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Drugs Affecting the Gastrointestinal System

Drugs Affecting the Gastrointestinal System. By Caiying Ye Department of Pharmacology, School of Basic Medicine, Peking Union Medical College. Drugs Affecting the Gastrointestinal System. 分类 Antiulcerants 消化性溃疡药 Digestives 助消化药 Antiemetics 止吐药 Purgatives 泻药 Antidiarrheals 止泻药

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Drugs Affecting the Gastrointestinal System

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  1. Drugs Affecting the Gastrointestinal System By Caiying Ye Department of Pharmacology, School of Basic Medicine, Peking Union Medical College

  2. Drugs Affecting the Gastrointestinal System 分类 • Antiulcerants 消化性溃疡药 • Digestives 助消化药 • Antiemetics 止吐药 • Purgatives 泻药 • Antidiarrheals 止泻药 • Cholagogues 利胆药

  3. Peptic Ulcers • 常见病，发病率约10%~12%. • Pathogenesis of ulcers Aggressive FactorsDefensive Factors • Mucus,bicarbonate layer • Blood flow,cell renewal • Prostaglandins • Phospholipid • Free radical scavengers • Acid,pepsin • Bile salts • Drugs (NSAIDs) • H.pylori

  4. Peptic Ulcers • 溃疡胃酸分泌过多胃、十二指肠粘膜侵蚀，胃蛋白酶和幽门螺旋杆菌升高 消化性溃疡 治疗目的： • Therapy is directed at enhancing host defense or eliminating aggressive factors; i.e., H. pylori.

  5. Drugs Used in Peptic Ulcers • Antacids • Inhibitors of gastric acid production H2-receptor antagonists Proton pump inhibitors Muscarinic antagonists Gastrin receptor antagonist • Mucosal Protectants • Anti-Helicobacter pylori. drugs

  6. Drugs Used in Peptic Ulcers 代表药物 • Antacids 抗酸药：aluminum hydroxide（氢氧化铝）、magnesium hydroxide（ 氢氧化镁）等 • H2- receptor antagonists H2 -受体阻断药：cimetidine（西咪替丁）、ranitidine（雷尼替丁）等 • Muscarinic antagonists M-胆碱受体阻断药：atropine （阿托品）等

  7. Drugs Used in Peptic Ulcers 代表药物 • Proton pump inhibitors 胃壁细胞H+泵抑制剂：omeprazole（奥美拉唑） • Gastrin receptor antagonist 胃泌素阻断药：proglumide（丙谷胺） • Mucosal Protectants胃粘膜保护药：Prostaglandin Analog(前列腺素衍生物 ) misoprostol（米索前列醇） • Anti-Helicobacter pylori. Drugs抗幽门螺杆菌药：antibiotics

  8. General characteristics Antacids are weak bases that are taken orally and that partially neutralize gastric acid and reduce pepsin activity. Antacids reduce the pain associated with ulcers and may promote healing. High doses are required for healing: 40 mEq of base seven times daily. 抗酸药Antacids

  9. 抗酸药 Antacids • 氢氧化镁magnesium hydroxide ① 抗酸作用强，较快，镁离子有导泻作用，与氢氧化铝合用，相互纠正副作用。 ② 小分子Mg2+可被吸收 肾排泄肾功能不良的病人 血清中Mg2+上升。 • 三硅酸镁magnesium trisilicate： 起效缓慢，作用持久，在胃内生成胶状二氧化硅，对溃疡具有保护作用。

  10. 抗酸药 Antacids • 氢氧化铝aluminum hydroxide: 抗酸作用强，缓慢，持久，中和胃酸，具有收敛、止血和引起便秘作用。长时间应用影响磷酸吸收。禁止与四环素、地高辛、异烟肼、强的松等合用。 • 碳酸钙calcium carbonate： 抗酸作用强，快而持久，产生CO2气体，进入小肠，促进胃泌素分泌，反跳性胃酸分泌增加。 • 碳酸氢钠sodium bicarbonate（小苏打）： 作用强，快而短暂，产生CO2，碱血症。

  11. H2-receptor antagonists Mechanism of action • Competitively block the histamine (H2) receptor of acid-producing parietal cells rendering cells less responsive to not only histamine but also to the stimulation of acetylcholine and gastrin. • Also up to 90% inhibition of vagal stimulated and gastrin stimulated acid secretion. complete inhibition has not been shown

  12. H2-receptor antagonists Four FDA-approved: Cimetidine西咪替丁 （Tagamet®） Ranitidine雷尼替丁 （Zantac®） Famotidine法莫替丁（Pepcid®） Nizatidine尼扎替丁 （Axid®） Roxatidine罗沙替丁

  13. H2-receptor antagonists Therapeutic effects: • Promote the healing of gastric and duodenal ulcers (胃和十二指肠溃疡) • Gastroesophageal reflux dz [GERD] (反流性食道炎) • Upper GI bleed [GIB] (上消化道出血) • May be effective in stress ulcers (应激性溃疡) & peptic esophagitis (消化性食道炎)

  14. H2-receptor antagonists Side effect: • Overall low < 3% • CNS: < 1% total headache, lethargy 乏力，confusion, depression 抑郁，hallucinations 幻觉 • ENDO： Impotence 阳痿，increased prolactin 催泌乳素，gynecomastia • HEME: Thrombocytopenia 血小板减少

  15. Muscarinic antagonists Atropine： • Block the M1 class receptors • reduce acid production • abolish gastrointestinal spasm relatively unpopular as a first choice because of high incidence of anticholinergic side effects (dry mouth and blurred vision)

  16. Proton pump inhibitors • H+,K+-ATPase (Proton Pump) inhibitor • Irreversible inhibition Must synthesize new enzyme Long duration Omeprazole奥美拉唑 (Prilosec®) Lansoprazole兰索拉唑 (Prevacid®) Pantoprazole泮托拉唑 Rabeprazole雷贝拉唑

  17. Mechanism of Action

  18. 奥美拉唑 Omeprazole又称洛赛克（losec）第一代质子泵抑制剂 • Irreversibly binds to H+/K+ ATPase • Prevents H+ ion production & secrection • Block all acid secretion = achlorhydria (胃酸缺乏) to return to normal must synthesize new H+/K+ ATPase • Inhibit H. pylori

  19. Therapeutic uses • Gastroesophageal reflux dz [GERD] (反流性食道炎),有效率达75~85％。 • Peptic ulcer（消化性溃疡）,服用1~6月，溃疡愈合率达97％，其它类药物无效用4周，愈合率达90％。 • Infection with H. pylori plus(Hp) (幽门螺杆菌感染),幽门螺旋杆菌83%~88％转阴。 • Upper GI bleed [GIB] (上消化道出血)

  20. Side effects • 1~2％头痛、头晕、口干、恶心、腹胀、失眠，偶见皮疹，男性乳头女性化 • 长期服用，胃内细菌过度生长。

  21. 兰索拉唑 Lansoprazole • Lansoprazole是第二代质子泵抑制药。 • 抑制胃酸分泌、升高血胃泌素、胃粘膜保护作用及抗幽门螺杆菌作用 • 抑制胃酸分泌作用及抗幽门螺杆菌作用较omeprazole强。

  22. 潘多拉唑 Pantoprazole • 与雷贝拉唑（rabeprazole）属第三代质子泵抑制药。 • 抗溃疡病作用与奥美拉唑相似， • Rabeprazole在抗胃酸分泌能力和缓解症状、治愈粘膜损害的临床效果方面远优于其他抗酸药物。

  23. Gastrin receptor antagonist 丙谷胺（proglumide） • 竞争性与胃泌素受体结合.减少胃酸分泌. • 对胃粘膜有保护作用和促进溃疡愈合； • 用于胃溃疡、十二指肠溃疡、胃炎、急性上消化道出血

  24. 丙谷胺（proglumide） 【Side effects】 • 恶心、腹痛等胃肠道症状。 • 神经系统反应:头痛、头晕、失眠、外周神经炎。 • 偶见皮疹、白细胞减少、血清转氨酶和胆红素升高等。

  25. Mucosal Protective Agents • 增强胃粘膜屏障功能的药物 细胞屏障 胃粘膜屏障 粘液－HCO3- 盐屏障 胃粘膜屏障作用 抵抗和防止胃酸和胃蛋白酶的侵蚀作用

  26. 米索前列醇（misoprostol） • A congener of prostaglandin E1 • PG’s: • inhibit gastric acid secretion • exhibit ‘cytoprotective’ activity • enhance local production of mucus or bicarbonate • promote local cell regeneration • help to maintain mucosal blood flow

  27. 米索前列醇（misoprostol） • Misoprostol is approved for use in patients taking NASIDs who are at risk for gastric ulcers • Misoprostol produces diarrhea and stimulation of uterine contraction.

  28. 硫糖铝 sucralfate • 与溃疡面的亲和力是正常粘膜的6倍，形成保护屏障； • 促进胃和十二指肠粘膜合成PFE2； • 增强表皮生长因子、碱性成纤维细胞生长因子作用，使之聚集于溃疡区，促进溃疡愈合；

  29. Sucralfate 硫糖铝 • cytoprotective agent • stress ulcerations & PUD • inhibit H. pylori • Bismuth 胶体次枸橼酸铋（Pepto-Bismol®） • inhibit pepsin activity • inhibit H. pylori

  30. Agents Used in infection of Helicobacter Pylori • 幽门螺杆菌（helicobacter pylori，HP）为革兰阴性厌氧菌， • 在胃十二指肠的粘液层与粘膜细胞之间生长，可产生多种酶及细胞毒素，使粘膜损伤。 • 是慢性胃炎、消化性溃疡和胃腺癌等胃部疾患发生发展中的一个重要致病因子。

  31. Agents Used in infection of Helicobacter Pylori Aimed at eliminating H. pylori Bismuth胶体次枸橼酸铋( Pepto-Bismol®) Gentamicin庆大霉素 Amotriptyline阿莫替林 (Amoxil ® ) Clarithromycin 克拉霉素 Tetracycline四环素 (Achromycin V ®) Metronidazole甲硝唑 (Flagyl ® )

  32. FDA-Approved Treatment Regimens for H.pylori Infection • Omeprazole 20mg b.i.d + Clarithromycin 500mg b.i.d + Amoxicillin 1g b.i.d for 10 days • Lansoprazole 30mg b.i.d + Clarithromycin 500mg b.i.d + Amoxicillin 1g b.i.d for 10 days • Bismuth subsalicylate 525mg q.i.d + Metronidazole 250mg q.i.d + Tetracycline 500mg q.i.d × 14 days + H2 receptor antagonist × 4 wks

  33. Digestives 助消化药 胃蛋白酶pepsin • 牛、猪、羊等胃粘膜提取； • 临床消化功能减弱； • 对胃癌、恶心贫血可改善消化不良 胰酶pancreatin • 动物牛、猪、羊胰腺提取物； • 能消化蛋白质、淀粉、脂肪； • 临床用于胰腺炎、胰腺纤维化、消化障碍。

  34. Digestives 助消化药 乳酶生lactasin • 乳酸杆菌干燥物，可分解糖类，产生乳酸，提高肠内酸性，抑制腐败细菌生长、繁殖及防止蛋白质发酵，减少肠内产气，促进消化和止泻作用。 • 临床应用：消化不良、腹胀、小儿消化不良性 酵母 • 酵母菌：含多种B族维生素，B1、B2、B6、B12、叶酸等。 • 临床应用：食欲不振、消化不良。

  35. Antiemetic Drugs • Vomiting reflex a coordinated reflex controlled by a bilateral vomiting center in the dorsal portion of the lateral reticular formation in the medulla • Pharmacologic intervention relies on inhibition of inputs or depression of the vomiting center.

  36. Antiemetic Drugs • Histamine1-receptor antagonist (H1受体阻断药) • Cholinergic antagonist (M 受体阻断药) • Dopamine antagonists (多巴胺受体阻断药) • 5-HT3 antagonists (5-HT3受体拮抗药) • Cannabinoids (大麻酚)

  37. Dopamine Receptor Antagonists • 甲氧氯普胺 Metoclopramide (灭吐灵、胃复安) [Pharmacological effect] CNS：作用于中枢化学感受区( CTZ), 阻 断D2受体,高剂量阻断5-HT3受体;胃肠道：促进运动，增加贲门括约肌张力 松弛幽门，加速胃排空和肠内容物运动。为前动药。

  38. 甲氧氯普胺 Metoclopramide [Therapeutic uses] • 慢性消化不良引起的恶心、呕吐。 • 预防各种原因引起的呕吐(包括妊娠)。 • 常用于肿瘤放疗)等引起的呕吐。 [Side effects] 锥体外系症状(大剂量或长期应用)，疲劳、精神抑郁。偶见溢乳，男性乳房发育。

  39. Domperidone多潘立酮, 吗丁啉（motilium） • A domamine (D2)-receptor antagonist (periphery) • A weaker antiemetic, but it has fewer extrapyramidal effects. • Accelerates gastric emptying; has little effect on the colon

  40. Thanks!

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