H 2 antagonists , sometimes referred to as H2RA and also called H 2 block >, is a class of drugs that block the action of histamine in the histamine H 2 parietal cell receptor in the stomach. This lowers the production of stomach acid. The antagonist H 2 may be used in the treatment of dyspepsia, peptic ulcer and gastroesophageal reflux disease. They have been exceeded by proton pump inhibitors (PPIs); PPI omeprazole was found to be more effective at healing and reducing the symptoms of ulcer and reflux esophagitis compared with H 2 ranitidine blockers and cimetidine.
The antagonist H 2 is a type of antihistamine, although in general use the term "antihistamine" is often reserved for H 1 antagonists, alleviating allergic reactions. Like the H 1 antagonists, some H 2 antagonists serve as inverse agonists rather than receptor antagonists, due to the constitutive activity of these receptors.
The prototype H 2 antagonist, called cimetidine, was developed by Sir James Black at Smith, Kline & amp; France (now GlaxoSmithKline) in the mid to late 1960s. It was first marketed in 1976 and sold under the trade name Tagamet, which became the first blockbuster drug. The use of quantitative activity-structure relations (QSAR) leads to the development of other agents - starting with ranitidine, first sold as Zantac, which has fewer side effects and drug interactions and is stronger.
Video H2 antagonist
class members
- cimetidine
- ranitidine
- famotidine
- nizatidine
Maps H2 antagonist
History and development
Cimetidine is a histamine H 2 histamine receptor antagonist from which the drug is then developed. Cimetidine is the culmination of the project at Smith, Kline & amp; France (SK & F, now GlaxoSmithKline) by James W. Black, C. Robin Ganellin, and others to develop a histamine receptor antagonist that will suppress gastric acid secretion.
In 1964, it was known that histamine stimulates gastric acid secretion, and also that traditional antihistamines have no effect on acid production. From these facts SK & amp; F postulates the existence of two different types of histamine receptors. They determined that follow-up by traditional antihistamines as H 1 , and which was followed up by histamine to stimulate gastric acid secretion as H 2 .
SK & amp; F uses classic design processes ranging from histamine structures. Hundreds of modified compounds were synthesized in an attempt to develop an unknown H 2 receptor model. The first breakthrough was N ? -guanylhistamine, partial receptor antagonist H 2 . From this lead, the receptor model is further refined, leading ultimately to the development of burimamide, a specific competitive antagonist of H 2 receptors. Burimamide 100 times stronger than N ? -guanylhistamine, proving its efficacy at H 2 receptors.
The potential for burimamide is still too low for oral administration. And further improvement efforts of the structure, based on modification of the structure in the stomach due to the dissociation constant of the compound acid, led to the development of methachine. Methacide is an effective agent; However, it is 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 be the first clinically successful H 2 antagonist.
Ranitidine (common brand name Zantac) was developed by Glaxo (also now GlaxoSmithKline), in an effort to match Smith's success, Kline & amp; France with cimetidine. Ranitidine is also the result of a rational drug design process using histamine prescription models H 2 histamine H and quantitative activity-structure relations (QSAR).
Glaxo refined the model further by replacing the cimetidine-imidazole ring with a furan-ring with a nitrogen-containing substituent, and in developing ranitidine. Ranitidine was found to have a much better tolerability profile (ie fewer adverse drug reactions), longer action, and ten cimetidine activity.
Ranitidine was introduced in 1981 and was the best-selling prescription drug in the world in 1988. The receptor antagonist H 2 has since been replaced by a more effective proton pump inhibitor, with omeprazole being the largest - selling drugs for years -year.
Pharmacology
The antagonist H 2 is a histamine competitive antagonist on the p <
Clinical use
H 2 -antagonis is used by physicians in the treatment of gastrointestinal conditions associated with acids, including:
- Peptic ulcer disease (PUD)
- Gastroesophageal reflux disease (GERD/GORD)
- Dispepsia
- Prevention of stress ulcer (a specific indication of ranitidine)
People who suffer from ulcer disease can rarely use an antacid or H2 receptor antagonist for treatment. The H 2 -antagonists offer several advantages over antacids, including longer duration of action (6-10 hours vs 1-2 hours for antacids), greater efficacy, and the ability to be used for prophylaxis before meals to reduce the likelihood of heartburn. Proton pump inhibitors, however, are the preferred treatment for erosive esophagitis as they have been shown to promote better healing than H 2 -antagonis.
Adverse effects
Antagonists H 2 , in general, are well tolerated, except for cimetidine, where all of the following adverse drug reactions (ADRs) are common . Rarely are ADRs including hypotension. Rare ADR includes: headache, fatigue, dizziness, confusion, diarrhea, constipation, and rash. In addition, gynecomastia occurs in 0.1% to 0.5% of men treated for noncretecretory conditions with cimetidine for 1 month or more and in about 2% of men treated for pathologic hypersecretory conditions; even in fewer men, cimetidine can also cause loss of libido, and impotence, all of which are reversible after discontinuation.
A 31-study study found that overall risk of pneumonia was about 1 in 4 higher among users of H 2 antagonists.
Drug interactions
With regard to pharmacokinetics, cimetidine specifically interferes with some metabolic mechanisms and drug elimination through the cytochrome P450 (CYP) liver pathway. To be more specific, cimetidine is an inhibitor of the P450 enzyme CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4. By reducing drug metabolism through these enzymes, cimetidine may increase their serum concentrations to toxic levels. Many drugs are affected, including warfarin, theophylline, phenytoin, lidocaine, quinidine, propranolol, labetalol, metoprolol, methadone, tricyclic antidepressants, some benzodiazepines, dihydropyridine calcium channel blockers, sulfonylureas, metronidazole and some recreational drugs such as ethanol and methylenedioxymethamphetamine (MDMA). ).
Newer developing H 2 receptor antagonists tend not to change CYP metabolism. Ranitidine is not as powerful as CYP inhibitors such as cimetidine, although it still has some of the last interactions (such as warfarin, theophylline, phenytoin, metoprolol, and midazolam). Famotidine has a negligible effect on the CYP system, and does not seem to have any significant interactions.
References
Source of the article : Wikipedia
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