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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. H2 antagonists are used in the treatment of dyspepsia, although they have been surpassed in popularity by the more effective proton pump inhibitors.
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 has fewer adverse effects and drug interactions and is 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) by James W. Black, C. Robin Ganellin, and others to develop a histamine receptor antagonist that would suppress stomach acid secretion.
In 1964 it was known that histamine stimulated 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 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 & 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.
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; 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.
- Peptic ulcer disease (PUD)
- Gastroesophageal reflux disease (GERD/GORD)
- Prevention of stress ulcer (a specific indication of ranitidine)
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.
The H2 antagonist Ranitidine is prescribed by some urologists for patients with interstitial cystitis. Interstitial cystitis (IC) patients have been found to have significantly more mast cells than non-IC individuals. Mast cells explode with histamine. Studies have suggested that antihistamines improve IC-related pelvic pain. 
H2 antagonists are, in general, well tolerated, except for cimetidine, wherein 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. H2 antagonists, as well as other antacid preparations that function by suppressing acid mediated break down of proteins, lead to an elevated risk of developing food and drug allergies. This happens due to undigested proteins then passing into the gastrointestinal tract. It is unclear whether this risk occurs with only long-term use or with short-term use as well. In addition, cimetidine may also cause gynecomastia in males, loss of libido, and impotence, which are reversible upon discontinuation.
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 (CYP) pathway. To be specific, cimetidine is an inhibitor of the P450 enzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4. By reducing the metabolism of drugs through these enzymes, cimetidine may increase their serum concentrations to toxic levels. Many drugs are affected, including warfarin, theophylline, phenytoin, lidocaine, quinidine, propranolol, labetalol, methadone, metoprolol, tricyclic antidepressants, some benzodiazepines, dihydropyridine calcium channel blockers, sulfonylureas, metronidazole, and some recreational drugs such as ethanol (drinking alcohol) and methylenedioxymethamphetamine (MDMA).
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.
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