药理考试题09中枢提纲

药理ZCentralnervousdepressantsCycleofSleep

CHAPTERREM(rapideyemovementsleep),24%ofthetotalsleep,aboutlasts20min.NREM(non-rapideyemovementsleep),70%-75%oftotalsleep,about80-120min.Stage1“descending”sleep,dozinganddrowsiness.Stage2unequivocalmajorfraction,50%ofsleep.Stage3deepsleeptransition.Stage4“cerebral”sleepslowwovesleep,somnambulismandInman,thephysiologicalsleepconsistsof4-5cyclesofalternativeREMandNREMsleep.SpecificityofSedative-hypnoticdrugsGradeddose-dependentdepressionofCNSfunctionTypeA sedationhypnosisanaesthesiacomaparalysisfailure.TypeB sedationhypnosisanaesthesia.metabolictolerance(enzymeinducer)pharmacodynamictolerancePsychologicaldependencePhysiologicaldependence

Section1 diazepam（，安定）ClassificationsofBZsShort-acting(t1/2<6hrs):triazolam2.3±0.4Intermediate-acting(t1/2=6-20hrs):lorazepam,oxazepam,clonazepam.Long-acting(t1/2>20hrs):diazepam,chlordiazepoxide,flurazepam.PharmacologicalEffectsandAntianxietysmallAnxiety:nervous,anxious,Sedationandprolongphse2sleep,shortenphase4sleep,littleinfluencesonREM,littlerebound.Usedinthetreatmentofnsomniaandamnesia(短暂性缺失)Advantagesofhighertherapeuticindex,noanaesthesiainlargelowafter↓thedurationofslow-wave littleinfluencesondonotinducehepaticdependenceisAnticonvulsanteffectandantiepilepticCentralmusclerelaxation.MechanismsofactionIncreasetheefficiencyofGABA-ergicinhibition.EnhanceRaffinityforGABA.IncreasethefrequencyofCLchannelopening.NotsubstituteforGABA.Theratesoforalabsorption,Cmaxabout1hour:rapidtriazolam.Lipidsolubilityysamajorrole,centalbarrier/breastmilk.highsmaproteinbinding.AdverseDrugCNSdepression:drowsiness,fatigure,dizziness,motorincoordination.inhibitionofrespirationandcardiovascularfunction.ToleranceandDependenceTheonlyantagonist

UsefordiagnosisandtherapyofBZAshorthalflife,sorequiringrepeatedadministrationCauseabstinenceseizuresSection2PharmacokineticsAbsorbedeasilyfollowingpoandimMetaboliteslackDrugswithhighlipophilicity:livermetabolism.Drugswithlowlipophilicity:kidneyexcretion.Phenobarbitalintoxication:alkalinizationoftheurine.↑GABAergicinhibition(durationofchannelopening↑),GABAmimetic(highdose),inhibitexicitatoryneurotransmitter.SedationandhypnosisAnticonvulsantAnesthesisandadministrationpre-anesthesisthiopental（硫喷妥）EnhancetheeffectsofotherCNSdepressants.AdversedrugAfterToleranceanddependenceInhibitionofrespirationfunctionAllergicreactionHepaticenzymeSection3Chloralhydrate（水合氯醛）Hypnosisandanticonvulsanteffects.IrritationtomucousmembraneInhibitcardiacClinicalusesofsedative-ReliefofSedationandamnesiabeforemedicalandsurgicalTreatmentofepilepsyandseizureAsacomponentofbalancedanesthesia(intravenousForcontrolofethanolorothersedative-hypnoticwithdrawalFormusclerelaxationinspecificneuromuscularAsdiagnosticaidsorfortreatmentinCentralStimulantsCorticalstimulants(皮层兴奋药):Caffeine（、Methylphenidate（哌甲酯）stimulants（：、Lobeline（stimulants（：strychnine（Caffeine（PharmacologicalEffectsCNSeffectsPeripheraleffectsCardiacstimulationSmoothmusclerelaxation.MechanismsofActionAC,intracellularcAMPandantagonismofadenosine.CNSMigrainewithergotamineHeadachewithaspirinAdverseReaction

Methylphenidate(Ritalin，哌甲酯,CNSstimulationweaker,psychoticMechanismmayberelatedtoincreaseofNE,DA,5-HTrelease.CNSdepressionEnuresisinHyperkineticsyndromeinNikethamide（Stimulatestherespiratorycenterinmeddula.Activatescarotidbodyandaorticarchchemoceptors.IncreasethesensitivityofrespiratorycentertopCO2.Centralrespiratoryfailure,acutecentraldepressantsintoxication,morphineinducedrespiratorydepression,acuterespiratoryinsufficiencyinpatientswithchronicobstractivepulmonarydiseases.Dimefline（二甲Stimulatetherespiratorycenter.BlockGABA-RActivatescarotid

Lobeline（Uses:newbornsuffocation,respiratoryfailureinducedbyinfectious.diseasesinchildren,andrespiratorydepressionbyCOintoxication.TheNotspecialantagonistsforCNSOverdoseinduceIncreaseoxygenCHAPTERAntiepileptic&AnticonvulsiveDrugsSectionAntiepilepticDrugsEpilepsy癫痫Epilepsyisaheterogeneoussymptomcomplex,achronicdisordercharacterizedbytransitandrecurrentseizurewhichisepisodesofbraindysfunctionresultingfromabnormaldischargeoffocalcerebralneuronanddiffusiontonormalneuronaltissues.Somatic,sensory,automaticandpsychoticsymptoms.Etiology:incidence0.5%-1%.PrimaryepilepsySecondaryepilepsySymptomsandEEGClassificationsofepilepsyPartialseizuresSimplepartialseizuresSomaticseizures运动性发作Sensoryseizures感觉性发作Automaticseizures植物神经性发作Psychoticseizures精神性发作ComplexpartialseizuresPsychomoticseizuresSensoryseizuressecondarilysimpleseizure继发于单纯部分性发作的意识Generalizedseizures(1)Generalizedtonic-clonicseizures(gradmal)：强直-阵挛性发作（大发作(2)Absenceseizures(petitmal)：失神发作（小发作(3)Tonicseizures：强直发作(4)Myoclonicseizures：阵挛发作(5)AtonicseizuresStatusepilepticus：AtypicalInfantilspasm:ExperimentalmodelsFocusseizuremodels:Co,All,Electricstimulate(alelectroshockseizure,MES):gradPentylenetetrazol(PTZ):absenceHistoryofAntiepilepticDrugs1857potassiumbromide191235ogsofphenobarbital1938phenytoinDevelopmentinthepast4decades:valproate(64),Antiepilepsrin(75)Carbamazepin(80),TheClassificationsofantiepilepticsAnticonvulsivebarbituratesNewActionMechanismsofAntiepilepticToabolishorattenuatetheseizurediffusionbymodificationofionchannelinhibitdischargeininhibitdiffusioninnormalneuron:inhibitoryofNa+andCa2+ToaffectinhibitorysysteminvolvingGABA-ergicEnhancementofGABA-ergicDirectactionontheGABA-R-chloridechannelActionsonthereuptakeormetabolismofDiminutionofglutaminergicAMPA-RblockadeNMDA-RPhenytoinSodium（Dilantin,大仑丁MechanismsofPromotethestablizationoftheBlockvoltage-sensitiveNa+channel(use-dependenteffect)andblockCa2+channel,inhibitPotentiateGABAinhibitingfunction.ClinicalUsesEpilepsy:drugchoiceforgeneralizedtonic-clonicseizures,simplepartialseizuresandcomplexpartialseizuresexceptabsenceseizure.Centralpainsyndrome:neuralgias,trigeminalAbsorptionpKa8.3,slowandunpredictableafteroraladministration,Fvariable,tmaxaround3-12hrs,Css5-7d,stimulationbyoralandim.DistributionPPBR90%,Vd0.6-Metabolismbyhepatomicroenzymesabout60%-70%,5%Eliminationisdose-dependent,smaconcentrationlessthan10g/mL,FOK,6-24hrs,morethan10g/mL,OOK,t1/220-60hrs.AdverseReactionsAdversereactionrelatedtodrugsmaconcentration.Cmax(E)10g/mL;CTox20g/mLGastrointestinalGingivalhypersiabyinhibitingthetheinductionofcollagenasebyCNSsymptoms20g/mL,﹥40g/mL:psychotic,﹥50g/mL:Bloodsystem:leukopenia,agranulocytosis,megalblasticanemia,asticanemia:folicaciddyefficacy.Bonesystemand togenesis,(fetalhydantoinsyndrome)arrhythmia,andhypotension.DrugIn Hepatomicrosomalenzymeinducer:Glucocorticoids,carbamazepine,vitaminBroad–spectrumantiepilepticagentinhibitNa+potentiateGABAinhibitoryfunction.ActionsandUsesAntiepilepticeffectsgradmal,partialseizureswithcomplexsymptomatology,maniaandCentralalgesia:trigeminalneuralgiamoreeffectivethanphenytoin.Tmaxaround2-6hrs,PPBR80%,activecyclooxidemetabolite,t1/235hrsatbeginning,thenmayshortenby50%duetoenzymeinducer.AdverseCNSreactions:drowsness,verigo,nause,vomit,Bloodsystem:leukopenia,agranulocytosis,thrombocytopenia,asticGastrointestinalPhenobarbital(比妥Broad-spectrumandmucheffectiveingradMalandpartialseizures,butnotdrugchoiceforgradmal,alternativeandivinthetreatmentofstatusepilepticus。IncreasethethresholdandinhibitthespreadofseizuretonormaltissuePotentiatetheGABAinhibitoryfunction:pre-synapticGABA-REffectiveforalltypesofepilepsiesexceptabsencemal,moreeffectivethanphenobarbitalincomplexpartialseizures.MechanismsimilartophenobarbitalandNa+in,Primidoneismetabolizedtophenobarbitalandphenylethylmalonamides(PEMA,二酰胺asactivemetabolites.AdverseReactions depression,ataxia,drowsness,Blood thrombocytopenia,megalblasticTheonlyindication:absenceepilepsy.ReducingtheT-typeCa2+currentInhibitingGABAaminotransferaseAdverseReactionsGastricdistress,CNSdistress,bloodsystemleukopenia,thrombocytopenia,megalblasticSodiumValproate（丙戊酸钠，Valproicacid,sodiumdipropylacetate,DPA）Broad–spectrumantiepilepticagent,Effectiveforalltypesofepilepsy,moreeffectivethanethosuxide,lesseffectiveforgradmalandpartialmal.PotentiateGABAfunctionbyinhibitingGABA-aminotransferas(GABA-T)andsuccinicsemialdehydedehydrogenase(SSADH).inhibitvoltage-dependentNa+andL-Ca2+channel.AdverseReactionsHepaticCNSandbloodsystemDiazepamdrugchoiceforstatusepilepticusbyClonazepamandclobazam:absenceseizure,atonicandakineticNitrazepam:myoclonicseizure,atypicalabsenceseizureandinfantileOtherNewDrugsUsedasanadjunctagainstpartialseizuressuchascomplexpartialseizure，mechanismLamotrigine(三嗪Usedasanadd-ontherapyormonotherapyinthetreatmentofabsenceormyoclonicseizureinchildren.Themechanismmayberelatedtoinhibitvoltage-dependentNa+Usedinthetreatmentofpartialseizurewithorwithoutgeneralizedtonic-clonicGeneralprinciplesanddrugchoiceforthetherapyofAccurateThedrugchoiceforinitialtreatmentofgradmalandsimplepartialseizures:carbamazepine,phenytoinforgradmalphenobarbital,primidoneandvalproicacidasalternative.Absenceseizure:ethosuxide,valproicacid,Complexpartialseizures:carbamazepine,phenytoin,promidone,valproicStatusepilepticus:Diazepamiv,clonazepam,phenytoinandTonicseizure:valproicMyoclonicseizure:glucocorticoids,Durationoftherapy:2-3Changedrugoraddaseconddrugand/orWithdrawnordiscontinue---gradually(halfMonitoringtheserumdrugSection2Barbiturates,benzodiazepines,chloralhydrate.MagnesiumSulfateActionsandRelaxantofskeletalmuscleandCNSdepressionbyivorim:anticonvulsant.mechanismduetocalciumantagonism.usedinconvulsioncausedbyeclampsia,respiratoryinhibitionandhypotensionwhenCHAPTERDRUGSUSEDINTHETREATMENTOFCENTRALNERVOUSSYSTEMDEGENRATINGDISORDERSParkinson’sdiseaseFeatures(paralysisagitants):Tremor,rigidity,akinesiaandbradykinesia(ataxia).Pathogenesis(dopamineNigro-striatal(caudatenucleus,putamenandpallidum).DAneuronsdegenerationDopaminergicneuronsactivity↓Cholinergicneuronsactivity↑OxidativestresstheorySectionOneDopaminomimeticDrugsLevodopa（左旋多巴Levodopacouldpenetratesintothebrain,whereitisdecarboxylatedtodopamine.AbsorptionReadyfromsmallintestine,tmax0.5-2hrs,affectedbygastricemptying,gastricacidandaminoacids.DistributionandAbout1%throughbloodbrainbarrierbydopadecarboxylasetodopamine,99%peripheraltransforetodopamine，alittletomelonnin,mostmetabolizedbyCOMTandMAO.Eliminationkidney,t1/21-3hrs.PharmacologicalActionsandUsesLevodopaiswidelyusedfortreatmentofalltypeofparkinsonismexceptthatassociatedwithantipsychoticdrugtherapy.MosteffectiveformildandyoungerMoreeffectiveforrigidityandakinesia,lesseffectiveforOnsetslow,2-3wkstoeffect,1-6monthstoNoeffectiveforParkinson’ssyndromecausedbyHepaticLevodopametabolizedtoadrenalinetoreceoctopamine(falseneurotransmittertheory).AdverseReactionsGastrointestinalCardiovascularAbnormalinvoluntarymovement“on-off”PsychicdisordersandOtherDecarboxylaseCarbidopa（多巴）andbenserazide（苄丝肼）CompoundPreparation:Sinemet（息宁）: Levodopa:Carbidopa(10:1) Levodopa:Benserazide(4:1)Mechanismof↑releaseDAfromdopaminegic↓reuptakeofdopaminereceptoragonismClinicalUsesParkinson’sdisease,lesseffectivethanlevodopa,andmoreeffectivethananticholinergicagents.EffectiveforParkinson’ssyndromecausedbyphenothiazines,synergizedbyl-dopa.Onsetrapidly,2wks;Lastshortabout4-8wks.AdverseLivedoPsychoticBromocriptine(溴隐亭andPergolide(培高利特LargedosestimulateD2receptorinsubstantianigro-SmalldosestimulateD2receptorintuberoinfundibular,reducePRLandGHrelease treatPDandhyperprolactinemia.MAO-Binhibitorand

BlockingtheM-R,↓cholinergicneuronsinthebasalBenzatropine(苯扎托品andtrihexyphenidyl(苯海索)ImprovethetremorandrigidityofPD,littleeffectonbradykinesiaDrugTherapyinAlzheimer’sDiseaseAlzheimer’sdisease（AD）1/2,vasculardementia（VD）1/4>65y，3.0%5.0%;6570y,3.0%;7584y,19%;>85y,47%. CourseofADisabout320yInternationalSymposiumforAlzheimer’sDisease2000:“IftheeffectivemethodsforADtreatmentisnotfound,theADpatientswillbe22000000in2025;45000000in2050inwholeClinicalMentia,cognitiondysufficiency,behavioraldisorder.PathologicalFeatures que(SP,老年斑)wasfoundinbrain,neurofibrillarytangles(,神经元纤维缠结)andselectivedeathofneronNeurontoxicationofamyloidβ-protein(Aββ-AβAChEAβTherapyforPotentiatecholinergic AChEI、M-RPotentiatorofneuronalnutritionfactorandneuroncellgrowthActivatorbrainmetabolismDrugsimprovingmicrocirculation麦角类衍生物、都可喜等Calcium

Subjectiveexperienceproducedbyexternalstimulas“psychicaladjuvantofanimperativeprotectivereflex”.PerceptionofpainReactiontopainAcutepain(sharppain),superficialpain,quickresponseofsuddenonset,conductedbyAnervefibers.Chronicpain(dullpain),morelingeringandaching,conductedbyCnerve Drugstorelieveseverepainandfeelingreactionsbypainwithoutaffectingothersenseperception,andconsciousness.SyntheticcompoundsAdditionalCharacteristics：①Potent NarcoticAddictiongesics Opium

Section morphine,codeineBenzylisoquimolinespapaverineSourceandChemistryPapaversomniferum

Morphine(AbsorptionreadyfromGItractbutfirstpasseliminationinliver,sc,imabsorbedwell,distributionnospecialaffinityforbrain,distributedthroughoutofthebody. demeththylation,20% Mainlybyglomerularfiltration,afewbymilkandbile.t1/22.5-3.5hrs.PharmacologicalActionsCNSStrongerandMoreeffectiveincontinuousdullpainthansharpintermittentEuphoria:painstillpresent,butthepatientfeelmoreSedationdrowiness,cloudingofmentation,impairmentofreasoningRespiratory↓RespiratorycenteronthebrainstemtoincreaseinCO2Dose-related,mostdeathfrommorphinepoisonduetorespiratoryAntitussive TodepressthecoughreflexoncoughcenterinOthereffects:miosisduetoexcitatoryactiononthesegmentofnucleusofoculomotornevernauseaandvomitingduetostimulatingofCTZ.SM GI:gastricsecretionandmotilitydecreased,emptyingsmallintestinerestingtoneincrease,propulsiveperistalicwavelargeintestinepassagedelay,waterCNSBiliarytract:biliarycolicbyOddiconstrict.Urinary:Urinationdifficultandurinaryretention.Bronchia:bronchiasthma2.CardiovascularDirectvesseldilatationandinducereleasingofhistamineresultinperipheralreduction,BP↓orhypotension.IncreasecerebrospinalfluidpressureduetoCO2retention,↓Respiration,CO2↑cerebralvasodilationandincreaseintracranialpressureMechanismsofActionThegesicsiteofLaminaeIIIofperiventricularandperiaqueductalgraymaterbypharmacologistsinOpioidreceptorsfoundinearly70’,andsuccessfulclonedbyforeignscientistsinEndogenousopioid peptidefoundEnkephalines:M-orL-enkephelineendorphines:β-endorphine dynorphineAFourmajoropioid(mu): gesia,respiratoryinhibition,euphoria,miosis,physical(kappa): gesia,sedationand(delta): gesia,repiratorydepression,euphoria,physical gesia,dysphoria,hallucination,cardiacinhibition,1,2, OpioidreceptorsrelatedOpioidreceptorsatthalamic,laminaeI,II,III(substantiagalatinosa)ofspinalcordandperiventricularandperiaqueductalgraymatter:intergretion,perception,reactionandOpioidreceptorsatlimbicsystemincludinglocusceruleus,anteriortemporalandorbitalfrontalcortexpartsofhypothalamusandamydala:involvesemotion,psychitricactivity,mayberelatedtoeuphoria,toleranceanddependence.OpioidreceptorsatnucleussolitariusisthelocationofcoughTheareapostremaisthechemoceptortriggerzoneerningnauseaandSubstancePandendogenousgesicsystemClinicalUsesModeratetoseverepain,painofterminalillness,postoperationpain,anginaCardiacDilatingtheperipheralvesseltoreducethePre-andpostloadofRespiratoryConstipationeffecttotreatacuteorchronicdiarrhea.AdverseDrugReactionsSideRespiratorydepression,nausea,vomiting,dizziness,mentalclouding,constipation,biliaryspasm,urinationdifficulty.Tolerance,dependence,addictionandliabilityforabuse.DrugDependencePsychicdependence用药后使人产生一种对药物欣的渴求，这种精神上不能的强烈欲Physicaldependence者一旦停药，将发生一系列生理功能紊乱，称戒断症状(abstinencesyndrome)。Addiction:Drugabuse：Euphoriaaddictionstopuseabstinencesyndromecompulsivedrug-seekingbehavior.Abstinencesyndrome:diarrhea,vomiting,chillsfever,lacrimation,rhinorrhea,tremor,abdominalcrampsandpain.NarcoticsfromGreekword“AdministrationLawforNarcotics”byThemechanismsoftoleranceanddependence:mayberelatedtothenegativefeedbackofopioidreceptorsandendogenousopioidpeptides.TheTreatmentofThegoalsofFromdependenttoMaintenanceofnoRealopioidde-addictionde-addictionorcontrolabstinencephysicalandpsychologicalpreventionofrelapse。ThetreatmentofdependenceWithdrawthepatientfromMethadoneClonidineScopolaminePreventionofreuse:Opioidantagonists-PsychologicalandothermethodstoAcuteRespiratoryinhibition,coma,pinepointpupilisthecharacter,bloodpressureandtemperaturedecrease,deathduetorespiratoryparalysis.Treatment:artificialrespiration,O2,opioidreceptorantagonists.Newborn,infant,breastingperiod,productionpain,braininjury,bronchial pulmonaryheartdisease.Codeine可待因The gesia,about1/12ofmorphine,usedinmoderateProtypecentralantitussives,usedforsuppressingSection PethidineMeperidineDOLANTIN,哌替啶,度冷丁)PharmacologicalpropertiesCNSgesia,sedationanddepressionareweakerandshorterthanmorphine.NoantitussiveSmoothmuscleWeakerthanmorphine,noantidiarrhealeffects,mayinducebiliarycolic,Noantagonisteffectofoxytocin.CardiovascularsystemsimilartomorphineClinicalUsesSevereCardiacPremedicationinanesthesiaandartificialhibernation.AdverseReactionsThesideeffectsaresimilartoCNSexcitatorysymptoms:tremor,musclespasm,reflexaugumentationorconvulsion.SomeOtherNarcotic Fentanyl（芬太尼gesiaandrespiratoryinhibition100timesthanmorphine,shortduration(1-2hrs),usedforseverepainandcombinedwithanestheticstodecreasethedoseofanesthetics,orcombinedwithdroperidolasneuroleptgesia.Methadone(Pharmacologicalpropertiessimilartomorphine,gesiaanddurationequaltomorphine,slowtoleranceandaddiction,abstinencelightusedinseverepainandfordetoxificationandformaintenanceofchronicrecingaddict.Withmoderateandagonism,weakerantagonism,usedinchronicseverepain,onethirdgesiaofmorphineandhalfrespiratoryinhibitionofmorphine.Almostnodependence.Tramadol(gesiceffectsthesamedegreeaspentazocine,alsocausePotentgesicdevelopedbyscientists,10000timesgesiaandsevereaddiction.Non-narcoticgesicsRotundin(l-tetrahydropalmtine,FromtraditionalmedicineCorydalisambigua,moderate gesiaandsedation,durationof2-5hrs,usedforchronicdullpain,visceralpain,headacheandmenstrualpain.LongtermusemayinduceextrapyramidalsyndromesTheOpioidReceptorAntagonistsNaloxoneandNaltrexoneCompetitiveantagonizetheμδκreceptorsAntagonizetheopiateAsatoolagentinpharmacological preventrelapse. injection, t1/21.1hr F30%, t1/210hr gesictherapyforpainassociatedcancerThegoalraisedbyWHOin1982“nopainforcancerpatientsuptotheyearofThePublicHealthMinistryof indicated“usingthreestep therapyforcancerpatients”in1991.Three gesiaMildpainaspirin,acetaminophen,indomethacin,Moderatepaincodeine,tramadol,fortanodyn,bucinnazine,ammophenodeine(500+Severepainmorphine,methadone,pethidine,Theprinciplesofgesiaforcancerpatients.BystepByclockByoralIfnecessary,add gesicandantiinflammtorydrugs,non-steroidalanti-infl torydrugs.Aspirin-likedrugs.Classificationindifferentclassesaccordingtotheirchemicalstructuresandtotheselectivityofcyclo-oxygenase(COX).SelectiveCOXNon-selectiveCOXinhibitorsAccordingthechemicalstructure:AnilinepyrazolonsandotherorganicacidsTheyallinhibitthebiosynthesisofprostaglandins(PGs).TheactionsofNSAIDSarerelatedtothearachidonicacid(AA)metabolism.TheDifferentbiologicalActivitiesoftheProductsof Vasodilationhyperalgesiainhibitetaggregation etaggregationandvasoconstriction. Induceinfl tionfeverand painvasodilationandhyperalgesia. Bronchialconstrictionandvasoconstriction.LTs: Allergy,bronchcoconstrictionleukocytotaxisincreasevascularpermeabilityandinduceinfl Thedifferentanti-infl torymechanismofglucocorticoidsandNSAIDs.Glucocorticoids:inhibit NSAIDs:inhibitCOXandreducetheproductionofThePharmacologicalActionsofAntipyreticBodytemperatureMechanism:inhibitsynthesisofPGsintheCNS.TheyonlydecreasethebodytemperatureofthosewhohaveafeverandnoeffectonnormalTheDifferencebetweenNSAIDsandInhibitthethermotacticcenterandmakeitoutofCausethebodytemperaturetoalterwiththeenvironmenttemperature.NotonlydecreasetheBPofthosewhohaveafeverbutthenormalgesicEffectPropertiesofgesiaMild-to-moderateNoaddictionandnoNorespiratoryCauseofpain: insiteoftissueinjuryorinfl tionsomechemicalalgesiogenicsubstancesareproducedandreleasedsuchasbradykininandsoontogetherwithPGs.Bradykinin:causepainthroughstimulatingthealgesireceptorsPG:(1)(2)PG(E1,E2andF2α)alsohavealgesiogeniceffect.Mechanism:inhibitthesynthesisofPGsinperipheryOnlyeffectivetomildtomoderatepain.Non-narcoticandnoeuphoria.Norespiratory tory tionisthedefensivereactiontolesionfactorsoflivetissueshavingvascularTheroleofPGsin CausevasodilatationandtissueCoordinatewithbradykinintocause Mechanismofanti- toryeffectof(a)Reducingbiosynthesisofprostaglandinsby inhibitingCOX.(b)inhibitionoftheexpressionofsomecelladhesionmolecules.(c)Additionalpossiblemechanisms.Inhibitionofleukocytechemotaxis.Downregulationofinterleukin-1Decreasetheproductionofradicalsandsuperoxide.Interferencewithcalcium-mediatedintracellularevents.SymptomaticNSAIDsonlyrelievethemainclinicalsymptoms(erythema,edema,fever,painanddysfunction)ofinfl tion,buthavenoeffectontheautoimmunologicalprocessofrheumaticandrheumatoidarthritis.ComparisonbetweenCOX-1andCOX- ： causefeverandlationofetregulationofrenalbloodlationofperipheralNSAIDsinhibitionofCOX-2isthebaseoftheirtherapeuticeffectswhiletheirinhibitionofCOX-1isthereasonoftheiradversereactions.ButthisisnotabsolutetheantithrombosiseffectofaspirinisbasedonitsinhibitionofCOX-1AccordingtotheselectivityofCOXtheyareclassifiedintoselectiveCOX-2inhibitorandnon-selectiveCOXinhibitor.SECTIONNon-selectiveCOXInhibitorsPartISALICYLATES水杨酸类SalicylatesincludeaspirinandsodiumSodiumsalicylateisawillowbarkextractalonghistoryusagefirst edin1763.Severeadversereaction;rarelyused.Aspirin(Acetylsalicylicacid,阿司匹林,乙酰水杨酸)ProcessintheRapidly,Instomachandsmallintestine(mainlyinthelatter),tpeakis0.5~2hrsWidely,almostthroughoutthebody;synovialfluid,cerebrospinalfliud,passcenta.PPBRisHydrolyzedrapidlytoaceticacidandsalicylateby ses,smat1/2=15SalicylatesaremetabolizedbycytochromeP450intheliver,mostoftheproductsareboundtoglycinesfewofthemareboundtoglucuronicacids.Aspirinp.o.<1.0g: first-orderkinetics,t1/2=2~3hrs;Aspirinp.o.≥1.0g: zero-orderkinetics,t1/2=15~30hrs.ThemetabolitesaremainlyexcretedbyLowdose:mostareexcretedintheformofbound,fewintheformofsalicylate.Inlargedose:manyofthemwillbeexcretedintheformofsalicylate.UrinepHhaveastronginfluenceontheexcretionamountofsalicylatefromkidney.AlkalinepH:SAupto85%Acidic SAlowas5%Sowecouldreducethebloodconcentrationofsalicylatethroughalkalizingtheurine.PharmmacologicalEffectsAspirinandsalicylatesinhibitCOX-1andCOX-2 gesic,ant-infl toryandantirheumaticeffectsBoththeantipyreticand gesiceffectsofaspirinarestrongandrapid.Theant-infl toryandantirheumaticeffectare:(1)relativelystronger;(2)oftenusedtothetolerabledose.Inhibitetaggregationandpreventthrombosis ThereverseeffectsbetweenTXA2andPGI2.ThetheoryofinhibitingetaggregationandpreventinglongerinhibitionforCOXinetthanforCOXinvascularPre-systematiccircularacetylizationShortlifeonly8-11daysandnoproteinbiosynthesiscapacitycomparedwithAspirinadministratedinlowdosecanreduceTXA2remarkablybuthavenoapparentinfluenceonPGI2.ClinicalAntipyresisandHeadache,toothache,myalgia,neuralgia,dysmenorrheaandfeverof tionandDiagnosisandtherapyofacuterheumaticfever,rheumaticandrheumatoidarthritistorelievethesymptoms.Ischemiccardiopathyincludingstableandvariantanginapectorisandprogressivemyocardialinfarctionpatients.Itcanreducemortalityandre-ischemia.Intransientischemicattackpatientstopreventcerebralthrombosis.inangiosty,bypasstransntoperationstopreventthrombosisAlzheimer,sdisease(AD):ADisrelatedtotheover-expressionofCOX-2inbrain.Aspirin100mgp.o.dailyhasrepressioneffectonAD.Pregnancy-inducedhypertensionsyndromeandpreeclampsia:isrelatedtotheincreaseoftheratioofTXA2toPGI2inblood.Aspirin40-100mgp.o.dailycanreducetheincidenceofPIHandthedangerofpreeclamapsia.AdverseReactionsGastrointestinal①irritategastricmucosadirectly:causeepigastricdistressnauseaand②irritatechemoreceptortriggerzone(CTZ):causenauseaand③Gastriculcer:ASAcancauseanddeteriorateulcer.TakeitaftermealChewitintoTakeitalongwithTakeentericcoatingtabletscandecreaseorevenavoidaboveadverseBloodCoagulationInusualdose,inhibitetcoagulationandprolongthebleedingInhighdoseorinlongterm,alsoinhibittheformationofprothombinandprolongtheprothombintimevitaminKcanpreventit.Severehepaticdamage,prothrombinopenia,bleedingtendency,vitaminKdeficiency,stopuseoneweekbeforeoperationUrticaria,allergicAspirin-asthma:AsthmainducedbytheadministrationofaspirinorotherNSAIDSinsomeasthmapatients.Itisnotcausedbyallergicreactionbaseonantigen-antibodyCOX:Lipoxygenase:Endogenousbronchoconstrictantdominatecausebronchialspasmandinduceasthma. Adrenalinehasnouseonit,butwecantreatitwithantihistaminesandControundications:nasalpolyp,asthma,chronicurticaria,histroyofWhenthedoseofaspirinistoohigh,≥5mg/d,thepatientsmaysufferfromheadache,dizziness,nausea,vomiting,tinnitus,sightandhearingfailure.Severepatientsmaysufferfromhyperventilation,acid-baseinbalance,evenmentalconfusion,theseareallcalledsalicylism.Treatment:sodiumbicarbonateiv.Reye’sSeverehepaticdysfunctionwithcomplicationofencephalopathy,substituteaspirinwithDrugInCompetethebandingtosma cedicoumarol(双香豆素)enhanceitsanticoagulationeffectevencausehemorrhage. cetolbutamide（甲苯磺丁脲）andcausehypoglycemia. ceglucocorticoids(糖皮质激素)enhanceitsanti-infl toryeffectalsoenhanceitseffectofinducingulcerCompetetheautosecretioncarriersinrenalfurosemid（alkalinedrugsPartIIANLINESAcetaminophenandPhenacetin(对乙酰氨基 非那西丁InhibitthesynthesisofPGinCNSbuthaslittleeffectontheCOXinUsedinusualdosefewadversereactions,ifusedoverdose,itcancausehepaticinjury.Phenacetinitistrans