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AgentstoTreatGastricAcidityandGastroesophagealRefluxDisease

(GERD)PresentedbyAbbyRothAgentstoTreatGastricAciditOverviewIntroductionSymptomsCausesPepticUlcerDiseaseH.pyloriNSAIDsGERDTreatmentsOverviewIntroductionWhoisAffected?GastricacidityandGERDaffectspeopleofallages,races,andgenderWhoisAffected?GastricaciditSymptomsHeartburnAcidIndigestionRegurgitationNauseaSymptomsHeartburnRegurgitationSymptomsContinuedHoarsenessSoreThroatChestPainBadBreathDryCoughAsthma*SymptomsContinuedHoarsenessSymptomsinChildrenVomitingCoughingBreathingProblemsSymptomsinChildrenVomitingAcid-PepticDisordersPepticUlcerDiseaseOccurswhenthereisanimbalancebetweenthemucosaldefensefactorsandtheacidandpepsin.Acid-PepticDisordersPepticUlHelicobacterpyloriInfectionCauses80%ofpepticulcersSurvivestheacidenvironmentbyattachingtothesugarmoleculesthatlinethestomachwallUsesthemucuslayerasprotectionHelicobacterpyloriInfectionCH.pyloriProducelargeamountsofureaseUreaseH203NH3+CO2UreaH.pyloriProducelargeamountsH.pyloriSecretproteinsandtoxinsthatinteractwiththestomach’sepithelialcellsLeadstoinflammationanddamageH.pyloriSecretproteinsandtNSAIDsAspirin,Ibuprofen,NaproxenCanhaveanaffectatverylowdosesSuppressescylooxygenase-1DecreaseproductionofprostaglandinsNSAIDsAspirin,Ibuprofen,NaprWhatisGERD?Conditionwherethestomachacid/contentispushedbackor“refluxed”intotheesophagusAffects10millionAmericansApproximately7%havedailysymptomsLinkWhatisGERD?ConditionwheretGERDvs.NERDPatientssufferingsymptomsareplacedintwogroupsNon-erosiverefluxdisease,orNERDErosiveesophagitisErosiveesophagitisischaracterizedbyswellingandInflammation Barrett’sEsophagusPrecursortoEsophagealCancerGERDvs.NERDPatientssufferinCausesofGERDAbnormalitieswiththeLowerEsophagealSphincter,orLESStomachAbnormalitiesHiatalherniaLinkCausesofGERDAbnormalitieswiCauses

MedicationsNSAIDsCalciumChannelBlockers(highbloodpressure,angina)CausesMedicationsMedicationsAnticholinergics(urinarytractdisorders)BetaAdrenergicAgonists(asthma)Dopamine(Parkinson’sdisease)MedicationsAnticholinergics(uCausesFoodandDrinksCarbonatedbeveragesChocolateAlcoholCitrusFruitsCoffeeorTeaFattyfoodsContainingtomatoesMintSpicyFoodCausesFoodandDrinksCausesSmokingDamagesmucusmembranesImpairsmusclereflexesinthethroatIncreasesacidsecretionReducesLESfunctionandsalivationCausesSmokingCausesObesityLayingdownafteralargemealEatingclosetobedtimeExerciseCausesObesityReleaseofGastricAcidReleaseofGastricAcidReleaseofGastricacidHistaminestimulatesacidreleasebyinteractingwiththehistaminereceptor,H2AcetylcholineactivatesthecholinergicreceptorsGastrinisreleasedwhenfoodispresentinthestomachReleaseofGastricacidHistamiTreatments

AntacidsAlginatesSucralfateProtonPumpInhibitorsHistamineH2-RecptorAntagonistsProkineticsNewTreatmentsTreatments AntacidsAntacidsQuickbutshorttermBuffergastricacid,increasingthepHNeutralizeacidbythefollowingreactionAl(OH)3+3HCl AlCl3+3H2OAntacidsQuickbutshorttermAntacidsMaaloxAl(OH)3(aluminumhydroxide),Mg(OH)2(magnesiumhydroxide)AntacidsMaaloxAntacidsTumsCaCO3(calciumcarbonate)AntacidsTumsAntacidsPepto-BismolC7H5BiO4(bismuthsubsalicylate)AntacidsPepto-BismolAntacidsAlka-SeltzerNaHCO3(sodiumbicarbonate)AntacidsAlka-SeltzerAlginatesAlginatesUsuallycombinedwithanantacidFormsprotectivebarrierontopofgastriccontentsGavisconSodiumAlginate,SodiumBicarbonate,andCalciumCarbonateLinkAlginatesAlginatesAlginatesPolysaccharidefoundinthecellwallsofbrownalgaeSodiumalginateisthesodiumsaltofalginicacidAlginatesPolysaccharidefoundAlginicAcidAlginicAcidSucralfateReactswithstomachacidtofromacrosslinkedviscouspolymerthatactsasanacidbufferCanbindtoproteinsonthesurfaceofanulcertopreventfurtheraciddamageHasbeenshowntoaidinhealingbypromotingepidermalgrowthfactorsandprostaglandinsSucralfateReactswithstomachSucralfate(Carafate)Sucralfate(Carafate)ProtonPumpInhibitorsProtonpumpinhibitors(PPIs)Inhibitsthegastricacidpump,H+/K+ATPaseAreprodrugsProtonPumpInhibitorsProtonpPPIsDiffuseintotheparietalcellsofthestomachandaccumulatesActivatedbyproton-catalyzedformationofsulfenicacidThispreventsthedrugfromdiffusingoutActivatedformthenirreversiblybindsatthesulfhydrylgroupsofthecysteinsoftheH+/K+ATPaseLinkPPIsDiffuseintotheparietalCysteineCysteineGERD胃食管反流英文版课件PPIsRabeprazol(Acipex)PPIsRabeprazol(Acipex)PPIsLansoprazole(Prevacid)PPIsLansoprazole(Prevacid)PPIsEsomeprazole(Nexium)PPIsEsomeprazole(Nexium)PPIsOmeprazole(Prilosec)Omeprazole/sodiumbicarbonate(Zegerid)PPIsOmeprazole(Prilosec)OmeprPPIsPantoprazole(Protonix)PPIsPantoprazole(Protonix)TreatmentsHistamineH2-recptorantagonists(H2RAs)Thehormone,histaminestimulatesthereleaseofacidbyinteractingwiththehistaminereceptor,orH2receptor.InhibitacidsecretionbycompetitivelyandreversiblyblockingparietalcellH2-receptorsLesspotentthenPPI’sTreatmentsHistamineH2-recptorAgonistvs.AntagonistAnagonistisadrugthatproducesthesameresponseatareceptorasthenaturalmessengerAnantagonistisadrugwhichbindstoareceptorwithoutactivatingit,preventanagonistornaturalmessengerfrombindingAgonistvs.AntagonistAnagoniHistamineHistamineGERD胃食管反流英文版课件H2RAsCimetidine(Tagamet)H2RAsCimetidine(Tagamet)H2RAsNizatidine(Axid)H2RAsNizatidine(Axid)OtherH2RAsRanitidineHCl(Zantac)Famotidine(Pepcid)OtherH2RAsRanitidineHCl(ZanTreatmentsProkineticsIncreaseLESfunctionReleasestomachcontentsbyActivatingserotoninreceptorsActingondopaminergicreceptorsTreatmentsProkineticsProkineticsMetoclopramide(Reglan,Degan)ProkineticsMetoclopramide(RegProkineticsDomperidone(Motilium,Costi)ProkineticsDomperidone(MotiliProkineticsCisapride(Prepulsid,Propulsid)ProkineticsCisapride(PrepulsiProkineticsRarelyusedbecauseofseveresideeffectsFatigueTremorsParkinsonismTardiveDyskinesiaSeverecardiaceventsProkineticsRarelyusedbecausNewTreatmentsCholecystokinin2receptorantagonists(CCK2)Potassiumcompetitiveacidblockers(P-CABs)NewTreatmentsCholecystokinin2TreatmentsCholecystokinin2receptorantagonists(CCK2)BlocktheCCK2receptorsinhibitingacidsecretionStillinclinicaltrialsBestuseincombinationwithPPI’sTreatmentsCholecystokinin2recCCK2ItriglumideCCK2ItriglumideCCK2Z-360CCK2Z-360TreatmentsPotassiumcompetitiveacidblockers(P-CABs)TargetH+/K+ATPaseIonicallybindstotheprotonpumpSpecificfortheK+bindingregionandpreventsacidsecretionBindsreversiblyStillinclinicaltrialsTreatmentsPotassiumcompetitivP-CABsRevaprazanP-CABsRevaprazanP-CABsSoraprazanP-CABsSoraprazanTreatmentforH.pyloriAmoxicillin+clarithromycin+protonpumpinhibitorMetronidazole+clarithromycin+protonpumpinhibitorBismuthsubsalicylate+metronidazole+tetracycline+protonpumpinhibitorTreatmentforH.pyloriAmoxiciAssignedReadingVesper,J.B.etall,GastroesophagealRefluxDiesease,IsthereMoretotheStory?,ChemMedChem(2008),3,552-559.AssignedReadingVesper,J.B.eHomeworkQuestionsWhatisanantagonistandhowdotheH2RAs(histaminereceptorantagonists)actasone?Explaintheprecisebiologicalmechanismwherebyprokineticsachievetheireffect,includingthereceptorstheyactupon.Aretheyagonistsorantagonists?Ofwhichchemicalmessenger?Whatisaprodrug?WhatcausesthePPI’stobecomeanactivedrug?BacteriaintheupperGItractmayplayaroleinGERD.Explain.HomeworkQuestionsWhatisanaReferencesBak,Young-Tae.ManagementStrategiesforGastroesophagealRefluxDisease.JournalofGastroenterologyandHepatology(2004),19,S49-S53.Horn,J.UnderstandingthePharmacodynamicandPharmacokineticDifferencesbetweenprotonpumpinhibitors-focusonpKaandmetabolism.AP&T(2006),2,340-350.Pettit,M.TreatmentofGastroesophagealRefluxDisease.PharmWorldSci(2005)27,432-435.Vakil,N.,NewPharmacologicalAgentsfortheTreatmentofGastroesophagealRefluxDisease.AP&T(2006),19,1041-1049.Vesper,J.B.etall,GastroesophagealRefluxDiesease,IsthereMoretotheStory?,ChemMedChem(2008),3,552-559.GoodmanandGilmanpg967-980.Patrickpg643-671.ReferencesBak,Young-Tae.ManAgentstoTreatGastricAcidityandGastroesophagealRefluxDisease

(GERD)PresentedbyAbbyRothAgentstoTreatGastricAciditOverviewIntroductionSymptomsCausesPepticUlcerDiseaseH.pyloriNSAIDsGERDTreatmentsOverviewIntroductionWhoisAffected?GastricacidityandGERDaffectspeopleofallages,races,andgenderWhoisAffected?GastricaciditSymptomsHeartburnAcidIndigestionRegurgitationNauseaSymptomsHeartburnRegurgitationSymptomsContinuedHoarsenessSoreThroatChestPainBadBreathDryCoughAsthma*SymptomsContinuedHoarsenessSymptomsinChildrenVomitingCoughingBreathingProblemsSymptomsinChildrenVomitingAcid-PepticDisordersPepticUlcerDiseaseOccurswhenthereisanimbalancebetweenthemucosaldefensefactorsandtheacidandpepsin.Acid-PepticDisordersPepticUlHelicobacterpyloriInfectionCauses80%ofpepticulcersSurvivestheacidenvironmentbyattachingtothesugarmoleculesthatlinethestomachwallUsesthemucuslayerasprotectionHelicobacterpyloriInfectionCH.pyloriProducelargeamountsofureaseUreaseH203NH3+CO2UreaH.pyloriProducelargeamountsH.pyloriSecretproteinsandtoxinsthatinteractwiththestomach’sepithelialcellsLeadstoinflammationanddamageH.pyloriSecretproteinsandtNSAIDsAspirin,Ibuprofen,NaproxenCanhaveanaffectatverylowdosesSuppressescylooxygenase-1DecreaseproductionofprostaglandinsNSAIDsAspirin,Ibuprofen,NaprWhatisGERD?Conditionwherethestomachacid/contentispushedbackor“refluxed”intotheesophagusAffects10millionAmericansApproximately7%havedailysymptomsLinkWhatisGERD?ConditionwheretGERDvs.NERDPatientssufferingsymptomsareplacedintwogroupsNon-erosiverefluxdisease,orNERDErosiveesophagitisErosiveesophagitisischaracterizedbyswellingandInflammation Barrett’sEsophagusPrecursortoEsophagealCancerGERDvs.NERDPatientssufferinCausesofGERDAbnormalitieswiththeLowerEsophagealSphincter,orLESStomachAbnormalitiesHiatalherniaLinkCausesofGERDAbnormalitieswiCauses

MedicationsNSAIDsCalciumChannelBlockers(highbloodpressure,angina)CausesMedicationsMedicationsAnticholinergics(urinarytractdisorders)BetaAdrenergicAgonists(asthma)Dopamine(Parkinson’sdisease)MedicationsAnticholinergics(uCausesFoodandDrinksCarbonatedbeveragesChocolateAlcoholCitrusFruitsCoffeeorTeaFattyfoodsContainingtomatoesMintSpicyFoodCausesFoodandDrinksCausesSmokingDamagesmucusmembranesImpairsmusclereflexesinthethroatIncreasesacidsecretionReducesLESfunctionandsalivationCausesSmokingCausesObesityLayingdownafteralargemealEatingclosetobedtimeExerciseCausesObesityReleaseofGastricAcidReleaseofGastricAcidReleaseofGastricacidHistaminestimulatesacidreleasebyinteractingwiththehistaminereceptor,H2AcetylcholineactivatesthecholinergicreceptorsGastrinisreleasedwhenfoodispresentinthestomachReleaseofGastricacidHistamiTreatments

AntacidsAlginatesSucralfateProtonPumpInhibitorsHistamineH2-RecptorAntagonistsProkineticsNewTreatmentsTreatments AntacidsAntacidsQuickbutshorttermBuffergastricacid,increasingthepHNeutralizeacidbythefollowingreactionAl(OH)3+3HCl AlCl3+3H2OAntacidsQuickbutshorttermAntacidsMaaloxAl(OH)3(aluminumhydroxide),Mg(OH)2(magnesiumhydroxide)AntacidsMaaloxAntacidsTumsCaCO3(calciumcarbonate)AntacidsTumsAntacidsPepto-BismolC7H5BiO4(bismuthsubsalicylate)AntacidsPepto-BismolAntacidsAlka-SeltzerNaHCO3(sodiumbicarbonate)AntacidsAlka-SeltzerAlginatesAlginatesUsuallycombinedwithanantacidFormsprotectivebarrierontopofgastriccontentsGavisconSodiumAlginate,SodiumBicarbonate,andCalciumCarbonateLinkAlginatesAlginatesAlginatesPolysaccharidefoundinthecellwallsofbrownalgaeSodiumalginateisthesodiumsaltofalginicacidAlginatesPolysaccharidefoundAlginicAcidAlginicAcidSucralfateReactswithstomachacidtofromacrosslinkedviscouspolymerthatactsasanacidbufferCanbindtoproteinsonthesurfaceofanulcertopreventfurtheraciddamageHasbeenshowntoaidinhealingbypromotingepidermalgrowthfactorsandprostaglandinsSucralfateReactswithstomachSucralfate(Carafate)Sucralfate(Carafate)ProtonPumpInhibitorsProtonpumpinhibitors(PPIs)Inhibitsthegastricacidpump,H+/K+ATPaseAreprodrugsProtonPumpInhibitorsProtonpPPIsDiffuseintotheparietalcellsofthestomachandaccumulatesActivatedbyproton-catalyzedformationofsulfenicacidThispreventsthedrugfromdiffusingoutActivatedformthenirreversiblybindsatthesulfhydrylgroupsofthecysteinsoftheH+/K+ATPaseLinkPPIsDiffuseintotheparietalCysteineCysteineGERD胃食管反流英文版课件PPIsRabeprazol(Acipex)PPIsRabeprazol(Acipex)PPIsLansoprazole(Prevacid)PPIsLansoprazole(Prevacid)PPIsEsomeprazole(Nexium)PPIsEsomeprazole(Nexium)PPIsOmeprazole(Prilosec)Omeprazole/sodiumbicarbonate(Zegerid)PPIsOmeprazole(Prilosec)OmeprPPIsPantoprazole(Protonix)PPIsPantoprazole(Protonix)TreatmentsHistamineH2-recptorantagonists(H2RAs)Thehormone,histaminestimulatesthereleaseofacidbyinteractingwiththehistaminereceptor,orH2receptor.InhibitacidsecretionbycompetitivelyandreversiblyblockingparietalcellH2-receptorsLesspotentthenPPI’sTreatmentsHistamineH2-recptorAgonistvs.AntagonistAnagonistisadrugthatproducesthesameresponseatareceptorasthenaturalmessengerAnantagonistisadrugwhichbindstoareceptorwithoutactivatingit,preventanagonistornaturalmessengerfrombindingAgonistvs.AntagonistAnagoniHistamineHistamineGERD胃食管反流英文版课件H2RAsCimetidine(Tagamet)H2RAsCimetidine(Tagamet)H2RAsNizatidine(Axid)H2RAsNizatidine(Axid)OtherH2RAsRanitidineHCl(Zantac)Famotidine(Pepcid)OtherH2RAsRanitidineHCl(ZanTreatmentsProkineticsIncreaseLESfunctionReleasestomachcontentsbyActivatingserotoninreceptorsActingondopaminergicreceptorsTreatmentsProkineticsProkineticsMetoclopramide(Reglan,Degan)ProkineticsMetoclopramide(RegProkineticsDomperidone(Motilium,Costi)ProkineticsDomperidone(MotiliProkineticsCisapride(Prepulsid,Propulsid)ProkineticsCisapride(PrepulsiProkineticsRarelyusedbecauseofseveresideeffectsFatigueTremorsParkinsonismTardiveDyskinesiaSeverecardiaceventsProkineticsRarelyusedbecausNewTreatmentsCholecystokinin2receptorantagonists(CCK2)Potassiumcompetitiveacidblockers(P-CABs)NewTreatmentsCholecystokinin2TreatmentsCholecystokinin2receptorantagonists(CCK2)BlocktheCCK2receptorsinhibitingacidsecretionStillinclinicaltrialsBestuseincombinationwithPPI’sTreatmentsCholecystokinin2recCCK2ItriglumideCCK2ItriglumideCCK2Z-360CCK2Z-360TreatmentsPotassiumcompetitiveacidblockers(P-CABs)TargetH+/K+ATPaseIonicallybindstotheprotonpumpSpecificfortheK+bindingregionandp

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