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Gastrointestinal drugs

Gastrointestinal drugs. Department of Pharmacology Tang Huifang ( 汤慧芳) Email: tanghuifang@zju.edu.cn. Content. Part 1. Drugs used for peptic ulcers Part 2. Modulators of gastroenteric functions. Part 1. Drugs used for peptic ulcers. Peptic ulcers and treatment. Pathogenesis of

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Gastrointestinal drugs

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  1. Gastrointestinal drugs Department of Pharmacology Tang Huifang (汤慧芳) Email: tanghuifang@zju.edu.cn

  2. Content • Part 1. Drugs used for peptic ulcers • Part 2. Modulators of gastroenteric functions

  3. Part 1. Drugs used for peptic ulcers Peptic ulcers and treatment • Pathogenesis of • peptic ulcers • Infection with Hp; • Increased gastric acid secretion; • Inadequate mucosal defense to gastric acid. • Treatment • approaches • Eradicating Hp; • Neutralizing gastric acid, or reducing secretion of the acid; • Protectingthegastric mucosa from damage.

  4. I. Antacids: neutralizing the acid II. Drugs suppressing gastric acid secretion ①Muscarinic receptor antagonists ②H2 receptor antagonists ③Gastrin receptor antagonists ④H+-K+-ATPase inhibitors (proton pump inhibitors) III. Antimicrobial drugs (Helicobacter pylori) IV. Mucosal protective drugs Drugs used for peptic ulcers Classifiction of anti-ulcer drugs

  5. Ⅰ. Antacids(抗酸药) Basic substances that can reduce gastric acidity by neutralizing HCl; Drugs most in use: Aluminium hydroxide(氢氧化铝), Magnesium hydroxide(氢氧化镁), Magnesium trisilicate(三硅酸镁), Magnesium oxide(氧化镁), etc. Composition resparation,such as: Tab aluminium hydroxide compound(复方氢氧化铝片, 胃舒平), etc. Drugs used for peptic ulcers

  6. Drugs used for peptic ulcers (1) Antacids 1. Pharmacological effect Neutralizing gastric acid, diminish gastric acidity and inactivate pepsin（胃蛋白酶）activity 2. Clinical uses Used for peptic ulcer and acid-hypersecretory conditions.

  7. Drugs used for peptic ulcers 3. Adverse effects (1) Constipation and stomach cramp (salt of aluminum) (2) Diarrhea (salt of magnesium) (3) Hypercalcium which can cause renal failure (Calcium) (4) Hypernatremia (sodium-containing antacids) 4. Drug interactions Avoid concurrent administration of antacids and a variety of drugs . (1) Affect rates of dissolution and absorption, bioavailbility, and renal elimination of many drugs (2) By binding to drugs (for example, tetracycline四环素), form insoluble complexes that are not absorbed

  8. Drugs used for peptic ulcers Adminstration and dosage (1) Take antacids 1 h and 3 h after meals Seven times a day after meals and at bedtime. (2) Should not be taken continuously for more than 3 m for ulcer (3) To help avoid or reduce drug interaction, other medication should not be taken within 1-2 hours of taking an antacids

  9. Ⅱ. Drugs inhibiting gastric acid secretion Drugs used for peptic ulcers ①Muscarinic receptor antagonists ②H2 receptor antagonists ③Gastrin receptor antagonists ④H+-K+-ATPase inhibitors (proton pump inhibitors)

  10. atropine misoprostol atropine Sucralfate carbonoxolone

  11. Drugs most in use: Atropine(阿托品) Propantheline bromide(溴丙胺太林) Pirenzepine(哌仑西平) Telenzepine(替仑西平) A. Muscarinic receptor antagonists (M receptor blocker):

  12. Non-selective M receptor blocker: Block M1, M2, M3, M4, and M5 receptors. Block M3 receptor in Parietal cells( 壁细胞) Block M1 receptor in ganglion Block M receptors in ECL and G cells. Drugs used for peptic ulcers Atropine(阿托品)

  13. Drugs used for peptic ulcers Pirenzepine(哌仑西平) Selective M receptor blocker: Only block M1 and M2-receptors.

  14. misoprostol Sucralfate carbonoxolone

  15. Drugs used for peptic ulcers 1. Pharmacological effects high affinity for M1- and low affinity for M2-receptors of the smooth muscle of the ileum and urinary bladder. blocking of M1-muscarinic receptors in autonomicganglia,inhibitingthesecretion of HCl. 2. Clinical uses:peptic ulcers 3. Adverse effects Atropine-like effects, at larger doses. Telenzepine(替仑西平)

  16. Drugs used for peptic ulcers B. H2 receptor antagonists: (西咪替丁) (雷尼替丁)

  17. misoprostol Sucralfate carbonoxolone

  18. Drugs used for peptic ulcers Cimetidine(西咪替丁) 1. Pharmacological effects Blocking H2 receptors, decreasing H+ secretion 2. Clinical uses (1) Duodenal and gastric ulcer: —— relieving symptoms, promoting healing of ulcers, and preventing ulcers. (2) Zollinger-Ellison syndrome (3) Reflux esophagitis; (4) Acute stress ulcers, etc.

  19. Drugs used for peptic ulcers 3. Adverse effects (1)Side effects:constipation, diarhoea, tiredness, muscular pain, etc. (2)CNS effects:headache, dizziness, hal-lucination, etc. (elderly, long-term uses) (3)Endocretion effects:antiandrogen, gynecomastia(男性乳房发育), galactorrh-ea(溢乳), reduced sperm count, and male sexual dysfunction 4. Drug interactions Inhibiting hepatic P450:raising plasma concentrations ofwarfarin, phenytoin, diazepam, propranolol, quinidine and theophylline, etc.

  20. Drugs used for peptic ulcers

  21. Drugs used for peptic ulcers 5. Elimination Urinary excretion is the principal route of elimination of cimetidine, the dose should be modified in patients with renal impairment.

  22. Drugs used for peptic ulcers Other H2 receptor antagonists: Ranitidine(雷尼替丁) Similar to cimetidine, but 5～10 times more potent, longer acting; Minimal side effects, no antiandrogenic and prolactin-stimulating effects, less inhibiting P450. Famotidine(法莫替丁) Similar to ranitidine, but 4～8 times more potent. Nizatidine(尼扎替丁) The potent is similar to ranitidine. Bioavailability is near 100%, principally eliminated by kidney

  23. Drugs used for peptic ulcers 4 种H2-受体阻断药的比较 西咪替丁2 1400mg, bid 1 雷尼替丁2-35-10150mg, bid 0.1 法莫替丁2.5-4 4020mg, bid 0 尼扎替丁 2 5-10150mg, bid 0 对肝药 酶抑制 相对抑 酸活力 药 名 剂　量 t1/2(h)

  24. Drugs used for peptic ulcers C. H+-K+-ATPase inhibitors (proton pump inhibitors) Omeprazole(奥美拉唑)

  25. Drugs used for peptic ulcers Omepranzole × (the proton pump)

  26. Drugs used for peptic ulcers 质子泵的分子构型

  27. 1. Pharmacological effects (1)Inhibiting gastric acid secretion by various stimuli(such as: histamine, gastrin, aspirin, ethanol, stress, etc.) (2)Inhibiting Hp. (3) protection for gastric mucosa 2. Clinical uses (1)Highly effective for duodenal and gas-tric ulcer:relieving symptoms, and promoting healing of ulcers Used with antimicrobial agents to eradicate Hp. (2)Reflux esophagitis; (3)Zollinger-Ellison syndrome Drugs used for peptic ulcers

  28. 3. Adverse effects (1)Side effects: Less,such as: nausea, headache, diarrhoea, constipation and rash occur. (2)Increase of gastric carcinoid tumor (3)Others: hypersensitivity, gynecomastia(男性乳房发育) 4.Drug interactions Inhibiting hepatic P450,raising plasma concentrations ofwarfarin, phenytoin, diazepam,etc. Drugs used for peptic ulcers

  29. Others Lansoprazole(兰索拉唑) Pantoprazole(泮他拉唑) Rebeprazole(雷贝拉唑) Drugs used for peptic ulcers

  30. Metabolism of the five proton pump inhibitors. The darker arrows indicate the pathways that contribute more. Silvia Marelli & Fabio Pace (2012) Rabeprazole for the treatment of acidrelated disorders, Expert Review of Gastroenterology & Hepatology, 6:4, 423-435

  31. Comparison of the mean values for area under the plasma concentration–time curve after one oral dose of omeprazole, rabeprazole, lansoprazole and pantoprazole in extensive metabolizers versus poor metabolizers. AUC: Area under the curve. Silvia Marelli & Fabio Pace (2012) Rabeprazole for the treatment of acidrelated disorders, Expert Review of Gastroenterology & Hepatology, 6:4, 423-435

  32. Relative potencies of the five proton pump inhibitors based on a meta‑analysis of 57 studies measuring the mean 24-h gastric pH. Silvia Marelli & Fabio Pace (2012) Rabeprazole for the treatment of acidrelated disorders, Expert Review of Gastroenterology & Hepatology, 6:4, 423-435

  33. Rebeprazole(雷贝拉唑) Silvia Marelli & Fabio Pace (2012) Rabeprazole for the treatment of acidrelated disorders, Expert Review of Gastroenterology & Hepatology, 6:4, 423-435

  34. Rabeprazole is a more rapid and potent inhibitor of the gastric pump than other proton pump inhibitors. Clinical studies of rabeprazole show rapid onset of action, with faster symptom relief, even on the first day of therapy. Rabeprazole is safe and well tolerated, and due to its peculiar metabolism, reduced risks of drug–drug interactions are expected. In long-term maintenance therapy, rabeprazole is suitable for on-demand modality. Rabeprazole has shown clinical advantages in some subsets of gastroesophageal reflux disease patients, that is, polymedicated and overweight/obese subjects. Key issues

  35. t1/2有效抑酸 剂量 对肝药 (h)时间(h)(mg/d) 酶影响 奥美拉唑1.012～2420～40 + 兰索拉唑1.52430 潘托拉唑1.32420～40 雷贝拉唑 1.02420 Drugs used for peptic ulcers 几种质子泵抑制剂的比较 药　名

  36. D 胃泌素受体阻断药: 丙谷胺(Proglumide) 本品可与胃泌素竞争受体而抑制胃酸分泌; 也能促进黏液合成, 增强胃黏膜的黏液-HCO3-盐屏障, 从而发挥抗溃疡病的作用. 本品口服吸收迅速, 生物利用度为60%～74%, 达峰时间为2h.

  37. Twenty-four-hour intragastric acidity and plasma gastrin concentration before and during treatment with eitherranitidine or omeprazole Aliment Pharmacol Ther 1987;1:239

  38. Ⅲ. Mucosal protective drugs Misoprostol(米索前列醇) Enprostil 恩前列素 Sucralfate 硫糖铝 Colloidal bismuth subcitrate(CBS, 胶体次枸橼酸铋) Teprenone(替普瑞酮) Marzulene(麦滋林) Smectite(思密达) Drugs used for peptic ulcers

  39. misoprostol Sucralfate Bismuch, etc.

  40. Drugs used for peptic ulcers Misoprostol米索前列醇 A prostaglandin E analogues

  41. Drugs used for peptic ulcers Misoprostol米索前列醇 1. Pharmacological effects Inhibiting gastric acid secretion Promoting mucus and HCO3- secretion, and mucosal repair 2. Clinical uses Only approved for the prevention of NSAIDs-induced gastric Ulcer. 3. Adverse effects Side effects (13%):abdominal pain, diarrhea, nausea, headache, etc. Contraindicated in pregnancy women (Abortifacient 堕胎 property)

  42. Drugs used for peptic ulcers Sucralfate A sulfated disaccharide（二糖） complex of aluminum hydroxide

  43. Drugs used for peptic ulcers Sucralfate 1. Pharmacological effects 1) Binding to mucosal surface and forms a protective barrier 2) Enhancing cell restitution and re-epithelization. 3) Weakly inhibiting H.Pylory growth. 4) Promote PGE2 production 5) Binding to pepsin and then reduce its activity 2. Clinical uses and Adminstration peptic ulcers, but with the advent of more effective agents (proton pump inhibitors); reflux esophagitis; mucosa impairment. Take sucralfate 1 hour before meals Four times a day before meals and at bedtime 3. Adverse effects Constipation occurs in 2% due to the aluminum salt, not together with alkaline agents

  44. Drugs used for peptic ulcers Bismuth Compounds Colloidal bismuth subcitrate (CBS, 胶体次枸橼酸铋) Bismuth subslicylate 1. Pharmacological effects 1) Probably coats ulcers and erosions, creating a protective layer against acid and pepsin 2) Inhibit pepsin activity, stimulate prostaglandin, mucus, and bicarbonate secretion 3) Have direct antimicrobial activity against H pylori

  45. Drugs used for peptic ulcers Bismuth Compounds 2. Clinical uses 1) Treatment of dyspepsia, peptic ulcer, chronic gastritis. 2) Used in multidrug regimens for the eradication of H pylori infection. 3. Adverse effects Causes blackening of the stool, which may be confused with gastrointestinal bleeding Bismuth toxicity resulting in encephalopathy (ataxia, headaches, confusion, seizures).

  46. Drugs used for peptic ulcers Smectite(蒙脱石) Bind to the glycoprotein in the mucus to increase its coverage ability, enhancing cell restitution, antimicrobial activity against H pylori. 2) Use for acute or chronic diarrhea and ulcer.

  47. Drugs used for peptic ulcers Ⅳ. Antimicrobial(anti-Hp) drugs 1. Anti-ulcer drugs: H+-K+-ATPase inhibitors; bismuch(铋剂); sulralfate(硫糖铝), etc. Weaker, combined with antimicrobial drugs. 2. Antimicrobial drugs: Metronidazole(甲硝唑); Amoxicillin(阿莫西林); Tetracycline(四环素); Gentamicin (庆大霉素); Clarithromycin(克拉霉素), etc.

  48. misoprostol Sucralfate Bismuch, etc.

  49. --第四次全国幽门螺杆菌感染处理共识报告（2012年）--第四次全国幽门螺杆菌感染处理共识报告（2012年） 我国HP感染率总体上仍然很高，成人感染率在 40-60%。 推荐用于根除治疗的6种抗菌药物中，甲硝唑耐药率已达到60%-70%，克拉霉素达20%--38%，左氧氟沙星达到30%--38%，耐药显著影响根除率。 羟氨苄青霉素、呋喃唑酮和四环素的耐药率仍很低（1%-5%） 。 因此标准三联疗法（PPI+克拉霉素+羟氨苄) 或（PPI+克拉霉素+甲硝唑）根除率已低于或远低于80%。 共识： 推荐四联： PPI+铋剂+2种抗菌药物 抗菌药物组成： 羟氨苄青霉素+克拉霉素 羟氨苄青霉素+左氧氟沙星 羟氨苄青霉素+呋喃唑酮 四环素+甲哨唑或呋喃唑酮 新进展 HP根除治疗方案的变化

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