第十七章

治療中樞神經(jīng)系統(tǒng)退行性疾病藥

帕金森病(Parkinson’sdisease，PD)

阿爾茨海默病(Alzheimer’sdisease,AD)亨廷頓（Huntington’sDisease,HD）肌萎縮側(cè)索硬化癥（ALS）中樞神經(jīng)系統(tǒng)神經(jīng)退行性疾病多種假說(shuō)神經(jīng)興奮毒性假說(shuō)(exci-toxicity)細(xì)胞凋亡假說(shuō)(apoptosis)氧化應(yīng)激假說(shuō)(oxidativestress)Parkinson’sDisease

帕金森病(Parkinson’sdisease,PD)又稱(chēng)震顫麻痹（paralysisagitants）是一種主要表現(xiàn)為進(jìn)行性錐體外系功能障礙的中樞神經(jīng)系統(tǒng)退行性疾病。第一節(jié)抗帕金森病藥HistoricalPerspectiveDr.JamesParkinson(1755-1828)1817“involuntarytremulousmotion”“passfromawalkingtoarunningpace”“shakingpalsy”LondonhomeCardinalSignsofParkinson’sDisease靜止震顫(Restingtremor)肌肉僵直(Cogwheelrigidity)運(yùn)動(dòng)遲緩(Bradykinesia)共濟(jì)失調(diào)(Posturalinstability)EpidemiologyAverageageofonset62.5MenandwomenaffectedequallyGeneticLinkAfrican-AmericansandAsianslesslikelythanCaucasianstodevelopParkinson’sCaffeineandsmokingshowssomeprotectiveeffectsParkinson’sDiseasesubtypes原發(fā)性（帕金森病）：病因尚未闡明。繼發(fā)性（帕金森綜合征）：抗精神病藥、腦炎、腦動(dòng)脈硬化、CO、錳中毒、利血平等所致。該學(xué)說(shuō)認(rèn)為，帕金森病是由于紋狀體內(nèi)多巴胺(DA)減少所致，而紋狀體內(nèi)DA的減少主要是由于黑質(zhì)受損變性所致。該學(xué)說(shuō)得到以下事實(shí)強(qiáng)有力的支持：①左旋多巴或DA受體激動(dòng)劑可顯著緩解震顫麻痹的癥狀；②破壞黑質(zhì)紋狀體DA神經(jīng)元的神經(jīng)毒素和長(zhǎng)期應(yīng)用DA受體拮抗劑可致震顫麻痹。

多巴胺缺失學(xué)說(shuō)得到大多數(shù)學(xué)者的公認(rèn)。DopaminergicNeurotransmissionDopamineprojectionstothebasalganglia–involvedinmovementNigrostriatalProjectionsThenewimagingagentAltropanevisualizes,inhealthypeople,acrescent-shapedcollectionofdopamineneuronsinthebrain'sstriatum(theyellowandredcoloredarea).InpeoplewithParkinson's,thefewremainingneuronsyieldonlyadimsignal.Pathophysiology帕金森病中可見(jiàn)色素丟失

PigmentLossIsSeenInParkinson'sDisease

NormalInpeoplewithParkinson'sImpairedMotorSysteminPDAcetylcholine--Synthesizedandstoredinstriatum--ExcitatoryeffectDopamine--Synthesizedbysustantianigrawithprojectionsinstriatum--InhibitingeffectAchDopNormallyBalancedAchDopAch>Dop=Parkinson'sAchDopAch<Dop=ChoreaBalancingActs.....(BlockAchwithanticholinergicdrugsorincreaseDopamine)(Reducedopamineorblockdopaminereceptors)AssociationsAcetylcholineCholinergicParasympatheticCholinesteraseDopamineAdrenergicLevodopaTyrosineEpinephrine(Adrenalin)SympatheticCatecholaminesNorepinephrineDecarboxylaseAchDOPDopamineSystemDOPAMINERECEPTORSThereareatleastfivesubtypesofreceptors:

Receptor

D1 D2:MostextensivelystudiedStimulatedbyagonistsfortreatmentofParkinson'sBlockedbyantagonistsfortreatmentofSchizophrenia D3 D4 D5 DopamineanditsReceptorsHOHONH2{D2-likeinhibitscAMP

inhibitsGIRK(Gi,Goetc.linked)selectiveforsulpirideD4D3D2(l&s)D1-like{D1A(D1)increasescAMP(Gsetc.linked)selectiveforSCH23390D1B(D5)Pharmacological

FamilyCoding

GenesPharmacological&FunctionalActionsRegulationofDopamineNeurotransmissionDANerveTerminalDiffusionDrugtreatment:Correctdopamine–AChimbalancevia:Enhancedopamineaction左旋多巴(L-DOPA)溴隱亭（bromocriptine）金剛烷胺（amantadine）InhibitAChactionMuscarinicreceptorblockers(CNSactive)苯海索（benzhexol）ParkinsonianDrugs一、擬多巴胺藥(一)多巴胺前體藥：左旋多巴左旋多巴(Levodopa，L-dopa)是兒茶酚胺類(lèi)神經(jīng)遞質(zhì)酶促合成過(guò)程中的中間代謝產(chǎn)物，是DA遞質(zhì)的前體物質(zhì)DopamineMetabolismDOPATransportintotheBrainDopaanddopaminemetabolismFurthermetabolismFurthermetabolismFurthermetabolism[藥理作用與機(jī)制]作用機(jī)制：在腦內(nèi)轉(zhuǎn)變成DA，補(bǔ)充了紋狀體中DA的不足，抑制膽堿能神經(jīng)元的功能，因此產(chǎn)生治療震顫麻痹的作用。

1、治療帕金森病

2、治療肝昏迷臨床應(yīng)用特點(diǎn)①奏效慢，用藥2~3周后才出現(xiàn)體征的改善，1~6個(gè)月后獲得最大療效。②對(duì)輕癥及年輕患者療效好，對(duì)重癥及年老患者療效差。③對(duì)吩噻嗪類(lèi)等抗精神病藥所引起的帕金森綜合征無(wú)效；[不良反應(yīng)與注意事項(xiàng)]早期反應(yīng)胃腸道反應(yīng)：初期惡心、嘔吐、食欲減退；長(zhǎng)期偶見(jiàn)潰瘍、出血和穿孔。心血管反應(yīng)：體位性低血壓、心律失常。長(zhǎng)期反應(yīng)精神障礙：可能與多巴胺作用與大腦邊緣葉有關(guān)。運(yùn)動(dòng)障礙：不自主的異常運(yùn)動(dòng)，可有“開(kāi)—關(guān)現(xiàn)象”。[藥物相互作用]

1、維生素B6：多巴脫羧酶輔基，外周副作用加強(qiáng)

2、抗精神病藥：對(duì)抗左旋多巴作用

TheProblemWithLevodopaWhenLevadopaistakenorally,itischangedinthegutintodopaminebyanenzymecalleddopadecarboxylase.DopamineMetabolism（二）左旋多巴增效藥

1、脫酸酶抑制藥卡比多巴（Carbidopa）和芐絲肼（benserazide）外周多巴脫羧酶抑制劑，不易通過(guò)血腦屏障。單獨(dú)應(yīng)用對(duì)PD無(wú)治療作用，主要與左旋多巴按一定比例制成復(fù)方左旋多巴制劑供臨床應(yīng)用。

兩藥合用的優(yōu)點(diǎn)如下：1提高左旋多巴療效（增效）2減少外周副作用（心臟的毒副作用）3減少左旋多巴用量（70~80%）信尼麥（sinemet,心寧美）左旋多巴：卡比多巴=10：1（100mg：10mg）復(fù)方芐絲肼（美多巴，Madopar）左旋多巴：芐絲肼=4∶1（100mg∶25mg）DopamineMetabolismInhibitorsMAOBInhibitors

Selegiline

選擇性單胺氧化酶B型抑制劑。可在腦內(nèi)使多巴胺代謝降低而使紋狀體多巴胺增多，為帕金森病輔助治療藥。COMTInhibitors

Entacapone -usedonlyincombinationwithlevodopa -inhibitlevodopacatabolism/extenddurationof levodopaeffect -indicatedforpatientsexperiencing“wearing-off’’ effectoflevodopatherapy司來(lái)吉蘭安托卡朋溴隱亭Bromocriptine

DopamineAgonist多巴胺受體激動(dòng)劑。口服易吸收，可通過(guò)血腦屏障。小劑量主要激動(dòng)結(jié)節(jié)漏斗部的多巴胺受體，用于產(chǎn)后停乳和催乳素分泌過(guò)多癥；大劑量主要激動(dòng)黑質(zhì)—紋狀體通路的多巴胺受體，用于治療帕金森病。（三）多巴胺受體激動(dòng)藥金剛烷胺（Amantadine）[作用特點(diǎn)]1、療效不及左旋多巴，但優(yōu)于膽堿受體阻斷藥；2、見(jiàn)效快，持續(xù)短，數(shù)天可達(dá)最大療效；

3、與左旋多巴合用有協(xié)同作用。[機(jī)制]

促使紋狀體內(nèi)殘存的完整多巴胺能神經(jīng)元釋放多巴胺；并能抑制多巴胺的再攝??；且有直接激動(dòng)多巴胺受體的作用及較弱的抗膽堿作用。（四）多巴胺能神經(jīng)遞質(zhì)促釋藥三、膽堿受體阻斷藥膽堿受體阻斷藥可阻斷中樞膽堿受體，減弱紋狀體中乙酰膽堿的作用。適用于：1、輕癥患者；2、不能耐受左旋多巴或禁用左旋多巴的患者；3、合用左旋多巴，可使50%患者癥狀進(jìn)一步改善；4、對(duì)抗精神病藥引起的帕金森氏綜合癥有效。[作用]

抗震顫療效好，但改善強(qiáng)直及運(yùn)動(dòng)遲緩較差，對(duì)某些繼發(fā)性癥狀如過(guò)度流涎有改善作用。[不良反應(yīng)]外周抗膽堿作用引起口干、散瞳、尿潴留、便秘等。窄角型青光眼、前列腺肥大者慎用。苯海索（trihexyphenidyl）、又稱(chēng)安坦（artane）。第二節(jié)治療AD藥Definition:Alzheimer'sDiseaseisanirreversible,progressive,debilitatingbraindisorderresultinginthedeathofbraincells,dementia,andeventuallydeathoftheindividual.BackgroundAloisAlzheimerAlzheimersDilemma:

WeHaveaChoiceNursingHomes

Emerging

Technologiesvs.10LeadingCausesofDeaths,UnitedStates2019

AllRaces,BothSexesAges:1-85

Cause

Number

Percentage

AllDeaths 100.0%1.HeartDisease611,105

32.02.Cancers 584,881

30.63.COPD149,205

7.84.UnintentionalInjury130,557

6.85.Stroke128,978

6.86.Alzheimer'sDisease84,7674.47.Diabetes75,5784.08.Influenzaandpneumonia56,9793.09.Nephritis(Kidneydisorders)47,1122.510.Suicide41,1492.2Source:NationalVitalStatisticsSystem,NationalCenterforHealthStatistics,CDC.201910LeadingCausesofDeaths,UnitedStates2000

AllRaces,BothSexesAges:1-85

Cause

Number

Percentage

AllDeaths 2,374,960 100.0%1.HeartDisease 710,760 29.9%2.Cancers 553,091 23.3%3.Cerebrovascular 167,661 7.1%4.COPD 122,009 5.1%5.UnintentionalInjury 97,904 4.1%6.DiabetesMellitus 69,301 2.9%7.Influenza/Pneumonia 65,313 2.7%8.Alzheimer'sDisease 49,558 2.1%9.Nephritis 37,251 1.6%10.Septicemia 31.224 1.3%AllOthers 470,989 19.9%U.S.NationalCenterforHealthStatistics,NationalVitalStatisticsReport vol.50,no.15,Sept.16,2002CausesofDementiaADprognosis

Optimalcase

MiniMentalStateExaminationscore12345678925---------------------|Symptoms20|----------------------|Diagnosis15|-----------------------|Lossoffunctionalindependence10|--------------------------------|Behavioralproblems5|-------------------------------------------|0Death|------------------------------------------NursinghomeplacementFeidmanandGracon,1996YearsProjectedNumber

ofAmerican’swithADEvans,DA,etal.MilbankQuarterly68:267-289;1990.PrevalenceofAD95+53%9032%8519%809%AGEAGE %65 170 275 580 985 1890 3295+ 53Source:GAO,January1998老年性癡呆一種由器質(zhì)性腦損傷導(dǎo)致的智能障礙；表現(xiàn)為記憶力、判斷力、抽象思維能力等的喪失；可分為阿爾茨海默癡呆（AD）、血管性癡呆（VD）和二者混合性癡呆。臨床癥狀：認(rèn)知障礙、記憶障礙和行為障礙。解剖基礎(chǔ)：海馬組織結(jié)構(gòu)的萎縮。功能基礎(chǔ)：膽堿能神經(jīng)興奮傳遞障礙和中樞神經(jīng)系統(tǒng)內(nèi)乙酰膽堿受體變性，神經(jīng)元數(shù)目減少。

AlzheimerDiseaseEarlyStageMemorylossLanguageproblemsChangesinpersonalityHostilityAgitation

AlzheimerDiseaseIntermediateStageMemorylossUnabletoperformsomeADLsWanderingHostilityAgitation

AlzheimerDiseaseSevereStageUnabletowalkUnabletoperformanyADLsIncontinentTotallydependentNeuropathologicChanges

CharacteristicofADNormalADAPNFTAP=amyloidplaques;NFT=neurofibrillarytanglesCourtesyofGeorgeGrossbergM.D.;St.LouisUniversity.InAlzheimer’spatients,thegraymatter,hasshrunkandthespacesinbetweenenlargeandfillwithventricularfluid.PETImagingofAmyloidDepositsin

Alzheimer’sDiseasevsNormalControlsSource:Klunk,etal.AnnNeurol2004:55:306-319.PETimagingwithanoveltracer,PittsburghCompound-B(PIB),canprovidequantitativeinformationonamyloiddepositsinlivingsubjects.Plaquesandtangles:theclassicalneuropathologicallesionsofAlzheimer’sDiseaseADAmyloidplaqueAcomplexmixtureofdamagedneurons,proteins,andothermacromoleculesTheplaquecoreamyloidfibrilisaorderedaggregatecomprisingprimarilyvariantsofa4kDaprotein,collectivelydesignatedtheamyloidprotein.MorphologyofAfibrilsNeurofibrillaryTangles/alzdis/about/plaques_tanglesBorder.jpgNeurofibrillaryTangles/rmedia/mediaroom.htm#animationAmyloidhypothesisβ-amyloidproteintauhypothesistauproteinHypothesesTreatmentOptionsAlzheimer’shasnocureRecentadvancementshavebroughtdrugsthatcanhelpalleviateordelaytheonsetofdementiaTheeconomicbenefitsofthesedrugslieintheirabilitytodelaynursing-homeplacementAD—HistoryTimeline1992

AHCPRdevelopsscreeningguidelinesforAD~200AD

Galenassociates“morosis”(dementia)witholdage700BC2000AD1980

Alzheimer’s

Association

establishedEarly1960s

AwarenessofADasasingledisease1907

ADfirstdescribedbyDr.AloisAlzheimer1978?

Singleentityestablished—

seniledementiaoftheAlzheimer’stype(SDAT)1983

Cholinergicdeficitidentified1991

APOEimplicated1994

BraininflammatoryresponseidentifiedaspathogeneticResearchintotreatmentscontinues1993

FirstcholinesteraseinhibitorapprovedCurrentDrugTreatmentsforADAcetylcholinesteraseinhibitorsformildtomoderateAD(inhibiti