Advances in the therapeutic uses of histamine H 2-receptor antagonists

Abstract

The Hz-receptor antagonists are among the most widely prescribed of all drugs. By any standards, they have been an enormous therapeutic and commercial success and have become regarded as standard treatment for peptic ulceration in most countries. At present, there are four members of this class of drugs (cimetidine, ranitidine, famotidine and nizatidine) which are generally available. Others (e.g. roxatidine) have more limited availability. Although the molecular structures of these drugs differ, they have essentially similar pharmacology; all currently available Hz-receptor antagonists are competitive and reversible antagonists for histamine at the Hz receptor and are devoid of activity at the histamine Hi receptor. Although the Hz receptor is widely distributed in the body, the only known physiological action of histamine at this receptor is stimulation of acid secretion by parietal cells in the oxyntic mucosa of the stomach. Therefore, the principal pharmacological action of the Hz-receptor antagonist is inhibition of gastric acid secretion. Acid is of central importance in the pathogenesis of peptic ulceration and pharmacological, or less commonly surgical, reduction of acid secretion is widely used in the management of peptic ulceration. The Hz-receptor antagonists have been extensively studied in the treatment of duodenal ulcer and benign gastric ulcer. There are numerous published double-blind, endoscopically-controlled clinical trials which attest to the efficacy of these agents in healing duodenal and gastric ulcers. In addition, continuous maintenance treatment with Hz-receptor antagonists reduces ulcer relapse after healing, although such treatment is not appropriate or relevant to all patients (Howden, 1988). The clinical pharmacology and therapeutic applications of the Hz-receptor antagonists have been reviewed in detail elsewhere (Feldman and Burton, 1990a, 1990b; Howden and Hunt, 1991). Despite the enormous amount of attention that these drugs have attracted in the past, there continues to be a great deal of interest in new applications, new dosage schedules, adverse effects, drug interactions and complex issues of their human pharmacology, including ‘tolerance’ to continued use and possible rebound hypersecretion of acid after stopping treatment. It is the purpose of this chapter to critically review some of these areas in an attempt