药物的肝脏毒性消化系统用药（高分飞）

DrugsAffectingGastrointestinalFunctionGaoFen-FeiOUTLINEPepticUlcerDigestionVomitingDiarrheaBileReview-QuestionsUlcer-Background20世纪初，与应激、生活、饮食等有关，故主张镇静、休息、饮食治疗。1910年，Schwarz提出”NoAcidNoUlcer”1971年，Black等发现H2受体。1976年，第一代H2受体拮抗剂西咪替丁用于临床——第一次革命。诺贝尔奖。20世纪80年代中期，质子泵抑制剂（protonpumpinhibitor，PPI）奥美拉唑问世。1983年，澳大利亚学者Warren与Marshall分离出Hp，病因观念转变，再一次革命。根治成为可能。2005年，获诺贝尔奖。IntroductionofUlcerEpidemiologyincidenceofadisease:10%-12%EuropeandAmerica:

DU>GU;Japan:GU>DUEtiologyGeneralconsideration:NoAcidNoUlcerMainDestroyFactors:①HCl,②Pepsin,③HpProtectiveBarrier:Mucus-HCO3-PathogenesisofPepticUlcerReviewHowisthesecretionofgastricacidadjusted?Whatisthemechanismofsecretionofgastricacid?Howtotreatpepticulcer

?Anti-ulcerTargetsHClMucusHpAnti-ulcerClassificationAntacids---

Neutralize

HClGastricAntisecretoryDrugsHClsecretionAntagonizeRs.onParietalCell---H2,M3,GInhibitorofH+-PumpProtectorsofMucosaAgentskill

HPⅠ.AntacidsMechanism:Alkalizers——ToNeutralizeHClAgents:Mg(OH)2Al(OH)3CaCO3NaHCO3AdverseEffect:Systemicalkalosis,Diarrhea,CO2ConstituentNeutralizingCapacitySaltFormedinStomachSolubilityofSaltAdverseEffectsNaHCO3HighNaClHighSystemicalkalosis,fluidretentionCaCO3ModerateCaCl2ModerateHypercalcemia,nephrolithiasis,milk-alkalisyndromeAl(OH)3HighAlCl3LowConstipation,hypophosphatemia;drugadsorptionreducesbio-availabilityMg(OH)2HighMgCl2LowDiarrhea,hypermagnesemia(inpatientswithrenalinsufficiency)MajorconstituentsofantacidsⅡ.1.⑴H2-RAntagonists

Mechanism:PharmacologicEffects:Basalgastricacid

nocturnalsecretionAgents:Cimetidine，Ranitidine，FamotidineAdverseEffect:Gynecomastia,prolactin,CYP450,headacheⅡ.1.⑵AntimuscarinicAgentsMechanism:BlockingM3-RonParietalCell,M-RonECLcellandGcellPharmacologicEffects:HCl

spasmolysisAgents:Atropine，ProbanthinePirenzepine-M1,M2-RselectionAdverseEffect:Ⅱ.1.⑶AntagonistofG-RMechanism:CompetingGastrin-RonParietalCellPharmacologicEffects:HCl

Mucosal

Agents:ProglumideAdverseEffect:Ⅱ.2.ProtonPumpInhibitorsMechanism:H+,K+-ATPase H+K+

PharmacologicEffects:HCl&Hp

Agents:Omeprazole（losec）LansoprazolePantoprazole，RabeprazoleAdverseEffect:Ⅲ.MucosalProtectiveAgentsDerivativesofProstaglandin:Misoprostol(PGE1),EnprostilMechanism:

HCl;PepsinMucus-HCO3-;CytoprotectiveeffectPharmacologicEffects:PreventionofulcersiducedbyNSAIDsContraindication：Womenwithchildbearing2.

SucralfateMechanism:

Polymerization&gelatinebarrierPGE2

Mucus-HCO3-

HpPharmacologicEffects:EffectiveinDuodenalUlcersNotice:AcidpHEmptystomach3.

CBS

Mechanism:

PepsinPGE1

Mucus-HCO3-

CoatingHp（disputed）4.

Teprenone5.MarzuleneⅣ.Anti-HpDrugs90%DU,70%GU---Helicobacterpylori(G-)Anti-UlcerAgents:BismuthCompoundsProtonPumpInhibitorssucralfateAntibacterialDrugs:AmoxicillinGentamicinMetronidazoleCombinationTherapyTherapyoftriadOverseaPPI+two

AntibacterialDrugsDomesticCBS+PPIorH2-RAntagonist+AntibacterialDrugDigestionAidsContentsofDigestiveJuice:PepsinPancreatinHelpfulBacteriasinBowel:bioferminAntiemeticDrugsandDrugsPromotingGastrointestinalMotilityMedullaOblongata

VomitingCenterStimuliChemoreceptorTriggerZoneStomachandAbdomminalMusculaturePathogenesisofVomiting延髓呕吐中枢高级中枢催吐化学感受区(5-HT3,D2,M1)孤束核(5-HT3,D2,M,H1)咽喉胃肠道（5-HT3）迷走神经H1,M小脑内耳前庭前庭神经刺激刺激化学刺激物晃动AntagonistsofReceptorsof

H1:

Nucleusoftractus

solitarius,vestibulocerebellarpathway——

Diphenhydramine,DimenhydrinateM:Nucleusoftractus

solitarius,CTZ——ScopolamineD2

:CTZ,Nucleusoftractus

solitarius,Stomach,Smallintestine——Thiethylperazine，Metoclopramide

5-HT3

:Stomach,Smallintestine,CTZ,Nucleusoftractus

solitarius——Ondansetron，Granisetron

Prokinetics：Metoclopramide

BlockingGastrointestinalDomperidone

D2-RCisapride：Achrelease↑AntidiarrhealDrugsand

AdsorbentsOpiumpreparationandDerivativesOpiatereceptorsinGastrointestinaltract→tone↑motility↓（μ），secretion↓（δ），Achrelease↓Loperamide：DerivativesofHaloperidolAstringentsTannalbinBismuthsubsalicylate,BismuthsubcarbonateAdsorbantsMedicinalCharcoalKaolinLaxativesContactcatharticsIrritantorstimulant→intestinalmotility↑Phenolphthalein,Rhubarb,Senna,CastoroilOsmoticlaxativesnonabsorbable→distending→peristalsisMgSO4,Na2SO4,Lactulose,Celluloses

Surface-activeagentsLubricating,StoolsoftenLiquidparaffinCholereticdrugCholicAcidHMG-CoA

reductase(ratelimiting