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1、Drugs Affecting the Gastrointestinal SystemByCaiying YeDepartment of Pharmacology, School of Basic Medicine, Peking Union Medical CollegeDrugs Affecting the Gastrointestinal System分类分类 nAntiulcerants 消化性溃疡消化性溃疡药药nDigestives 助消化药助消化药nAntiemetics 止吐药止吐药nPurgatives 泻药泻药nAntidiarrheals 止泻药止泻药nCholagogue
2、s 利胆药利胆药 Peptic Ulcersn常见病，发病率约10%12%. nPathogenesis of ulcers Aggressive Factors Defensive FactorsAcid,pepsinBile saltsDrugs (NSAIDs)H.pyloriMucus,bicarbonate layerBlood flow,cell renewalProstaglandinsPhospholipidFree radical scavengersn溃疡 胃酸分泌过多 胃、十二指肠粘膜侵蚀，胃蛋白酶和幽门螺旋杆菌升高 消化性溃疡治疗目的：治疗目的：nTherapy is
3、directed at enhancing host defense or eliminating aggressive factors; i.e., H. pylori.Peptic UlcersDrugs Used in Peptic UlcersnAntacidsnInhibitors of gastric acid production H2-receptor antagonists Proton pump inhibitors Muscarinic antagonists Gastrin receptor antagonistnMucosal ProtectantsnAnti-Hel
4、icobacter pylori. drugs Drugs Used in Peptic Ulcers代表药物代表药物nAntacids 抗酸药抗酸药：aluminum hydroxide （氢氧化铝）、magnesium hydroxide（ 氢氧化镁）等nH2- receptor antagonists H2 -受体阻断药受体阻断药：cimetidine （西咪替丁）、ranitidine （雷尼替丁）等nMuscarinic antagonists M-胆碱受体阻断药胆碱受体阻断药：atropine （阿托品）等代表药物代表药物nProton pump inhibitors 胃壁细胞胃壁
5、细胞H+泵抑制剂泵抑制剂：omeprazole （奥美拉唑）nGastrin receptor antagonist 胃泌素阻断药胃泌素阻断药：proglumide （丙谷胺）nMucosal Protectants 胃胃粘膜保护药粘膜保护药：Prostaglandin Analog(前列腺素衍生物 ) misoprostol（米索前列醇）nAnti-Helicobacter pylori. Drugs 抗幽门螺杆菌药抗幽门螺杆菌药：antibioticsDrugs Used in Peptic Ulcers抗酸药抗酸药 AntacidsGeneral characteristicsnAnta
6、cids are weak bases that are taken orally and that partially neutralize gastric acid and reduce pepsin activity.nAntacids reduce the pain associated with ulcers and may promote healing. High doses are required for healing: 40 mEq of base seven times daily.n氢氧化镁氢氧化镁magnesium hydroxide 抗酸作用强，较快，镁离子有导泻
7、作用，与氢氧化铝合用，相互纠正副作用。 小分子Mg2+可被吸收 肾排泄肾功能不良的病人 血清中Mg2+上升。n三硅酸镁三硅酸镁magnesium trisilicate： 起效缓慢，作用持久，在胃内生成胶状二氧化硅，对溃疡具有保护作用。抗酸药抗酸药 Antacids抗酸药抗酸药 Antacidsn氢氧化铝氢氧化铝aluminum hydroxide: 抗酸作用强，缓慢，持久，中和胃酸，具有收敛、止血和引起便秘作用。长时间应用影响磷酸吸收。禁止与四环素、地高辛、异烟肼、强的松等合用。n碳酸钙碳酸钙calcium carbonate： 抗酸作用强，快而持久，产生CO2气体，进入小肠，促进胃泌素分泌
8、，反跳性胃酸分泌增加。n碳酸氢钠碳酸氢钠sodium bicarbonate（小苏打）：小苏打）： 作用强，快而短暂，产生CO2 ，碱血症。 H2-receptor antagonists Mechanism of actionnCompetitively block the histamine (H2) receptor of acid-producing parietal cells rendering cells less responsive to not only histamine but also to the stimulation of acetylcholine and g
9、astrin.nAlso up to 90% inhibition of vagal stimulated and gastrin stimulated acid secretion. complete inhibition has not been shownH2-receptor antagonistsFour FDA-approved:Cimetidine 西咪替丁西咪替丁 （Tagamet）Ranitidine 雷尼替丁雷尼替丁 （Zantac）Famotidine 法莫替丁（法莫替丁（Pepcid）Nizatidine 尼扎替丁尼扎替丁 （Axid）Roxatidine 罗沙替丁罗沙
10、替丁Therapeutic effects:nPromote the healing of gastric and duodenal ulcers (胃和十二指肠溃疡)nGastroesophageal reflux dz GERD (反流性食道炎)nUpper GI bleed GIB (上消化道出血) nMay be effective in stress ulcers (应激性溃疡) & peptic esophagitis (消化性食道炎) H2-receptor antagonists Side effect:nOverall low 3%nCNS: 1% total headach
11、e, lethargy 乏力，confusion, depression 抑郁，hallucinations 幻觉nENDO： Impotence 阳痿，increased prolactin 催泌乳素，gynecomastianHEME: Thrombocytopenia 血小板减少H2-receptor antagonists Muscarinic antagonistsAtropine：nBlock the M1 class receptorsnreduce acid productionnabolish gastrointestinal spasm relatively unpopul
12、ar as a first choice because of high incidence of anticholinergic side effects (dry mouth and blurred vision)nH+,K+-ATPase (Proton Pump) inhibitornIrreversible inhibition Must synthesize new enzyme Long duration Omeprazole 奥美拉唑 (Prilosec) Lansoprazole 兰索拉唑 (Prevacid) Pantoprazole 泮托拉唑 Rabeprazole 雷贝
13、拉唑Proton pump inhibitorsMechanism of Action奥美拉唑奥美拉唑 Omeprazole又称洛赛克（又称洛赛克（losec）第一代质子泵抑制剂第一代质子泵抑制剂nIrreversibly binds to H+/K+ ATPasenPrevents H+ ion production & secrectionnBlock all acid secretion = achlorhydria (胃酸缺乏) to return to normal must synthesize new H+/K+ ATPasenInhibit H. pyloriTherapeut
14、ic usesnGastroesophageal reflux dz GERD (反流性食道炎),有效率达7585。nPeptic ulcer（消化性溃疡）,服用16月，溃疡愈合率达97，其它类药物无效用4周，愈合率达90。nInfection with H. pylori plus(Hp) (幽门螺杆菌感染),幽门螺旋杆菌83%88转阴。nUpper GI bleed GIB (上消化道出血)Side effectsn12头痛、头晕、口干、恶心、腹胀、失眠，偶见皮疹，男性乳头女性化n长期服用，胃内细菌过度生长。 兰索拉唑兰索拉唑 LansoprazolenLansoprazole是第二代质子
15、泵抑制药。n抑制胃酸分泌、升高血胃泌素、胃粘膜保护作用及抗幽门螺杆菌作用n抑制胃酸分泌作用及抗幽门螺杆菌作用较omeprazole强。潘多拉唑潘多拉唑 Pantoprazolen与雷贝拉唑（rabeprazole）属第三代质子泵抑制药。n抗溃疡病作用与奥美拉唑相似，nRabeprazole在抗胃酸分泌能力和缓解症状、治愈粘膜损害的临床效果方面远优于其他抗酸药物。Gastrin receptor antagonist丙谷胺丙谷胺（proglumide） n竞争性与胃泌素受体结合.减少胃酸分泌.n对胃粘膜有保护作用和促进溃疡愈合；n用于胃溃疡、十二指肠溃疡、胃炎、急性上消化道出血丙谷胺丙谷胺（pr
16、oglumide）【Side effects】 n恶心、腹痛等胃肠道症状。n神经系统反应:头痛、头晕、失眠、外周神经炎。n偶见皮疹、白细胞减少、血清转氨酶和胆红素升高等。Mucosal Protective Agentsn增强胃粘膜屏障功能的药物胃粘膜屏障胃粘膜屏障细胞屏障细胞屏障粘液粘液HCO3- 盐屏障盐屏障抵抗和防止胃酸和胃蛋白酶的侵蚀作用抵抗和防止胃酸和胃蛋白酶的侵蚀作用胃粘膜屏障作用胃粘膜屏障作用nA congener of prostaglandin E1nPGs: inhibit gastric acid secretion exhibit cytoprotective acti
17、vity enhance local production of mucus or bicarbonate promote local cell regeneration help to maintain mucosal blood flow米索前列醇（米索前列醇（misoprostol）米索前列醇（米索前列醇（misoprostol）nMisoprostol is approved for use in patients taking NASIDs who are at risk for gastric ulcersnMisoprostol produces diarrhea and sti
18、mulation of uterine contraction.nn与溃疡面的亲和力是正常粘膜的与溃疡面的亲和力是正常粘膜的6 6倍，形成倍，形成保护屏障；保护屏障；nn促进胃和十二指肠粘膜合成促进胃和十二指肠粘膜合成PFEPFE2 2；nn增强表皮生长因子、碱性成纤维细胞生长因增强表皮生长因子、碱性成纤维细胞生长因子作用，使之聚集于溃疡区，促进溃疡愈合子作用，使之聚集于溃疡区，促进溃疡愈合；硫糖铝硫糖铝 sucralfatenSucralfate 硫糖铝硫糖铝 cytoprotective agent stress ulcerations & PUD inhibit H. pylorinBi
19、smuth 胶体次枸橼酸铋胶体次枸橼酸铋（Pepto-Bismol） inhibit pepsin activity inhibit H. pyloriAgents Used in infection of Helicobacter Pylorin幽门螺杆菌（helicobacter pylori，HP ）为革兰阴性厌氧菌，n在胃十二指肠的粘液层与粘膜细胞之间生长，可产生多种酶及细胞毒素，使粘膜损伤。n是慢性胃炎、消化性溃疡和胃腺癌等胃部疾患发生发展中的一个重要致病因子。Aimed at eliminating H. pyloriBismuth 胶体次枸橼酸铋( Pepto-Bismol)Ge
20、ntamicin 庆大霉素Amotriptyline 阿莫替林 (Amoxil )Clarithromycin 克拉霉素Tetracycline 四环素 (Achromycin V )Metronidazole 甲硝唑 (Flagyl )Agents Used in infection of Helicobacter PyloriFDA-Approved Treatment Regimens for H.pylori InfectionnOmeprazole 20mg b.i.d + Clarithromycin 500mg b.i.d + Amoxicillin 1g b.i.d for 1
21、0 daysnLansoprazole 30mg b.i.d + Clarithromycin 500mg b.i.d + Amoxicillin 1g b.i.d for 10 daysnBismuth subsalicylate 525mg q.i.d + Metronidazole 250mg q.i.d + Tetracycline 500mg q.i.d 14 days + H2 receptor antagonist 4 wksDigestives 助助消化药消化药胃蛋白酶胃蛋白酶pepsinn牛、猪、羊等胃粘膜提取；n临床消化功能减弱；n对胃癌、恶心贫血可改善消化不良胰酶胰酶pa
22、ncreatinn动物牛、猪、羊胰腺提取物；n能消化蛋白质、淀粉、脂肪；n临床用于胰腺炎、胰腺纤维化、消化障碍。 乳酶生乳酶生lactasinn乳酸杆菌干燥物，可分解糖类，产生乳酸，提高肠内酸性，抑制腐败细菌生长、繁殖及防止蛋白质发酵，减少肠内产气，促进消化和止泻作用。n临床应用：消化不良、腹胀、小儿消化不良性酵母酵母n酵母菌：含多种B族维生素，B1、B2、B6、B12 、叶酸等。n临床应用：食欲不振、消化不良。 Digestives 助助消化药消化药Antiemetic DrugsnVomiting reflex a coordinated reflex controlled by a bi
23、lateral vomiting center in the dorsal portion of the lateral reticular formation in the medullanPharmacologic intervention relies on inhibition of inputs or depression of the vomiting center.nHistamine1-receptor antagonist (H1 受受体体阻阻断药断药)nCholinergic antagonist (M 受体阻断药受体阻断药)nDopamine antagonists (多
24、巴胺受体阻断药多巴胺受体阻断药)n5-HT3 antagonists (5-HT3受体拮抗药受体拮抗药)nCannabinoids (大麻酚大麻酚)Antiemetic DrugsDopamine Receptor Antagonistsn甲氧氯普胺甲氧氯普胺 Metoclopramide (灭吐灵、胃复安) Pharmacological effect CNS：作用于中枢化学感受区( CTZ), 阻 断D2 受体,高剂量阻断5-HT3 受体;胃肠道：胃肠道：促进运动，增加贲门括约肌张力 松弛幽门，加速胃排空和肠内容物运动。为前动药。甲氧氯普胺甲氧氯普胺 MetoclopramideThera
25、peutic usesn慢性消化不良引起的恶心、呕吐。n预防各种原因引起的呕吐(包括妊娠)。n常用于肿瘤放疗)等引起的呕吐。Side effects 锥体外系症状(大剂量或长期应用)，疲劳、精神抑郁。偶见溢乳，男性乳房发育。Domperidone多潘立酮多潘立酮, 吗丁啉（motilium）nA domamine (D2)-receptor antagonist (periphery)nA weaker antiemetic, but it has fewer extrapyramidal effects.nAccelerates gastric emptying; has little effect on the colonThanks!
