抗中枢退行性疾病药

抗中枢退行性疾病药2024/3/28抗中枢退行性疾病药抗帕金森病药PARKINSONISM(ParalysisAgitants)Parkinsonismischaracterizedbyacombinationofrigidity,bradykinesia,tremor,andposturalinstabilitythatcanoccurforawidevarietyofreasonsbutisusuallyidiopathic.Thepathophysiologicbasisoftheidiopathicdisordermayrelatetoexposuretosomeunrecognizedneurotoxinortotheoccurrenceofoxidationreactionswiththegenerationoffreeradicals.Studiesintwinssuggestthatgeneticfactorsmayalsobeimportant,especiallywhenthediseaseoccursinpatientsunderage50.Parkinson'sdiseaseisgenerallyprogressive,leadingtoincreasingdisabilityunlesseffectivetreatmentisprovided.抗中枢退行性疾病药Thenormallyhighconcentrationofdopamineinthebasalgangliaofthebrainisreducedinparkinsonism,andpharmacologicattemptstorestoredopaminergicactivitywithlevodopaanddopamineagonistshavebeensuccessfulinalleviatingmanyoftheclinicalfeaturesofthedisorder.Analternativebutcomplementaryapproachhasbeentorestorethenormalbalanceofcholinergicanddopaminergicinfluencesonthebasalgangliawithantimuscarinicdrugs.Thepathophysiologicbasisforthesetherapiesisthatinidiopathicparkinsonism,dopaminergicneuronsinthesubstantianigrathatnormallyinhibittheoutputofγ-aminobutyricacid(GABA)ergiccellsinthecorpusstriatumarelost.抗中枢退行性疾病药Schematicrepresentationofthesequenceofneuronsinvolvedinparkinsonism.

Top:Dopaminergicneurons(color)originatinginthesubstantianigranormallyinhibittheGABAergicoutputfromthestriatum,whereascholinergicneurons(gray)exertanexcitatoryeffect.Middle:Inparkinsonism,thereisaselectivelossofdopaminergicneurons(dashed,color).

抗中枢退行性疾病药抗中枢退行性疾病药

Fateoforallyadministeredlevodopaandtheeffectofcarbidopa,estimatedfromanimaldata.

Thewidthofeachpathwayindicatestheabsoluteamountofthedrugpresentateachsite,whilethepercentagesshowndenotetherelativeproportionoftheadministereddose.Thebenefitsofcoadministrationofcarbidopaincludereductionoftheamountoflevodopadivertedtoperipheraltissuesandanincreaseinthefractionofthedosethatreachesthebrain.抗中枢退行性疾病药一、左旋多巴及其增效剂1.左旋多巴（L-dopa)

药理作用与机制

左旋多巴可使80%PD病人症状明显改善。其中20%的病人可恢复到正常运动状态。起病初期用药疗效更为显著，用药后患者感觉良好，抑制和淡漠症状改善，服药后先改善肌强直和运动迟缓，后改善肌震颤，由于情绪好转，能关心周围环境，思维清晰敏捷，听觉口语学习能力明显改善，生活质量明显提高。抗中枢退行性疾病药特点①奏效慢，用药2~3周后才出现体征的改善，1~6个月后获得最大疗效。②对轻症及年轻患者疗效好，对重症及年老患者疗效差。机制L-dopa属DA的前体药，本身无药理活性，脑内转化为DA，补充了纹状体中DA的不足，提高中枢DA神经功能，抑制胆碱能神经功能，产生抗震颤麻痹的作用。抗中枢退行性疾病药

体内过程

口服后主要在小肠经主动转运系统而迅速吸收。进入中枢量不到1%，99%在外周经脱羧换化为DA是引起不良反应的主要原因。因此，提出与外周多巴脱羧酶抑制剂合用达到增效，减少不良反应，还可减少左旋多巴的用量。抗中枢退行性疾病药临床应用1.帕金森病治疗广泛用于各种类型PD病人，运动障碍症状不明显者一般不用。对抗精神病药物所致锥体外系症状无效。病人长期用药效果有较大个体差异。服药6年后，约半数病人失效。2．肝昏迷辅助治疗肝昏迷病人，由于肝功能障碍，血中苯乙胺、酪胺升高，在神经细胞内经β-羟化酶作用生成苯乙醇胺和章胺（伪递质）妨碍正常神经功能。用左旋多巴后，转化为NA恢复正常神经功能，病人逐渐转为清醒。鱼抗中枢退行性疾病药不良反应

大多是由于左旋多巴在体内生成DA所致。1．胃肠道反应厌食、恶心、呕吐、腹部不适。是由于DA兴奋延脑催吐化学感受区所致。继续治疗，由于产生耐受性，胃肠道反应可减轻。2．心血管反应部分病人出现体位性低血压反应，表现头晕，偶见晕厥。少数病人心律失常(DA兴奋心脏β1受体)。3．不自主异常运动如咬牙、吐舌、点头、做怪相及舞蹈样动作，发生率约40~80%，多在长期用药后出现，主要是由于DA补充过度，须减量。少数病人长期用药后，可出现“开关现象”，表现为突然多动不安(开)，转为全身产生强直不动(关)，二者交替出现，机制尚无完满解释。4．精神障碍与DA过度兴奋中脑一边缘系统DA受体有关。抗中枢退行性疾病药2.外周多巴脱羧酶抑制剂卡比多巴（Carbidopa）、苄丝肼（benserazide）外周多巴脱羧酶抑制剂，不易通过血脑屏障。单独应用对PD无治疗作用，主要与左旋多巴按一定比例制成复方左旋多巴制剂供临床应用，可增加血和脑内L-dopa达3~4倍。信尼麦（sinemet,心宁美） 左旋多巴:卡比多巴=10:1（100mg:10mg）复方苄丝肼（美多巴，Madopar） 左旋多巴:苄丝肼=4∶1（100mg∶25mg）抗中枢退行性疾病药联合用药主要优点1、提高左旋多巴疗效（增效）2、减少外周副作用（减毒）3、减少左旋多巴用量（70~80%）抗中枢退行性疾病药3.COMT抑制剂

L-dopa代谢有两条途径：L-dopaDA3-OMD（3-O-甲基多巴）而3-OMD又可与L-dopa竞争转运载体而影响L-dopa的吸收和进入脑组织（生物利用度降低）-co2COMT抗中枢退行性疾病药

硝替卡朋（nitecapone）托卡朋（tocapone）安托卡朋（entocapone）可增加纹状体中L-dopa和DA。当与卡比多巴合用时，只抑制外周COMT，增加L-dopa生物利用度，而不影响脑内COMT（不易通过血脑屏障）。抗中枢退行性疾病药抗老年性痴呆药

DownsizedTarget

AtinyproteincalledADDLcouldbethekeytoAlzheimer's

ScientificAmerican2004抗中枢退行性疾病药ScientistshavelongsuspectedthattheproteinclumpsandtanglesidentifiedbyAloisAlzheimerin1907somehowcausethediseasethatbearshisname,probablybykillingneurons.Nowsomeresearchersareblamingamuchsmallerformofprotein,onethatapparentlyproducesmemorydeficitsmerelybybindingtoneuronsanddisruptingtheirabilitytotransmitsignals.Thesearchhasbegunforanantibodythatwoulddestroythesetinyproteins--orADDLs--therebypreventingtheonsetofAlzheimer'sdiseaseandpossiblyevenreversingtheearlysymptoms.

抗中枢退行性疾病药ThediscoveryofADDLsexplainsglaringanomaliesintheconventionalthinkingaboutAlzheimer's,whichholdsthatfragmentsofamyloidprecursorprotein,producedbynormalneurons,aggregateintosticky,insolubleplaquesthatdamageneurons.Theproblemwiththistheoryisthatvirtuallyeveryolderpersoncarriessomeamyloidplaque,butonlyafewdevelopAlzheimer's.Conversely,thosewithAlzheimer'softenhaverelativelyfewplaques.Anotherproposedculpritisthepresenceoftanglesoftauprotein,whichforminsideneuronsandcoincidewiththecollapseofmicrotubulesthatsupportthecellbodyandtransportnutrients.Thetautanglescorrelatemuchbetterwiththediseasebuttendtoappearlater,suggestingthattheyareaconsequence,notacause.抗中枢退行性疾病药In1994CalebE.Finch,aneurogerontologistattheUniversityofSouthernCalifornia,attemptedtocreateamyloidplaquebymixingasolutionofamyloidprecursorproteinfragmentswithclusterin,asubstanceproducedathigherlevelsinthebrainsofpeoplewithAlzheimer's.Theclusterindidnottriggertheformationofamyloidplaques,buttheresultingsolutionprofoundlydisruptedtheabilityoftheneuronstotransmitsignals.抗中枢退行性疾病药FinchreportedthisfindingtoGrantA.KrafftandWilliamL.Klein,twocolleaguesatNorthwesternUniversity,whosetouttodiscoverwhatwasinthesolution.Usinganatomic-forcemicroscope,theyobtainedextraordinarypicturesofglobulesnoonehadeverseen."Theylookedlikelittlemarbles,"Krafftrecalls."Itturnedouttheseglobulescontainedonlyafewoftheamyloidpeptidebuildingblocks,whereasthelongfibrilscontainedthousands,ifnotmillions,ofthesesubunits."ThethreescientistsdecidedtocallthesubstanceADDL,whichstandsforamyloidbeta-deriveddiffusibleligand.(Themoleculeisderivedfromamyloidprecursorprotein;itdiffusesthroughoutthebraininsteadofaggregatingintofixedplaques;asaligand,itattachestoreceptorsonneurons.)抗中枢退行性疾病药

KleindevelopedanantibodythatrevealedhowADDLsattachtodendritesinthehippocampus,therebydisruptingsignalsneededtoproduceshort-termmemories.AndlastsummerKlein,Krafft,