Many of the first-generation antihistamines, and now the second-generation agents, have been formulated in combination with a decongestant. The decongestants used in most preparations today predominantly include phenylpropanolamine hydrochloride, phenylephrine hydrochloride, and pseudoephedrine hydrochloride. These agents have saturated benzene rings without 3- or 4-hydroxyl groups, which is the reason for their weak a-adrenergic effect, improved oral absorption, and duration of action. Compared with other decongestants, these agents have less of an effect on blood pressure and are less apt to cause CNS excitation manifested as insomnia or agitation (110).
h2 receptor antagonists
H2 receptor antagonists are weak bases with water-soluble hydrochloride salts and tend to be less lipophilic than H antagonists (3). The early agents, which were developed for their gastric acid inhibitory properties, were either not strong enough for clinical use or hazardous because of serious associated side effects (e.g., neutropenia, bone marrow suppression) (111,112). Cimetidine (Tagamet) was introduced to the United States in 1982 and has been proved safe and effective in the treatment of peptic ulcer disease (15). Cimetidine and oxmetidine resemble the earliest agents structurally because they have an imidazole ring similar to histamine's structure. The newer agents vary structurally by having different internal ring components. For example, ranitidine (Zantac) has a furan ring, whereas famotidine (Pepcid) and nizatidine (Axid) are composed of thiozole rings (15). H2 antagonists act primarily by competitive inhibition of the H 2 receptors, with the exception of famotidine, which works noncompetitively (15). The four available H2 antagonists all have potent H2 antagonistic properties, varying mainly in their pharmacokinetics, and adverse effects such as drug interactions. Several of these H 2 antagonists are now available over the counter (3,15).
Numerous studies have been undertaken to examine the clinical utility of H 2 antagonists in allergic and immunologic diseases. Although several studies report that these agents have promising immunologic changes in vitro, these findings have not been substantiated clinically ( 3,22,113,114,115,116 and 117). Generally, H2 antagonists have limited or no utility in treating allergen-induced and histamine-mediated diseases in humans ( 118,119,120 and 121). One notable exception to this rule may be their use in combination with H antagonists in the treatment of chronic idiopathic urticaria (122). The studies evaluating the clinical efficacy of H 2 antagonists in allergic and immunologic disorders are extensively reviewed elsewhere ( 3,117).
h3 receptor antagonists
H3 receptors were first suspected by Arrang and colleagues in 1983 when they found histamine to inhibit, by negative feedback, its own synthesis and release in the brain (3,9). These actions by histamine could not be suppressed by H or H2 antagonists, leading researchers to postulate the existence of a third class of histamine receptors. Subsequent studies have been directed toward finding a selective H 3 antagonist. Two such agents have been synthesized: (R) a-methylhistamine (a-MeHA), a chiral agonist of histamine, and thioperamide, a derivative of imidazolylpiperidine. They both have demonstrated H 3 receptor selectivity but remain strictly for experimental use (9).
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