H2 antagonist

H2拮抗薬、H2遮断薬

関

H2 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

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

Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2014/05/12 07:46:06」(JST)

wiki en

[Wiki en表示]

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

The H₂ receptor antagonists (H2RA) are a class of drugs used to block the action of histamine on parietal cells (specifically the histamine H2 receptors) 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.

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.

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 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 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.

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.

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. H2 antagonists, as well as other antacid preparations that function by suppressing acid mediated break down of proteins, lead to an elevated risk of developing food and drug allergies. This happens due to undigested proteins then passing into the gastrointestinal tract. It is unclear whether this risk occurs with only long-term use or with short-term use as well. In addition, cimetidine may also cause gynecomastia in males, loss of libido, and impotence, which are reversible upon discontinuation.

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 (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, methadone, metoprolol, tricyclic antidepressants, some benzodiazepines, dihydropyridine calcium channel blockers, sulfonylureas, metronidazole, and some recreational drugs such as ethanol (drinking alcohol) 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
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English Journal

• Molecular hydrogen inhibits lipopolysaccharide-triggered NLRP3 inflammasome activation in macrophages by targeting the mitochondrial reactive oxygen species.

• Ren JD1, Wu XB2, Jiang R3, Hao DP4, Liu Y5.
• Biochimica et biophysica acta.Biochim Biophys Acta.2016 Jan;1863(1):50-5. doi: 10.1016/j.bbamcr.2015.10.012. Epub 2015 Oct 18.
• The NLRP3 inflammasome, an intracellular multi-protein complex controlling the maturation of cytokine interleukin-1β, plays an important role in lipopolysaccharide (LPS)-induced inflammatory cascades. Recently, the production of mitochondrial reactive oxygen species (mtROS) in macrophages stimulate
• PMID 26488087

• Electrochemistry of Simple Organometallic Models of Iron-Iron Hydrogenases in Organic Solvent and Water.

• Gloaguen F1.
• Inorganic chemistry.Inorg Chem.2015 Dec 7. [Epub ahead of print]
• Synthetic models of the active site of iron-iron hydrogenases are currently the subjects of numerous studies aimed at developing H2-production catalysts based on cheap and abundant materials. In this context, the present report offers an electrochemist's view of the catalysis of proton reduction by
• PMID 26641526

• Toward More GI-Friendly Anti-Inflammatory Medications.

• Wallace JL1,2,3, de Nucci G4, Sulaieva O5.
• Current treatment options in gastroenterology.Curr Treat Options Gastroenterol.2015 Dec;13(4):377-85. doi: 10.1007/s11938-015-0064-9.
• OPINION STATEMENT: Despite the introduction 20-30 years ago of potent inhibitors of gastric acid secretion and anti-inflammatory drugs that preferentially inhibit cyclo-oxygenase (COX)-2, the GI adverse effects of nonsteroidal anti-inflammatory drugs (NSAIDs) remain a significant clinical concern a
• PMID 26303996

Japanese Journal

• 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
• NAID 40019022613

• 潰瘍治療の変遷と内視鏡

• 丹羽 寛文
• 日本消化器内視鏡学会雑誌 = Gastroenterological endoscopy 53(9), 2963-2987, 2011-09-20
• … 相次いで種々な抗コリン薬が登場した．その結果抗コリン薬と制酸薬の合剤が広く使われ，さらに種々な防御因子増強薬が登場したが，その意義は明らかでなく今では全く意味を失った．その後近年になってH2受容体拮抗薬，ついでPPIが出現し，潰瘍の診療も診断に基づき的確に行われる様になった．しかし再発の問題が未解決であった．その後除菌療法が登場し再発の問題も片付いたと思われたが，新たに除菌後の …
• NAID 10029837183

Related Links

• H2 antagonist - Wikipedia, the free encyclopedia

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 ...

• H2-receptor antagonists - H2 Blockers - Heartburn - About.com

H2 blockers, also called H2 receptor antagonists, are medicines used to treat gastroesophageal reflux disease (GERD.)

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拮抗薬」
拡張検索	「histamine H2 antagonist」
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拮抗薬」

　　[★]

英

H2 antagonist H2-antagonist、H2 blocker

関

H2受容体拮抗薬、H2遮断薬、H2ブロッカー、ヒスタミンH2受容体遮断薬

「histamine H2 antagonist」

　　[★]

• ヒスタミンH2受容体遮断薬、ヒスタミンH2拮抗薬、ヒスタミンH2遮断薬

関

H2 blocker、histamine H2 receptor antagonist

「H」

　　[★]

• 食道裂孔
• ヒスチジン
• 水素