Ball-and-stick model of cimetidine, the prototypical H₂-receptor antagonist.

The prototypical H₂ antagonist was cimetidine, developed by Smith, Kline & French (now GlaxoSmithKline) in the mid-to-late 1960s and first marketed in 1976; sold under the trade name Tagamet, cimetidine would later become the first ever blockbuster drug. The use of quantitative structure-activity relationships (QSAR) led to the development of other agents?starting with ranitidine, first sold as Zantac?which had fewer adverse effects and drug interactions and were more potent.

History and development

Cimetidine was the prototypical histamine H₂-receptor antagonist from which the later members of the class were developed. Cimetidine was the culmination of a project at Smith, Kline & French (SK&F; now GlaxoSmithKline) to develop a histamine receptor antagonist that would suppress stomach acid secretion.

In 1964 it was known that histamine was able to stimulate the secretion of stomach acid, but also that traditional antihistamines 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 rational drug 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 N^?-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 N^?-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 pKa 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 & 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 reactions), 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 inhibitors, with omeprazole becoming the biggest-selling drug for many years.

Pharmacology

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 cells in the stomach is blocked from binding on parietal cell H₂ receptors which stimulate acid secretion, and other substances that promote acid secretion (such as gastrin and acetylcholine) have a reduced effect on parietal cells when the H₂ receptors are blocked.

Like the H₁-antihistamines, the H₂ antagonists are inverse agonists rather than true receptor antagonists.

Clinical use

H₂-antagonists are clinically used in the treatment of acid-related Gastrointestinal conditions. Specifically, these indications may include:^[1]

• Peptic ulcer disease (PUD)
• Gastroesophageal reflux disease (GERD/GORD)
• Dyspepsia
• Prevention of stress ulcer (a specific indication of ranitidine)

People that suffer from heartburn infrequently 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.

Some studies suggest that H₂-antagonists might be effective in treating herpes viruses, such as shingles and herpes simplex http://www.lef.org/magazine/mag2001/mar2001_report_tagamet_1.html.

Adverse effects

The H₂ antagonists are generally well-tolerated, except for cimetidine where all of the following adverse drug reactions (ADRs) are common. Infrequent ADRs include hypotension. Rare ADRs include: headache, tiredness, dizziness, confusion, diarrhea, constipation, and rash.^[1] Additionally, cimetidine may also cause gynecomastia in males, loss of libido, and impotence, which are reversible upon discontinuation.

In a longitudinal study of elderly African Americans published in 2007, long-term use of H₂ blockers appeared to increase the risk of cognitive decline.^[2]

Drug interactions

Skeletal formula of famotidine. Unlike cimetidine, famotidine has no significant interactions with other drugs.

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).^[4] Famotidine has negligible effect on the CYP system, and appears to have no significant interactions.^[3]

Notes

1. ↑ ^{a b} Rossi S (Ed.) (2005). Australian Medicines Handbook 2005. Adelaide: Australian Medicines Handbook. ISBN 0-9578521-9-3
2. ↑
3. ↑ ^{a b}
4. ↑

References

• Katzung, Bertram G. (2004). Basic and Clinical Pharmacology, 9th ed. ISBN 0-07-141092-9

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