藥理學(xué)教學(xué)課件：3 parkinson's disease

Drugsfor

Parkinson’sDiseaseAndAlzheimer’sdiseaseParkinson’sdisease,PD帕金森病

(paralysisagitants震顫麻痹)tremorragiditybradykinesiaProgressiveneurologicdisorderofmusclemovement,characterizedby:Restingtremors;Muscularrigidity;BradykinesiaPosturalandgaitabnormalitiesMemoryinterruptionanddementia癡呆

MuhammadAli,thegreatestboxerwhosuffersfromparkinsonism,littheOlympicflameatthe1996SummergamesinAtlanta...

degenerationandlossinbrainand/orspinalneuronParkinson’sdisease,PDAlzheimer’sdisease,ADHuntingtondisease,HDAmyotrophiclateralsclerosis,ALSEtiology:exitotoxicity,apoptosis,oxidativestressParkinsonismParkinson’ssyndromeEtiologyLossofdopaminergicneuronsinsubstantianigraImbalancebetweentheexcitatorycholinergicneuronsandthegreatlydiminishednumberofinhibitorydopaminergicneuronsDopamineAcetylcholineAcetylcholineAChDAAChDAAChDADA-ACh

平衡帕金森

癥候群舞蹈病運(yùn)動(dòng)機(jī)能正常正常帕金森癥候群多巴胺AChGABA黒質(zhì)紋狀體StrategyDA+drugAChImproveDAAChDAdrugAntagonismAChDA+drugAChdrugCombinationDrugs—L-dopa—carbidopa—bromocriptine—selegiline—amantadineTrihexyphenidyl/benzhexolDA：(DAreplacementtherapy/DAagonisttherapy)ACh：(Anticholinergictherapy)Tyrosine

L-dopa

Dopamine

NADopaminergicagents擬多巴胺藥

levodopa,(L-dopa)左旋多巴tyrosinehydroxylasedopadecarboxylasedopamineβ-hydroxylaseLevodopaMechanismPharmacokineticsAdministeredorallyandrapidlyabsorbedfromsmallintestine(fooddelaysabsorption)Onlyabout1%-3%ofadministeredlevodopaactuallyentersthebrainunaltered,theremainderbeingmetabolizedextracerebrally,predominantlybydecarboxylationtodopamine,whichdosenotpenetratetheblood-brainbarrier.LevodopaClinicaluseParkinsonismThebestresultsareobtainedinthefirstfewyearsoftreatment.Thebenefitsoflevodopatreatmentoftenbegintodiminishafter3or4yearsoftherapy.givenincombinationwithcarbidopa.HepaticcomaDopamineNAAdverseEffectsGastrointestinaleffectsOrthostatichypotension體位性低血壓arrhythmia心律不齊Abnormalinvoluntarymovementshyperkinesia運(yùn)動(dòng)過多癥on-offphenomena“開－關(guān)現(xiàn)象”Psychogenia精神障礙EarlystageLatestageInteractions

VB6

increasesperipheralbreakdownoflevodopa

MAOinhibitors

decrease

dopamineinactivationandproduceahypertensivecrisisAntipsychoticdrugs

blockdopaminereceptorsandproduceaparkinsoniansyndromebythemselvesContraindications:psychoticdiseases,glaucoma,melanomaNotcrosstheblood-brainbarrierinhibitsdecarboxylasesinperipherydecreasesdoseofLevodopaby75%;reducesorpreventsthesideeffectsoflevodopaincreasestheavailabilityoflevodopatotheCNSDecarboxylasesinhibitorCarbidopa卡比多巴Bromocriptine溴隱亭D2-Ragonist,acrosstheblood-brainbarriereasilyCombinationwithlevodopaHaveanimportantroleasfirst-linetherapyLowerincidenceoftheadverseeffectswithlong-termlevodopatherapy

nitecapone硝替卡朋

COMT兒茶酚氧位甲基轉(zhuǎn)移酶inhibitor

COMTinhibitorinperipheryandincreaseavailabilityofL-dopainbrain,noeffectonCOMTinCNSAADCL-dopaDA3-OMDCOMTinhibitorCOMTCNSperipheralCOMT抑制劑作用機(jī)制AADC：aminodecarboxylase；3-OMD：3-O-methyldopacarrierselegiline司來吉蘭MAOI單胺氧化酶抑制劑

,selectiveinhibitorofmonoamineoxidaseB(MAO-B)

retardsthebreakdownofdopamine,increasestherapeuticeffectsoflevodopadecreasesthedoseoflevodopa,reducestheadverseeffects.DopamineH2O2，O2-·OxidativestressremovalFe3+MAOselegilineAmantadine金剛烷胺enhancethereleaseofdopaminefromthesurvivingneuronssideeffectsarefewCentralanticholinergicdrug中樞抗膽堿藥

trihexyphenidyl

苯海索（Artane安坦）BlockageofcholinergictransmissionproducessimilartoaugmentationofdopaminergictransmissionPeripheralsideeffectslikeatropineCOMT抗帕金森病藥物效價(jià)臨床用藥傾向于在PD早期應(yīng)用低效價(jià)藥物（司來吉蘭，金剛烷胺，抗膽堿能藥），后期應(yīng)用左旋多巴與卡比多巴復(fù)方，多巴胺能激動(dòng)劑左旋多巴Levodopa>溴隱亭Bromocriptine>金剛烷胺Amantadine>抗膽堿能藥ArtaneAlzheimer’disease(AD)

阿爾茨海默病

CNSdegenerativediseasecognitivedisorderinprogress進(jìn)行性認(rèn)知障礙memoryimpairment記憶力損害Maincourse:cholinergicinsufficiencyCholinesteraseinhibitordrug膽堿酯酶抑制藥

Tacrine他克林

bestchoiceforADatpresentMechanism：inhibiting

cholinesterasestimulatingMandNreceptorsdirectlypromotingAchreleaseAdverseeffects:hepatotoxicityCholinergicreceptoragonist膽堿受體激動(dòng)藥

xanomeline占諾美林stimulatingM1receptorselectively

NervecellGFpotentiator

神經(jīng)細(xì)胞生長因子增強(qiáng)劑neotrofin（AIT