H2 receptor antagonist

H2受容体遮断薬、H2受容体拮抗薬

関

H2 blocker、H2 receptor blocker

WordNet

1. a drug that neutralizes or counteracts the effects of another drug
2. a muscle that relaxes while another contracts; "when bending the elbow the triceps are the antagonist"
3. the 8th letter of the Roman alphabet (同)h
4. a cellular structure that is postulated to exist in order to mediate between a chemical agent that acts on nervous tissue and the physiological response

PrepTutorEJDIC

1. 対立する人,敵対者,競争相手(opponent)
2. hydrogenの化学記号
3. 鉛筆の硬度 / 《俗》heroin
4. =sense organ / 受信装置

Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2012/03/15 10:40:05」(JST)

wiki en

[Wiki en表示]

Ball-and-stick model of cimetidine, the prototypical H₂-receptor antagonist.

The H₂ receptor antagonists are a class of drugs used to block the action of histamine on parietal cells 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. In the United States, all four FDA-approved members of the group—cimetidine, ranitidine, famotidine, and nizatidine—are available over the counter in relatively low doses.

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^{[citation needed]}.

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 N^α-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 N^α-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 pKa 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.

Pharmacology

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.

Like the H₁-antihistamines, the H₂ antagonists are inverse agonists rather than true receptor antagonists.^{[citation needed]}

Clinical use

H₂-antagonists are used by clinicians in the treatment of acid-related Gastrointestinal conditions. To be specific, these indications may include:

• Peptic ulcer disease (PUD)
• Gastroesophageal reflux disease (GERD/GORD)
• Dyspepsia
• Prevention of stress ulcer (a specific indication of ranitidine)

People that 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.

Histamine H2 receptor blockers may have therapeutic benefits for CHF by blocking the action of histamine in the heart.

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.

Adverse effects

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. In addition, cimetidine may also cause gynecomastia in males, loss of libido, and impotence, which are reversible upon discontinuation.^{[citation needed]}

In a longitudinal study of elderly African Americans published in 2007, long-term use of H₂ blockers appeared to increase the risk of cognitive decline.

Drug interactions

Skeletal formula of famotidine. Unlike cimetidine, famotidine has no significant interactions with other drugs.

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. To be specific, 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. 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 ethyl alcohol and methylenedioxymethamphetamine.

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.

See also

• Antihistamine

References

UpToDate Contents

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• 1. Antiulcer medications: Mechanism of action, pharmacology, and side effects
• 2. 成人における胃食道逆流症の内科的マネージメント medical management of gastroesophageal reflux disease in adults
• 3. 小児および思春期における胃食道逆流症のマネージメント management of gastroesophageal reflux disease in children and adolescents
• 4. 成人における難治性胃食道逆流症へのアプローチ approach to refractory gastroesophageal reflux disease in adults
• 5. 成人における選択的脊椎手術のための麻酔 anesthesia for elective spine surgery in adults

English Journal

• Efficacy of leukotriene receptor antagonist with anti-H1 receptor antagonist plus anti-H2 receptor antagonist for treatment of refractory chronic idiopathic urticaria.

• Wan KS1, Chang YS.Author information 1Department of Pediatrics, Taipei City Hospital , Renai Branch , Taiwan and.AbstractBACKGROUND: The efficacy of the combination of leukotriene receptor antagonist (LRA) and H1 antihistamine was similar to the synergistic regimen of H1 and H2 antihistamine for treatment of chronic idiopathic urticaria (CIU). However, the effective rates of these two regimens were only 53.3% and 63.3%, respectively.
• The Journal of dermatological treatment.J Dermatolog Treat.2014 Dec;25(6):459-61. doi: 10.3109/09546634.2013.849791. Epub 2013 Nov 5.
• BACKGROUND: The efficacy of the combination of leukotriene receptor antagonist (LRA) and H1 antihistamine was similar to the synergistic regimen of H1 and H2 antihistamine for treatment of chronic idiopathic urticaria (CIU). However, the effective rates of these two regimens were only 53.3% and 63.3
• PMID 24192062

• The inhibitory effect of simvastatin and aspirin on histamine responsiveness in human vascular endothelial cells.

• Absi M1, Bruce JI, Ward DT.Author information 1Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom; and.AbstractStatins and aspirin deliver well-established cardiovascular benefits resulting in their increased use as combined polypills to decrease risk of stroke and heart disease. However, the direct endothelial effect of combined statin/aspirin cotreatment remains unclear. Histamine is an inflammatory mediator that increases vascular permeability, and so we examined the effect of treating human umbilical vein endothelial cells (HUVECs) for 24 h with 1 μM simvastatin and 100 μM aspirin on histamine responsiveness. Subsequent histamine (1 μM) challenge increased intracellular calcium (Ca(2+)i) concentration, an effect that was significantly inhibited by combined simvastatin/aspirin pretreatment but not when then the compounds were given separately, even at 10-fold higher concentrations. In contrast, the Ca(2+)i mobilization response to ATP challenge (10 μM) was not inhibited by combined simvastatin/aspirin pretreatment. The H1 receptor antagonist pyrilamine significantly inhibited both histamine-induced Ca(2+)i mobilization and extracellular signal-regulated kinase (ERK) activation, whereas ranitidine (H2 receptor antagonist) was without effect. However, combined simvastatin/aspirin pretreatment failed to decrease H1 receptor protein expression ruling out receptor downregulation as the mechanism of action. Histamine-induced ERK activation was also inhibited by atorvastatin pretreatment, while simvastatin further inhibited histamine-induced vascular endothelial cadherin phosphorylation as well as altered HUVEC morphology and inhibited actin polymerization. Therefore, in addition to the known therapeutic benefits of statins and aspirin, here we provide initial cellular evidence that combined statin/aspirin treatment inhibits histamine responsiveness in HUVECs.
• American journal of physiology. Cell physiology.Am J Physiol Cell Physiol.2014 Apr;306(7):C679-86. doi: 10.1152/ajpcell.00304.2013. Epub 2014 Jan 29.
• Statins and aspirin deliver well-established cardiovascular benefits resulting in their increased use as combined polypills to decrease risk of stroke and heart disease. However, the direct endothelial effect of combined statin/aspirin cotreatment remains unclear. Histamine is an inflammatory mediat
• PMID 24477236

• Nonsteroidal anti-inflammatory drugs, gastroprotection, and benefit-risk.

• Moore RA1, Derry S, Simon LS, Emery P.Author information 1Pain Research and Nuffield Division of Anaesthetics, University of Oxford, Oxford, U.K.AbstractBACKGROUND: Gastroprotective agents (GPA) substantially reduce morbidity and mortality with long-term nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin.
• Pain practice : the official journal of World Institute of Pain.Pain Pract.2014 Apr;14(4):378-95. doi: 10.1111/papr.12100. Epub 2013 Aug 14.
• BACKGROUND: Gastroprotective agents (GPA) substantially reduce morbidity and mortality with long-term nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin.OBJECTIVE: To evaluate efficacy of NSAIDs, protection against NSAID-induced gastrointestinal harm, and balance of benefit and risk.METHODS:
• PMID 23941628

Japanese Journal

• Roles of Histamine in Exercise-Induced Fatigue: Favouring Endurance and Protecting against Exhaustion

• Niijima-Yaoita Fukie,Tsuchiya Masahiro,Ohtsu Hiroshi,Yanai Kazuhiko,Sugawara Shunji,Endo Yasuo,Tadano Takeshi
• Biological and Pharmaceutical Bulletin 35(1), 91-97, 2012
• … Mice given a histamine H1-receptor antagonist [fexofenadine (peripherally acting) or pyrilamine (peripherally and centrally acting)] or an irreversible HDC inhibitor (α-fluoromethylhistidine) displayed less PW endurance than control mice. … Ranitidine (H2-receptor antagonist) tended to reduce endurance. … Other histamine-receptor (H3 and H4) antagonists had no significant effects on endurance. …
• NAID 130001872348

• The Antioxidant Effect of Carnosol in Bovine Aortic Endothelial Cells Is Mainly Mediated via Estrogen Receptor α Pathway

• ZHAO Pi-wen,Yue-wei LEE David,MA Zhong-ze,HUANG Lian-sha,SUN Li-ping,LI Ya-dong,CHEN Jia-xu,NIU Jian-zhao
• Biological and Pharmaceutical Bulletin 35(11), 1947-1955, 2012
• … Antioxidant action is critical for maintaining the normal cardiovascular function and vascular endothelial cell is an important target of estrogen action through estrogen receptor (ER) pathway. … The results indicate that carnosol can effectively attenuate H2O2 induced slowing down of cell growth and increasing of cell apoptosis. … At the meantime, carnosol pretreating can also effectively reduce the H2O2 induced intracellular ROS elevation in BAECs. …
• NAID 130001872253

• H2ブロッカーlafutidineによる薬剤誘発性せん妄--癌術後の3症例 (特集 症状性を含む器質性精神障害の症例)

• 上田 諭,肥田 道彦,大久保 善朗
• 臨床精神医学 40(10), 1359-1363, 2011-10-00
• NAID 40019022613

Related Links

• H2 receptor antagonist - definition of H2 receptor antagonist ...

antagonist [an-tag´o-nist] antagonistic muscle. (see illustration.) 1. a substance that tends to nullify the action of another, as a drug that binds to a cellular receptor for a hormone, neurotransmitter, or another drug blocking the action ...

• H2 receptor antagonist - definition of H2 receptor antagonist ...

Meaning of H2 receptor antagonist. Pronunciation of H2 receptor antagonist. Translations of H2 receptor antagonist. H2 receptor antagonist synonyms, H2 receptor antagonist antonyms. Information about H2 receptor antagonist in ...

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★リンクテーブル★

リンク元	「H2受容体拮抗薬」「H2 receptor blocker」
拡張検索	「H2 receptor antagonists」
関連記事	「H」

「H2受容体拮抗薬」

　　[★]

英

H2 blocker H2-blockers

同

H2受容体ブロッカー H2 receptor blocker、H2受容体拮抗薬 H2 receptor antagonist H2RA、ヒスタミンH2受容体遮断薬 ヒスタミンH2受容体拮抗薬 histamine H2-receptor antagonists histamine H2 receptor antagonist histamine H2 antagonist、H2拮抗薬 H2 antagonist H2-antagonist、H2遮断薬、H2ブロッカー

関

抗ヒスタミン薬

[show details]

H2受容体拮抗薬 : 約 249,000 件
H2受容体遮断薬 : 約 24,400 件

GOO.chapter36 p.971

• 消化性潰瘍治療薬
• 命名法は" -tidine"
• 特徴

十二指腸潰瘍の治癒率を向上する (⇔プロトンポンプ阻害薬)

H2受容体拮抗薬

• シメチジン cimetidine
• ラニチジン ranitidine
• ファモチジン famotidine　ガスター
• ニザチジン nizatidine
• ロキサチジン roxitidine
• ラフチジン lafutidine　プロテカジン 防御因子増強作用を有する。肝代謝なので腎機能障害があっても使用可能

構造

• イミダゾール環をもち、ヒスタミンに似る

作用機序

• H1受容体にはほとんど作用しない
• H2受容体に可逆的、競合的に結合してヒスタミンを阻害する。
• 胃粘膜の局所の肥満細胞、ECL細胞

• histamine→H2R→Csα→AC→cAMP↑→PKA→H+,K+-ATPase
• histamine→H2R→[Ca2+]i↑→H+,K+-ATPase　　　←補助的pathway

• H2RとMRとGRは相互作用しており、胃酸を分泌する。

注意

• 副作用5%↓
• 薬剤耐性
• リバウンド

• 中止すると再発率が高い。そのため半年かけて漸減させゆっくり離脱

胃粘膜が減弱している

• 薬物相互作用

副作用

• 副作用5%↓
• 汎血球減少症、無顆粒球症
• 肝障害、抗アンドロゲン作用(女性化乳房、乳汁分泌)
• 中止すると再発率が高い。そのため半年かけて漸減させゆっくり離脱

胃粘膜が減弱しているから

相互作用

• シメチジン：CYP2D6, CYP3A4阻害作用。 CYPs(CYP1A2,CYP2C9,CYP2D6)の阻害 (GOO.972)
• ラニチジン：CYPs。しかし、シメチジンの10%程度
• ファモチジン、ニザチジン：なし

「H2 receptor blocker」

　　[★]

H2受容体遮断薬

関

H2 receptor antagonist

「H2 receptor antagonists」

　　[★]

関

Histamine 2

同

histamine-2

「H」

　　[★]

• 食道裂孔
• ヒスチジン
• 水素