In 1964 it was known that histamine+ stimulated the secretion of stomach acid, but also that traditional antihistamine+s had no effect on acid production. From these facts the SK&F scientists postulated the existence of two histamine receptors. They designated the one acted on by the traditional antihistamines H1, and the one acted on by histamine to stimulate the secretion of stomach acid H2.
The SK&F team used a classical design+ process starting from the structure of histamine. Hundreds of modified compounds were synthesised in an effort to develop a model of the then-unknown H2 receptor. The first breakthrough was ''Nα''-guanylhistamine, a partial H2-receptor antagonist. From this lead the receptor model was further refined and eventually led to the development of burimamide+, a specific competitive antagonist+ at the H2 receptor 100-times more potent than ''Nα''-guanylhistamine, proving the existence of the H2 receptor.
Burimamide was still insufficiently potent for oral administration and further modification of the structure, based on modifying the acid dissociation constant+ of the compound, led to the development of metiamide+. Metiamide was an effective agent; however, it was associated with unacceptable nephrotoxicity+ and agranulocytosis+. It was proposed that the toxicity arose from the thiourea+ group, and similar guanidine+ analogues were investigated until the discovery of cimetidine+, which would become the first clinically successful H2 antagonist.
Ranitidine+ (common brand name Zantac) was developed by Glaxo (also now GlaxoSmithKline+) in an effort to match the success of Smith, Kline and French with cimetidine. Ranitidine was also the result of a rational drug design process utilising the by-then-fairly-refined model of the histamine H2 receptor and quantitative structure-activity relationships (QSAR+).
Glaxo refined the model further by replacing the imidazole+-ring of cimetidine with a furan+-ring with a nitrogen+-containing substituent, and in doing so developed ranitidine. Ranitidine was found to have a far-improved tolerability profile (i.e. fewer adverse drug reaction+s), longer-lasting action, and ten times the activity of cimetidine.
Ranitidine was introduced in 1981 and was the world's biggest-selling prescription drug by 1988. The H2-receptor antagonists have since largely been superseded by the even more effective proton pump inhibitor+s, with omeprazole+ becoming the biggest-selling drug for many years.
The H2 antagonists are competitive antagonists of histamine+ at the parietal cell+ H2 receptor. They suppress the normal secretion of acid by parietal cells and the meal-stimulated secretion of acid. They accomplish this by two mechanisms: Histamine released by ECL cell+s in the stomach is blocked from binding on parietal cell H2 receptors, which stimulate acid secretion; therefore, other substances that promote acid secretion (such as gastrin+ and acetylcholine+) have a reduced effect on parietal cells when the H2 receptors are blocked.
People who suffer from infrequent heartburn may take either antacids+ or H2-receptor antagonists for treatment. The H2-antagonists offer several advantages over antacids, including longer duration of action (6–10 hours vs 1–2 hours for antacids), greater efficacy, and ability to be used prophylactically before meals to reduce the chance of heartburn occurring. Proton pump inhibitors+, however, are the preferred treatment for erosive esophagitis+ since they have been shown to promote healing better than H2-antagonists.
H2 antagonists are, in general, well tolerated, except for cimetidine+, wherein all of the following adverse drug reaction+s (ADRs) are ''common''. Infrequent ADRs include hypotension+. Rare ADRs include: headache+, tiredness, dizziness, confusion, diarrhea+, constipation, and rash. In addition, gynecomastia+ occurred in 0.1% to .5% of men treated for nonhypersecretory conditions with cimetidine for 1 month or longer and in about 2% of men treated for pathologic hypersecretory conditions; in even fewer men, cimetidine may also cause loss of libido, and impotence+, all of which are reversible upon discontinuation.
The more recently developed H2-receptor antagonists are less likely to alter CYP metabolism. Ranitidine+ is not as potent a CYP inhibitor as cimetidine, although it still shares several of the latter's interactions (such as with warfarin, theophylline, phenytoin, metoprolol, and midazolam). Famotidine+ has negligible effect on the CYP system, and appears to have no significant interactions.
H2 antagonist+ The H2 receptor antagonists (H2RA) are a class of drugs used to block the action of histamine on parietal cells (specifically the histamine H2 receptors) in the stomach, decreasing the production of acid by these cells.