H2RA

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/03/22 23:05:17」(JST)

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

H₂ antagonists, also called H₂ blockers, are a class of medications that block the action of histamine at the histamine H₂ receptors of the parietal cells in the stomach. This decreases the production of stomach acid. H₂ antagonists can be used in the treatment of dyspepsia, but have been surpassed by the more effective proton pump inhibitors for that indication. They are also used to treat peptic ulcer disease and gastroesophageal reflux disease.

H2 antagonists are a type of antihistamine, although in common use the term "antihistamine" is often reserved for H₁ antagonists. Like the H₁ antagonists, some H₂ antagonists function as inverse agonists rather than receptor antagonists, due to the constitutive activity of these receptors.

The prototypical H₂ antagonist, called cimetidine, was developed by Sir James Black at Smith, Kline & French (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 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.

Class members

This list may not be exhaustive.

• cimetidine
• ranitidine
• famotidine
• nizatidine

History and development

Cimetidine was the prototypical histamine H₂-receptor antagonist from which later drugs 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, and also that traditional antihistamines had no effect on acid production. From these facts the SK&F scientists postulated the existence of two different types of histamine receptors. They designated the one acted upon by the traditional antihistamines as H₁, and the one acted upon by histamine to stimulate the secretion of stomach acid as 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, which eventually led to the development of burimamide, a specific competitive antagonist at the H₂ receptor. Burimamide is 100 times more potent than N^α-guanylhistamine, proving its efficacy on the H₂ receptor.

The potency of burimamide was still too low for oral administration. And efforts on further improvement of the structure, based on the structure modification in the stomach due to the acid dissociation constant 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's 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.

Clinical use

H₂-antagonists are used by clinicians in the treatment of acid-related gastrointestinal conditions, including:

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

People who 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.

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, gynecomastia occurred in 0.1% to .5% of men treated for nonhypersecretory conditions with cimetidine for 1 month or longer and in about 2% of men treated for pathologic hypersecretory conditions; in even fewer men, cimetidine may also cause loss of libido, and impotence, all of which are reversible upon discontinuation.

A 31-study review found that overall risk of pneumonia is about 1 in 4 higher among H₂ antagonist users.

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 (CYP) pathway. To be specific, cimetidine is an inhibitor of the P450 enzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, 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, metoprolol, methadone, tricyclic antidepressants, some benzodiazepines, dihydropyridine calcium channel blockers, sulfonylureas, metronidazole, and some recreational drugs such as ethanol and methylenedioxymethamphetamine (MDMA).

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. 抗潰瘍剤の薬理学 pharmacology of antiulcer medications
• 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. 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
• 4. 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
• 5. Eosinophil biology and causes of eosinophilia

English Journal

• Evidence-based clinical practice guidelines for functional dyspepsia.

• Miwa H1, Kusano M, Arisawa T, Oshima T, Kato M, Joh T, Suzuki H, Tominaga K, Nakada K, Nagahara A, Futagami S, Manabe N, Inui A, Haruma K, Higuchi K, Yakabi K, Hongo M, Uemura N, Kinoshita Y, Sugano K, Shimosegawa T.
• Journal of gastroenterology.J Gastroenterol.2015 Jan 14. [Epub ahead of print]
• General interest in functional gastrointestinal disorders is increasing among Japanese doctors as well as patients. This increase can be attributed to a number of factors, including recent increased interest in quality of life and advances in our understanding of the pathophysiology of gastrointesti
• PMID 25586651

• Proton pump inhibitors and histamine 2 blockers are associated with improved overall survival in patients with head and neck squamous carcinoma.

• Papagerakis S1, Bellile E2, Peterson LA3, Pliakas M3, Balaskas K3, Selman S3, Hanauer D4, Taylor JM5, Duffy S6, Wolf G3.
• Cancer prevention research (Philadelphia, Pa.).Cancer Prev Res (Phila).2014 Dec;7(12):1258-69. doi: 10.1158/1940-6207.CAPR-14-0002.
• It has been postulated that gastroesophageal reflux plays a role in the etiology of head and neck squamous cell carcinomas (HNSCC) and contributes to complications after surgery or during radiotherapy. Antacid medications are commonly used in patients with HNSCC for the management of acid reflux; ho
• PMID 25468899

• Comparison of teprenone and famotidine against gastroduodenal mucosal damage in patients taking low-dose aspirin.

• Takeuchi T1, Ota K, Harada S, Kojima Y, Inoue T, Iwakiri R, Sakata Y, Fujimoto K, Fujita T, Azuma T, Higuchi K.
• Journal of gastroenterology and hepatology.J Gastroenterol Hepatol.2014 Dec;29 Suppl 4:11-5. doi: 10.1111/jgh.12768.
• BACKGROUND AND AIM: Proton-pump inhibitors are known to be effective in the treatment and prevention of ulcers related to low-dose aspirin (LDA), but few reports address H2 -receptor antagonists (H2RAs) and gastroprotective agents (GPs). This study was intended to compare the therapeutic effects of
• PMID 25521726

Japanese Journal

• 難治性GERDの治療戦略 (特集 難治性GERDの治療戦略)

• 関野 雄典,稲盛 正彦
• 消化器内科 52(4), 377-381, 2011-04
• NAID 40018857364

• 低用量アスピリンによる消化管障害に対する酸分泌阻害薬の抑制効果に関する検討

• 中村 浩規,横山 晴子,矢口 武廣,鈴木 優司,徳岡 健太郎,渡邊 昌之,北川 泰久,山田 安彦
• YAKUGAKU ZASSHI 131(3), 445-452, 2011
• …   In this study, we investigated the effect of histamin H2 receptor antagonist (H2RA) or proton pump inhibitor (PPI) for the prevention of upper gastrointestinal lesions associated with low-dose aspirin. … We classified them into three groups: aspirin alone group (n=1103), aspirin with H2RA group (n=844) and aspirin with PPI group (n=864). … The incidence in aspirin alone group, aspirin with H2RA group and aspirin with PPI group was 2.54%, 1.54% and 1.04%, respectively; …
• NAID 130000678910

Related Links

• PPIとH2RAの使い分け - Welcome to Our Company : HOME

H2受容体拮抗薬 プロトンポンプ阻害薬 作用発現時間 早い （2～3時間） 遅い （6時間～） 作用持続性 数時間 24時間以上 作用の時間帯と強さ 日中＜夜間 日中＞夜間 内視鏡判定治癒率 4週：PPI＞H2RA 8週：PPI≒H2RA 代謝 ...

• H2ブロッカーによる胃酸分泌抑制作用は胃の生理機能を妨げない ...

このサイトは医療関係者向けです。 ... H 2 RA による胃酸分泌抑制メカニズム ガストリンは強力な胃酸分泌刺激物質だが、ヒスタミンを介してその作用を発揮するため、H 2 RA は強力な胃酸分泌抑制作用を持つ。

Related Pictures

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★リンクテーブル★

リンク元	「H2受容体拮抗薬」

「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