H₂-receptor antagonist

  An H₂-receptor antagonist, (H₂RA) often shortened to H₂ antagonist, is a drug used to block the action of histamine on parietal cells in the stomach, decreasing acid production by these cells. These drugs are used in the treatment of dyspepsia; however, their use has waned since the advent of the more effective proton pump inhibitors.

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

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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 to 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 - the only design lead, since nothing was known of the then hypothetical H₂ receptor. Hundreds of modified compounds were synthesised in an effort to develop a model of the receptor. The first breakthrough was N^α-guanylhistamine, a partial H₂-receptor antagonist. From this lead the receptor model was further refined and eventually led to the development of burimamide - the first H₂-receptor antagonist. Burimamide, a specific competitive antagonist at the H₂ receptor 100-times more potent than N^α-guanylhistamine, proved 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, lead 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 ultimate discovery of Cimetidine (common brand name Tagamet).

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 inhibitors 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.

Clinical use of H₂-antagonists

Indications

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)
• Dyspepsia
• Stress Ulcer Prophylaxis (Ranitidine)

People that suffer from heartburn (GERD) infrequently may take either antacids or H₂-receptor antagonists for treatment. 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 also suggest that H₂-antagonists might be effective in treating herpes viruses, such as shingles and herpes simplex [1].

Adverse drug reactions

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, diarrhoea, constipation, and rash.^[1] Additionally, cimetidine may also cause gynecomastia in males, loss of libido, and impotence, which are reversible upon discontinuation.

Drug interactions

With regard to pharmacokinetics, cimetidine in particular interferes with some of the body's mechanisms of drug metabolism and elimination through the liver cytochrome P450 pathway. Specifically, cimetidine is an inhibitor of the P450 enzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4. By reducing the metabolism of drugs through these enzymes, cimetidine may increase their serum concentrations to toxic levels. Examples of drugs affected include: warfarin, theophylline, phenytoin, lidocaine, quinidine, propranolol, labetalol, metoprolol, tricyclic antidepressants, some benzodiazepines, dihydropyridine calcium channel blockers, sulfonylureas, metronidazole, and some recreational drugs such as ethanol and MDMA.

The more recently developed H2-receptor antagonists, such as famotidine, are much less likely to alter CYP metabolism.^[2]

Examples

Cimetidine was the prototypical member of the H₂ antagonists. Further developments, using quantitative structure-activity relationships (QSAR) led to the development of further agents with improved tolerability-profiles. In the United States, all four members of the group are available over the counter in relatively low doses, and have become extremely popular medications marketed to heartburn sufferers.

• cimetidine (Tagamet)
• ranitidine (Zantac)
• famotidine (Pepcid)
• nizatidine (Axid, Tazac)

References

1. ^ ^{a b} Rossi S (Ed.) (2005). Australian Medicines Handbook 2005. Adelaide: Australian Medicines Handbook. ISBN 0-9578521-9-3
2. ^ Review article: drug interactions with agents used to treat acid-related diseases, Alimentary Pharmacology & Therapeutics 13 (s3), 18–26, http://www.blackwell-synergy.com/doi/abs/10.1046/j.1365-2036.1999.00021.x

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