Gastrointestinal drugs

1. Gastrointestinal drugs Weiwei HU Phone: 0571-88208226 E-mail:huww@zju.edu.cn

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 acid-peptic disorders 2. Modulators of gastrointestinal functions

4. 1) Peptic ulcer disease (PUD, 消化性溃疡) 1. Acid-peptic disorders 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. 3) Drug-induced mucosal injury, especially by non-steroidal anti-inflammatory drugs (NSAIDs)

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

10. 5) Acute stress ulcers

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

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

13. Mucus-bicarbonate barrier

14. Helicobacter pylori infection

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

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

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

18. (1) Antacids (Weak bases) Chemistry of antacids: Salts of aluminum (aluminum hydroxide) , Salts of magnesium (carbonate, hydroxide, trisilicate) , aluminum magnesium carbonate (Al2Mg6(OH)16CO3·4H2O) calcium(carbonate) sodium (bicarbonate)

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

20. (1) Antacids 1. Pharmacological effect Neutralizing gastric acid, diminish gastric acidity and inactivate pepsin（胃蛋白酶）activity The effect depends on the dose and dosing frequency. Starting effect within 5-15 min after taking the drugs. 2. Clinical uses Commonly used for acid-peptic disorders (peptic ulcer), gastritis, duodenitis.

21. 3. Adverse effects (1) Constipation and stomach cramp (salt of aluminum) (2) Diarrhea (salt of magnesium ) Combination products such as maalox (3) Hypercalcium which can cause renal failure (Calcium) (4) Hypernatremia (sodium-containing antacids) All antacids are generally regarded as safe in pregnancy. 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

22. Adminstration and dosage • Take antacids after meals and at bedtime • Should taken continuously for a long time • To help avoid or reduce drug interaction, other medication should not be taken within 1-2 hours of taking an antacids

23. (2) Drugs affecting gastric acid secretion ② H2 receptor antagonists Cimetidine

24. cimetidine × (Proton pump) Mechamism of action

25. Cimetidine 1. Pharmacological effect Blocking H2 receptors, decreasing H+ secretion 2. Clinical uses 1) Duodenal and gastric ulcer 2) Zollinger-Ellison syndrome, 3) Acute stress ulcers 4) Gastroesophageal reflux disease (heartburn)

26. 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)Endocretion effects: antiandrogen（抗雄激素）, gynecomastia, galactorrhea,reduced sperm count, and male sexual dysfunction 4. Drug interactions Inhibiting hepatic P450, raising plasma concentrations of warfarin, phenytoin, diazepam, propranolol, quinidine and theophylline

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

29. Other H2 receptor antagonists Ranitidine 4-10 times more potent than cimetidine Minimal side effects, weakly inhibiting CYP Famotidine 7-10 times more potent than ranitidine, but no inhibiting CYP Nizatidine Bioavailability is near 100%, principally eliminated by kidney

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

31. Omepranzole × (the proton pump)

32. Omeprazole • 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, with antimicrobial regimens to eradicate H. pylori • (2) Gastro-esophageal reflux disease • (3) Zollinger-ellison syndrome

33. Omeprazole • 3. Adverse effects • (1) Side effects: nausea, headache, diarrhea, 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.

34. Others proton pump inhibitors

35. M receptor antagonists • 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)

36. (3) Mucosal protective drugs 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

37. (3) Mucosal protective drugs Misoprostol米索前列醇 A prostaglandin E1 analogues

38. (3) Mucosal protective drugs 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, headache, nauseaetc. Contraindicated in pregnancy women (Abortifacient 堕胎 property)

39. (3) Mucosal protective drugs Sucralfate A sulfated disaccharide（二糖） complex of aluminum hydroxide

40. (3) Mucosal protective drugs Sucralfate 1. Pharmacological effects 1) Binding to tissue 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 more effective agents (proton pump inhibitors. Gastro-esophageal reflux disease. H pylori infection. 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

41. (3) Mucosal protective drugs Colloidal bismuth subcitrate (CBS 胶体次枸橼酸铋) 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

42. Bismuth Compounds 2. Clinical uses 1) Peptic ulcers, chronic gastritis, duodenitis, functional dyspepsia 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).

43. (3) Mucosal protective drugs Smectite • 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.

44. (4) 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)

45. 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.

46. 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.

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

48. Abnormalities ofgastrointestinal functions Nausea and vomiting Constipation Diarrhea

49. Modulators ofgastrointestinal functions 1. Antiemetic drugs 2. Prokinetic drugs 3. Anti-diarrheals 4. Laxatives

50. Antiemetic drugs • There are various sources of input to the vomiting center: • 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. • 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. • The Cranial nerve X (vagus nerve) is activated when the pharynx is irritated, leading to a gag reflex. • 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. • The CNS mediates vomiting that arises from psychiatric disorders and stress from higher brain centers.