番茄花园课件

CHAPTER20

ANTIPSYCHIATRICDRUGS

PsychoticDisorders1.Schizophrenia(thinkingdisorder)2.Mania(mooddisorder)3.Depression(mooddisorder)4.Anxiety

Section1

AntipsychoticDrugsSchizophrenia

PersonalitychangeandbehaviordisorderswithenvironmentPositivesymptoms:thinkingdisorder,cognitiondisturbance,hallucination,paranoia,delusion(妄想）Negativesymptoms:disturbanceoffeeling,

discommunication

NaturesofSchizophrenia

Dopaminetheoryofschizophreniapathogenesisoveractivityof

themeso-limbicdopaminergicneurons

NaturesofSchizophreniaraphetamine：promoteDAreleaseandinduceSchizophrenia.decreasesynthesisandstorageofDAcanimprovetheconditionDA-Rincreaseinputamenandnucleusaccumbens

septi

TheMainPathwaysofDA

andFunctionsinBrain1.Nigra-striatum（黑质-纹状体）DA

system

FromA9ofmeso-nigrosubstantiatocaudatenucleus,putamen.Extrapyramidalfunction（regulationofmovement

）

Decrease-PDAugmentation-Chorea（舞蹈症）(irregular,involuntarymuclejerksandimpairvoluntaryactivity)

TheMainPathwaysofDA

andFunctionsinBrain3.Meso-cortical（中脑皮层）DAsystemCognition,thinkingandconsciousness

System2

and3

augmentation-schizophrenia4.Tubero-infundibular

(结节-漏斗

)DA

systemRegulatepituitaryhormonereleaseTheSubtypesofDAReceptorIntheearly,DAreceptorsareclassifiedtofoursubtypes:D1-4Accordingtoproteinstructure,transmembranesignalingmechanisms,effectpropertiesandsitesofreceptors,DA

receptorclassifiedtoD1

andD2

subtypes.TheSubtypesofDAReceptorD1

isGS

couplingreceptor，AC，cAMP

inbrain.D2

isGi

couplingreceptor，AC，cAMP

inbrain.TheSubtypesofDAReceptor分子克隆技术证实脑内存在D1，D2，D3，D4，D5亚型受体。D1-likereceptors：D1和D5的分子同源性超过80%，与GS偶联，药理学特性符合D1。D2-likereceptors：D2、D3、D4同源性45%，与Gi偶联，药理学特性符合D2。TheSubtypesofDAReceptorMigro-striatalsystem：D1-likereceptors(D1,D5)andD2-likereceptors(D2、D3、D4).Meso-cortical

andmesolimbicsystemD2-likereceptors(D2、D3、D4).Tubero-infundibularsystem:

D2.Mechanismsof

AntipsychoticDrugs

1.BlockMeso-limbic

andMeso-corticalDAreceptor2.Block5-HTreceptorChlorpromazine(氯丙嗪)

（Wintermine,冬眠灵）HistoryOriginally

developedasanantihypertensiveagent.In1952chlorpromazinewasusedtotreatschizophreniainFrance

Chlorpromazine(氯丙嗪)（Wintermine,冬眠灵）

1.BlocksD2receptorinthemesolimbicandMeso-cortical

2.Blockα-R3.BlockM-RPharmacologicalActionsc.forschizophreniapatients:Antipsychoticeffect(neurolepticeffect):6wks-6mstoEmax.Mechanism:

BlockD2receptorinthemesolimbicandmeso-corticalpathwaysofbrain.Chlorpromazine

(2)AntiemeticactionBlocksD2receptorofCTZonareapostremaofmedulla(IVventricule)Largedosesinhibitthevomitingcenterdirectly.Chlorpromazine(4)PotentiatetheeffectsofCNSdepressantssedationandsynergismwithotherCNSdepressants(analgesics,sedative-hypnotics,anesthetics)

Chlorpromazine(5)OnextrapyramidalsystemBlockDAreceptorsonNigra-striatalDA

system

PharmacologicalActions2.Autonomicnervoussystem(1)Blockα-Rresultinorthostatichypotension.(2)BlockM-Rinduceatropine-likeeffects.PharmacologicalActions3.Endocrinesystemc.↓luteinizinghormone-releasingfactor.d.↓follicl-stimulatinghormone-releasingfactor

Pharmacokinetics1.Absorptionslowandunpredictableafteroraladministration2.DistributionPPBR>90%3.lipidsolubilityplaysamajorrole

ClinicalUses1.Schizophrenia

mania,paraniodstates,schizophreniaandpsychoseswithchronicalcoholism.2.Vomitingandintractablehiccups3.Artificialhibernation

Lyticcocktail

(chlorpromazineplus

dolantin

pluspromethazine)

AdverseReactions1.CommonadversereactionsExcessivesedationMblockeffects

AdverseReactions2.Extrapyramidalreactions(1)Parkinson’ssyndrome(2)Akathisia(3)Acutedystonia

facialgrimacingandtorticollis

blockDAreceptorsinthenigrostriatum

artane

AdverseReactions(4)Tardivedyskinesia

suckingandmackingofthelipsandotherinvoluntaryfacialmovements.3.PsychoticDisorders

AdverseReactions4.Convulsionandepilepsy5.Allergicreactions6.CardiovascularandEndocrinesystem7.Acuteintoxation

Contraindictions1.EpilepsyandConvulsion2.Glaucoma

3.Cyclomastopathyandbreastcarcinoma4.Coronaryheartdisease

吩噻嗪类抗精神病作用比较药物抗精神病副作用

剂量（mg/d)镇静锥体外作用降压作用氯丙嗪300-800+++++++(iv)++(po)氟奋乃静1-20+++++三氟拉嗪6-20+++++奋乃静8-32++++++硫利达嗪200-600+++++Thioxanthenes(硫杂蒽类)Chloprothixene(氯普噻吨，tardan,泰尔登)1.Strongersedativeaction.2.Weakanti-depressanteffect.Butyrophenones(丁酰苯类)Haloperidol(氟哌啶醇)1.Moreeffectsinantipsychotic,totreattheschizophreniaandthemania.2.Theextrapyramidalreactionisverysevere.3.Strongantiemeticactivity.OtherAntipsychoticDrugs

Clozapine(氯氮平)Itisanatypicalantipsychoticagent.1.LowaffinityforD2,highaffinityforD4and5-HT2A.2.Moreeffectiveforpositiveandnegativesymptomsofschizophrenia

Clozapine3.Onsetrapidly:aweek4.Lackinginextrapyramidaladverseeffects5.Majoradverseeffectisagranulocytosis(粒细胞缺乏）

Sulpiride1.Strongerantipsychoticandantiemeticactivity.2.Havingantidepressantefficacy.3.Theextrapyramidalreactionisslight.Risperidone（利培酮）1.Effectiveagainstnegativeaswellaspositivesymptoms2.Improvethecognitiondisturbance3.FewadversereactionsNewTheoryofPsychosisD1function↓,D2function↑Newdrugs(byJinGuo-zhang)

l-stepholidine(l-SPD,左旋千金藤啶碱）

StimuliD1,block

D2

Section2

AntimanicDrugsManic-depressivedisorder(bipolaraffective),emotionaldisorders

Biochemicalbases:aminetheoryMania5-HT↓NE↑Depression5-HT↓NE↓Lithiumcarbonate(碳酸锂)

“Mood-stabilizing”agent1.Effectsonneurotransmittersandtheirrelease.↓NEandDAreleasefromsynapseinthebrain,↑thosereuptake.Lithiumcarbonate(碳酸锂)

2.Effectsonsecondmessengersthatmediatetransmitteractiona.inhibitsthetransformationofinositolmonophosphate(IP)toPIP2,leadstoareductionofPIP2,thenIP3andDAGdecrease.

b.inhibitsACLithiumCarbonateClinicalUses1.mania2.manic-depressivepsychosisLithiumCarbonateAdversereactions

Lithiumtoxicityduetooverdose:nausea,vomit,abdominalpain,profusediarrhea,andataxia

moresevere:mentalconfussion,hyper-reflexia,tremor,convulsionLithiumCarbonateIntoxicationcanbeusuallybereversedbyosmoticdiuresisorinmorecasesbydislysis.UseNaclbyintravenoustotreatSerumconcentrationiscarefullymaintaintedbetween0.8and1.5mmol/L.Section3

AntidepressantAgents1.TricyclicagentsNon-selectivemonoaminereuptakeinhibitorsImipramine(丙米嗪,米帕明)Doxepin(多塞平)AntidepressantAgents2.NorepinepherinereuptakeinhibitorsDesipramine(地昔帕明)3.5–HTreuptakeinhibi