View source for H2 antagonist

[[Image:Cimetidine structure.svg|thumb|[[Cimetidine]], the prototypical H<sub>2</sub>-receptor antagonist.]]
{{SI}}
{{CMG}}



An '''H<sub>2</sub>-receptor antagonist''', (H<sub>2</sub>RA) shortened to '''H<sub>2</sub> antagonist''', is a classification of [[medication|drugs]] 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 antagonist|H<sub>1</sub>-antihistamines]], the H<sub>2</sub> antagonists are [[inverse agonist]]s rather than true [[receptor antagonist]]s.

==History and development==

[[Cimetidine]] was the prototypical [[histamine]] H<sub>2</sub>-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]] [[receptor antagonist|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 [[H1 antagonist|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 H<sub>1</sub>, and the one acted on by [[histamine]] to stimulate the secretion of stomach acid H<sub>2</sub>.

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 H<sub>2</sub> receptor. Hundreds of modified compounds were synthesized in an effort to develop a model of the receptor. The first breakthrough was ''N<sup>&alpha;</sup>''-guanylhistamine, a partial H<sub>2</sub>-receptor antagonist. From this lead the receptor model was further refined and eventually led to the development of [[burimamide]] - the first H<sub>2</sub>-receptor antagonist. [[Burimamide]], a specific [[competitive antagonist]] at the H<sub>2</sub> receptor 100-times more potent than ''N<sup>&alpha;</sup>''-guanylhistamine, proved the existence of the H<sub>2</sub> 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 utilizing the by-then-fairly-refined model of the histamine H<sub>2</sub> 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 H<sub>2</sub>-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 H<sub>2</sub> antagonists are competitive inhibitors of [[histamine]] at the [[parietal cell]] H<sub>2</sub> 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 cell]]s in the stomach is blocked from binding on parietal cell H<sub>2</sub> 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 H<sub>2</sub> receptors are blocked.

==Clinical use of H<sub>2</sub>-antagonists==
===Indications===
H<sub>2</sub>-Antagonists are clinically used in the treatment of acid-related [[Gastrointestinal]] conditions. Specifically, these indications may include:<ref name="Rossi">Rossi S (Ed.) (2005). [[Australian Medicines Handbook]] 2005. Adelaide: Australian Medicines Handbook. ISBN 0-9578521-9-3</ref>
*[[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 H<sub>2</sub>-receptor antagonists for treatment. H<sub>2</sub>-antagonists offer several advantages over antacids including longer duration of action (6&ndash;10 hours vs 1&ndash;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 H<sub>2</sub>-antagonists.

Some studies also suggest that H<sub>2</sub>-antagonists might be effective in treating [[herpes virus]]es, such as [[shingles]] and [[herpes simplex]] [http://www.lef.org/magazine/mag2001/mar2001_report_tagamet_1.html].

===Adverse drug reactions===
H<sub>2</sub> antagonists are generally well-tolerated, except for [[cimetidine]] where all of the following [[adverse drug reaction]]s (ADRs) are ''common''. Infrequent ADRs include [[hypotension]]. Rare ADRs include: [[headache]], [[tiredness]], [[dizziness]], [[confusion]], [[diarrhoea]], [[constipation]], and rash.<ref name="Rossi"> </ref>  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 [[blood plasma|serum]] [[concentration]]s to [[toxic]] levels.  

Examples of drugs affected include: [[warfarin]], [[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]].

The more recently developed H2-receptor antagonists, such as [[famotidine]], are much less likely to alter CYP metabolism.<ref>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</ref><!-- source only mentions famotidine, so I supplied it as an example -->

==Examples==

[[Cimetidine]] was the prototypical member of the H<sub>2</sub> 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==
<references/>

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

{{Major Drug Groups}}
{{H2-receptor antagonist}}
{{Receptor agonists and antagonists}}


[[Category:Antihistamines| ]]
[[Category:H2 receptor antagonists| ]]

[[fr:Antihistaminique H2]]
[[ja:ヒスタミンH2受容体拮抗薬]]
[[pl:Antagoniści receptora H₂]]
[[pt:Antihistaminico H2]]
[[th:เอช2 รีเซพเตอร์แอนตาโกนิสต์]]
[[tr:H₂-reseptör antagonisti]]

{{jb1}}
{{WH}}
{{WikiDoc Sources}}