Information AboutH2-receptor Antagonist |
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An H2-receptor antagonist, (H2RA) often shortened to '''H2 antagonist''', is a Drug used to block the action of Histamine on Parietal Cell s 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 Inhibitor s. Like the H1-antihistamines , the H2 antagonists are Inverse Agonist s rather than true Receptor Antagonist s. 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 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 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 ''Nα''-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 ''Nα''-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 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. PHARMACOLOGY The H2 antagonists are competitive inhibitors of s 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 H<SUB>2</SUB>-ANTAGONISTS Indications H2-antagonists are clinically used in the treatment of acid-related 2005. Adelaide: Australian Medicines Handbook. ISBN 0-9578521-9-3
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. Some studies also suggest that H2-antagonists might be effective in treating Herpes Virus es, such as Shingles and Herpes Simplex {Link without Title} . Adverse drug reactions H2 antagonists are generally well-tolerated, except for , tiredness, dizziness, confusion, Diarrhoea , constipation, and rash. Additionally, cimetidine may also cause Gynecomastia in males, loss of libido, and Impotence , which are reversible upon discontinuation. Drug interactions With regard to , Theophylline , Phenytoin , Lidocaine , Quinidine , Propranolol , Labetalol , Metoprolol , Tricyclic Antidepressants , some Benzodiazepines , dihydropyridine Calcium Channel Blocker s, 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.
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