PHARMACOLOGY OF ANTIPSYCHOTIC DRUGS …抗精神病藥物藥理學(xué)…

抗精神失常藥

PHARMACOLOGYOFANTIPSYCHOTICDRUGS(NEUROLEPTICS)???????????????????????????SOMEDEFINITIONSNeuroleptic:synonymforantipsychoticdrug;originallyindicateddrugw/antipsychoticefficacybutwithneurologic(extrapyramidalmotor)sideeffectsTypicalneuroleptic:olderagentsfittingthisdescriptionAtypicalneuroleptic:neweragents:antipsychoticefficacywithreducedornoneurologicsideeffectsNEUROLEPTICSONTHEUUHSCDRUGLISTTYPICALNEUROLEPTICS:PHENOTHIAZINES:Chlorpromazine(Thorazine?)Thioridazine(Mellaril?)Fluphenazine(Prolixin?)THIOXANTHENEThiothixene(Navane?)OTHERHaloperidol(Haldol?)NEUROLEPTICSONTHEUUHSCDRUGLIST(Continued)ATYPICALNEUROLEPTICS:Risperidone(Risperdal?;mostfrequentlyprescribedinU.S.)Clozapine(Clozaril?)Olanzapine(Zyprexa?)Quetiapine(Seroquel?)KEYCONCEPTS:

Allneurolepticsareequallyeffectiveintreatingpsychoses,includingschizophrenia,butdifferintheirtolerability.AllneurolepticsblockoneormoretypesofDOPAMINEreceptor,butdifferintheirotherneurochemicaleffects.Allneurolepticsshowasignificantdelaybeforetheybecomeeffective.Allneurolepticsproducesignificantadverseeffects.

GENERALCHARACTERISTICSOFTYPICALNEUROLEPTICSTheolder,typicalneurolepticsareeffectiveantipsychoticagentswithneurologicsideeffectsinvolvingtheextrapyramidalmotorsystem.Typicalneurolepticsblockthedopamine-2receptor.GENERALCHARACTERISTICSOFTYPICALNEUROLEPTICSTypicalneurolepticsdonotproduceageneraldepressionoftheCNS,e.g.respiratorydepressionAbuse,addiction,physicaldependencedonotdeveloptotypicalneuroleptics.GENERALCHARACTERISTICSOFTYPICALNEUROLEPTICSTypicalneurolepticsaregenerallymoreeffectiveagainstpositive(active)symptomsofschizophreniathanthenegative(passive)symptoms.Positive/activesymptomsincludethoughtdisturbances,delusions,hallucinationsNegative/passivesymptomsincludesocialwithdrawal,lossofdrive,diminishedaffect,paucityofspeech.impairedpersonalhygieneTHERAPEUTICEFFECTSOFTYPICALNEUROLEPTICSAllappearequallyeffective;choiceusuallybasedontolerabilityofsideeffectsMostcommonarehaloperidol(Haldol?),chlorpromazine(Thorazine?)andthioridazine(Mellaril?)Latencytobeneficialeffects;4-6weekdelayuntilfullresponseiscommon70-80%ofpatientsrespond,but30-40%showonlypartialresponse

THERAPEUTICEFFECTSOFTYPICALNEUROLEPTICS(Continued)Relapse,recurrenceofsymptomsiscommon(approx.50%withintwoyears).Noncomplianceiscommon.Adverseeffectsarecommon.

ADVERSEEFFECTSOFTYPICALNEUROLEPTICSAnticholinergic(antimuscarinic)sideeffects:Drymouth,blurredvision,tachycardia,constipation,urinaryretention,impotenceADVERSEEFFECTSOFTYPICALNEUROLEPTICSAntiadrenergic(Alpha-1)sideeffects:Orthostatichypotensionw/reflextachycardiasedationADVERSEEFFECTSOFTYPICALNEUROLEPTICSAntihistamineeffect:sedation,weightgainKEYCONCEPT:DOPAMINE-2

RECEPTORBLOCKADEINTHEBASALGANGLIARESULTSINEXTRAPYRAMIDALMOTORSIDEEFFECTS(EPS).DYSTONIANEUROLEPTICMALIGNANTSYNDROMEPARKINSONISMTARDIVEDYSKINESIAAKATHISIAADVERSEEFFECTSOFTYPICALNEUROLEPTICS(Continued)Increasedprolactinsecretion(commonwithall;fromdopamineblockade)Weightgain(common,antihistamineeffect?)Photosensitivity(v.commonw/phenothiazines)Loweredseizurethreshold(commonwithall)Leucopenia,agranulocytosis(rare;w/phenothiazines)Retinalpigmentopathy(rare;w/phenothiazines)ADVERSEEFFECTSOFTYPICALNEUROLEPTICS(Continued)Chlorpromazineandthioridazineproducemarkedautonomicsideeffectsandsedation;EPStendtobeweak(thioridazine)ormoderate(chlorpromazine).Haloperidol,thiothixeneandfluphenazineproduceweakautonomicandsedativeeffects,butEPSaremarked.MECHANISMSOFACTION

OFTYPICALNEUROLEPTICSDOPAMINE-2receptorblockadeinmeso-limbicandmeso-corticalsystemsforantipsychoticeffect.DOPAMINE-2receptorblockadeinbasalganglia(nigro-striatalsystem)forEPSDOPAMINE-2receptorsupersensitivityinnigrostriatalsystemfortardivedyskinesiaLONGTERMEFFECTSOFD2RECEPTORBLOCKADE:Dopamineneuronsreduceactivity.PostsynapticD-2receptornumbersincrease(compensatoryresponse).WhenD2blockadeisreduced,DAneuronsresumefiringandstimulateincreased#ofreceptors>>hyper-dopaminestate>>tardivedyskinesiaMANAGEMENTOFEPSDystoniaandparkinsonism:anticholinergicantiparkinsondrugsNeurolepticmalignantsyndrome:musclerelaxants,DAagonists,supportiveAkathisia:benzodiazepines,propranololTardivedyskinesia:increaseneurolepticdose;switchtoclozapineADDITIONALCLINICALUSESOFTYPICALNEUROLEPTICSAdjunctiveinRxofacutemanicepisodeTourette’ssyndrome(esp.Haldol?)Rxofdrug-inducedpsychosesPhenothiazinesareeffectiveanti-emetics,Esp.prochlorperazine(Compazine?)Also,anti-migraineeffectGENERALCHARACTERISTICSOFATYPICALNEUROLEPTICSEffectiveantipsychoticagentswithgreatlyreducedorabsentEPS,esp.reducedParkinsonismandtardivedyskinesiaAllatypicalneurolepticsblockdopamineandserotoninreceptors;otherneurochemicaleffectsdifferAreeffectiveagainstpositiveandnegativesymptomsofschizophrenia;andinpatientsrefractorytotypicalneurolepticsPHARMACOLOGYOF

CLOZAPINE(CLOZARIL?)

FDA-approvedforpatientsnotrespondingtootheragentsorwithseveretardivedyskinesiaEffectiveagainstnegativesymptomsAlsoeffectiveinbipolardisorderLittleornoparkinsonism,tardivedyskinesia,PRLelevation,neuro-malignantsyndrome;someakathisiaBlockadeofalpha-1adrenergicreceptorsBlockadeofmuscariniccholinergicreceptorsBlockadeofhistamine-1receptorsPHARMACOLOGYOFCLOZAPINE(Continued)Otheradverseeffects;WeightgainIncreasedsalivationIncreasedriskofseizuresRiskofagranulocytosisrequirescontinualmonitoringPHARMACOLOGYOFOLANZAPINE(ZYPREXA?)Olanzapineisclozapinewithouttheagranulocytosis.SametherapeuticeffectivenessSamesideeffectprofilePHARMACOLOGYOFQUETIAPINE(SEROQUEL?)Quetiapineisolanzapinewithouttheanticholinergiceffects.SametherapeuticeffectivenessSamesideeffectprofileHighlyeffectiveagainstpositiveandnegativesymptomsAdverseeffects:EPSincidenceisdose-relatedAlpha-1receptorblockadeLittleornoanticholinergicorantihistamineeffectsWeightgain,PRLelevationHYPOTHESIZEDMECHANISMSOFACTIONOFATYPICALNEUROLEPTICSCombinationofDopamine-4andSerotonin-2receptorblockadeincorticalandlimbicareasforthe“pines〞CombinationofDopamine-2andSerotonin-2receptorblockade(esp.risperidone)GeneralTherapeuticPrinciplesforUseofNeurolepticsinSchizophrenia

(NIHConsensusStatement,1999)Useatypicalfor:1stacuteepisodew/+or+/-symptomsSwitchtoatypicalif:BreakthroughafterRxw/typicalUsetypical(depotprep)when:PatientisnoncompliantGeneralTherapeuticPrinciplesforUseofNeurolepticsinSchizophreniaIfresponseisinadequateto:Typical;switchtoAtypicalAtypical;raisedoseorswitchtoanotherAtypicalTypicalandAtypical;switchtoClozaril?

Formaintenance,lifetimeRxisrequired.ExtrapyramidalSymptomsDescriptionandManagementAkathesia/DystoniaAkathesia

-feelingofrestlessness,desiretomovelegsorwalkDystonia

-slowsustainedcontractionsorspasmsthatresultininvoluntarymovementDrugInducedParkinsonismMusclestiffness/CogwheelingShufflinggaitStoopedpostureMaskedfaciesTremorManagementofAkathesia/Dystonia/DrugInducedParkinsonismAkathesia -Symptomsusuallyabatewithreductionofdoseordiscontinuationofthemedication -Additionofanxiolyticorb-blockermaybehelpfulDystonia/DrugInducedParkinsonism -requireimmediateintervention -administrationofanticholinergicor

antiparkinsonmedication -reducedoseorchangemedicationTardiveDyskinesiaRepetitiverhythmicinvoluntarymovements

Examples

-Tonguethrusting

-Lipsmacking

-Chewingmovements

-Grunting/HummingMangementofTardiveDyskinesiaPreventionisthekeyScreeningrecommendedevery3to6monthsusingtoolssuchastheAbnormalInvoluntaryMovementScale(AIMS)Whenidentified,reduceoreliminatethecausativeagentNeurolepticMalignantSyndromeHighFeverMuscleRigidityChangeinMentalStatusAutonomicInstabilityProfuseDiaphoresisFatalityrateof10-30%ManagementofMalignantNeurolepticSyndromeHospitaltransferWithholdneurolepticmedicationHydrationtocorrectfluidlossesandhypotensionBenzodiazepinesandphysicalrestraintsasneededCoolingwithantipyretics,coolingblanketsDopamineagonists(Bromocriptine,amatadine)AvoidDantrolenePsychiatry,neurology,andrenalconsultsasappropriate(Benzor2021)HyperprolactinemiaSymptomsandmanagementHyperprolactinemiaSymptomsMenWomenGalactorrheaGalactorrheaGynecomastiaAmenorrhea/OligomennorrheaDecreasedlibidoAcne/HirsutismInfertilityInfertilityErectileDysfunctionDyspareuniaOsteoporosisOsteoporosisHyperprolactinemiaManagementDonotcheckprolactinlevelsinasymptomaticpatientsInsymptomaticpatients,evaluateotherpotentialcausesofsymptoms(thyroiddisease,pregnancy,lowtestosterone)ConsideranMRIinpatientswhosehistorymaysuggestapituitarylesionornotwellexplainedbythedruginquestionConsiderendocrinologyreferralConsiderdiscontinuingdruginconsultationwithpatientandpsychiatrist(Miller2004)MetabolicSyndromeMonitoringandManagementMetabolicSyndromeIn2004,FDAissuedablackboxwarningonhyperglycemiaanddiabetesassociatedwithatypicalantipsychoticsTheAmericanDiabeticAssociationpublishedaconsensusstatementinconjuctionwiththeAmericanPsychiatricAssociation,theAmericanCollegeofEndocrinologyoutliningmanagementofmetabolicsequelaeofantipsychoticuse(ADA,DiabetesCare2004)BaselineMonitoringDocumentanyPersonal/FamilyHistoryofObesity,Diabetes,Hyperlipidemia,orHeartDiseaseWeightandHeightMeasurements(BMI)WaistCircumferenceFastingPlasmaGlucoseFastingLipidProfileBaselineMonitoringInitiatestandardtreatmentforanypatientsfoundtobehypertensive,diabetic,orwithelevatedlipidsNutritionalandphysicalactivitycounselingforpatientswhoareoverweightorobesePatientsandfamilyshouldbeinformedoftherisksofweightgainanddiabetes.Patientsandfamiliesshouldbeadvisedonhowtorecognizethesignsandsymptomsofdiabetes.WeightmeasurementsWeightshouldbemonitoredmonthlyforthe1st3monthsForpatientswhohavegained>5%;considerchangingagentRapiddiscontinuationofmedicationshouldbeavoided3MonthsWeightFastingplasmaglucoseLipidprofileBloodPressurePatientswhodevelopworseningbloodsugarorlipidsshouldconsiderswitchingagentsAnnualAssessmentsFamily/PersonalhistoryWeightBloodpressureFastingPlasmaLevelsWaistCircumferenceLipids(maybedoneevery5years)MonitoringScheduleBaseline4weeks8weeks12weeksEvery3MonthsEveryYearEvery5yearsPersonal/FamilyhistoryxxWeightxxxxxxWaistxxBloodPressurexxxFastingglucosexxxLipidProfilexxxEpilogueMorratoetalexaminedthetestingoffastingglucoseandlipidsinpatientsreceivingatypicalantipsychoticmedicationsLaboratoryclaimsfor18,876USpatientsenrolledinacommercialhealthplanreceivingantipsychoticmedicationsfrom2001through2006ComparisonsbeforeandaftertheFDAlettercampaignandADAconsensusstatementSurveyQuestion#3WhichofthefollowingbestdescribesthepercentageofpatientsonantipsychoticmedicationwhohadanannualfastingglucoseinstudybyMorratoetal?20%40%60%80%95%EffectofADAandFDAonAnnualGlucoseScreeningExtrapyramidalsyndromesincludethefollowing:Acutedystonia:sustainedmusclecontractionscausetwistingandrepetitivemovementsorabnormalposturesThisconditionisoft