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1、Chapter 5 Digestive System Agents1OutlinelSection 1 Anti-ulcer Agents(抗溃疡药)lSection 2 Antiemetics(止吐药)lSection 3 Prokinetics(促动力药)lSection 4 Adjuvant for Hepatic and Biliary Disease(肝胆疾病辅助治疗药物) 23Section 1Anti-ulcer Agents(抗溃疡药)4Request and PurposenTo master the structure, chemical name, physico-che
2、mical property, metabolism in vivo, and clinical application of Cimetidine (西咪替丁) and Omeprazole(奥美拉唑). nTo be familiar with Ranitidine Hydrochloride (盐酸雷尼替丁).nGet information about synthesis of Cimetidine and Omeprazole.5Peptic ulcer (PU,消化性溃疡)nConcept:nFactors:Hypersecretion of acid and pepsinResi
3、stance of intestinal mucosa(肠粘膜) is lower Pylorus(幽门) and duodenum(十二指肠)PU is a group of upper GI tract disorders that result from the erosive(侵蚀的)action of acid and pepsin(胃蛋白酶).Duodenal ulcer (DU) and gastric ulcer (GU) are the most common forms, although may occur in the esophagus(食道) or small in
4、testine.GI infection by Helicobacter Pylori (HP, 幽门螺杆菌) 6食管食管幽门十二指肠7Helicobacter Pylori (HP 幽门螺杆菌)uA Gram-negative spiral bacterium.uInfection by HP can damage the feedback mechanism of gastric acid secretion(胃酸分泌).uHP found in virtually all patients with DU, and approximately 75% of patients with G
5、U.8Risk factors with recurrence of PUnCigarette smokingnChronic use of ulcerogenic drugsnMale gender/agenAlcohol consumptionnEmotional stressnFamily historyNon-steroidal anti-inflammatory drugs (NSAIDs)Peptic Ulcer91011Physiology of Gastric Acid Secretionl Gastric acid is produced by parietal cells
6、(胃壁细胞) in the stomach. l Parietal cells contain an extensive secretory network from which the gastric acid is secreted into the lumen(腔) of the stomach. l These cells are part of epithelial fundic glands(胃底腺) in the gastric mucosa. l The pH of gastric acid is 2 to 3 in the human stomach lumen, the a
7、cidity being maintained by the proton pump H+/K+ ATPase. 12Hormonal regulation of acid secretion by Gastric Parietal Cells(胃壁细胞)HistamineH+/K+ ATPaseParietal cellEndocrine cell13ClassificationAntiacidsAntiacidsInhibit the different linkInhibit the different linkof acid secretion of acid secretionMuc
8、ous membraneMucous membrane( (黏膜)protective drugs protective drugsAnticholinergic agents(抗胆碱能药)H2-receptor antagonists Antigastrin agents(抗胃泌素)Proton pump inhibitorsCimetidine(西咪替丁)Omeprazole(奥美拉唑)Pirenzepine(哌仑西平)Proglumide(丙谷胺)Prostaglandin E（前列腺素E）/Sucralfate（硫糖铝）/Alginic Acid（藻朊酸）Mechanism ofact
9、ionNaHCO3/MgO14Common antiulcer drugsBismuth Potassium Citrate 枸橼酸铋钾Cimetidine Ranitidine Famotidine Omeprazole Pirenzepine Proglumide(丙谷胺)Misoprostol (米索前列醇) 15Histamine: H1=H2 agonism5-Methylhistamine: H2H1 agonismN-Guanylhistamine: Partial H2- receptor agonist (weak antagonist)Burimamide: Full H2
10、 antagonist But low potency and poor oral bioavai- labilityMetiamide: Full H2 antagonist And higher potency, improved oral bio- availability But toxic (thiourea)H2-receptor antagonistsCimetidine16Development of CimetidineItem startThe first lead compoundClinical testGo on the marketUK and USA17Cimet
11、idine (西咪替丁)nN-Cyano-N-methyl-N-2-(5-methyl-1H- imidazol-4-yl)-methyl thioethyl guanidine(胍)nIt is a colorless crystalline solid.13 4518nCimetidine (TagametTM ) became the first billion-dollar drug in the 1980s.nThis medication is also available without a prescription. 19Physio-chemical propertynSol
12、ubility:nStability:nHeating release H2S gas, make lead acetate testing paper show black.Slightly soluble in water(1.14%), but soluble in dilute acid.protonate the imidazole ringAqueous solutions stable for at least 7d at pH7.But in excess dilute hydrochloric acid:20Pharmacological actionTreatment of
13、 DU,GU and RE (reflux esophagitis反流性食管炎). Prophylaxis and treatment of stress ulcer. Prophylaxis of recurrence of ulcer.A weak anti-androgenic effect and gynaecomastia (男子女性型乳房)and asynodia (阳痿) may occur for long and large dose use.Exhibits high oral bioavailability (60-70%). Half-life is 2h, which
14、 is increased in renal and hepatic impairment (in the elderly).21Drug interactionsnReduces the hepatic metabolism of drugs biotransformed by the cytochrome P-450 mixed-oxidase system. nLead to delay elimination and increase serum levelsBenzodiazepines Metronidazole Sulfonylurea Caffeine Moricizine T
15、acrine Calcium channel blockers Pentoxifylline Theophylline Carbamazepine Phenytoin Triamterene Chloroquine Propafenone Tricyclic antidepressants Labetalol Propranolol Valproic acid Lidocaine Quinidine Warfarin Metoprolol Quinine(Cimetidine drug interactions)22Chemical synthesis23Structural modificationRegarded imidazole as essential group, focus on its side chainFuran ring replace Imidazole ring, get more excellent Ranitidine 5-8 fold stronger than Cimetidine In 1986 and 1988, F
