1. Gastrointestinal drugs Weiwei HU E-mail:huww@zju.edu.cn Phone: 0571-88208228

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

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

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

5. 1)

6. The feature of peptic ulcer disease: High incidence, Recurrence frequently, Drug treatment is the main way 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. 2) Gastroesophageal reflux disease (GERD) Abnormal reflux in the esophagus

8. 4) Pathologic acid-hypersecretory conditions (e.g. Zollinger-Ellison syndrome) Tumor Gastrin Gastic acid Peptic ulcer

9. 2. Gastric acid secretion and regulation Gastric cells of mucosa (1)Surface epithelial cells (secrete mucus) (2)Mucus neck cells (secret mucus and are the source of proliferating cells); (3)Chief cells (secret pepsinogens) (4)G cells (release gastrin in the antrum); (5)Parietal cells in the gastric fundus ( secrete HCI and intrinsic factor)

10. 2. Gastric acid secretion and regulation Basolateral membane (the proton pump)

11. Mucus-bicarbonate barrier

12. Helicobacter pylori infection

13. Gastric acid Pepsin Helicobacter pylori Mucus bicarbonate Mucosa 2.Pathogenesis of peptic ulcers Aggressive factors Defensive factors

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

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

16. §(1) Antacids (Weak bases) Chemistry of antacids: Salts of aluminum (aluminum hydroxide), Salts of magnesium (carbonate, hydroxide, trisilicate), aluminum magnesium carbonate ( Al 2 Mg 6 (OH)16CO 3 ·4H 2 O ) calcium(carbonate) sodium (bicarbonate)

17. §(1) Antacids × Antacids Mechamism of action (the proton pump)

18. (1) Antacids 1. Pharmacological effect Neutralizing gastric acid, diminish gastric acidity and inactivate pepsin （胃蛋白酶） activity Neutralizing gastric acid, diminish gastric acidity and inactivate pepsin （胃蛋白酶） activity 2. Clinical uses U sed for peptic ulcer and acid-hypersecretory conditions. U sed for peptic ulcer and acid-hypersecretory conditions.

19. 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. 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

20. 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

21. Cimetidine (2) Drugs affecting gastric acid secretion ② H 2 receptor antagonists

22. (Proton pump) × cimetidine Mechamism of action

23. 1. Pharmacological effect Blocking H 2 receptors, decreasing H + secretion Blocking H 2 receptors, decreasing H + secretion 2. Clinical uses 1) Duodenal and gastric ulcer 1) Duodenal and gastric ulcer 2) Zollinger-Ellison syndrome, 2) Zollinger-Ellison syndrome, 3) Acute stress ulcers 3) Acute stress ulcers 4) Gastroesophageal reflux disease (heartburn) 4) Gastroesophageal reflux disease (heartburn) Cimetidine

24. 3. Adverse effects (1) Common side effects: constipation, diarrhea, tiredness, muscular pain, etc. (1) Common side effects: constipation, diarrhea, tiredness, muscular pain, etc. (2) CNS effects: headache, dizziness, confusion, hallucination, etc. (elderly, long-term uses) (2) CNS effects: headache, dizziness, confusion, hallucination, etc. (elderly, long-term uses) (3) Endocretion effects: antiandrogen （抗雄激素）, gynecomastia, galactorrhea, reduced sperm count, and male sexual dysfunction (3) Endocretion effects: antiandrogen （抗雄激素）, gynecomastia, galactorrhea, reduced sperm count, and male sexual dysfunction 4. Drug interactions Inhibiting hepatic P 450, raising plasma concentrations of warfarin, phenytoin, diazepam, propranolol, quinidine and theophylline Inhibiting hepatic P 450, raising plasma concentrations of warfarin, phenytoin, diazepam, propranolol, quinidine and theophylline Cimetidine

26. 5. Elimination Urinary excretion is the principal route of elimination of cimetidine, the dose should be modified in patients with renal impairment.

27. Other H 2 receptor antagonists Ranitidine 4 ～ 10 times more potent; Duration of action is comparable. 4 ～ 10 times more potent; Duration of action is comparable. Minimal side effects, weakly inhibiting CYP Minimal side effects, weakly inhibiting CYPFamotidine Similar to ranitidine, but no inhibiting CYP Similar to ranitidine, but no inhibiting CYPNizatidine Bioavailability is near 100%, principally eliminated by kidney as primary form Bioavailability is near 100%, principally eliminated by kidney as primary form

28. Omeprazole 奥美拉唑 (2) Drugs affecting gastric acid secretion ③ H + -K + -ATPase inhibitors ③ H + -K + -ATPase inhibitors (proton pump inhibitors) (proton pump inhibitors)

29. Omepranzole × (the proton pump)

30. §1. Pharmacological effects §(1) Inhibiting gastric acid secretion by various stimuli (histamine, gastrin, aspirin, ethanol, stress) §(2) Inhibiting H. pylori §(3) protection for gastric mucosa §2. Clinical uses §(1) Highly effective for duodenal and gastric ulcer (relieving symptoms, promoting healing of ulcers), reflux esophagitis, Zollinger-Ellison syndrome reflux esophagitis, Zollinger-Ellison syndrome §(2) Used with antimicrobial regimens to eradicate H. pylori Omeprazole

31. §3. Adverse effects §(1) Side effects: nausea, headache, diarrhoea, constipation and rash occur but are uncommon §(2) Increase of gastric carcinoid tumor: prolongated hypochlorhydria and secondary hypergastrinemia (only found by animal experiments)  (3) Others: gynecomastia ( 男性乳房发育 ), hypersensitivity §4. Drug interactions §It is metabolized by hepatic P450; §Inhibiting hepatic P450, raising plasma concentrations of warfarin, phenytoin, diazepam, etc. Omeprazole

32. Others proton pump inhibitors

33. §Non-selective: atropine (block M3 receptor in Parietal cells, block M1 receptor in ganglion, block M receptors in ECL and G cells), seldom use now. §Selective: pirenzepine (block M1 receptor) M receptor antagonists

34. (3) Mucosal protective drugs Effects: Protecting the gastric and duodenal mucosa from damage by acid and pepsin Effects: Protecting 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

35. (3) Mucosal protective drugs Misoprostol 米索前列醇 A prostaglandin E analogues

36. Misoprostol 米索前列醇 1. Pharmacological effects Inhibiting gastric acid secretion Promoting mucus and HCO 3 - 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) (Abortifacient 堕胎 property) (3) Mucosal protective drugs

37. Sucralfate A sulfated disaccharide （二糖） complex of aluminum hydroxide

38. 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 (3) Mucosal protective drugs Sucralfate

39. (3) Mucosal protective drugs 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

40. 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). Bismuth Compounds

41. (3) Mucosal protective drugs Smectite 1)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.

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

43. The best treatment regimen consists of a 7–14 day regimen of "triple therapy": 1) Bismuth subsalicylate (2 tablets; 262 mg each), 2) Tetracycline (500 mg), 3) Metronidazole (250 mg), each taken four times daily for 14 days. Program 2 Program 1 1) A proton pump inhibitor twice daily, 2) Clarithromycin 500 mg twice daily, 3) Amoxicillin 1 g twice daily. Daily for 7 d. For patients who are allergic to penicillin, metronidazole 500 mg twice daily should be substituted for amoxicillin.

44. 1)A proton pump inhibitor twice daily 2) Bismuth subsalicylate (2 tablets; 262 mg each), 3) Clarithromycin 500 mg twice daily, 4) Amoxicillin 1 g twice daily for 14 days. For patients with resistant infections, "quadruple therapy”

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

46. Abnormalities of gastrointestinal functions Nausea and vomitingConstipation Diarrhea

47. Modulators of gastrointestinal functions 1. Antiemetic drugs 2. Prokinetic drugs 3. Anti-diarrheals 4. Laxatives

48. Antiemetic drugs There are various sources of input to the vomiting center: 1.The chemoreceptor trigger zone at the base of the fourth ventricle has numerous dopamine D2 receptors, serotonin 5-HT3 receptors, opioid receptors, acetylcholine receptors, and receptors for substance P. Stimulation of different receptors are involved in different pathways leading to emesis, in the final common pathway substance P appears involved. 2.The vestibular system, which sends information to the brain via cranial nerve VIII (vestibulocochlear nerve), plays a major role in motion sickness, and is rich in muscarinic receptors and histamine H1 receptors. 3.The cranial nerve X (vagus nerve) is activated when the pharynx is irritated, leading to a gag reflex. 4.The Vagal and enteric nervous system inputs transmit information regarding the state of the gastrointestinal system. Irritation of the GI mucosa by chemotherapy, radiation, distention, or acute infectious gastroenteritis activates the 5-HT3 receptors of these inputs. 5.The CNS mediates vomiting that arises from psychiatric disorders and stress from higher brain centers.

49. Antiemetic drugs 1.H1 antagonists: sedative effect, antiemetic effect, use for motion sickness and Meniere disease. 2.M receptor antagonists: scopolamine, use for motion sickness. 3.D receptor antagonists: chloropromazine, thiethylperazine （硫乙拉嗪）. 4.5-HT3 receptor antagonists: ondansetron （昂丹司琼）, granisetron （格拉司琼）, tropisetron （托烷司琼）, et al. Use for vomiting induced by chemotherapy for cancer, but not for motion sickness.

50. GI tract smooth muscle cells NANC neuron Cholinergic neuron Post-ganglionic primary motor neuron Prokinetic drugs

51. prokinetic drugs Metoclopramide 甲氧氯普胺 Mechanism of action 1)Block D2 receptor, to stimulate 5-HT 4 receptors and enhance coordinated transmission in cholinergic nerve plexues 2) An dopaminergic neuron antagonist in the central nervous system; at higher doses, 5-HT3 antagonist activity may also contribute to the anti-emetic effect. Clinical uses 1) Used for treatment of diabetic gastroparesis 2) Used for the prevention of nausea and vomiting associated with cancer chemotherapy or occurring post-operatively.

52. Adverse effects 1) Fatigue, dizziness, faintness 2) Various extrapyramidal syndromes caused by its central anti-dopaminergic activity. Parkinsonism (reversible) tardive dyskinesia (irreversible) 3) Increased serum prolactin levels (chronic uses) Metoclopramide

53. Domperidone 多潘立酮 prokinetic drugs Mechanism of action A peripherial dopamine antagonist, has no procholinergic Effects Clinical uses 1) Used for treatment of diabetic gastroparesis gastroesophageal reflux disease 2) Used for the prevention of nausea and vomiting induced by dyspepsia, chemotherapy, gastroesophageal reflux disease. Adverse effects Has few side effects because it can not cross the BBB Has few side effects because it can not cross the BBB Increased serum prolactin levels (6% of patients) Rare cases of prolongation of QT interval.

54. Anti-diarrheals Modulators of gastrointestinal functions Modulators of gastrointestinal functions Diarrhea 1) An increase in the active secretion, or an inhibition of absorption 2) Abnormally high motility

55. Modulators of gastrointestinal functions Modulators of gastrointestinal functions Antimotility drugs 1. Antimotility drugs Astringents 2. Astringents Absorbants 3. Absorbants Anti-diarrheals

56. Antimotility drugs: Mechanisms: Agonists for  receptors in GI tract (1) Opium preparation 阿片制剂 (1) Opium preparation 阿片制剂 (2) Diphenoxylate 地芬诺酯 (2) Diphenoxylate 地芬诺酯 Diphenoxylate dose not cross the blood-brain-barrier as easly as most opioids do and is relatively selective for peripheral opioid receptors. Has CNS effects at larger doses) Anti-diarrheals

57. (3) Loperamide 洛哌丁胺 Anti-diarrheals Antimotility drugs: It is two to three times potent than diphenoxylate, and its action is more rapid in onset and more prolonged. Use for acute or chronic diarrhea but not induced by infection. It has less CNS or cardiovascular effects It has less CNS or cardiovascular effects.

58. Astringents: Mechanism: astriction (1) Tannalbin 鞣酸蛋白 (1) Tannalbin 鞣酸蛋白 (2) Bismuch subsalicylate; bismuch (2) Bismuch subsalicylate; bismuch subcarbonate ( 铋制剂 ) subcarbonate ( 铋制剂 ) Absorbants ： (1) Medical charchol 药用炭（活性炭） (1) Medical charchol 药用炭（活性炭） (2) Agysical 矽炭银 (2) Agysical 矽炭银 Anti-diarrheals

59. Modulators of gastrointestinal functions Constipation Laxatives Treatment 1)Increase the intake of fluids and dietary fiber Regular exercise 2) Laxatives An decrease in the active secretion, or an enhancement of absorption

60. Modulators of gastrointestinal functions Modulators of gastrointestinal functions 2. Laxatives that work osmotically 3. Laxatives that decrease absorption Laxatives 1. Laxatives that increase secretion

61. Laxatives Phenolphthalein 酚酞 Phenolphthalein 酚酞 ( No longer used because of concerns about carcigenicity) ( No longer used because of concerns about carcigenicity) Bisacodyl 必沙可啶 Bisacodyl 必沙可啶 (It is active after deacetylation, stimulating enteric nerves to cause colonic mass movements; increases fluid and NaCl secretion. ) (It is active after deacetylation, stimulating enteric nerves to cause colonic mass movements; increases fluid and NaCl secretion. ) 1. Laxatives that increase secretion

62. Laxatives Anthraquinones 蒽醌类（中药成分） promote colon movements promote colon movements Cascara （鼠李皮） Rhubarb （大黄） Senna （番泻叶）

63. 2. Laxatives that work osmotically 1) Salt laxatives: magnesium sulfate 硫酸镁 ; 1) Salt laxatives: magnesium sulfate 硫酸镁 ; sodium sulfate 硫酸钠； sodium sulfate 硫酸钠； Laxatives These agents contain ions that are only slowly absorbed from the intestine. These ions retain fluid in the bowel lumen and cause a large volume of fluid to enter the colon. magnesium sulfate

64. 2. Laxatives that work osmotically 2) Lactulose 乳果糖 ; 2) Lactulose 乳果糖 ; Laxatives In the small bowel, it is resistant to hydrolysis and has an osmotic effect. In the large intestine, lactulose is acted upon by the endogenous flora with the production of lactic acid, Lactic acid also has an osmotic effect. It is used to reduce ammonia blood levels in the prevention and treatment of hepatic encephalopathy

65. 3. Laxatives that decrease absorption Liquid petrolatum ( Lubricate the fecal mass, prevent excessive dehydration of the material, and may inhibit water reabsorption by coating the gut wall)