H2 antagonists

An H2-receptor antagonist, 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.

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.

At the time (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. In the process, the SK&F scientists also proved the existence of histamine H2 receptors.

The SK&F team used a rational drug-design structure 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&alpha;-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&alpha;-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.

Ranitidine was developed by Glaxo (also now GlaxoSmithKline) in an effort to match the success of Smith, Kline & French with cimetidine. Ranitidine was the 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.

Indications
H2-antagonists are clinically used in the treatment of acid-related gastrointestinal conditions. Specifically, these indications may include: (Rossi, 2005)
 * peptic ulcer disease (PUD)
 * gastroesophageal reflux disease (GERD)
 * dyspepsia
 * stress ulcer prophylaxis (raniditine)

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 oesophagitis since they have been shown to promote healing better than H2-antagonists.

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. (Rossi, 2005) 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.

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)