藥理學(xué)教學(xué)課件：Chapter 20 Drugs for the Treatment of neurodegenerative diseases

Chapter20DrugsfortheTreatmentofneurodegenerativediseasesCNSdegenerativediseaseParkinson’sdisease(PD)帕金森病Alzheimer’sdisease(AD)阿爾茨海默病Huntingtondisease(HD)亨廷頓病即大舞蹈癥Amyotrophiclateralsclerosis(ALS)

肌萎縮側(cè)索硬化癥MechanismsExcitotoxicityApoptosisOxidativestressFourtheories(1)freeradicals:H2O2,·O2-,Fe2+(2)eitheranexternaloraninternaltoxinselectivelydestroysdopaminergicneurons.(3)geneticfactors.(4)age-relatedwearingawayofdopamine-producingneurons.

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

PrimaryPDParkinsonism

Cerebralarteriosclerosis(腦動脈硬化)

encephalitis(腦炎)

drugpoison(藥物中毒)

Section1

Anti-Parkinsonismagents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(rèn)為稱麻痹并不合適，所以建議將該病命名為“帕金森病”。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).

Pathogenesis(dopaminetheory)DAneuronaldegenerationSubstantianigra-striatal

(caudatenucleus尾狀核,putamen殼核，pallidum蒼白球)

Dopaminergicneuronactivity↓Cholinergicneuronactivity↑

平衡

多巴胺能神經(jīng)元

膽堿能神經(jīng)元

?TypicalsymptomParkinson’sdisease(PD)isalsotermedasparalysisagitans震顫麻痹,isaslowlyprogressivedisorderthataffectsmovement,musclecontrol,andbalance.Restingtremor(靜止震顫)Rigidity(肌肉僵直)Bradykinesia(運(yùn)動遲緩)Ataxia(共濟(jì)失調(diào))

Dopaminetyrosinedopadopamine

(酪氨酸)noradrenaline（NA)andadrenaline(Adr)Dopaminereceptorsfivemainsubtypes:D1~D5.D1receptor：

D1andD5cAMPexcitationD2receptor：

D2~D4

cAMPinhibition1.Precursorofdopamine

Levodopa(L-dopa,左旋多巴)Dopamineitselfdoesnotcrosstheblood-brainbarrier.L-dopaisametabolicprecursorofdopamine.It

couldpenetratesintothebrain,whereitisdecarboxylatedtodopamine,restoresdopaminelevelsintheextrapyramidalcenters(substantianigra).Pharmacokinetics

(1)Absorption

Thedrugabsorbedfromthesmallintestine,tmax1-2h,affectedbygastricemptying,gastricacidandaminoacids.(2)Distributionandmetabolism

About1%throughbloodbrainbarrierbydopadecarboxylasetodopamine.99%ofthedrugistransformedtodopamineintheperiphery,resultinginperipheralsideeffects.mostmetabolizedbyCOMTandMAO.

(3)Eliminationbykidney,t1/21-3hrs.Decarboxylase

LevodopaDALiver99%

1%Decarboxylase

Blood-brainDABarrierBrainPharmacologicalActionsandUses

(1)Parkinson’sdisease

LevodopaiswidelyusedfortreatmentofalltypeofParkinsonism,candecreasetherigidityandothersymptomsofParkinsonism.

exceptthatassociatedwithantipsychoticdrugtherapy,Properties1)Mosteffectiveformildandyoungerpatients.2)Moreeffectiveforrigidityandakinesia(運(yùn)動遲緩),lesseffectivefortremor.3)Onsetslow,2-3weekstoeffect,1-6monthstoEmax4)NoeffectiveforParkinson’ssyndromecausedbyphenothiazines吩噻嗪類.(2)Hepaticencephalopathy(Hepaticcoma)

LevodopametabolizedtoNAtoreplaceoctopamine(羥苯乙醇胺,蟑胺)(falseneurotransmittertheory)AdverseReactions(1)Earlyreactions1)GastrointestinalEffects:Anorexia(食欲缺乏),nausea,andvomiting.2)CardiovascularEffects:Tachycardia,ventricularextrasystoles期外收縮,andhypotension.(2)long-termreactions1)dyskinesia運(yùn)動障礙:Abnormalinvoluntarymovement2)Symptomfluctuation癥狀波動：on-offresponse3)CNSeffects:

Psychicdisordersandepilepsy2.Decarboxylaseinhibitors(AADCinhibitors)Thedopaminedecarboxylaseinhibitorsdonotcrosstheblood-brainbarrier.Carbidopa(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)

DrugInteractions

CarbidopaVitB6MAOI(unselective)

(-)(+)MAO

L-dopaDADA+REffectsDecarboxylase(-)

Antipsychoticdrugs

excretion(-)3.DA-RagonistsNotproducefreeradicalLongt1/2----longstimulusonreceptorPossiblehaveneuralprotectioneffect

DA-Ragonists

Bromocriptine(溴隱亭)

1.Smalldose：stimulateD2receptorintubero-infundibular,reduceprolactin(PRL)andGHrelease2.Largedose：stimulateD2receptorinsubstantianigra-striatalUsedtotreatPDandhyperprolactinemia（高催乳素血癥）DA-Ragonistspramipexole（普拉克索）和Ropinirole（羅匹尼羅）1.onlyagonistonD2likereceptor（especiallyD3）noeffectonD1likereceptor.2.on-offresponseisfewpiribedil（吡貝地爾）Pergolide(培高利特)Apomorphine（阿撲嗎啡）

4.MAO-Binhibitors

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:CNS

5.COMTinhibitorsEntacapone恩他卡朋：onlyinhibitperipheralCOMTTocapone（托卡朋）：inhibitCOMTbothperipheralandCNSProlongedthedurationoflevodopabydiminishinginperipheralmetabolismMaybehelpfulinpatientsreceivinglevodopawhohavedevelopedresponsefluctuation.6.Others:DrugsenhancingDAreleaseAmantadine(金剛烷胺)

theantiviraldrug.1.↑releaseDAfromdopaminergicterminals.2.↓reuptakeofDA.3.dopaminereceptoragonism.

ClinicalUses--Parkinson’sdisease:lesseffectivethanlevodopa,andmoreeffectivethananticholinergicagents.Onsetrapidly;synergizedbyL-dopa.CentralM-Rblockers:

Benzhexol(苯海索,Artane安坦)Actions

BlockingtheM-R,↓cholinergicneuronsinthebasalganglia.ImprovethetremorofPD,littleeffectonbradykinesia運(yùn)動遲緩.2.CentralAnticholinergicDrugsUses--Theseagentsaremuchlesseffectivethanlevodopaandplayanadjuvantruleinantiparkinsonismtherapy.--TheycaninhibitthefunctionsofacetylcholineinCNS.Section2

Anti-Alzheimer’sdiseaseSeniledementia(老年癡呆)includesAlzheimer’sdisease(AD,?)andVasculardementia(VD,?).ADisassociatedwithbrainshrinkage,andlocalizedlossofneurons,mainlyinthehippocampusandbasalforebrain.

Incidence>65y3.0%～5.0%65～70y3.0%75～84y19%>85y47%Courseofdisease:3～20y

ClinicalFeaturesDementia,cognitiondysufficiency,memorydamage

PathologicalFeaturesClinicalmanifestations:

Dementia,cognitiondysufficiency,behavioraldisorder.Brainatrophy(腦萎縮)Senileplaque(SP,老年斑)Neurofibrillarytangles(NFT,神經(jīng)元纖維纏結(jié))Selectivedeathofneuron.

PathologicalFeatures1.Neurontoxicationof

amyloidβprotein(Aβ)

AβcholinergicfunctionAChEAβ2.NeurotransmittersactivityAChandGluCholinergicneuronsregress

TherapyforAD1.Potentiatecholinergicfunction:AChEI、M-Ragonists2.NMDAreceptorantagonists:Memantine美金剛3.Potentiatorofneuronalnutritionfactorandneuroncellgrowthfactor4.Brainmetabolismactivator吡拉西坦(腦復(fù)康)5.Drugsimprovingmicrocirculation

麥角類衍生物、都可喜等6.Calciumantagonists(尼莫地平)

AChE-inhibitorsTacrine(他克林)——firstgeneration1.inhibitAChE（selectivityislow）2.exciteM-R,N-R3.promoteglucoseuseAdversereaction:hepatotoxicity

AChE-inhibitorsDonepezil（多奈哌齊）----secondgeneration，whichisnothepatotoxicinhibitAChE（selectivityishigh）Huperzine

A石杉堿甲highreversibilityAChEinhibitors，Bothantioxidantandanti-apoptosis,protectnervecells.Clinicalusedinage-relatedmemorylossandvariousADpatients.AChE-inhibitorsGalanthamine加蘭他敏-secondgeneration1)highselectivityforAChEinCNS.2)haveno