified with the ethylenediamine antihistamines it should be noted that the formula of Atarax (hydroxyzine hydrochloride) is l-p-chlorobenzyhydryl-4,2 (2(2-hy-Avo yQihoxy)tihy )diethylenediamine dihydrochloride. It therefore would be prudent to avoid the use of hydroxyzine antihistamines in individuals with ethylene-diamine sensitivity. 

The piperazine (cyclizine) antihistamines are listed in Table 4. The piperazine antihistamines, like the hydroxyzines, are closely related to the ethylenediamine antihistamines. It is felt that, since ethylenediamine is on the metabolic pathway of both piperazine and hydroxyzine, it is advisable to avoid the use of piperazine antihistamines in ethylenediamine-sensitive individuals. 

Ethylenediamine antihistamine, aminophylline Aminophylline, pyribenzamine, Tagathen, Antistine, Atarax, Mycolog, Surfadil, Allergen and Phenergan creams, Preferin eyedrops, piperazine... 

Further illustration for the lack of structural specificity required for antihistaminic activity comes from the finding that ethylenediamines carrying both a benzylamine and an additional aromatic substituent on one of the nitrogens afford a series of useful therapeutic agents. Alkylation of benzylaniline with JV-... 

Hf and H Receptors. Histamine exerts its actions by binding to receptors on cell membranes. Two types of histamine receptors, the Hi and H2 receptors, are known specific agonists and antagonists exist for each of these receptors. Black et al. (55) differentiated H and H2 receptors with the compounds, 2-methylhistamine and 4 methylhistamine. 2-Methylhistamine is active on tissues with H receptors 4-methylhistamine is active on tissues with H2 receptors. Classical antihistaminic drugs were developed in the 1930 s these compounds block H but not H2 receptors. Among the clinically used H -blockers are derivatives of ethanolamine, ethylenediamine, alkylamine, piperazine and phenothiazine (32). These agents are valuable in the treatment of... 

Ethanolamines—(diphenhydramine was the prototypical agent in this group). Ethylenediamines, which were the first group of clinically effective Hj antihistamines developed, (pyrilamine). 

Cross-reactions between phenothiazine tranquillizers and first-generation antihistamines are possible, as well as reactions between antihistamines and ethylenediamine present in some creams and ointments. As local sensitization is quite common, topical use of antihistamines is not recommended. Despite these disadvantages they are stiU available in many countries as over-the-counter products. Topical antihistamines in sufficient doses can also cause systemic adverse effects. 

Mebhydrolin is an antihistamine, an ethylenediamine derivative, with antimuscarinic and sedative properties. 

A variety of more potent and less toxic antihistaminic agents have been tailored by effecting molecular modifications of the general ethylenediamine structure whereby the dimethylamino function is essentially replaced by a small compact heterocyclic ring. 

SAR of Buclizine. Importantly, buclizine-a member of the piperazine class of antihistaminics are very much structurally related to both the ethylenediamines as well as the benzyhydryl ethers of ethanolamines. Its structure essentially include the 2 carbon separation existing between the N-atoms, that forms a part of the piperazine ring. 

The laige number of potent antihistaminic agents used in the therapeutic armamentarium belong to various defined chemical categories, namely aminoalkylethers, ethylenediamines, thiophene analogs, cyclic basic chain analogs and phenothiazine derivatives. However, it is now possible to derive some important conclusions with respect to their structural requirements for optimal activity and pharmacological actions, namely ... 

Structural classes of Hi antihistamines can be represented by a general structure of two aromatic groups linked through a short chain to a tertiary aliphatic amine (Fig. 37.6). The aromatic groups (An, Ar2) usually are phenyl or substituted phenyl, thienyl, or pyridyl. These substituents are attached to the X group, which is a nitrogen atom in the ethylenediamines, a carbon attached to... 

Topical application of Hi antihistamines to the eye is made to relieve itching, congestion of the conjunctiva, and erythema (15,42). The density of mast cells in the conjunctiva is high, and the histamine concentrations in tear film are significant in the ocular allergic response. From eye drops, only small amounts of the antihistamine (1-5%) penetrate the cornea. More of the compound is absorbed via the conjunctiva and nasal mucosa, and still more ends up swallowed from tear duct and nasal drainage. Until recently, topical ocular antihistamines were limited to two classical agents antazoline (Table 37.2), from the ethylenediamine series, and pheniramine (Fig. 37.9), from the alkylamine series. Both are used in combination with sympathomimetic vasoconstrictors. 

The sedative property which is so highly expressed in diphenhydramine existed in a less measure in other antihistamines. In an endeavour to lessen it, to help those who need medication at times when they must be alert, chlor-phenamine (9.57) (chlorpheniramine, Chlortrimeton ) was introduced. In this type, the second polar atom (N or O) has been eliminated from the aliphatic chain. The pAa values (4.0 and 9.2) resemble those of earlier compounds. Another type with a decreased incidence of drowsiness has the two nitrogen atoms of ethylenediamine joined by two saturated carbon atoms to give a piperazine ring. Chlorcyclizine 9.56a) ( Histantin , Diparalene ) provides an example. The search for Hi antagonists that could not cross the blood-brain barrier, and hence would be non-sedative, has produced the sterically-hindered astemizole ( Hismanol ) which is l-(p-fluorobenzyl)-2-[l-(l-/ methoxyphen-ethyl)-4-piperidylamino]benzimidazole, used for hay fever (Laduron et al., 1982). 

Many antihistamines are frequent sensitizers following topical administration. Antihistamines include ethylenediamine derivatives, aminalkyl ether derivatives, phe-nothiazine derivatives, and piperazine derivatives. Contact allergy to these compounds is described in Chap. 14. 

Nitrogen-linked ethylenediamines Oxygen-linked ethanolamines Carbon-linked alkylamines Phenothiazine antihistamines Cyclizines (piperazines) Piperidines Miscellaneous... 

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