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抗精神失常药
PHARMACOLOGYOFANTIPSYCHOTICDRUGS(NEUROLEPTICS)
抗精神失常药
PHARMACOLOGYOFANTIP1SOMEDEFINITIONSNeuroleptic:synonymforantipsychoticdrug;originallyindicateddrugw/antipsychoticefficacybutwithneurologic(extrapyramidalmotor)sideeffectsTypicalneuroleptic:olderagentsfittingthisdescriptionAtypicalneuroleptic:neweragents:antipsychoticefficacywithreducedornoneurologicsideeffectsSOMEDEFINITIONSNeuroleptic:2NEUROLEPTICSONTHEUUHSCDRUGLISTTYPICALNEUROLEPTICS:PHENOTHIAZINES:Chlorpromazine(Thorazine®)Thioridazine(Mellaril®)Fluphenazine(Prolixin®)THIOXANTHENEThiothixene(Navane®)OTHERHaloperidol(Haldol®)NEUROLEPTICSONTHEUUHSCDRUG3NEUROLEPTICSONTHEUUHSCDRUGLIST(Continued)ATYPICALNEUROLEPTICS:Risperidone(Risperdal®;mostfrequentlyprescribedinU.S.)Clozapine(Clozaril®)Olanzapine(Zyprexa®)Quetiapine(Seroquel®)NEUROLEPTICSONTHEUUHSCDRUG4KEYCONCEPTS:
Allneurolepticsareequallyeffectiveintreatingpsychoses,includingschizophrenia,butdifferintheirtolerability.AllneurolepticsblockoneormoretypesofDOPAMINEreceptor,butdifferintheirotherneurochemicaleffects.Allneurolepticsshowasignificantdelaybeforetheybecomeeffective.Allneurolepticsproducesignificantadverseeffects.
KEYCONCEPTS:Allneurolepti5GENERALCHARACTERISTICSOFTYPICALNEUROLEPTICSTheolder,typicalneurolepticsareeffectiveantipsychoticagentswithneurologicsideeffectsinvolvingtheextrapyramidalmotorsystem.Typicalneurolepticsblockthedopamine-2receptor.GENERALCHARACTERISTICSOFTYP6GENERALCHARACTERISTICSOFTYPICALNEUROLEPTICSTypicalneurolepticsdonotproduceageneraldepressionoftheCNS,e.g.respiratorydepressionAbuse,addiction,physicaldependencedonotdeveloptotypicalneuroleptics.GENERALCHARACTERISTICSOFTYP7GENERALCHARACTERISTICSOFTYPICALNEUROLEPTICSTypicalneurolepticsaregenerallymoreeffectiveagainstpositive(active)symptomsofschizophreniathanthenegative(passive)symptoms.GENERALCHARACTERISTICSOFTYP8Positive/activesymptomsincludethoughtdisturbances,delusions,hallucinationsNegative/passivesymptomsincludesocialwithdrawal,lossofdrive,diminishedaffect,paucityofspeech.impairedpersonalhygienePositive/activesymptomsinclu9THERAPEUTICEFFECTSOFTYPICALNEUROLEPTICSAllappearequallyeffective;choiceusuallybasedontolerabilityofsideeffectsMostcommonarehaloperidol(Haldol®),chlorpromazine(Thorazine®)andthioridazine(Mellaril®)Latencytobeneficialeffects;4-6weekdelayuntilfullresponseiscommon70-80%ofpatientsrespond,but30-40%showonlypartialresponse
THERAPEUTICEFFECTSOFTYPICA10THERAPEUTICEFFECTSOFTYPICALNEUROLEPTICS(Continued)Relapse,recurrenceofsymptomsiscommon(approx.50%withintwoyears).Noncomplianceiscommon.Adverseeffectsarecommon.
THERAPEUTICEFFECTSOFTYPICA11ADVERSEEFFECTSOFTYPICALNEUROLEPTICSAnticholinergic(antimuscarinic)sideeffects:Drymouth,blurredvision,tachycardia,constipation,urinaryretention,impotenceADVERSEEFFECTSOFTYPICAL12ADVERSEEFFECTSOFTYPICALNEUROLEPTICSAntiadrenergic(Alpha-1)sideeffects:Orthostatichypotensionw/reflextachycardiasedationADVERSEEFFECTSOFTYPICAL13ADVERSEEFFECTSOFTYPICALNEUROLEPTICSAntihistamineeffect:sedation,weightgainADVERSEEFFECTSOFTYPICAL14KEYCONCEPT:DOPAMINE-2
RECEPTORBLOCKADEINTHEBASALGANGLIARESULTSINEXTRAPYRAMIDALMOTORSIDEEFFECTS(EPS).DYSTONIANEUROLEPTICMALIGNANTSYNDROMEPARKINSONISMTARDIVEDYSKINESIAAKATHISIAKEYCONCEPT:DOPAMINE-2
RECEP15ADVERSEEFFECTSOFTYPICALNEUROLEPTICS(Continued)Increasedprolactinsecretion(commonwithall;fromdopamineblockade)Weightgain(common,antihistamineeffect?)Photosensitivity(monw/phenothiazines)Loweredseizurethreshold(commonwithall)Leucopenia,agranulocytosis(rare;w/phenothiazines)Retinalpigmentopathy(rare;w/phenothiazines)ADVERSEEFFECTSOFTYPICAL16ADVERSEEFFECTSOFTYPICALNEUROLEPTICS(Continued)Chlorpromazineandthioridazineproducemarkedautonomicsideeffectsandsedation;EPStendtobeweak(thioridazine)ormoderate(chlorpromazine).Haloperidol,thiothixeneandfluphenazineproduceweakautonomicandsedativeeffects,butEPSaremarked.ADVERSEEFFECTSOFTYPICAL17大学药理学抗精神失常药课件18MECHANISMSOFACTION
OFTYPICALNEUROLEPTICSDOPAMINE-2receptorblockadeinmeso-limbicandmeso-corticalsystemsforantipsychoticeffect.DOPAMINE-2receptorblockadeinbasalganglia(nigro-striatalsystem)forEPSDOPAMINE-2receptorsupersensitivityinnigrostriatalsystemfortardivedyskinesiaMECHANISMSOFACTION
OFTYPIC19LONGTERMEFFECTSOFD2RECEPTORBLOCKADE:Dopamineneuronsreduceactivity.PostsynapticD-2receptornumbersincrease(compensatoryresponse).WhenD2blockadeisreduced,DAneuronsresumefiringandstimulateincreased#ofreceptors>>hyper-dopaminestate>>tardivedyskinesiaLONGTERMEFFECTSOFD2RECEPT20MANAGEMENTOFEPSDystoniaandparkinsonism:anticholinergicantiparkinsondrugsNeurolepticmalignantsyndrome:musclerelaxants,DAagonists,supportiveAkathisia:benzodiazepines,propranololTardivedyskinesia:increaseneurolepticdose;switchtoclozapineMANAGEMENTOFEPSDystoniaand21ADDITIONALCLINICALUSESOFTYPICALNEUROLEPTICSAdjunctiveinRxofacutemanicepisodeTourette’ssyndrome(esp.Haldol®)Rxofdrug-inducedpsychosesPhenothiazinesareeffectiveanti-emetics,Echlorperazine(Compazine®)Also,anti-migraineeffectADDITIONALCLINICALUSESOFTY22大学药理学抗精神失常药课件23GENERALCHARACTERISTICSOFATYPICALNEUROLEPTICSEffectiveantipsychoticagentswithgreatlyreducedorabsentEPS,esp.reducedParkinsonismandtardivedyskinesiaAllatypicalneurolepticsblockdopamineandserotoninreceptors;otherneurochemicaleffectsdifferAreeffectiveagainstpositiveandnegativesymptomsofschizophrenia;andinpatientsrefractorytotypicalneurolepticsGENERALCHARACTERISTICSOFATY24PHARMACOLOGYOF
CLOZAPINE(CLOZARIL®)
FDA-approvedforpatientsnotrespondingtootheragentsorwithseveretardivedyskinesiaEffectiveagainstnegativesymptomsAlsoeffectiveinbipolardisorderLittleornoparkinsonism,tardivedyskinesia,PRLelevation,neuro-malignantsyndrome;someakathisiaPHARMACOLOGYOF
CLOZAPINE(CL25Blockadeofalpha-1adrenergicreceptorsBlockadeofmuscariniccholinergicreceptorsBlockadeofhistamine-1receptors大学药理学抗精神失常药课件26PHARMACOLOGYOFCLOZAPINE(Continued)Otheradverseeffects;WeightgainIncreasedsalivationIncreasedriskofseizuresRiskofagranulocytosisrequirescontinualmonitoringPHARMACOLOGYOFCLOZAPINE(Con27PHARMACOLOGYOFOLANZAPINE(ZYPREXA®)Olanzapineisclozapinewithouttheagranulocytosis.SametherapeuticeffectivenessSamesideeffectprofilePHARMACOLOGYOFOLANZAPINE(ZY28PHARMACOLOGYOFQUETIAPINE(SEROQUEL®)Quetiapineisolanzapinewithouttheanticholinergiceffects.SametherapeuticeffectivenessSamesideeffectprofilePHARMACOLOGYOFQUETIAPINE(SE29HighlyeffectiveagainstpositiveandnegativesymptomsAdverseeffects:EPSincidenceisdose-relatedAlpha-1receptorblockadeLittleornoanticholinergicorantihistamineeffectsWeightgain,PRLelevation大学药理学抗精神失常药课件30HYPOTHESIZEDMECHANISMSOFACTIONOFATYPICALNEUROLEPTICSCombinationofDopamine-4andSerotonin-2receptorblockadeincorticalandlimbicareasforthe“pines”CombinationofDopamine-2andSerotonin-2receptorblockade(esp.risperidone)HYPOTHESIZEDMECHANISMSOFACT31GeneralTherapeuticPrinciplesforUseofNeurolepticsinSchizophrenia
(NIHConsensusStatement,1999)Useatypicalfor:1stacuteepisodew/+or+/-symptomsSwitchtoatypicalif:BreakthroughafterRxw/typicalUsetypical(depotprep)when:PatientisnoncompliantGeneralTherapeuticPrinciples32GeneralTherapeuticPrinciplesforUseofNeurolepticsinSchizophreniaIfresponseisinadequateto:Typical;switchtoAtypicalAtypical;raisedoseorswitchtoanotherAtypicalTypicalandAtypical;switchtoClozaril®Formaintenance,lifetimeRxisrequired.GeneralTherapeuticPrinciples33
抗精神失常药
PHARMACOLOGYOFANTIPSYCHOTICDRUGS(NEUROLEPTICS)
抗精神失常药
PHARMACOLOGYOFANTIP34SOMEDEFINITIONSNeuroleptic:synonymforantipsychoticdrug;originallyindicateddrugw/antipsychoticefficacybutwithneurologic(extrapyramidalmotor)sideeffectsTypicalneuroleptic:olderagentsfittingthisdescriptionAtypicalneuroleptic:neweragents:antipsychoticefficacywithreducedornoneurologicsideeffectsSOMEDEFINITIONSNeuroleptic:35NEUROLEPTICSONTHEUUHSCDRUGLISTTYPICALNEUROLEPTICS:PHENOTHIAZINES:Chlorpromazine(Thorazine®)Thioridazine(Mellaril®)Fluphenazine(Prolixin®)THIOXANTHENEThiothixene(Navane®)OTHERHaloperidol(Haldol®)NEUROLEPTICSONTHEUUHSCDRUG36NEUROLEPTICSONTHEUUHSCDRUGLIST(Continued)ATYPICALNEUROLEPTICS:Risperidone(Risperdal®;mostfrequentlyprescribedinU.S.)Clozapine(Clozaril®)Olanzapine(Zyprexa®)Quetiapine(Seroquel®)NEUROLEPTICSONTHEUUHSCDRUG37KEYCONCEPTS:
Allneurolepticsareequallyeffectiveintreatingpsychoses,includingschizophrenia,butdifferintheirtolerability.AllneurolepticsblockoneormoretypesofDOPAMINEreceptor,butdifferintheirotherneurochemicaleffects.Allneurolepticsshowasignificantdelaybeforetheybecomeeffective.Allneurolepticsproducesignificantadverseeffects.
KEYCONCEPTS:Allneurolepti38GENERALCHARACTERISTICSOFTYPICALNEUROLEPTICSTheolder,typicalneurolepticsareeffectiveantipsychoticagentswithneurologicsideeffectsinvolvingtheextrapyramidalmotorsystem.Typicalneurolepticsblockthedopamine-2receptor.GENERALCHARACTERISTICSOFTYP39GENERALCHARACTERISTICSOFTYPICALNEUROLEPTICSTypicalneurolepticsdonotproduceageneraldepressionoftheCNS,e.g.respiratorydepressionAbuse,addiction,physicaldependencedonotdeveloptotypicalneuroleptics.GENERALCHARACTERISTICSOFTYP40GENERALCHARACTERISTICSOFTYPICALNEUROLEPTICSTypicalneurolepticsaregenerallymoreeffectiveagainstpositive(active)symptomsofschizophreniathanthenegative(passive)symptoms.GENERALCHARACTERISTICSOFTYP41Positive/activesymptomsincludethoughtdisturbances,delusions,hallucinationsNegative/passivesymptomsincludesocialwithdrawal,lossofdrive,diminishedaffect,paucityofspeech.impairedpersonalhygienePositive/activesymptomsinclu42THERAPEUTICEFFECTSOFTYPICALNEUROLEPTICSAllappearequallyeffective;choiceusuallybasedontolerabilityofsideeffectsMostcommonarehaloperidol(Haldol®),chlorpromazine(Thorazine®)andthioridazine(Mellaril®)Latencytobeneficialeffects;4-6weekdelayuntilfullresponseiscommon70-80%ofpatientsrespond,but30-40%showonlypartialresponse
THERAPEUTICEFFECTSOFTYPICA43THERAPEUTICEFFECTSOFTYPICALNEUROLEPTICS(Continued)Relapse,recurrenceofsymptomsiscommon(approx.50%withintwoyears).Noncomplianceiscommon.Adverseeffectsarecommon.
THERAPEUTICEFFECTSOFTYPICA44ADVERSEEFFECTSOFTYPICALNEUROLEPTICSAnticholinergic(antimuscarinic)sideeffects:Drymouth,blurredvision,tachycardia,constipation,urinaryretention,impotenceADVERSEEFFECTSOFTYPICAL45ADVERSEEFFECTSOFTYPICALNEUROLEPTICSAntiadrenergic(Alpha-1)sideeffects:Orthostatichypotensionw/reflextachycardiasedationADVERSEEFFECTSOFTYPICAL46ADVERSEEFFECTSOFTYPICALNEUROLEPTICSAntihistamineeffect:sedation,weightgainADVERSEEFFECTSOFTYPICAL47KEYCONCEPT:DOPAMINE-2
RECEPTORBLOCKADEINTHEBASALGANGLIARESULTSINEXTRAPYRAMIDALMOTORSIDEEFFECTS(EPS).DYSTONIANEUROLEPTICMALIGNANTSYNDROMEPARKINSONISMTARDIVEDYSKINESIAAKATHISIAKEYCONCEPT:DOPAMINE-2
RECEP48ADVERSEEFFECTSOFTYPICALNEUROLEPTICS(Continued)Increasedprolactinsecretion(commonwithall;fromdopamineblockade)Weightgain(common,antihistamineeffect?)Photosensitivity(monw/phenothiazines)Loweredseizurethreshold(commonwithall)Leucopenia,agranulocytosis(rare;w/phenothiazines)Retinalpigmentopathy(rare;w/phenothiazines)ADVERSEEFFECTSOFTYPICAL49ADVERSEEFFECTSOFTYPICALNEUROLEPTICS(Continued)Chlorpromazineandthioridazineproducemarkedautonomicsideeffectsandsedation;EPStendtobeweak(thioridazine)ormoderate(chlorpromazine).Haloperidol,thiothixeneandfluphenazineproduceweakautonomicandsedativeeffects,butEPSaremarked.ADVERSEEFFECTSOFTYPICAL50大学药理学抗精神失常药课件51MECHANISMSOFACTION
OFTYPICALNEUROLEPTICSDOPAMINE-2receptorblockadeinmeso-limbicandmeso-corticalsystemsforantipsychoticeffect.DOPAMINE-2receptorblockadeinbasalganglia(nigro-striatalsystem)forEPSDOPAMINE-2receptorsupersensitivityinnigrostriatalsystemfortardivedyskinesiaMECHANISMSOFACTION
OFTYPIC52LONGTERMEFFECTSOFD2RECEPTORBLOCKADE:Dopamineneuronsreduceactivity.PostsynapticD-2receptornumbersincrease(compensatoryresponse).WhenD2blockadeisreduced,DAneuronsresumefiringandstimulateincreased#ofreceptors>>hyper-dopaminestate>>tardivedyskinesiaLONGTERMEFFECTSOFD2RECEPT53MANAGEMENTOFEPSDystoniaandparkinsonism:anticholinergicantiparkinsondrugsNeurolepticmalignantsyndrome:musclerelaxants,DAagonists,supportiveAkathisia:benzodiazepines,propranololTardivedyskinesia:increaseneurolepticdose;switchtoclozapineMANAGEMENTOFEPSDystoniaand54ADDITIONALCLINICALUSESOFTYPICALNEUROLEPTICSAdjunctiveinRxofacutemanicepisodeTourette’ssyndrome(esp.Haldol®)Rxofdrug-inducedpsychosesPhenothiazinesareeffectiveanti-emetics,Echlorperazine(Compazine®)Also,anti-migraineeffectADDITIONALCLINICALUSESOFTY55大学药理学抗精神失常药课件56GENERALCHARACTERISTICSOFATYPICALNEUROLEPTICSEffectiveantipsychoticagentswithgreatlyreducedorabsentEPS,esp.reducedParkinsonismandtardivedyskinesiaAllatypicalneurolepticsblockdopamineandserotoninreceptors;otherneurochemicaleffectsdifferAreeffectiveagainstpositiveandnegativesymptomsofschizophrenia;andinpatientsrefractorytotypicalneurolepticsGENERALCHARACTERISTICSOFATY57PHARMACOLOGYOF
CLOZAPINE(CLOZARIL®)
FDA-approvedforpatientsnotrespondingtootheragentsorwithseveretardivedyskinesiaEffectiveagainstnegativesymptomsAlsoeffectiveinbipolardisorderLittleornoparkinsonism,tardivedyskinesia,PRLelevation,neuro-malignantsyndrome;someakathisiaPHARMACOLOGYOF
CLOZAPINE(CL58Blockadeofalpha-1adrenergicreceptorsBlockadeofmuscariniccholinergicreceptorsBlockadeofhistamine-1receptors大学药理学抗精神失常药课件59PHARMACOLOGYOFCLO
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