第五章消化系统药暨南大学药学院

1 Chapter5 DigestiveSystemAgents 2 Outline Section1Anti ulcerAgents 抗溃疡药 Section2Antiemetics 止吐药 Section3Prokinetics 促动力药 Section4AdjuvantforHepaticandBiliaryDisease 肝胆疾病辅助治疗药物 3 4 Section1 Anti ulcerAgents 抗溃疡药 5 RequestandPurpose Tomasterthestructure chemicalname physico chemicalproperty metabolisminvivo andclinicalapplicationofCimetidine 西咪替丁 andOmeprazole 奥美拉唑 TobefamiliarwithRanitidineHydrochloride 盐酸雷尼替丁 GetinformationaboutsynthesisofCimetidineandOmeprazole 6 Pepticulcer PU 消化性溃疡 Concept Factors Hypersecretionofacidandpepsin Resistanceofintestinalmucosa 肠粘膜 islower Pylorus 幽门 andduodenum 十二指肠 PUisagroupofupperGItractdisordersthatresultfromtheerosive 侵蚀的 actionofacidandpepsin 胃蛋白酶 Duodenalulcer DU andgastriculcer GU arethemostcommonforms althoughmayoccurintheesophagus 食道 orsmallintestine GIinfectionbyHelicobacterPylori HP 幽门螺杆菌 7 食管 食管 幽门 十二指肠 8 HelicobacterPylori HP幽门螺杆菌 AGram negativespiralbacterium InfectionbyHPcandamagethefeedbackmechanismofgastricacidsecretion 胃酸分泌 HPfoundinvirtuallyallpatientswithDU andapproximately75 ofpatientswithGU 9 RiskfactorswithrecurrenceofPU CigarettesmokingChronicuseofulcerogenicdrugsMalegender ageAlcoholconsumptionEmotionalstressFamilyhistory Non steroidalanti inflammatorydrugs NSAIDs PepticUlcer 10 11 12 PhysiologyofGastricAcidSecretion Gastricacidisproducedbyparietalcells 胃壁细胞 inthestomach Parietalcellscontainanextensivesecretorynetworkfromwhichthegastricacidissecretedintothelumen 腔 ofthestomach Thesecellsarepartofepithelialfundicglands 胃底腺 inthegastricmucosa ThepHofgastricacidis2to3inthehumanstomachlumen theaciditybeingmaintainedbytheprotonpumpH K ATPase 13 HormonalregulationofacidsecretionbyGastricParietalCells 胃壁细胞 Histamine H K ATPase Parietalcell Endocrinecell 14 Classification Antiacids Inhibitthedifferentlinkofacidsecretion Mucousmembrane 黏膜 protectivedrugs Anticholinergicagents 抗胆碱能药 H2 receptorantagonists Antigastrinagents 抗胃泌素 Protonpumpinhibitors Cimetidine 西咪替丁 Omeprazole 奥美拉唑 Pirenzepine 哌仑西平 Proglumide 丙谷胺 ProstaglandinE 前列腺素E Sucralfate 硫糖铝 AlginicAcid 藻朊酸 Mechanismofaction NaHCO3 MgO 15 Commonantiulcerdrugs BismuthPotassiumCitrate枸橼酸铋钾 Cimetidine Ranitidine Famotidine Omeprazole Pirenzepine Proglumide 丙谷胺 Misoprostol 米索前列醇 16 Histamine H1 H2agonism 5 Methylhistamine H2 H1agonism N Guanylhistamine PartialH2 receptoragonist weakantagonist Burimamide FullH2antagonist Butlowpotencyandpoororalbioavai lability Metiamide FullH2antagonist Andhigherpotency improvedoralbio availability Buttoxic thiourea H2 receptorantagonists Cimetidine 17 DevelopmentofCimetidine Itemstart Thefirstleadcompound Clinicaltest Goonthemarket UKandUSA 18 Cimetidine 西咪替丁 N Cyano N methyl N 2 5 methyl 1H imidazol 4 yl methyl thio ethyl guanidine 胍 Itisacolorlesscrystallinesolid 1 3 4 5 19 Cimetidine TagametTM becamethefirstbillion dollardruginthe1980s Thismedicationisalsoavailablewithoutaprescription 20 Physio chemicalproperty Solubility Stability HeatingreleaseH2Sgas makeleadacetatetestingpapershowblack Slightlysolubleinwater 1 14 butsolubleindiluteacid protonatetheimidazolering Aqueoussolutionsstableforatleast7datpH7 Butinexcessdilutehydrochloricacid 21 Pharmacologicalaction TreatmentofDU GUandRE refluxesophagitis反流性食管炎 Prophylaxisandtreatmentofstressulcer Prophylaxisofrecurrenceofulcer Aweakanti androgeniceffectandgynaecomastia 男子女性型乳房 andasynodia 阳痿 mayoccurforlongandlargedoseuse Exhibitshighoralbioavailability 60 70 Half lifeis2h whichisincreasedinrenalandhepaticimpairment intheelderly 22 Druginteractions ReducesthehepaticmetabolismofdrugsbiotransformedbythecytochromeP 450mixed oxidasesystem Leadtodelayeliminationandincreaseserumlevels BenzodiazepinesMetronidazoleSulfonylureaCaffeineMoricizineTacrineCalciumchannelblockersPentoxifyllineTheophyllineCarbamazepinePhenytoinTriamtereneChloroquinePropafenoneTricyclicantidepressantsLabetalolPropranololValproicacidLidocaineQuinidineWarfarinMetoprololQuinine Cimetidinedruginteractions 23 Chemicalsynthesis 24 Structuralmodification Regardedimidazoleasessentialgroup focusonitssidechain FuranringreplaceImidazolering getmoreexcellentRanitidine 5 8foldstrongerthanCimetidine In1986and1988 FamotidineandNizatidinelaunched Nomoreexcellent 25 RanitidineHydrochloride 盐酸雷尼替丁 N 2 5 dimethylamino methyl 2 furanyl methyl thio ethyl N methyl 2 nitro 1 1 ethenediaminemonohydrochlorideAnaminoalkylfuranderivativewithpKavaluesof2 7and8 2 sidechainanddimethylamino 26 Physico chemicalproperty RanitidineHydrochlorideisawhitesolidandhighlysolubleinwater Twoisomers cis isavailableinclinic buttrans noactivityContainingmercapto 巯基 likecimetidine produceH2Sbyscorchingheat 27 MetabolismandBioavailability Bioavailability byoral isabout50 60 Someantacidsmayreduceitsabsorption Half lifeis2to3hours ItisamorepotentH2 receptorantagonist andhaslittleinteractionwithotherdrugsduetoitsloweraffinitywithP450enzyme Ranitidine 28 Ranitidine 29 Protonpump PP inhibitors AnH K ATPase catalyzesexchangeofhydrogenionswithpotassiumions Thisextrusionofprotonsisinthefinalstepinacidsecretionintheparietalcell Actsbeyondthesiteofactionofsecondmessages eg Ca2 andcAMP Independentoftheactionofsecretogogues 促分泌 histamine gastrin 胃泌素 andacetylcholine 乙酰胆碱 30 Protonpump PP inhibitors Agroupofdrugswhosemainactionisapronouncedandlong lastingreductionofgastricacidproduction SignificantlymoreeffectivethanH2antagonistsandreducegastricacidsecretionbyupto99 Themostpotentinhibitorsofacidsecretion andthemostwidely sellingdrugsintheworld Theyaregenerallyconsideredsafeandeffective Majorityofthesedrugsarebenzimidazolederivatives however newresearchindicatesthatimidazopyridinederivativesmaybemoreeffective 31 DevelopmentofPPInhibitor Hepatotoxicity 肝毒性 Anantiviraldrugoriginally Benzimidazolederivative Subsequentlyconvertedtosulfoxide exhibitinghighlypotent irreversibleinhibition 32 PPInhibitor 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 benzimidazoleAwhitetooff whitecrystallinepowderwithveryslightsolubilityinwater 1 2 3 4 5 34 Physico chemicalproperty Racemicmixtureinclinic S isomerismoreactive Esomeprazole pureS isomer islaunchedin2000 pyridineN pKa4 13 imidazoleN H pKa1 68 acidlabile Formulatedasdelayed releasedrugwithenteric coating 35 Mechanismofaction 36 Pharmacologicaction Substantialfirst passbiotransformation oraladministrationis30 40 about1hour Itsantisecretoryactionspersistfor24 72hrs whichisconsistentwithitssuggestedmechanismofactioninvolvingirreversibleinhibitionoftheprotonpump ApprovedforthetreatmentandreductionofriskofrecurrenceofDU GERD 胃食管反流病 GUandpathologicalhypersecretoryconditions 37 Chemicalsynthesis 38 Section2 Antiemetic 止吐药 39 Vomit Ainstinct removingendogastricharmfulsubstance Butmaybeleadtowaterdepletion electrolytechaos disproportionofacid baseequilibrium nutritionobstacle etc Somedisease pregnancy radiotherapyanddrugtreatmentforcancercancausenauseaandvomiting 40 Mechanismtostopvomitting Theactivityofvomitnervousreflexcircellus 环 determinedbymanyneurotransmitter NT 神经递质 antiemetic blockthisreflex Dopamine 多巴胺 5 HT3 5 羟色胺 Histamine 组胺 Acetylcholine 乙酰胆碱 41 Classification Nauseaandvomitrelatedtomotion Causedbychemotherapy Difenidol 地芬尼多 Thiethylperazine 硫乙拉嗪 Ondansetron 昂丹司琼 Causedbychemoandradiotherapy 42 Ondansetron 昂丹司琼 dl 1 2 3 4 tetrahydro 9 methyl 3 2 methylimidazol 1 yl methyl carbazol 4 oneRacemicmixtureinclinic nowR isomerisapplyingforanewdrug 1 2 3 4 5 8 9 Chiralcarbon Chiralcarbon 43 Ondansetronisaserotonin5 HT3receptorantagonist Itseffectsareonbothperipheralandcentralnerves Itreducestheactivityofthevagusnerve 迷走神经 whichactivatesthevomitingcenterinthemedullaoblongata 延髓 Italsoblocksserotoninreceptors 血清素受体 inthechemoreceptortrigger