Gastrointestinal drugs

1. Gastrointestinal drugs 张世红 shzhang713@zju.edu.cn

2. Digestive diseases 1.Hepatic, pancreatic and biliary disorders 2.Acid-peptic disorders 3.Gastrointesinal motility disorders 4.Inflammatory bowel diseases

3. （痔疮） （便秘） （肠易激综合征） （胃炎） （消化不良） （胆石症） （消化性溃疡） （疝气）

4. Gastrointestinal drugs 1. Drugs used for acid-peptic disorders 2. Modulators of gastrointestinal functions

5. 1) Peptic ulcer disease (PUD) 1. Acid-peptic disorders 2) Gastroesophageal reflux disease (GERD) 3) Pathologic acid-hypersecretory conditions (e.g. Zollinger-Ellison syndrome) 4) Drug-induced mucosal injury, especially by non-steroidal anti-inflammatory drugs (NSAIDs) 5) Acute stress ulcers

6. Peptic ulcer disease Symptoms: Upper abdominal burning or hunger pain Emesia (呕吐), belching (嗳气) Ulcer complication Ulcer bleeding (出血) Ulcer perforation (穿孔) Pyloristenosis (幽门狭窄) Canceration (癌变)

7. Mucosa Submucosa Muscle

9. Gastroesophageal reflux disease (GERD)

10. Pathologic acid-hypersecretory conditions (e.g. Zollinger-Ellison syndrome) Tumor Gastrin Gastric acid Peptic ulcer

11. 2. Pathogenesis of peptic ulcers Defensive factors Aggressive factors Mucus Gastric acid Bicarbonate Pepsin （胃蛋白酶） Mucosa Helicobacter pylori （幽门螺旋杆菌）

12. Mucus-bicarbonate barrier

13. Gastric acid secretion and regulation (the proton pump)

14. Helicobacter pylori infection

15. Marshall BJ Warren JR The Nobel prize in 2005: for their discovery of the bacterium Helicobacter pylori and its role in gastritis and peptic ulcer disease

16. Treatment approaches Pathogenesis of peptic ulcers (1) Reducing secretion of gastric acid or neutralizing the acid (1) Increased gastric acid secretion (2) Infection with Helicobacter pylori (2) Eradicating根除H. pylori infection (3) Inadequate mucosal defense against gastric acid (3) Protecting the gastric mucosa from damage

17. 4. Drugs used for peptic ulcers (1) Antacids: neutralize中和 the acid (2) Drugs suppressing gastric acid secretion ① H2 receptor antagonists ② H+-K+-ATPase inhibitors (proton pump inhibitors) ③ Muscarinic receptor antagonists ④ Gastrin receptor antagonists (3) Mucosal protective drugs (4) Antimicrobial drugs (Helicobacter pylori)

18. Antacids (weak bases) Chemistry of antacids: Aluminum salts (aluminum hydroxide) Magnesium salts (carbonate, hydroxide or oxide) Calcium salts (carbonate) Sodium salts (bicarbonate)

19. Antacids (weak bases) 1. Pharmacological effects - Neutralize gastric acid, diminishing gastric acidity and inactivating pepsin（胃蛋白酶） - Form a protective membrane on the gastric mucosa - Depend on the dose and dosing frequency. - Effect starting within 5-15 min, lasting 1-3 h. 2. Clinical uses Commonly used for minor episodes of heartburn.

20. Antacids (weak bases) 3. Adverse effects (1) Constipation and stomach cramp (Al/Ca salts ) (2) Diarrhea(Mg salts) (3) Hypercalcium (calcium salts) (4) Hypernatremia (sodium salts) 4. Drug interactions Affect rates of dissolution and absorption, bioavailability, and renal elimination of many drugs

21. NOTICE (1) Take antacids 1 hour after meals Four times a day after meals and at bedtime. (2) Should not be taken continuously for more than 2 weeks (3) To help avoid or reduce drug interaction, other medication should be taken 1-2 hours after taking an antacid

22. Proton pump inhibitors Antacids × × Drugs suppressing gastric acid secretion M receptor antagonists × × H2 receptor antagonists × Gastrin receptor antagonists

23. H2 receptor antagonists Cimetidine 西咪替丁，甲腈咪胍

24. Cimetidine 1. Pharmacological effect Blocks H2 receptors, decreases H+ and pepsin secretion, promots ulcer healing. 2. Clinical uses 1) Duodenal and gastric ulcer （high rate of relapse） 2) Zollinger-Ellison syndrome 3) Acute stress ulcers 4) Gastroesophageal reflux disease (heartburn) 5) Decreased immune function

25. Cimetidine 3. Adverse effects (1) common side effects: constipation, diarrhea, tiredness, muscular pain, etc. (2) CNS effects: headache, dizziness, confusion, hallucination, etc. (elderly, long-term uses) (3) Antiandrogen（抗雄激素）effects 4. Drug interactions Inhibits hepatic P450, raises plasma concentrations of warfarin, phenytoin, diazepam, propranolol, quinidine and theophylline, etc.

26. Other H2 receptor antagonists Ranitidine (雷尼替丁) 4～10 times more potent than cimetidine; Minimal side effects, weakly inhibits CYP Famotidine (法莫替丁) 40-50 times more potent than cimetidine; no inhibition of CYP Nizatidine(尼扎替丁) High bioavailability (near 100%)

27. H+-K+-ATPase inhibitors Omeprazole 奥美拉唑，洛赛克

28. Omeprazole 1. Pharmacological effects (1) Inhibits gastric acid secretion induced by various stimuli (histamine, gastrin, aspirin, ethanol, stress) (2) Inhibits H. pylori 2. Clinical uses (1) Highly effective for duodenal and gastric ulcer, reflux esophagitis: relieves symptoms,promots healing of ulcers (2) Used with antimicrobial regimens to eradicate H. pylori

29. Omeprazole 3. Adverse effects (1) Side effects: nausea, headache, diarrhea, constipation and rash (rare) (2) Increase of gastric carcinoid tumor: prolongated hypochlorhydria 胃酸过少症and secondary hypergastrinemia 高胃泌素症(only found in animal experiments) (3) Others: gynecomastia (男性乳房发育),hypersensitivity 4. Drug interactions Inhibits hepatic P450, raises plasma concentrations of warfarin, phenytoin, diazepam, etc.

30. Others proton pump inhibitors

31. M receptor antagonists Pirenzepine哌仑西平

32. Mucosal protective drugs Effects:Protect the gastric and duodenal mucosa from damage by acid and pepsin Misoprostol 米索前列醇 Sucralfate 硫糖铝 Colloidal bismuth subcitrate胶体次枸橼酸铋

33. Mucosal protective drugs Misoprostol米索前列醇 A prostaglandin E analogues

34. Misoprostol米索前列醇 1. Pharmacological effects Inhibits gastric acid secretion Promots mucus and HCO3- secretion, mucosal repair 2. Clinical uses Approved for the prevention of NSAIDs-induced gastric ulcer. 3. Adverse effects Side effects (13%): abdominal pain, diarrhea, headache, nausea,etc. Contraindicated in pregnancy women: Abortifacient (堕胎) effect

35. Mucosal protective drugs Sucralfate (硫糖铝) A sulfated disaccharide（硫酸蔗糖） complex of aluminum hydroxide

36. Sucralfate 1. Pharmacological effects 1) Binds to tissue proteins and forms a protective barrier 2) Enhances cell restitution修复 and re-epithelization重上皮化 3) Weakly inhibits H.Pylory growth. 2. Clinical uses and adminstration Peptic ulcers 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

37. Mucosal protective drugs Bismuth Compounds 铋制剂 Colloidal bismuth subcitrate (CBS, 胶体次枸橼酸铋) Bismuth subsalicylate次水杨酸铋 1. Pharmacological effects 1) Probably coats ulcers and erosions, creating a protective layer against acid and pepsin 2) Stimulates prostaglandin, mucus, and bicarbonate secretion 3) Kills H. pylori

38. Bismuth Compounds 2. Clinical uses 1) Nonspecific treatment of peptic ulcers, dyspepsia and acute diarrhea. 2) Used in multidrug regimens for the eradication of H pylori infection. 3. Adverse effects Causes blackening of the stool Bismuth toxicity resulting in encephalopathy (脑病，ataxia, headaches, confusion, seizures)- used for short period and contraindicated in patients with renal insufficiency.

39. Other mucosal protective drugs Teprenone （替普瑞酮） Marzulene-S （麦滋林-S） Smectite （蒙脱石，思密达）

40. Antimicrobial drugs (for Helicobacter pylori) 1. Anti-ulcer drugs H+-K+-ATPase inhibitors; bismuch; sulralfate Weaker, combined with antimicrobial drugs 2. Antibiotics metronidazole (甲硝唑); amoxicillin (阿莫西林); tetracycline (四环素); gentamicin (庆大霉素); clarithromycin (克拉霉素)

41. The best treatment regimen consists of a 10-14 day regimen of "triple therapy": Program 1 1) A proton pump inhibitor twice daily, 2) Clarithromycin 500 mg twice daily, 3) Amoxicillin 1 g twice daily. For patients who are allergic to penicillin, metronidazole 500 mg twice daily should be substituted for amoxicillin. Program 2 1) Bismuth subsalicylate (2 tablets; 262 mg each), 2) Tetracycline (500 mg), 3) Metronidazole (250 mg), each taken four times daily for 14 days.

42. For patients with resistant infections, "quadruple therapy” • A proton pump inhibitor twice daily • 2) Bismuth subsalicylate (2 tablets; 262 mg each), • 3) Tetracycline (500 mg), • 4) Metronidazole (250 mg), each taken four times daily for 14 days.

43. Gastrointestinal drugs 1. Drugs used for acid-peptic disorders 2. Modulators of gastrointestinal functions

44. Abnormalities ofgastrointestinal functions Nausea and vomiting Diarrhea Constipation

45. Modulators of gastrointestinal functions 1. Digestants （助消化药） 2. Antiemetics （止吐药） 3. Prokinetic drugs (胃肠动力药) 4. Anti-diarrheals （止泻药） 5. Laxatives （泻药）

46. Modulators ofgastrointestinal functions Digestants（助消化药） • Pepsin（胃蛋白酶） • Pancreatin （胰酶）： • Lactasin（乳酶生）：乳酸杆菌制剂 • Carnitine（肉碱，卡尼丁）

47. Modulators ofgastrointestinal functions Antiemetic drugs H1 receptor antagonists: diphenhydramine 苯海拉明; dimenhydrinate 茶苯海明; meclozine 美克洛嗪 Muscarinic receptor antagonists: scopolamine东莨菪碱 D2 receptor antagonists: chlorpromazine氯丙嗪 5-HT3 receptor antagonists：ondansetron昂丹司琼; grasetron格拉司琼; tropisetron托烷司琼

48. Prokinetic drugs (Central or peripheral) NANC neuron ( - ) Metoclopramide 甲氧氯普胺 Postganglionic primary motor neuron GI tract smooth muscle cells

49. Metoclopramide 甲氧氯普胺 Mechanism of action • A 5-HT4 receptor agonist and 5-HT3 receptor antagonist, enhances coordinated transmission in cholinergic nerve plexus • A D2 receptor antagonist • Clinical uses • Used for treatment of diabetic gastroparesis (胃瘫) • Used for the prevention of nausea and vomiting associated with cancer chemotherapy or occurring post-operatively.

50. Metoclopramide 甲氧氯普胺 Adverse effects 1) Fatigue, dizziness, faintness 2) Various extrapyramidal syndromes锥体外系综合征: Parkinsonism帕金森症 (reversible) tardive dyskinesia迟发性运动障碍 (irreversible) 3) Increased serum prolactin催乳素 levels (chronic uses)