医学课件消化系统药digestivesystem

1,Chapter 5,Digestive System Agents,2,Outline,Section 1 Anti-ulcer Agents(抗溃疡药) Section 2 Antiemetics(止吐药) Section 3 Prokinetics(促动力药) Section 4 Adjuvant for Hepatic and Biliary Disease(肝胆疾病辅助治疗药物),3,4,Section 1,Anti-ulcer Agents (抗溃疡药),5,Request and Purpose,To master the structure, chemical name, physico-chemical property, metabolism in vivo, and clinical application of Cimetidine (西咪替丁) and Omeprazole(奥美拉唑). To be familiar with Ranitidine Hydrochloride (盐酸雷尼替丁). Get information about synthesis of Cimetidine and Omeprazole.,6,Peptic ulcer (PU,消化性溃疡),Concept: Factors:,Hypersecretion of acid and pepsin,Resistance 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 intestine.,GI infection by Helicobacter Pylori (HP, 幽门螺杆菌),7,食管,食管,幽门,十二指肠,8,Helicobacter Pylori (HP 幽门螺杆菌),A Gram-negative spiral bacterium. Infection by HP can damage the feedback mechanism of gastric acid secretion(胃酸分泌). HP found in virtually all patients with DU, and approximately 75% of patients with GU.,9,Risk factors with recurrence of PU,Cigarette smoking Chronic use of ulcerogenic drugs Male gender/age Alcohol consumption Emotional stress Family history,Non-steroidal anti-inflammatory drugs (NSAIDs),Peptic Ulcer,10,11,12,Physiology of Gastric Acid Secretion,Gastric acid is produced by parietal cells (胃壁细胞) in the stomach. Parietal cells contain an extensive secretory network from which the gastric acid is secreted into the lumen(腔) of the stomach. These cells are part of epithelial fundic glands(胃底腺) in the gastric mucosa. The pH of gastric acid is 2 to 3 in the human stomach lumen, the acidity being maintained by the proton pump H+/K+ ATPase.,13,Hormonal regulation of acid secretion by Gastric Parietal Cells(胃壁细胞),Histamine,H+/K+ ATPase,Parietal cell,Endocrine cell,14,Classification,Antiacids,Inhibit the different link of acid secretion,Mucous membrane(黏膜) protective drugs,Anticholinergic agents(抗胆碱能药),H2-receptor antagonists,Antigastrin agents(抗胃泌素),Proton pump inhibitors,Cimetidine(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 of action,NaHCO3/MgO,15,Common antiulcer drugs,Bismuth Potassium Citrate枸橼酸铋钾,Cimetidine,Ranitidine,Famotidine,Omeprazole,Pirenzepine,Proglumide(丙谷胺),Misoprostol (米索前列醇),16,Histamine: H1=H2 agonism,5-Methylhistamine: H2H1 agonism,N-Guanylhistamine: Partial H2- receptor agonist (weak antagonist),Burimamide: Full H2 antagonist,But low potency and poor oral bioavai- lability,Metiamide: Full H2 antagonist,And higher potency, improved oral bio- availability,But toxic (thiourea),H2-receptor antagonists,Cimetidine,17,Development of Cimetidine,Item start,The first lead compound,Clinical test,Go on the market,UK and USA,18,Cimetidine (西咪替丁),N-Cyano-N-methyl-N-2-(5-methyl-1H-imidazol-4-yl)-methyl thioethyl guanidine(胍) It is a colorless crystalline solid.,1,3,4,5,19,Cimetidine (TagametTM ) became the first billion-dollar drug in the 1980s. This medication is also available without a prescription.,20,Physio-chemical property,Solubility: Stability: Heating release H2S gas, make lead acetate testing paper show black.,Slightly soluble in water(1.14%), but soluble in dilute acid.,protonate the imidazole ring,Aqueous solutions stable for at least 7d at pH7.,But in excess dilute hydrochloric acid:,21,Pharmacological action,Treatment of 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 is increased in renal and hepatic impairment (in the elderly).,22,Drug interactions,Reduces the hepatic metabolism of drugs biotransformed by the cytochrome P-450 mixed-oxidase system. Lead to delay elimination and increase serum levels,Benzodiazepines Metronidazole Sulfonylurea Caffeine Moricizine Tacrine Calcium channel blockers Pentoxifylline Theophylline Carbamazepine Phenytoin Triamterene Chloroquine Propafenone Tricyclic antidepressants Labetalol Propranolol Valproic acid Lidocaine Quinidine Warfarin Metoprolol Quinine,(Cimetidine drug interactions),23,Chemical synthesis,24,Structural modification,Regarded imidazole as essential group, focus on its side chain,Furan ring replace Imidazole ring, get more excellent Ranitidine,5-8 fold stronger than Cimetidine,In 1986 and 1988, Famotidine and Nizatidine launched,No more excellent,25,Ranitidine Hydrochloride(盐酸雷尼替丁),N-2-5-(dimethylamino)methyl-2-furanyl methylthioethyl-N- methyl-2-nitro-1,1-ethenediamine monohydrochloride An aminoalkyl furan derivative with pKa values of 2.7 and 8.2.,(side chain and dimethylamino),26,Physico-chemical property,Ranitidine Hydrochloride is a white solid and highly soluble in water. Two isomers: cis- is available in clinic, but trans- no activity Containing mercapto(巯基)- like cimetidine, produce H2S by scorching heat.,27,Metabolism and Bioavailability,Bioavailability (by oral) is about 50-60%. Some antacids may reduce its absorption. Half-life is 2 to 3 hours. It is a more potent H2-receptor antagonist, and has little interaction with other drugs due to its lower affinity with P450 enzyme.,Ranitidine:,28,Ranitidine,29,Proton pump (PP) inhibitors,An H+/K+-ATPase, catalyzes exchange of hydrogen ions with potassium ions. This extrusion of protons is in the final step in acid secretion in the parietal cell.,Acts beyond the site of action of second messages (eg. Ca2+ and cAMP) . Independent of the action of secretogogues（促分泌） histamine, gastrin(胃泌素), and acetylcholine(乙酰胆碱).,30,Proton pump (PP) inhibitors,A group of drugs whose main action is a pronounced and long-lasting reduction of gastric acid production. Significantly more effective than H2 antagonists and reduce gastric acid secretion by up to 99%. The most potent inhibitors of acid secretion, and the most widely-selling drugs in the world. They are generally considered safe and effective. Majority of these drugs are benzimidazole derivatives; however, new research indicates that imidazopyridine derivatives may be more effective.,31,Development of PP Inhibitor,Hepatotoxicity (肝毒性),An antiviral drug originally,Benzimidazole derivative,Subsequently converted to sulfoxide, exhibiting highly potent, irreversible inhibition.,32,PP Inhibitor-continued,Trifluoroalkoxylation,Omeprazole(奥美拉唑),Lansoprazole(兰索拉唑),Pantoprazole(泮托拉唑),33,Omeprazole (奥美拉唑),(R,S)-5-methoxy-2-(4-methoxy-3,5-dimethyl-2-pyridylmethylsulfinyl)benzimidazole A white to off-white crystalline powder with very slight solubility in water,1,2,3,4,5,34,Physico-chemical property,Racemic mixture in clinic. S-isomer is more active.,Esomeprazole( pure S-isomer) is launched in 2000.,pyridine N, pKa 4.13,imidazole N-H, pKa 1.68,acid labile,Formulated as delayed-release drug with enteric-coating.,35,Mechanism of action,36,Pharmacologic action,Substantial first-pass biotransformation, oral administration is 30-40%.,about 1 hour,Its antisecretory actions persist for 24-72 hrs, which is consistent with its suggested mechanism of action involving irreversible inhibition of the proton pump.,Approved for the treatment and reduction of risk of recurrence of DU, GERD(胃食管反流病), GU and pathological hypersecretory conditions.,37,Chemical synthesis,38,Section 2,Antiemetic (止吐药),39,Vomit,A instinct, removing endogastric harmful substance. But maybe lead to water depletion, electrolyte chaos, disproportion of acid-base equilibrium, nutrition obstacle, etc. Some disease, pregnancy, radiotherapy and drug treatment for cancer can cause nausea and vomiting.,40,Mechanism to stop vomitting,The activity of vomit nervous reflex circellus(环) determined by many neurotransmitter (NT, 神经递质),antiemetic,block this reflex,Dopamine (多巴胺) 5-HT3 (5-羟色胺) Histamine (组胺) Acetylcholine (乙酰胆碱),41,Classification,Nausea and vomit related to motion,Caused by chemotherapy,Difenidol(地芬尼多),Thiethylperazine(硫乙拉嗪),Ondansetron(昂丹司琼),Caused by chemo and radiotherapy,42,Ondansetron(昂丹司琼),(dl)-1, 2, 3, 4-tetrahydro-9-methyl-3-(2-methylimidazol-1-yl)methyl- carbazol-4-one Racemic mixture in clinic, now R-isomer is applying for a new drug.,1,2,3,4,5,8,9,Chiral carbon,Chiral carbon,43,Ondansetron is a serotonin 5-HT3 receptor antagonist. Its effects are on both peripheral and central nerves. It reduces the activity of the vagus nerve(迷走神经), which activates the vomiting center in the medulla oblongata(延髓). It also blocks serotonin receptors(血清素受体) in the chemoreceptor trigger zone. It has