药理学教学课件：4 digestive drugs 1.5

DrugsusedtotreatpepticulcerPepticulceroccursinthatpartofthegastrointestinaltractwhichisexposedtogastricacidandpepsin,i.e.,thestomachandduodenum.

Pepticulcerresultsprobablyduetoanimbalancebetweentheaggressive

(acid,pepsinandHelicobacterpylori)andthedefensive(gastric

mucus-bicarbonatebarrier,prostaglandins,bloodflow,innateresistanceofthemucosalcells)factors.

RegulationofgastricacidsecretionGastricacidsecretionbyparietalcellsofthegastricmucosaisstimulatedbyacetylcholine,histamine,andgastrinThereceptor-mediatedbindingofacetylcholine,histamine,orgastrinresultsintheactivationofproteinkinases,whichinturnstimulatestheH+/K+-ATPase(protonpump)tosecretehydrogenionsinexchangeforK+intothelumenofthestomach.Incontrast,receptorbindingofprostaglandinE2andsomatostatindiminishgastricacidproduction.Drugsusedinthetreatmentofacidpepticdisordersmaybedividedintothreeclasses:

agentsthatreduceintragastricacidityagentsthatpromotemucosaldefenseanti-helicobacterpylori

drugsI.agentsthatreduceintragastricacidity1.Reduceintragastricacidity

1)H2-receptorantagonist:Cimetidine2)protonpumpinhibitors:Omeprazole3)muscarinicantagonist:Pirenzepine2.Antacids:Mg(OH)2,Al(OH)3,NaHCO3II.Promotemucosaldefense

mucosalstrengtheners:MisoprostolIII.Anti-Helicobacterpylori

drugsI.Antacids

areweakbasesthatneutralizegastricacidtoformasaltandwaterandraisepHofgastriccontents.Antacidproductsvarywidelyintheirchemicalcomposition,acid-neutralizingcapacity,sodiumcontent,palatability,andprice.Theacid-neutralizingabilityofanantaciddependsonitscapacitytoneutralizegastricHClandonwhetherthestomachisfullorempty(fooddelaysstomachemptying,allowingmoretimefortheantacidtoreact).EffectadverseeffectAttentionMg(OH)2strong++,fastdiarrhea

kidneyexcretionAl(OH)3strong,slowconstipationkidneyexcretionMg2Si3O8weak++,slowdiarrheakidneyexcretionCaCO3strong+,fast,longhypercalcaemia

nolongtermuseNaHCO3strong,fast,shortalkalemiaseldomuseAntacidcombination:

Mg(OH)2+Al(OH)3

fast+slowsustainedeffectdiarrhea+constipationannuleachother’sadverseeffectsandbowelmovementmaybeleastaffected.

ClinicalUse:

Pepticulcer:

nolongerusedforhealingpeptideulcerbecausetheyareneededinlargeandfrequentdoses,areinconvenient,cancauseacidrebound,bowelupsetandhavepoorpatientacceptability.Employedonlyforintercurrentpainrelief.Theevidenceforefficacyinthetreatmentofacutegastriculcersislesscompelling;therefore,theseagentsareusedaslast-linetherapy.II.Acidsecretioninhibitors:

H2-receptorantagonist:CimetidineProtonpumpinhibitors:OmeprazoleMuscarinicantagonist:Pirenzepine

H2-receptorantagonist:

Cimetidine,Famotidine,Ranitidine

Pharmacokinetics

rapidlyabsorbedundergofirst-passhepaticmetabolismresultinginabioavailabilityofapproximately50%.clearedbyacombinationofhepaticmetabolism,glomerularfiltration,andrenaltubularsecretion.H2-receptor

antagonistsexertcompetitiveinhibitionontheparietalcellH2-receptor.Theseagentscompletelyinhibitgastricacidsecretioninducedbyhistamineorgastrin.However,theyonlypartiallyinhibitgastricacidsecretioninducedbyacetylcholine.Allphases(basal,neurogenic,gastric)ofsecretionaresuppresseddosedependently.Clinicaluses:

arewidelyusedinconditionsinwhichitisprofitabletosuppressgastricacidsecretion.Thoughotherformsoftherapyaresometimesequallyeffective,theH2blockersarepreferredbecauseofconvenienceandgoodpatientacceptability.

Pepticulcerdisease

Nocturnalacidsuppressionaffordseffectiveulcerhealinginthemajorityofpatientswithuncomplicatedgastricandduodenalulcer.Alltheagentsmaybeadministeredoncedailyatbedtimeforacute,uncomplicatedulcer,resultinginulcerhealingratesgreaterthan80-90%after6-8weeksoftherapy.Clinicaluses:

Gastrointestinalbleeding,StressulcersandgastritisCause:hepaticcoma,severeburns,traumaetc.significantlyreducetheincidenceofbleedingfromstress-relatedgastritis.Aregiveniv.,eitherasintermittentinjectionsorcontinuousinfusion.

Gastroesophagealrefluxdiseaseaffordsymptomaticreliefandfacilitatehealingofesophagealerosionsbyreducingacidityofgastriccontentsthatarerefluxed.TheyareindicatedonlyinmildGERD

Interactions:

CimetidineinhibitscytochromeP450andcanslowmetabolism(and,thus,potentiatetheaction)ofseveraldrugs(forexample,warfarin,diazepam,phenytoin,quinidine,carbamazepine),sometimesresultinginseriousadverseclinicaleffects.

Themostcommonsideeffectsareheadache,dizziness,diarrhea,andmuscularpain.Centralnervoussystem

Mentalstatuschanges(confusion,hallucinations,agitation)mayoccurespeciallyinelderlypatients,inthosewithrenalorhepaticimpairmentorafterintravenousadministrationAdverseeffect:Sideeffectsoccuronlyinasmallnumberofpatientsandgenerallydonotrequirediscontinuationofthedrug.EndocrineeffectsWhenusedlongtermorinhighdoses,itmaycausegynecomastiaorimpotenceinmenandgalactorrheainwomen.(cimetidine)

Pregnancyandnursingmothersaresecretedintobreastmilkorcrossplacenta,thereforeshouldnotbeadministeredtopregnantwomenornursingmotherunlessabsolutelynecessary.

ProtonPumpInhibitors(PPI)

OmeprazoleisthefirstofaclassofdrugsthatbindtotheH+/K+-ATPaseenzymesystem(protonpump)oftheparietalcell,therebysuppressingsecretionofhydrogenionsintothegastriclumen.FouradditionalPPIsarenowavailable:lansoprazole,rabeprazolepantoprazole

andesomeprazoleMechanismcauseirreversibleinhibitionofH+/K+ATPase

thatisresponsibleforH+secretionfromparietalcell.Thisinhibitionishighlyspecificandlocalized.inhibitthefinalcommonstepingastricacidsecretionandhaveovertakenH2blockersforacid-pepticdisorders.protectinggastricmucosaanti-HpyloriPharmacodynamics:Itisapowerfulinhibitorofgastricacidsecretion,bothrestingaswellasthatstimulatedbyanyofthesecretagogues,withoutmucheffectonpepsin,intrinsicfactor,juicevolumeandgastricmotility.Havealongdurationofaction.PromoteeradicationofHpylori

PPIpromoteeradicationofHpylori.mechanisms:DirectantimicrobialpropertiesByraisingintragastricpH–loweringtheminimalinhibitoryconcentrationsofantibioticsagainstHpylori.

Clinicaluses:

Pepticulcer

equallyormoreeffectivethanH2blockers.reliefofpainisrapidandexcellent.PPIareanintegralcomponentofanti-Hpylori

therapy.PPIarethedrugsofchoiceforNSAIDsinducedgastric/duodenalulcers.

Refluxgastroesophagitis

totreatmoderateandsevereGERD

Zollinger-ellisonsyndrom(gastrinoma)

Adverseeffects:nausea/vomiting/headache

OmeprazoleinhibitP450enzymesystem,reducingthemetabolismofdrugssuchas

warfarin,phenytoin,diazepam

Muscarinicantagonists(anticholinergics)

PirenzepineselectivelyblocksM3-receptoronGastricgland.inhibitsgastricacidandpepsinsecretionwithoutproducingtypicalatropinicsideeffects.nearlyequallyeffectiveascimetidineinrelievingpepticulcerpainandpromotingulcerhealing.

Ⅲ.Mucosalprotectiveagents

Misoprostol

ProstaglandinE2,producedbythegastricmucosa,inhibitssecretionofHClandstimulatessecretionofmucusandbicarbonate(cytoprotectiveeffect).Adeficiencyofprostaglandinsisthoughttobeinvolvedinthepathogenesisofpepticulcers.

Misoprostol

isamethylanalogofprostaglandinE.

Pharmacodynamics:

Inhibitbothbasalandmeal-stimulatedsecretion

hasmucosalprotectivepropertiesstimulatemucusandbicarbonatesecretionenhancemucosalbloodflow

Itimitatestheactionofendogenousprostaglandin(PGE2andPGI2)inmaintainingtheintegrityofgastroduodenalmucosalbarrierandpromoteshealing.ClinicalUses:

ItislesseffectivethanH2antagonistsandthePPIsforacutetreatmentofpepticulcers.MisoprostolaswellassomePPIs,areapprovedforpreventionofgastriculcersinducedbyNSAIDs.

MisoprostolreducestheincidenceofNSAID-inducedulcerstolessthan3%andtheincidenceofulcercomplicationsby50%.

Adverseeffect

DiarrheaCrampingabdominalpainStimulatesuterinecontraction,itshouldnotbeusedduringpregnancyorinwomenofchildbearingpotential.

Ⅳ.

Anti-Helicobacterpylori

drugs

H.pyloriisagramnegativebacillusuniquelyadaptedtosurvivalinthehostileenvironmentofstomach.

H.pylori

isanimportantcontributortothecausationofchronicgastritis,dyspepsia,pepticulcer.

Over70%ofpepticulcerarecausedbyinfectionwiththebacterium