These drugs bind selectively and competitively to the histamine H2 receptor on the basolateral membrane of the parietal cell. As well as inhibiting gastric acid release from histamine they inhibit acetylcholine- and gastrin-mediated acid secretion. This inhibitory effect can be overcome, particularly when gastrin levels are high, as occurs postprandially. In addition, tolerance may develop, probably as a result of down-regulation of receptors. Peptic ulcer healing with H2 receptor antagonists correlates best with suppression of nocturnal acid secretion and these drugs are often given in a single evening dose. The usual ulcer-healing course is 8 weeks.
Cimetidine was the first H2 receptor antagonist to be used in clinical practice. It is rapidly absorbed from the gastrointestinal tract and its plasma t1/, is 2 h.
Adverse effects and interactions are few in short-term use. Minor complaints include headache, dizziness, constipation, diarrhoea, tiredness and muscular pain. Bradycardia and cardiac conduction defects may also occur. Cimetidine is a weak antiandrogen, and may cause gynaecomastia and sexual dysfunction in males. In the elderly particularly, it may cause CNS disturbances including lethargy, confusion and hallucinations. Cimetidine inhibits cytochromes P450, in particular CYP 1A2 and CYP 3A4 and there is potential for increased effect from any drug with a low therapeutic index that is inactivated by these isoenzymes, e.g. warfarin, phenytoin, lidocaine, propranolol, 5-fluorouracil and theophylline.
Ranitidine, famotidine, nizatidine
The modes of action, uses and therapeutic efficacy of these histamine H2 receptor antagonists are essentially those of cimetidine. Differences from cimetidine lie chiefly in dose and profile of unwanted effects. Ranitidine (t% 2 h) is 50%, famotidine (tV2 3 h) is 25% and nizatidine (t\ 1 h) is 10% metabolised, in each case the remainder being excreted unchanged by the kidney.
The drugs are well tolerated but headache, dizziness, reversible confusion, constipation and diarrhoea may occur. In addition, urticaria, sweating and somnolence are reported with nizatidine. The drugs do not inhibit hepatic microsomal enzymes and do not block androgen receptors.
H2 receptor antagonists are available as over-the-counter preparations in the UK, albeit of lower strength than those available on prescription. The potential danger is that patients with serious pathology such as gastric carcinoma will self-medicate, allowing their disease to progress. Pharmacists are trained to advise patients to consult their doctor if they have recurrent symptoms or other worrying manifestations such as weight loss.
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