治療帕金森病的藥物課件

1MotorsystemsII:ThebasalgangliaandDrugsusedforthetreatmentofParkinson’sdiseaseZhangBin（張斌）InstituteofPharmacologySchoolofMedicineShandongUniversity1MotorsystemsII:Thebasalg治療帕金森病的藥物課件1.ComponentsofBasalGanglia3neostriatumstriatum(paleostriatum)1.ComponentsofBasalGanglia1.CaudateNucleus(尾狀核）2.Putamen

(殼核,豆狀核殼）3.GlobusPallidus(GP)

（蒼白球，舊紋狀體）4.SubstantiaNigra(SN)（黑質(zhì)）

ParsCompacta

(p.c.)

(致密部）

ParsReticulata(p.r.)

（網(wǎng)狀部）5.SubthalamicNucleus(STN)(丘腦底核）4新紋狀體新紋狀體是基底節(jié)的核心，許多神經(jīng)傳入進來，也會發(fā)出神經(jīng)纖維到其他部位，構成回路調(diào)控軀體運動1.CaudateNucleus(尾狀核）4新紋狀體新2.

Mediumspinyneuroninstriatum

(MSN,中型多棘神經(jīng)元)

1)MSN

isthemainefferentneuronsinneostriatum2)MSN（Dendrites）接受的afferent神經(jīng):Glu

neuronsincortexDA

neuronsinSNcAch

neuronsinstriatumGABA

neurons

instriatum

3)MSNaxonscomposeefferentsystem,withGABAastheneurotransmitter

52.Mediumspinyneuroninstri4)TwotypesofDAreceptorsonMSN:D1

andD2-R

D1-R:enhancedirectpathway→Gpi(蒼白球內(nèi)側部)D2-R:inhibitindirectpathway→GPe(蒼白球外側部)64)TwotypesofDAreceptorso73.CircuitrelatedwithBasalganglia’sfunctionincontrolofmovement73.CircuitrelatedwithBasal81)directpathway(直接通路):當新紋狀體活動↑→皮層運動前區(qū)活動↑2)indirectpathway

(間接通路):當新紋狀體活動↑→皮層運動前區(qū)活動↓。此通路部分抵消直接通路對皮層的興奮作用3)Substantianigra-Neostriatumpathway(黑質(zhì)-新紋狀體通路):此通路對上述兩通路起調(diào)控作用DA通過D1受體增強直接通路，通過D2受體抑制間接通路81)directpathway(直接通路):當新94.Diseasesrelatedwithdysfunction

ofBasalgangliaHuntington’sdisease(Chorea)運動過多，肌張力降低Parkinsondisease運動減少，肌張力增高94.Diseasesrelatedwithdysf101011Parkinson’sDisease11Parkinson’sDisease12CNSdegenerativediseaseAlzheimer’sdisease(AD,阿爾茨海默病)Parkinson’sdisease(PD,帕金森病)Huntingtondisease(HD,亨廷頓病)Amyotrophiclateralsclerosis(ALS,

肌萎縮側索硬化癥)12CNSdegenerativediseaseAMuhammadAliinAlantaOlympicParkinson’sDiseaseKatharineHepburn

Michael·J·FoxMuhammadAliinAlantaOlympic14Firstdescribedin1817byanEnglishphysician,JamesParkinson,in“AnEssayontheShakingPalsy.”

“paralysisagitans”(震顫麻痹)Parkinson’sDisease

-History

JamesC.Parkinson14Firstdescribedin1817bya15ThefamousFrenchneurologist,Charcot,furtherdescribedthesyndromein1868

(rigidity)named”Parkinsondisease”.1919:確定病變部位主要在黑質(zhì)1960:發(fā)現(xiàn)與黑質(zhì)紋狀體中DA含量顯著降低有關世界帕金森病日每年的4月11日——15ThefamousFrenchneurologis16

Parkinson’sDisease-

Symptoms1.Restingtremor(靜止震顫)2.Bradykinesia(運動遲緩)3.Rigidity(肌肉強直)Cogwheelphenomenon(Leadpipephenomenon)4.Ataxia(共濟失調(diào))顫，慢，硬，共濟失調(diào)16Parkinson’sDisease-Sympt175.OthersAbnormalityofpostureandgaitHandwritingMemoryimpairment,confusion(精神混亂),disorientationCognitivedeficitsDepression175.Others1818PresymptomaticphaseOnsetSleepOlfactory*MoodAutonomicsystemDiagnosisEarlynonmotorsymptomsSpecificsymptomsMotorPDsymptoms

DopaminergicneuronlossinPD%Remaining

DopaminergicNeuronsTime(years)NonmotorAdaptedimagereprintedfromNeurotherapeutics,Vol.6,HalperinI,MorelliM,KorczynAD,YoudimMB,MandelSA.BiomarkersforevaluationofclinicalefficacyofmultipotentialneuroprotectivedrugsforAlzheimer'sandParkinson'sdiseases,pages128-140,Copyright2009,withpermissionfromElsevier.*OlfactorydysfunctionmaypredateclinicalPDbyatleast4years.Halperinetal.Neurotherapeutics.2009;6:128-140.Lang.Neurology.2007;68:948-952.Rossetal.AnnNeurol.2008;63:167-173.PresymptomaticphaseOnsetSleep20PD

-

EpidemiologyThesecondmostcommonneurodegenerativedisorderafterAD.Increasewithagepopulation>65yearsold:1%meanageatonset:60yearsold85%ofpatientsareover65yearsold20PD-EpidemiologyThesecond21PD

-

EtiologyUnknownIncreasingage(rareinthose<50;earlyoryoungonset)MoreoftentooccurinfamilieswithrelativeswithPDEnvironmentalfactors(pesticides,ruralresidence)Headtrauma,InfectionCaffeineandsmokinghavebeenfoundtobeprotective21PD-EtiologyUnknown22RiskofParkinson’sDiseaseIncreasedriskAgeHighBodyMassIndexMalegenderFamilyhistoryDepressionEnvironmentfactorsrurallivingwell-waterdrinkingwelding（焊接）headinjuryDecreasedriskCaffeineintakeSmokingcigarettesAnti-oxidantsindiet

(如類黃酮)22RiskofParkinson’sDiseaseI23

PD-Classification1.PrimaryPD：unknown2.Secondary:ParkinsonismCerebralarteriosclerosis

Encephalitis(腦炎)Drugpoison:氰化物、利舍平、吩噻嗪類抗精神病藥等Chemicals:Mn2+、除草劑、殺蟲劑等23PD-Classification1.Primar241.Dopamine(DA)theory

PD-

Pathophysiology(1)DAneuronaldegenerationinsubstantianigra

reducedorlackofdopamine

inthestriatum

↓functionofDAinnigro-striatalDApathway

↑thefunctionofAch

musculartension241.Dopamine(DA)theoryPD-25NormalPDsubstantianigra正常人中腦有一條狹長的黑色素沉著部位，是正常數(shù)量的黑質(zhì)神經(jīng)元聚集的部位。而在帕金森病人中腦的相應部位則顏色淺淡，是黑質(zhì)神經(jīng)元減少的緣故.25NormalPDsubstantianigra正常人中26DopaminetheoryAch黑質(zhì)紋狀體DADA(—)(＋)調(diào)節(jié)運動功能脊髓前角運動神經(jīng)元GABA26DopaminetheoryAch黑質(zhì)紋狀體DADA(27DA氧化代謝H2O2、O2-·

·OH

Fe2+促進神經(jīng)膜類脂氧化破壞DA神經(jīng)細胞膜功能

ComplexⅠ

抗氧化物（谷胱甘肽）黑質(zhì)2.Oxidativestress-freeradicaltheory

PD-

Pathophysiology(2)抗氧化治療(MAO-BI,VitE):早期PD首選治療方案。盡量延緩使用L-DOPA。是PD治療較大的進展和傳統(tǒng)觀念的轉變27DA氧化代謝H2O2、O2-··OHFe2+促進28PD-AnimalmodelMPTP6-OHDARotenoneParaquat28PD-AnimalmodelMPTP29PD-TreatmentNocureforPDDopaminergicmedicationNon-dopaminergicmedicationOtherstrategiesSurgicalintervention(外科手術)Regularexercise(定期訓練)29PD-TreatmentNocureforPD30AntiparkinsonismdrugsDAAchDopaminomimeticDrugsCentralAnticholinergicDrugs30AntiparkinsonismdrugsDAAchD31AADCTH:酪氨酸羥化酶THAADC:L-芳香族氨基酸脫羧酶31AADCTH:酪氨酸羥化酶THAADC:L-芳香族氨基酸32

ⅠDopaminomimeticDrugs

1.

PrecursorofDA

2.SynergeticagentsofL-dopa

(左旋多巴的增效藥）

3.DAreceptoragonists

4.DrugsenhancingDArelease32ⅠDopaminomimeticDrug331.

PrecursorofDA

levodopa（L-dopa,左旋多巴）LevodopaDopamine331.PrecursorofDAlevodop34【Pharmacologicalactionsandmechanism】PenetrateBBBintothebrainDecarboxylated

(脫羧)

byAADCtoDASupplyDAtostriatum

34【Pharmacologicalactionsan35【Clinicaluse】widelyusedforalmostalltypesofPDpatients

1.Parkinson’sdisease:symptomatictreatment(1)earlystage:goodandstableeffect80%canbesignificantlyimproved,ofwhich20%recoverdtothenormalstate(2)laterstage:effectgraduallydecreased,littleeffect

after3-5years用藥初期和用藥后期療效差距很大35【Clinicaluse】widelyusedf36Characteristics:

(1)havegoodeffectonmildandyoungerpatients,lesseffectonsevereandelderlypatients(2)moreeffectiveformuscularrigidityandakinesia(運動不能),lesseffectiveforrestingtremor,difficulttoimprovedementia(3)slowonset,initialeffectivetimeis2-3w,1-6mtoEmax

(4)noteffectiveforParkinsonismcausedbyphenothiazinesantipsychoticdrugs(5)drugcombination:combinedwithperipheralAADCinhibitor,reducethedosageofL-DOPAby75%.Cabidopa(卡比多巴)orbenserazide(芐絲肼)36Characteristics:(1)haveg372.Hepaticcoma(肝昏迷):symptomatictreatmentfalseneurotransmittertheory

(偽遞質(zhì)學說）Levodopametabolizedtonoradrenaline

(NA)toreplacefalseneurotransmitter372.Hepaticcoma(肝昏迷):symp38食物中芳香族氨基酸脫羧酶酪胺和苯乙胺被肝中MAO清除腸菌肝功能血濃度腦組織羥化酶苯乙醇胺羥苯乙胺(鱆胺)神經(jīng)傳導障礙肝昏迷左旋多巴去甲腎上腺素改善神經(jīng)傳導腦內(nèi)轉變作為偽遞質(zhì)取代去甲腎上腺素肝功能正常38食物中芳香族氨基酸脫羧酶酪胺和苯乙胺被肝中MAO清除腸菌39【Pharmacokinetics】1.Absorptionoral,absorbedbysmallintestine,t1/21-3hBioavailabilityisaffectedbygastricemptying,gastricacidpH

(delayofemptyandlowPHcandecreasebioavailability)39【Pharmacokinetics】1402.DistributionandmetabolismLevodopaCOMTreuptakeMAOMAO:單胺氧化酶COMT:兒茶酚胺-O-甲基轉移酶3.Elimination:kidney—AADCPeripheralCOMTDA402.Distributionandmetaboli41【Adversereactions】1.earlyreactions：(1)Gastrointestinaleffect:80%anorexia(厭食),nausea,vomitingtoleranceafterseveralweeks

domperidone(多潘立酮)外周D2-Rblocker(2)Cardiovasculareffects:orthostatichypotension30%arrhythmias41【Adversereactions】1.42

【Adversereactions】2.long-termreactions(1)Hyperkinesia(運動過多癥,dyskinesia,運動障礙):50%(2-4m),90%(＞2years)

hand,feet,body—abnormalchoreoathetoidmovements(舞蹈手足徐動癥)involuntarymovement(不隨意運動)orofacial(triad)

:sucking,lickingthetongue,chewingDA-RblockeroverstimulationofDA-R42【Adversereactions】2.43(2)Fluctuationsinresponse

(癥狀波動):

on-offphenomena40%-80%(3-5years)(3)Psychicdisorders

Clozapine(氯氮平)：D4MAOIinhibitorDA-Ragonistivd,frequency43(2)Fluctuationsinresponse44

【Druginteractions】VitB6:

coenzymeofAADC,theactivityofAADCAntipsychoticdrugs:blockDA-RofNigro-striatalsystem,weakenL-DOPAfunction44【Druginteracti452.SynergeticagentsofL-dopa

(左旋多巴的增效藥）AADC(芳香氨基酸脫羧酶)inhibitors

cabidopa,benserazide(芐絲肼)

(2)MAO-Binhibitors

selegiline(司來吉蘭)(3)COMTinhibitors

nitecapone(硝替卡朋）452.SynergeticagentsofL-do46MetabolismofL-dopaL-DOPADAAADCCOMT3-OMDL-DOPA3-OMDDAAADCdegradationMAO-BCOMTreuptake(3-O-甲基多巴)BBBBrainPeripherycompeteCarrier46MetabolismofL-dopaL-DOPADAX47(1)AADCinhibitors(≠BBB)L-DOPADAAADCCOMT3-OMDL-DOPAcompeteCarrier3-OMDDAAADCdegradationMAO-BCOMTreuptake(3-O-甲基多巴)BBBBrainPeripheryX47(1)AADCinhibitors(≠BBB)L48Carbidopa(卡比多巴):

notpenetrateBBB,onlyinhibitperipheryAADC,

increaseL-dopaintothebrain,reducethedosageofL-dopaby75%Benserazide(芐絲肼):

similar

CompoundPreparationsSinemet(息寧，心寧美)Levodopa:Carbidopa(10:1)Madopar(美多巴)Levodopa:Benserazide(4:1)48Carbidopa(卡比多巴):Compoun49(2)MAO-Binhibitors(＝BBB)L-DOPADAAADCCOMT3-OMDL-DOPA3-OMDDAAADCXdegradationMAO-BCOMTreuptake(3-O-甲基多巴)BBBBrainPeripherycompeteCarrier49(2)MAO-Binhibitors(＝BBB)L50Selegiline(司來吉蘭)

BBBpermeable,inhibitMAO-B:CNSreduceL-dopadoseand“on-offphenomena”

lowdose(＜10mg/d)—onlyinhibitMAO-B→DA↑highdose(＞10mg/d)—inhibitMAO-A,too→

hypertensivecrisis

antioxidanteffect50Selegiline(司來吉蘭)BBBpermea5151治療帕金森病的藥物課件X53(3)COMTinhibitors(≠or＝

BBB)L-DOPADAAADCCOMT3-OMDL-DOPA3-OMDDAAADCXdegradationMAO-BCOMTreuptake(3-O-甲基多巴)BBBBrainPeripherycompeteCarrierX53(3)COMTinhibitors(≠or＝B54Periphery:CNS:DAdegradation↓→DAinCNS↑L-DOPAdegradation↓3-OMD(3-O-甲基多巴)↓carrieravailableforL-DOPA↑L-DOPAthatreachthebrain↑nitecapone(硝替卡朋):peripheryEntacapone(恩他卡朋):peripheryTocapone(托卡朋):peripheryandCNS54Periphery:L-DOPAdegradatio55Dopaminereceptorsfivemainsubtypes:D1~D5

D1-likereceptors:D1,D5D2-likereceptors:D2,D3,D43.DAreceptoragonistsNigro-striatalsystem:激活D1-likereceptor(D1,D5):興奮激活D2-likereceptor(D2,D3):抑制55Dopaminereceptorsfivemain56Bromocriptine(溴隱亭):

D2agonism,D1partialantagonismPramipexole(普拉克索，森福羅):D2agonismRopinirole(羅平尼咯):D2agonismLisuride(利修來得):D2agonism,D1weakantagonismLessdyskinesiaandon-offphenomenonImportantinfirstlinetherapy56Bromocriptine(溴隱亭):D2a57

Bromocriptine(溴隱亭)1.Smalldose:stimulateD2-likeRintuberoinfundibular（結節(jié)漏斗部）

prolactin(PRL)andGHrelease2.Largedose:stimulateD2-likeRinsubstantianigro-striatal

Uses:PD,hyperprolactinemia(高催乳素血癥)acromegaly(肢端肥大癥)57Bromocriptine(溴隱亭)584.DrugsenhancingDAreleaseAmantadine(金剛烷胺)Mechanism:

1.↑releaseDAfromdopaminergicterminals.2.↓reuptakeofDA.3.dopaminereceptoragonismCharacteristics:

1.effect<L-dopabut>anticholinergicagents.2.rapidonset,synergisticactionwithL-dopa584.DrugsenhancingDAreleas59

ⅡCentralAnticholinergicDrugs5960

Benzhexol(苯海索,artane,安坦)BlockingtheM-R,↓cholinergicfunctioninthenigrostriatal.ImprovethetremorofPD,littleeffectonbradykinesia

andrigidity

EffectiveforParkinsonismcausedbyphenothiazinesNotverystrong60Benzhexol(苯海索,artane,61AADCTH:酪氨酸羥化酶THAADC:L-芳香族氨基酸脫羧酶61AADCTH:酪氨酸羥化酶THAADC:L-芳香族氨基酸62Thankyou!62Thankyou!636364MotorsystemsII:ThebasalgangliaandDrugsusedforthetreatmentofParkinson’sdiseaseZhangBin（張斌）InstituteofPharmacologySchoolofMedicineShandongUniversity1MotorsystemsII:Thebasalg治療帕金森病的藥物課件1.ComponentsofBasalGanglia66neostriatumstriatum(paleostriatum)1.ComponentsofBasalGanglia1.CaudateNucleus(尾狀核）2.Putamen

(殼核,豆狀核殼）3.GlobusPallidus(GP)

（蒼白球，舊紋狀體）4.SubstantiaNigra(SN)（黑質(zhì)）

ParsCompacta

(p.c.)

(致密部）

ParsReticulata(p.r.)

（網(wǎng)狀部）5.SubthalamicNucleus(STN)(丘腦底核）67新紋狀體新紋狀體是基底節(jié)的核心，許多神經(jīng)傳入進來，也會發(fā)出神經(jīng)纖維到其他部位，構成回路調(diào)控軀體運動1.CaudateNucleus(尾狀核）4新紋狀體新2.

Mediumspinyneuroninstriatum

(MSN,中型多棘神經(jīng)元)

1)MSN

isthemainefferentneuronsinneostriatum2)MSN（Dendrites）接受的afferent神經(jīng):Glu

neuronsincortexDA

neuronsinSNcAch

neuronsinstriatumGABA

neurons

instriatum

3)MSNaxonscomposeefferentsystem,withGABAastheneurotransmitter

682.Mediumspinyneuroninstri4)TwotypesofDAreceptorsonMSN:D1

andD2-R

D1-R:enhancedirectpathway→Gpi(蒼白球內(nèi)側部)D2-R:inhibitindirectpathway→GPe(蒼白球外側部)694)TwotypesofDAreceptorso703.CircuitrelatedwithBasalganglia’sfunctionincontrolofmovement73.CircuitrelatedwithBasal711)directpathway(直接通路):當新紋狀體活動↑→皮層運動前區(qū)活動↑2)indirectpathway

(間接通路):當新紋狀體活動↑→皮層運動前區(qū)活動↓。此通路部分抵消直接通路對皮層的興奮作用3)Substantianigra-Neostriatumpathway(黑質(zhì)-新紋狀體通路):此通路對上述兩通路起調(diào)控作用DA通過D1受體增強直接通路，通過D2受體抑制間接通路81)directpathway(直接通路):當新724.Diseasesrelatedwithdysfunction

ofBasalgangliaHuntington’sdisease(Chorea)運動過多，肌張力降低Parkinsondisease運動減少，肌張力增高94.Diseasesrelatedwithdysf731074Parkinson’sDisease11Parkinson’sDisease75CNSdegenerativediseaseAlzheimer’sdisease(AD,阿爾茨海默病)Parkinson’sdisease(PD,帕金森病)Huntingtondisease(HD,亨廷頓病)Amyotrophiclateralsclerosis(ALS,

肌萎縮側索硬化癥)12CNSdegenerativediseaseAMuhammadAliinAlantaOlympicParkinson’sDiseaseKatharineHepburn

Michael·J·FoxMuhammadAliinAlantaOlympic77Firstdescribedin1817byanEnglishphysician,JamesParkinson,in“AnEssayontheShakingPalsy.”

“paralysisagitans”(震顫麻痹)Parkinson’sDisease

-History

JamesC.Parkinson14Firstdescribedin1817bya78ThefamousFrenchneurologist,Charcot,furtherdescribedthesyndromein1868

(rigidity)named”Parkinsondisease”.1919:確定病變部位主要在黑質(zhì)1960:發(fā)現(xiàn)與黑質(zhì)紋狀體中DA含量顯著降低有關世界帕金森病日每年的4月11日——15ThefamousFrenchneurologis79

Parkinson’sDisease-

Symptoms1.Restingtremor(靜止震顫)2.Bradykinesia(運動遲緩)3.Rigidity(肌肉強直)Cogwheelphenomenon(Leadpipephenomenon)4.Ataxia(共濟失調(diào))顫，慢，硬，共濟失調(diào)16Parkinson’sDisease-Sympt805.OthersAbnormalityofpostureandgaitHandwritingMemoryimpairment,confusion(精神混亂),disorientationCognitivedeficitsDepression175.Others8118PresymptomaticphaseOnsetSleepOlfactory*MoodAutonomicsystemDiagnosisEarlynonmotorsymptomsSpecificsymptomsMotorPDsymptoms

DopaminergicneuronlossinPD%Remaining

DopaminergicNeuronsTime(years)NonmotorAdaptedimagereprintedfromNeurotherapeutics,Vol.6,HalperinI,MorelliM,KorczynAD,YoudimMB,MandelSA.BiomarkersforevaluationofclinicalefficacyofmultipotentialneuroprotectivedrugsforAlzheimer'sandParkinson'sdiseases,pages128-140,Copyright2009,withpermissionfromElsevier.*OlfactorydysfunctionmaypredateclinicalPDbyatleast4years.Halperinetal.Neurotherapeutics.2009;6:128-140.Lang.Neurology.2007;68:948-952.Rossetal.AnnNeurol.2008;63:167-173.PresymptomaticphaseOnsetSleep83PD

-

EpidemiologyThesecondmostcommonneurodegenerativedisorderafterAD.Increasewithagepopulation>65yearsold:1%meanageatonset:60yearsold85%ofpatientsareover65yearsold20PD-EpidemiologyThesecond84PD

-

EtiologyUnknownIncreasingage(rareinthose<50;earlyoryoungonset)MoreoftentooccurinfamilieswithrelativeswithPDEnvironmentalfactors(pesticides,ruralresidence)Headtrauma,InfectionCaffeineandsmokinghavebeenfoundtobeprotective21PD-EtiologyUnknown85RiskofParkinson’sDiseaseIncreasedriskAgeHighBodyMassIndexMalegenderFamilyhistoryDepressionEnvironmentfactorsrurallivingwell-waterdrinkingwelding（焊接）headinjuryDecreasedriskCaffeineintakeSmokingcigarettesAnti-oxidantsindiet

(如類黃酮)22RiskofParkinson’sDiseaseI86

PD-Classification1.PrimaryPD：unknown2.Secondary:ParkinsonismCerebralarteriosclerosis

Encephalitis(腦炎)Drugpoison:氰化物、利舍平、吩噻嗪類抗精神病藥等Chemicals:Mn2+、除草劑、殺蟲劑等23PD-Classification1.Primar871.Dopamine(DA)theory

PD-

Pathophysiology(1)DAneuronaldegenerationinsubstantianigra

reducedorlackofdopamine

inthestriatum

↓functionofDAinnigro-striatalDApathway

↑thefunctionofAch

musculartension241.Dopamine(DA)theoryPD-88NormalPDsubstantianigra正常人中腦有一條狹長的黑色素沉著部位，是正常數(shù)量的黑質(zhì)神經(jīng)元聚集的部位。而在帕金森病人中腦的相應部位則顏色淺淡，是黑質(zhì)神經(jīng)元減少的緣故.25NormalPDsubstantianigra正常人中89DopaminetheoryAch黑質(zhì)紋狀體DADA(—)(＋)調(diào)節(jié)運動功能脊髓前角運動神經(jīng)元GABA26DopaminetheoryAch黑質(zhì)紋狀體DADA(90DA氧化代謝H2O2、O2-·

·OH

Fe2+促進神經(jīng)膜類脂氧化破壞DA神經(jīng)細胞膜功能

ComplexⅠ

抗氧化物（谷胱甘肽）黑質(zhì)2.Oxidativestress-freeradicaltheory

PD-

Pathophysiology(2)抗氧化治療(MAO-BI,VitE):早期PD首選治療方案。盡量延緩使用L-DOPA。是PD治療較大的進展和傳統(tǒng)觀念的轉變27DA氧化代謝H2O2、O2-··OHFe2+促進91PD-AnimalmodelMPTP6-OHDARotenoneParaquat28PD-AnimalmodelMPTP92PD-TreatmentNocureforPDDopaminergicmedicationNon-dopaminergicmedicationOtherstrategiesSurgicalintervention(外科手術)Regularexercise(定期訓練)29PD-TreatmentNocureforPD93AntiparkinsonismdrugsDAAchDopaminomimeticDrugsCentralAnticholinergicDrugs30AntiparkinsonismdrugsDAAchD94AADCTH:酪氨酸羥化酶THAADC:L-芳香族氨基酸脫羧酶31AADCTH:酪氨酸羥化酶THAADC:L-芳香族氨基酸95

ⅠDopaminomimeticDrugs

1.

PrecursorofDA

2.SynergeticagentsofL-dopa

(左旋多巴的增效藥）

3.DAreceptoragonists

4.DrugsenhancingDArelease32ⅠDopaminomimeticDrug961.

PrecursorofDA

levodopa（L-dopa,左旋多巴）LevodopaDopamine331.PrecursorofDAlevodop97【Pharmacologicalactionsandmechanism】PenetrateBBBintothebrainDecarboxylated

(脫羧)

byAADCtoDASupplyDAtostriatum

34【Pharmacologicalactionsan98【Clinicaluse】widelyusedforalmostalltypesofPDpatients

1.Parkinson’sdisease:symptomatictreatment(1)earlystage:goodandstableeffect80%canbesignificantlyimproved,ofwhich20%recoverdtothenormalstate(2)laterstage:effectgraduallydecreased,littleeffect

after3-5years用藥初期和用藥后期療效差距很大35【Clinicaluse】widelyusedf99Characteristics:

(1)havegoodeffectonmildandyoungerpatients,lesseffectonsevereandelderlypatients(2)moreeffectiveformuscularrigidityandakinesia(運動不能),lesseffectiveforrestingtremor,difficulttoimprovedementia(3)slowonset,initialeffectivetimeis2-3w,1-6mtoEmax

(4)noteffectiveforParkinsonismcausedbyphenothiazinesantipsychoticdrugs(5)drugcombination:combinedwithperipheralAADCinhibitor,reducethedosageofL-DOPAby75%.Cabidopa(卡比多巴)orbenserazide(芐絲肼)36Characteristics:(1)haveg1002.Hepaticcoma(肝昏迷):symptomatictreatmentfalseneurotransmittertheory

(偽遞質(zhì)學說）Levodopametabolizedtonoradrenaline

(NA)toreplacefalseneurotransmitter372.Hepaticcoma(肝昏迷):symp101食物中芳香族氨基酸脫羧酶酪胺和苯乙胺被肝中MAO清除腸菌肝功能血濃度腦組織羥化酶苯乙醇胺羥苯乙胺(鱆胺)神經(jīng)傳導障礙肝昏迷左旋多巴去甲腎上腺素改善神經(jīng)傳導腦內(nèi)轉變作為偽遞質(zhì)取代去甲腎上腺素肝功能正常38食物中芳香族氨基酸脫羧酶酪胺和苯乙胺被肝中MAO清除腸菌102【Pharmacokinetics】1.Absorptionoral,absorbedbysmallintestine,t1/21-3hBioavailabilityisaffectedbygastricemptying,gastricacidpH

(delayofemptyandlowPHcandecreasebioavailability)39【Pharmacokinetics】11032.DistributionandmetabolismLevodopaCOMTreuptakeMAOMAO:單胺氧化酶COMT:兒茶酚胺-O-甲基轉移酶3.Elimination:kidney—AADCPeripheralCOMTDA402.Distributionandmetaboli104【Adversereactions】1.earlyreactions：(1)Gastrointestinaleffect:80%anorexia(厭食),nausea,vomitingtoleranceafterseveralweeks

domperidone(多潘立酮)外周D2-Rblocker(2)Cardiovasculareffects:orthostatichypotension30%arrhythmias41【Adversereactions】1.105

【Adversereactions】2.long-termreactions(1)Hyperkinesia(運動過多癥,dyskinesia,運動障礙):50%(2-4m),90%(＞2years)

hand,feet,body—abnormalchoreoathetoidmovements(舞蹈手足徐動癥)involuntarymovement(不隨意運動)orofacial(triad)

:sucking,lickingthetongue,chewingDA-RblockeroverstimulationofDA-R42【Adversereactions】2.106(2)Fluctuationsinresponse

(癥狀波動):

on-offphenomena40%-80%(3-5years)(3)Psychicdisorders

Clozapine(氯氮平)：D4MAOIinhibitorDA-Ragonistivd,frequency43(2)Fluctuationsinresponse107

【Druginteractions】VitB6:

coenzymeofAADC,theactivityofAADCAntipsychoticdrugs:blockDA-RofNigro-striatalsystem,weakenL-DOPAfunction44【Druginteracti1082.SynergeticagentsofL-dopa

(左旋多巴的增效藥）AADC(芳香氨基酸脫羧酶)inhibitors

cabidopa,benserazide(芐絲肼)

(2)MAO-Binhibitors

selegiline(司來吉蘭)(3)COMTinhibitors

nitecapone(硝替卡朋）452.SynergeticagentsofL-do109MetabolismofL-dopaL-DOPADAAADCCOMT3-OMDL-DOPA3-OMDDAAADCdegradationMAO-BCOMTreuptake(3-O-甲基多巴)BBBBrainPeripherycompeteCarrier46MetabolismofL-dopaL-DOPADAX110(1)AADCinhibitors(≠BBB)L-DOPADAAADCCOMT3-OMDL-DOPAcompeteCarrier3-OMDDAAADCdegradationMAO-BCOMTreuptake(3-O-甲基多巴)BBBBrainPeripheryX47(1)AADCinhibitors(≠BBB)L111Carbidopa(卡比多巴):

notpenetrateBBB,onlyinhibitperipheryAADC,

increaseL-dopaintothebrain,reducethedosageofL-dopaby75%Benserazide(芐絲肼):

similar

CompoundPreparationsSinemet(息寧，心寧美)Levodopa:Carbidopa(10:1)Madopar(美多巴)Levodopa:Benserazide(4:1)48Carbidopa(卡比多巴):Compoun112(2)MAO-Binhibitors(＝BBB)L-DOPADAAADCCOMT3-OMDL-DOPA3-OMDDAAADCXdegradationMAO-BCOMTreuptake(3-O-甲基