藥理學教學課件：Chapter 18 Antipsychiatric Drugs

Chapter18

AntipsychiatricDrugs

PsychoticDisorders1.Schizophrenia精神分裂癥:psychosisorthinkingdisorder.“dividedmind”2.mooddisorder心境障礙:

affectivedisorder.(1)Mania(2)Depression(3)Anxiety

AntipsychiatricDrugsAntischizophrenicdrugsAntimanicdrugsAntidepressivedrugsAntianxietydrugsSection1.

AntipsychoticDrugsSchizophreniaisthepersonalitychangeandbehaviordisorderswithenvironment.Twosymptoms:PositivesymptomsandNegativesymptoms.

Positivesymptoms:

thinkingdisorder,cognitiondisturbance,Hallucination(幻覺),paranoia(偏執(zhí)),delusion(妄想).Negativesymptoms:

disturbanceoffeeling,

discommunication(交流障礙).PathogenesisofSchizophreniaDopaminehypothesis(theory):

Theincreaseofbraindopaminergicfunctioninschizophrenia.AntipsychoticdrugsblockD2receptorinthemesolimbic中腦邊緣andmesocortical中腦皮質(zhì)pathways.TheSubtypesofDAReceptorAccordingtoproteinstructure,transmembranesignalingmechanisms,effectpropertiesandsitesofreceptors,DA

receptorclassifiedtoD1

andD2

subtypes.D1

isGS

couplingreceptor，

AC,cAMP

inbrainD2

isGi

couplingreceptor，

AC，cAMP

inbrainMolecularcloningtechniqueverifiedD1，D2，D3，D4，D5

subtypereceptorsinbrain.D1-likereceptorsD1

andD5

subtype

receptors.Molecular

homologue＞80%，coupledwithGS,similarpharmacologicalnatures.D2-likereceptors：D2、D3、D4

receptorsinbrain.Molecular

homologue＞45%,

coupledwithGi,similarpharmacologicalnatures.TheMainPathwaysofDA

inBrain(1)Substantianigra-striatalDA

system(黑質(zhì)-紋狀體系統(tǒng)):

--Involvinginextrapyramidalfunction.--DecreaseofDAfunctionleadstoParkinson’sdisease(PD);--Augmentation↑-Chorea(舞蹈癥).2.Meso-corticalDA

system(中腦皮質(zhì)系統(tǒng)):

Regulatecognition,thinkingandconsciousness.3.Meso-limbic

DA

system(中腦-邊緣葉系統(tǒng)):

Belongtothecenterofemotion

andfeeling.

---Augmentation(↑)ofsystem2

and3functionleadstoschizophrenia.4.Tubero-infundibular

DA

system(結節(jié)-漏斗系統(tǒng)):

Regulatepituitaryhormonerelease.5.

Areapostremaofmedulla

(chemoreceptortriggerzone,CTZ)

DAergicstimulating:centralvomiting.D1-likereceptors

andD2-likereceptorsinSubstantianigra-striatalsystem.D2-likereceptors

andD4

inmesocortical

andmesolimbicsystem.

D2

intubero-infundibularsystem.ReceptorDistributionAntischizophrenicAgentsClassic：1.Phenothiazines（吩噻嗪類）(1)Dimethylaminederivatives(二甲胺類):chlorpromazine(氯丙嗪,Wintermine,冬眠靈);(2)Piperazinederivatives(哌嗪類):perphenazine(奮乃靜),fluphenazine(氟奮乃靜),trifluoperazine

(三氟拉嗪)(3)Piperidinederivatives(哌啶類):

thioridazine(硫利達嗪)2.Thioxanthenes(硫雜蒽類)chlorprothixene(氯普噻噸

)3.Butyrophenones(丁酰苯類)haloperidol(氟哌啶醇),droperidol(氟哌利多)4.benzamides(苯甲酰胺類)sulpiride(舒必利),tiapride(泰必利)1.dibenzoxazepines(二苯二氮卓類)clozapine

(氯氮平)2.Benzoisoxazoles(苯丙異噁唑類)

risperidone

(利培酮)3.diphenylbutylpiperidines(二苯丁哌啶類)penfluridol(五氟利多),pimozide(匹莫齊特)4.Others：

aripiprazole阿立哌唑NewornonclassicChlorpromazine氯丙嗪

In1952chlorpromazinewasusedtotreatschizophreniainFrance.PharmacokineticsAbsorptionandDistributionEasyabsorbed：oral，imHighlipid-solubleandproteinbound(90%).Havealargevolumeofdistribution(＞7L/kg).ReadilypenetrateBBB.MetabolismChlorpromazinewasmetabolizedtomorepolarmetabolitesbyhepatomicrosomeenzyme,suchas7-hydroxychlorpromazine,etc.Excretionareexcretedinverylittleofunchangedform,almostcompletelymetabolites.PharmacologicalActions

1.Centralnervoussystem

(1)Behavioralandpsychologicaleffects

1)Fornormalperson:sedation,inducetosleep.

2)Forschizophreniapatients:

Antipsychoticeffect(neurolepticeffect):noanesthesiainlargedose.

(2)Antiemeticaction--BlocksD2receptorofCTZ(chemoreceptortriggerzone)onareapostremaofmedulla--Largedosesinhibitthevomitingcenterdirectly.

(3)temperatureregulation1)Thetemperaturechangeisdependentwithenvironmenttemperature.

2)Hypothermiaisnotonlyinfeverpatients,butalsoinnormalindividuals.MechanismofHypothermia1)↓temperature--inhibitregulatingcenterinhypothalamus;2)αreceptorblocking,vesseldilatation;3)inhibitbasicmetabolism.

(4)PotentiatetheeffectsofCNSdepressants

2.Autonomicnervoussystem

(1)Blockadeofα-Rresultsinorthostatichypotension.(2)BlockadeofM-Rinducesatropine-likeeffects.3.EndocrinesystemBlockadeoftubero-infundibularDApathway.1)↓prolactin催乳素release-inhibitingfactor.2)↓gonadotropin促性腺激素-releasehormone.3)↓corticotropin促腎上腺皮質(zhì)激素andgrowthhormone.ClinicalUses(1)Schizophrenia(2)Vomitingandintractablehiccups(頑固性呃逆)(3)Artificialhibernation(冬眠)AdverseReactions(1)CommonadversereactionsExcessivesedation,nasalstuffiness(鼻塞),orthostatichypotension,drymouth,cardiacdepression,M-Rblockingeffectsandendocrineeffects.

(2)ExtrapyramidalreactionsBlockDAreceptorsonsubstantianigra-striatalsystem.1)Parkinson’ssyndrome2)Akathisia(靜坐不能)3)Acutedystonia(肌張力障礙)Thetreatmentmayusecholinoceptor-blockingdrugs,suchasartane(安坦

)，notuselevodopa(左旋多巴).4)TardivedyskinesiaThetreatmentcannotuseartane.(3)Allergicreactions(4)DisorderofEndocrine吩噻嗪類抗精神病作用比較藥物抗精神病副作用

劑量（mg/d)鎮(zhèn)靜錐體外作用降壓作用

氯丙嗪300-800+++++++(iv)++(po)氟奮乃靜1-20+++++三氟拉嗪6-20+++++奮乃靜8-32++++++硫利達嗪200-600+++++

2.Thioxanthenes(硫雜蒽類)

Chloprothixene

(氯普噻噸,tardan,泰爾登)(1)Strongersedativeaction.(2)Weakantipsychoticeffect.(3)Also,weakanti-depressanteffect.

Butyrophenones(丁酰苯類)Haloperidol(氟哌啶醇)(1)Moreeffectsinantipsychotic,totreattheschizophreniaandthemania.(2)Theextrapyramidalreactionisverysevere.(3)Strongantiemeticactivity.Droperidol氟哌利多Neuroleptanalgesia:droperidol＋fentanyl芬太尼(50:1)

Sulpiride(舒必利)

AselectiveD2receptorantagonist(1)Strongerantipsychoticandantiemeticactivity.(2)Havingantidepressantefficacy.(3)Theextrapyramidalreactionisslight.

OtherAntipsychoticDrugs

Clozapine(氯氮平)

Itisanatypicalantipsychoticagent.(1)LowaffinityforD2,highaffinityforD4and5-HT2A.(2)MoreeffectiveforpositiveandnegativesymptomsofschizophreniaAntipsychoticDrugs-second

generationClozapine(氯氮平)

(3)Onsetrapidly:aweek(4)Lackinginextrapyramidaladverseeffects(5)Majoradverseeffectisagranulocytosis

Risperidone(利培酮)(1)Effectiveagainstnegativeaswellaspositivesymptoms(2)Improvethecognitiondisturbance(3)FewadversereactionsPenfluridol(五氟利多)(1)Longactingantipsychoticagent.(2)Usedforacuteandchronicschizophrenia.

NewtheoryofpsychosisD1function↓,D2function↑

Newdrugs

L-stepholidine(L-SPD,左旋千金藤啶堿）

StimulateD1,blockD2Section2.

AntidepressantAgentsManic-depressivedisorder(bipolaraffective),emotionaldisordersBiochemicalbases:monoaminetheoryMania:5-HT↓NA↑Depression:5-HT↓NA↓(1)Selective5-HTreuptakeinhibitors

fluoxetine氟西汀、paroxetine帕羅西汀

(2)5-HTandNAreuptakeinhibitorsvenlafaxine文拉法辛AntidepressantAgents

(3)NAreuptakeinhibitorsImipramine(丙米嗪,米帕明)Doxepin(多塞平)、Amitriptyline(阿米替林)、Desipramine(地昔帕明)

(4)5-HT2receptorantagonisttrazodone曲唑酮

(5)MonoamineOxidaseinhibitor,MAOI

(6)Othersmianserin米安色林，inhibitα2receptorinpresynapticmembrane

Imipramine(丙米嗪,米帕明)

Pharmacologicaleffectsandmechanisms

(1)CNSeffects--ItblocksthereuptakeofNAor5-HT.--Elevatingthemoodthatisdepressed.

(2)AutonomicnervoussystemblockM-R,Anticholinergicactivity

(3)Cardiovascularsystem

inhibitcardiovascularreflex,Tachycardia,arrhythmias,quinidine-likeaction.ClinicalUsesEndogenousdepressionandreactivedepression.Adversereactions(1)Atropine-likeaction(2)Cardiovascularreaction

Thecomparisonsoftricyclics

DrugsSedationAnticho-Blockofaminelinergiceffectpump5-HTNAImipramine++++++++(丙米嗪)Desipramine++0+++(地昔帕明)Amitriptyline++++++++++(阿米替林)Doxepine++++++++(多塞平)Newdevelopeda