醫(yī)學(xué)課件帕金森及其藥物治療

CHAPTER19

ANTIPARKINSONISMDRUGSANDDRUGTHERAPYINALZHEIMER’SDISEASECHAPTER19

1CNSdegenerativediseaseParkinson’sdisease(PD)帕金森病Alzheimer’sdisease(AD)阿爾茨海默病Huntingtondisease(HD)亨廷頓病Amyotrophiclateralsclerosis(ALS)

肌萎縮側(cè)索硬化癥CNSdegenerativediseasePar2MechanismsExcitotoxicityApoptosisOxidativestressMechanismsExcitotoxic3

Parkinson’sdiseaseParkinson’sdisease(PD)Paralysisagitans(震顫麻痹）Classification

PrimaryPDParkinsonismcerebralarteriosclerosis(腦動脈硬化)

encephalitis(腦炎)

drugpoison(藥物中毒)Parkinson’sdiseasePar4

Typicalsymptomrestingtremor(靜止震顫)rigidity(肌肉僵直)bradykinesia(運動遲緩)ataxia(共濟失調(diào))Typicalsymptomrest5dopaminetyrosinedopadopamine

(酪氨酸)noradrenalinandadrenalindopaminetyr6

Pathogenesis(dopaminetheory)DAneuronaldegeneration

Nigro-striatal

(caudatenucleus,putamen，pallidum)Dopaminergicneuronactivity↓Cholinergicneuronactivity↑EvidencePathogenesis(dopaminetheor7Oxidativestresstheory

Nervousdegenerationbyoxygenfreeradical:H2O2,·O2-,Fe2+Oxidativestresstheory

N8Dopaminereceptorsfivemainsubtypes:D1~D5.

D1receptorD1andD5cAMPexcitationD2receptorD2~D4

cAMPinhibitionDopaminereceptorsfive9

Dopaminomimetic

Drugs

Therapeutic

Drugs

Centralanti-cholinergic

DrugsDopam10醫(yī)學(xué)課件帕金森及其藥物治療11I.DopaminomimeticDrugsI.DopaminomimeticDrugs12

Levodopa（L-dopa）

theimmediateprecursorofdopamine.penetratesintothebrain,whereitisdecarboxylatedtoDA.

correctsdopaminedeficiencyinnigra-striatum.Levodopa（L-dopa）

theimme13PharmacokineticsAbsorptionReadyfromsmallintestine,tmax0.5-2hrs,affectedbygastricemptying,gastricacidandaminoacids

PharmacokineticsAbsor14Pharmacokinetics2.Distributionandmetabolismuptake，metabolizedbyCOMTandMAO3.Eliminationkidney,t1/21-3hrs.Pharmacokinetics215

Pharmacokinetics

Decarboxylase

LevodopaDALiver99%

1%Decarboxylase

Blood-brainDABarrierBrainPharmacokinetics16PharmacologicalActionsandUses

1.Parkinson’sdisease

LevodopaiswidelyusedfortreatmentofalltypeofParkinsonismexceptthatassociatedwithantipsychoticdrugtherapy.PharmacologicalActionsand17

Properties(1)Mosteffectiveformildandyoungerpatients(2)Moreeffectiveforrigidityandakinesia,lesseffectivefortremorProperties(1)M18Properties(3)Onsetslow,2-3weekstoeffect,1-6monthstoEmax.therapeuticeffect(4)NoeffectiveforParkinson’ssyndromecausedbyphenothiazines.Properties(3)19ActionsandUses

2.Hepaticcoma

falseneurotransmittertheory：正常機體蛋白質(zhì)代謝產(chǎn)物苯乙胺和酪胺都在肝內(nèi)被氧化解毒。肝功能障礙時，血中苯乙胺和酪胺升高，在神經(jīng)細胞內(nèi)經(jīng)β-羥化酶分別生成偽遞質(zhì)——苯乙醇胺和羥苯乙醇胺（鱆胺），它們?nèi)〈苏＿f質(zhì)去甲腎上腺素，為興奮性遞質(zhì)，如興奮沖動不能傳遞，則可出現(xiàn)意識障礙和昏迷。Levodopametabolizedtonoradrenalinetoreplaceoctopamine(鱆胺)

ActionsandUses2.20

AdverseReactions1.Earlyreactions

Gastrointestinalreaction（early）—domperidone

Cardiovasculareffects

（early）—

tachycardia,arrhythmias,orthostatichypotension—blockerAdverseReactions1.Ear21AdverseReactions2.long-termreactions

a.Hyperkinesia:involuntarymovementb.on-offresponsec.PsychicdisordersandepilepsyAdverseReactions2.lon22

DrugInteractions

CarbidopaVitB6MAOI(unselective)

(-)(+)MAO

L-dopaDADA+R

Effects

Decarboxylase(-)

Antipsychoticdrugs

excretion(-)DrugInteraction231.AADCinhibitorsCarbidopa（卡比多巴）Benserazide（芐絲肼）CompoundPreparationsSinemet（息寧，心寧美）

Levodopa:Carbidopa(10:1)Madopar（美多巴）

Levodopa:Benserazide(4:1)

1.AADCinhibitorsCarbidopa（卡比多24醫(yī)學(xué)課件帕金森及其藥物治療25

2.MAO-B

inhibitors

Selegiline

(司來吉蘭)Mechanism：MAO-Binhibitor(MAO-B—inNigrostriatal)lowdose（＜10mg/d）—onlyinhibitMAO-Bhighdose（＞10mg/d）—inhibitMAO-AtooMAO:MAO-A:Intestines

MAO-B:CNSAntioxidantsDATATOP2.MAO-Binhibitors

Selegilin263.COMTinhibitorsNitecapone（硝替卡朋）：onlyinhibitperipheralCOMTTocapone（托卡朋）：inhibitCOMTbothperipheralandCNSProlongedthedurationofoflevodopabydiminishinginperipheralmetabolismMaybehelpfulinpatientsreceivinglevodopawhohavedevelopedresponsefluctuation.3.COMTinhibitorsNitecapone（硝27DA-RagonistsNotproducefreeradicalLongt1/2----longstimulusonreceptorPossiblehaveneuralprotectioneffectDA-RagonistsNotp28

DA-RagonistsBromocriptine(溴隱亭)1.Smalldose：stimulateD2receptorintuberoinfundibular,reducePRLandGHrelease2.Largedose：stimulateD2receptorinsubstantianigro-striatalUsedtotreatPDandhyperprolactinemia（高催乳素血癥）DA-RagonistsBromoc29DA-RagonistsLisuride（利修來得）：strongerthanBromocriptinePergolide(培高利特)：strongerthanLisurideRopinirole（羅匹尼羅）和pramipexole（普拉克索）

1.onlyagonistonD2receptor，noeffectonD1

2.on-offresponseisfewApomorphine（阿撲嗎啡）DA-RagonistsLis30

DrugsenhancingDAreleaseAmantadine(金剛烷胺)

1.↑releaseDAfromdopaminergicterminals.2.↓reuptakeofDA.3.dopaminereceptoragonismDrugsenhancingDAreleas31

ClinicalUsesParkinson’sdisease,lesseffectivethanlevodopa,andmoreeffectivethananticholinergicagents.Onsetrapidly;synergisedbyL-dopa.

ClinicalUses32

II.CentralAnticholinergicDrugs

33

Actions

BlockingtheM-R,↓cholinergicneuronsinthenigrostriatal.Trihexyphenidyl(苯海索)Benzatropine(苯扎托品)

ImprovethetremorandrigidityofPD,littleeffectonbradykinesia.

Actions34

DrugTherapyin

Alzheimer’sDiseaseAlzheimer’sdisease（AD）3/4Vasculardementia（VD）1/4Dr.AloisAlzheimer,aGermandoctor,diagnosedAlzheimer’sdiseasein1906DrugTherapyin

35

Incidence65y5.0%75y19%85y47%95y90%Courseofdisease:3~20yIncidence36

InternationalSymposiumforAlzheimer’sDisease

2000

“IftheeffectivemethodsforADtreatmentisnotfound,theADpatientswillbe22000000in2025;45000000in2050inwholeworld.”InternationalSymp37

ClinicalFeaturesDementia,cognitiondysufficiency,memorydamageClinicalFeat38

PathologicalFeaturesBrainatrophy(腦萎縮)Senileplaque(SP,老年斑)Neurofibrillarytangles(NFT,神經(jīng)元纖維纏結(jié))Selectivedeathofneuron.PathologicalFeaturesBrain39PathologicalFeatures1.Neurontoxicationof

amyloidβ-protein(Aβ)。AβcholinergicfunctionAchEAβPathologicalFeatures1.N40PathologicalFeatures2.NeurotransmittoractivityAchandGluCholinergicneuronsregressPathologicalFeatures41

TherapyforAD1.Potentiatecholinergicfunction

:AChEI、M-Ragonists2.Potentiatorofneuronalnutritionfactorandneuroncellgrowthfactor3.brainmetabolismactivator吡拉西坦(腦復(fù)康)4.Drugsimprovingmicrocirculation

麥角類衍生物、都可喜等5.Calciumantagonists(尼莫地平)TherapyforAD1.Poten42AChE-inhibitorsTacrine(他克林)——firstgeneration1.inhibitAChE（selectivityislow）2.exciteM-R,N-R3.promoteglucoseuseadversereaction:hepatotoxicityAChE-inhibitorsTac43

AChE-inhibitorsdonepezil（多奈哌齊）——secondgenerationinhibitAChE（selectivityishigh）Rivastigmine（利凡斯的明）—secondgenerationinhibitAChE（mainlytocortexandhippocamp）AChE-inhibitorsdonep44

AChE-inhibitorsgalanthamine—secondgeneration1)highselectivityforAChEInCNS.2)havenohepatotoxicity.3)mildandmoderateAD4)nausea,vomitting,diarrhea,dizzyAChE-inhibitorsgal45M-RagonistXanomeline（占諾美林）Sabcomedine（沙可美林）selectiveM1-RagonistM-RagonistXanomeline（46醫(yī)學(xué)課件帕金森及其藥物治療47

ThankYou!ThankYou!48醫(yī)學(xué)課件帕金森及其藥物治療49英國的內(nèi)科醫(yī)生JamesParkinson于1871年最早系統(tǒng)描述該病.“震顫麻痹”。后來，人們對該病進行了更為細致的觀察，發(fā)現(xiàn)除了震顫外，尚有肌肉僵直、寫字越寫越小等其它癥狀，但是四肢的肌肉的力量并沒有受損，認為稱麻痹并不合適，所以建議將該病命名為“帕金森病”。

英國的內(nèi)科醫(yī)生JamesParkinson于1871年最早系50醫(yī)學(xué)課件帕金森及其藥物治療51醫(yī)學(xué)課件帕金森及其藥物治療52醫(yī)學(xué)課件帕金森及其藥物治療53醫(yī)學(xué)課件帕金森及其藥物治療54醫(yī)學(xué)課件帕金森及其藥物治療55Dr.AloisAlzheimer,aGermandoctor,diagnosedAlzheimer’sdiseasein1906Dr.AloisAlzheimer,aGermand56

Parkinson’sdisease世界帕金森病日從１９９７年開始，每年的４月１１日被確定為“世界帕金森病日”(WorldParkinson'sDiseaseDay)。這一天是帕金森病的發(fā)現(xiàn)者——英國內(nèi)科醫(yī)生詹姆斯·帕金森博士的生日。Parkinson’sdisease57

CHAPTER19

ANTIPARKINSONISMDRUGSANDDRUGTHERAPYINALZHEIMER’SDISEASECHAPTER19

58CNSdegenerativediseaseParkinson’sdisease(PD)帕金森病Alzheimer’sdisease(AD)阿爾茨海默病Huntingtondisease(HD)亨廷頓病Amyotrophiclateralsclerosis(ALS)

肌萎縮側(cè)索硬化癥CNSdegenerativediseasePar59MechanismsExcitotoxicityApoptosisOxidativestressMechanismsExcitotoxic60

Parkinson’sdiseaseParkinson’sdisease(PD)Paralysisagitans(震顫麻痹）Classification

PrimaryPDParkinsonismcerebralarteriosclerosis(腦動脈硬化)

encephalitis(腦炎)

drugpoison(藥物中毒)Parkinson’sdiseasePar61

Typicalsymptomrestingtremor(靜止震顫)rigidity(肌肉僵直)bradykinesia(運動遲緩)ataxia(共濟失調(diào))Typicalsymptomrest62dopaminetyrosinedopadopamine

(酪氨酸)noradrenalinandadrenalindopaminetyr63

Pathogenesis(dopaminetheory)DAneuronaldegeneration

Nigro-striatal

(caudatenucleus,putamen，pallidum)Dopaminergicneuronactivity↓Cholinergicneuronactivity↑EvidencePathogenesis(dopaminetheor64Oxidativestresstheory

Nervousdegenerationbyoxygenfreeradical:H2O2,·O2-,Fe2+Oxidativestresstheory

N65Dopaminereceptorsfivemainsubtypes:D1~D5.

D1receptorD1andD5cAMPexcitationD2receptorD2~D4

cAMPinhibitionDopaminereceptorsfive66

Dopaminomimetic

Drugs

Therapeutic

Drugs

Centralanti-cholinergic

DrugsDopam67醫(yī)學(xué)課件帕金森及其藥物治療68I.DopaminomimeticDrugsI.DopaminomimeticDrugs69

Levodopa（L-dopa）

theimmediateprecursorofdopamine.penetratesintothebrain,whereitisdecarboxylatedtoDA.

correctsdopaminedeficiencyinnigra-striatum.Levodopa（L-dopa）

theimme70PharmacokineticsAbsorptionReadyfromsmallintestine,tmax0.5-2hrs,affectedbygastricemptying,gastricacidandaminoacids

PharmacokineticsAbsor71Pharmacokinetics2.Distributionandmetabolismuptake，metabolizedbyCOMTandMAO3.Eliminationkidney,t1/21-3hrs.Pharmacokinetics272

Pharmacokinetics

Decarboxylase

LevodopaDALiver99%

1%Decarboxylase

Blood-brainDABarrierBrainPharmacokinetics73PharmacologicalActionsandUses

1.Parkinson’sdisease

LevodopaiswidelyusedfortreatmentofalltypeofParkinsonismexceptthatassociatedwithantipsychoticdrugtherapy.PharmacologicalActionsand74

Properties(1)Mosteffectiveformildandyoungerpatients(2)Moreeffectiveforrigidityandakinesia,lesseffectivefortremorProperties(1)M75Properties(3)Onsetslow,2-3weekstoeffect,1-6monthstoEmax.therapeuticeffect(4)NoeffectiveforParkinson’ssyndromecausedbyphenothiazines.Properties(3)76ActionsandUses

2.Hepaticcoma

falseneurotransmittertheory：正常機體蛋白質(zhì)代謝產(chǎn)物苯乙胺和酪胺都在肝內(nèi)被氧化解毒。肝功能障礙時，血中苯乙胺和酪胺升高，在神經(jīng)細胞內(nèi)經(jīng)β-羥化酶分別生成偽遞質(zhì)——苯乙醇胺和羥苯乙醇胺（鱆胺），它們?nèi)〈苏＿f質(zhì)去甲腎上腺素，為興奮性遞質(zhì)，如興奮沖動不能傳遞，則可出現(xiàn)意識障礙和昏迷。Levodopametabolizedtonoradrenalinetoreplaceoctopamine(鱆胺)

ActionsandUses2.77

AdverseReactions1.Earlyreactions

Gastrointestinalreaction（early）—domperidone

Cardiovasculareffects

（early）—

tachycardia,arrhythmias,orthostatichypotension—blockerAdverseReactions1.Ear78AdverseReactions2.long-termreactions

a.Hyperkinesia:involuntarymovementb.on-offresponsec.PsychicdisordersandepilepsyAdverseReactions2.lon79

DrugInteractions

CarbidopaVitB6MAOI(unselective)

(-)(+)MAO

L-dopaDADA+R

Effects

Decarboxylase(-)

Antipsychoticdrugs

excretion(-)DrugInteraction801.AADCinhibitorsCarbidopa（卡比多巴）Benserazide（芐絲肼）CompoundPreparationsSinemet（息寧，心寧美）

Levodopa:Carbidopa(10:1)Madopar（美多巴）

Levodopa:Benserazide(4:1)

1.AADCinhibitorsCarbidopa（卡比多81醫(yī)學(xué)課件帕金森及其藥物治療82

2.MAO-B

inhibitors

Selegiline

(司來吉蘭)Mechanism：MAO-Binhibitor(MAO-B—inNigrostriatal)lowdose（＜10mg/d）—onlyinhibitMAO-Bhighdose（＞10mg/d）—inhibitMAO-AtooMAO:MAO-A:Intestines

MAO-B:CNSAntioxidantsDATATOP2.MAO-Binhibitors

Selegilin833.COMTinhibitorsNitecapone（硝替卡朋）：onlyinhibitperipheralCOMTTocapone（托卡朋）：inhibitCOMTbothperipheralandCNSProlongedthedurationofoflevodopabydiminishinginperipheralmetabolismMaybehelpfulinpatientsreceivinglevodopawhohavedevelopedresponsefluctuation.3.COMTinhibitorsNitecapone（硝84DA-RagonistsNotproducefreeradicalLongt1/2----longstimulusonreceptorPossiblehaveneuralprotectioneffectDA-RagonistsNotp85

DA-RagonistsBromocriptine(溴隱亭)1.Smalldose：stimulateD2receptorintuberoinfundibular,reducePRLandGHrelease2.Largedose：stimulateD2receptorinsubstantianigro-striatalUsedtotreatPDandhyperprolactinemia（高催乳素血癥）DA-RagonistsBromoc86DA-RagonistsLisuride（利修來得）：strongerthanBromocriptinePergolide(培高利特)：strongerthanLisurideRopinirole（羅匹尼羅）和pramipexole（普拉克索）

1.onlyagonistonD2receptor，noeffectonD1

2.on-offresponseisfewApomorphine（阿撲嗎啡）DA-RagonistsLis87

DrugsenhancingDAreleaseAmantadine(金剛烷胺)

1.↑releaseDAfromdopaminergicterminals.2.↓reuptakeofDA.3.dopaminereceptoragonismDrugsenhancingDAreleas88

ClinicalUsesParkinson’sdisease,lesseffectivethanlevodopa,andmoreeffectivethananticholinergicagents.Onsetrapidly;synergisedbyL-dopa.

ClinicalUses89

II.CentralAnticholinergicDrugs

90

Actions

BlockingtheM-R,↓cholinergicneuronsinthenigrostriatal.Trihexyphenidyl(苯海索)Benzatropine(苯扎托品)

ImprovethetremorandrigidityofPD,littleeffectonbradykinesia.

Actions91

DrugTherapyin

Alzheimer’sDiseaseAlzheimer’sdisease（AD）3/4Vasculardementia（VD）1/4Dr.AloisAlzheimer,aGermandoctor,diagnosedAlzheimer’sdiseasein1906DrugTherapyin

92

Incidence65y5.0%75y19%85y47%95y90%Courseofdisease:3~20yIncidence93

InternationalSymposiumforAlzheimer’sDisease

2000

“IftheeffectivemethodsforADtreatmentisnotfound,theADpatientswillbe22000000in2025;45000000in2050inwholeworld.”InternationalSymp94

ClinicalFeaturesDementia,cognitiondysufficiency,memorydamageClinicalFeat95

PathologicalFeaturesBrainatrophy(腦萎縮)Senileplaque(SP,老年斑)Neurofibrillarytangles(NFT,神經(jīng)元纖維纏結(jié))Selectivedeathofneuron.PathologicalFeaturesBrain96PathologicalFeatu