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 3,Prokinetics (促动力药),5,6,7,Concept and classification,ProkineticsClassification,D2 receptor antagonists,Metoclopramide(甲氧氯普胺),Periphery D2 receptor antagonists,Domperidone(多潘立酮),Acetylcholine agonists,Cisapride(西沙必利),Promote GI content to push forward, used in the treatment of GI dyskinesis(动力障碍) such as reflux esophagitis(返流食道炎), dyspepsia(消化不良), intestinal obstruction(肠梗阻), etc.,8,Common Prokinetics,9,10,Prokinetics,11,Metoclopramide (甲氧氯普胺),procainamide,metoclopramide,also used as an antiemetic,胃复安,Structure is similar, but has no function for anti-cardiac arrhythmias,12,Metoclopramide,It is an antiemetic and gastroprokinetic agent. To treat nausea and vomiting, and to facilitate gastric emptying in patients with gastroparesis. Various trade names:Maxolon (Shire/Valeant), Reglan (Schwarz Pharma), Degan (Lek), Maxeran (Sanofi Aventis), Primperan (Sanofi Aventis), and Pylomid (Bosnalijek).,13,14,Cisapride,15,Cisapride (西沙必利),1,2,3,4,5,1,2,3,4,3 and 4-C are both chiral C,3 and 4-substituents on the same side of pyridine ring,4-amino-5-chloro-N-(3S,4S)-1-3-(4-fluoro phenoxy)propyl-3-methoxypiperidin-4-yl)-2-methoxybenzamide,16,2-cis isomers in clinic,4-isomers of Cisapride,17,Metabolism of Cisapride,18,Cisapride in Clinic,Cisapride is a parasympathomimetic and gastroprokinetic agent that acts as a serotonin 5-HT4 receptor agonist. Stimulation of the serotonin receptors increases acetylcholine release in the enteric nervous system. It is sold under the trade names Prepulsid (Janssen-Ortho) and Propulsid (in the U.S.). It was discovered by Janssen Pharmaceutica in 1980.,19,In Clinic,Various GI dyskinesis(动力障碍)such as Gastroparesis(胃肌轻瘫)and regurgitation(反胃).Side effect：an exceptional life-threatening ventricular arrhythmia (室性心律失常).,20,Cisapride in Clinic,In 1995, it was recorded in BP and EP. In 1997, it became top 25 of 500 best-selling drugs with 1.04 billion dollars. In 2000, 386 severe ADR, 125 death. It was suspended in USA and UK in same year.,21,New “Pride” Prokinetic Drugs,Much safer,22,23,Domperidone (多潘立酮),5-chloro-1-(1-3-(2-oxo-2,3-dihydro-1H-benzodimidazol-1-yl)propyl piperidin-4-yl)-1H-benzodimidazol-2(3H)-one,吗丁啉,24,Anti-dopaminergic drug,25,Domperidones action,Domperidone is an anti-dopaminergic(多巴胺能) drug. It has strong affinities for the D2 and D3 dopamine receptors. It is developed by Janssen(杨森) Pharmaceutica. It is used orally, rectally(直肠给药) or intravenously(静脉), generally to suppress nausea and vomiting. It has also been used to stimulate lactation(泌乳).,26,For oral dosage form (tablets): Treatment of gastrointestinal motility disorders: Adults10 milligrams (mg) three to four times daily. Some patients may require higher doses up to 20 mg three or four times daily. Nausea and vomiting: Adults20 milligrams (mg) three to four times daily.,Domperidone,27,Section 4,Adjuvant for Hepatic and Biliary Diseases (肝胆疾病辅助治疗药物),28,Adjuvant for Hepatic Diseases,Cause of hepatic diseases,Virus, bacterium and ectosarc(原虫) infection,Toxin, chemicals,Genetic gene defect,Abnormal autoimmune antibody reaction,29,Common drugs,Glutamic Acid (谷氨酸),Glucurolactone (葡醛内酯),Lactulose (乳果糖),Bifendate (联苯双酯),Silibinin (水飞蓟宾),30,Bifendate (联苯双酯),4，4-dimethoxy-5, 6, 5, 6-dimethylenedioxy-2, 2-dimethoxy carboxyl-biphenyl,1,2,3,4,5,6,1,4,5,6,3,2,31,Development,From Schisandra chinensis (五味子),In the early of 1970s, discover that it lower SGPT,Alcohol extract from its fruit kernel, “Schizandrol”（五味子醇，健肝灵） tablet go on the market.,serum glutamic-pyruvic transaminase,32,Deoxyschizandrin -SchizandrinSchizandrinAomisinPseudo-SchizandrinSchisantherin ANeoschisandrinSchisandrolSchisantherin,33,Development of Bifendate,No activity,34,Development,Intermediate of -schisandrin C, Bifendate go on the market,1970s,Initial research,1975,1977,1983,Synthesized, and found it hepatoprotective effect,Use in clinic,Develop new form of drop pill,In 1995, accepted in pharmacopoeia,35,Physico-chemical property,Characteristic ultraviolet absorption of diphenyl 2781nm, used for qualitative and quantitative analysis.Hydroxamic acid iron salt test,produce purple product. To check Carboxyl derivatives.,36,Quantitative determination is the formation of a red-purple colouration when chromotropic acid in 75% sulfuric acid reacts with formaldehyde. The colouration is specific to this aldehyde (not produced from ketones and carboxylic acids).,chromotropic acid,Formaldehyde & Chromotropic acid,methylenedioxy,Conc.H2SO4,formaldehyde,37,Pharmacologic action,Lower the activity of Serum Glutamic-Pyruvate Transaminase (SGPT, 血清谷丙转氨酶) , and reinforce the antitoxic function of liver. Clinic：Curative effect is instable,GPT may go up after withdrawal, but also down with administration again,