抗中樞退行性疾病藥

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

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

抗中樞退行性疾病藥抗中樞退行性疾病藥

Fateoforallyadministeredlevodopaandtheeffectofcarbidopa,estimatedfromanimaldata.

Thewidthofeachpathwayindicatestheabsoluteamountofthedrugpresentateachsite,whilethepercentagesshowndenotetherelativeproportionoftheadministereddose.Thebenefitsofcoadministrationofcarbidopaincludereductionoftheamountoflevodopadivertedtoperipheraltissuesandanincreaseinthefractionofthedosethatreachesthebrain.抗中樞退行性疾病藥一、左旋多巴及其增效劑1.左旋多巴（L-dopa)

藥理作用與機(jī)制

左旋多巴可使80%PD病人癥狀明顯改善。其中20%的病人可恢復(fù)到正常運(yùn)動(dòng)狀態(tài)。起病初期用藥療效更為顯著，用藥后患者感覺良好，抑制和淡漠癥狀改善，服藥后先改善肌強(qiáng)直和運(yùn)動(dòng)遲緩，后改善肌震顫，由于情緒好轉(zhuǎn)，能關(guān)心周圍環(huán)境，思維清晰敏捷，聽覺口語(yǔ)學(xué)習(xí)能力明顯改善，生活質(zhì)量明顯提高。抗中樞退行性疾病藥特點(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。機(jī)制L-dopa屬DA的前體藥，本身無(wú)藥理活性，腦內(nèi)轉(zhuǎn)化為DA，補(bǔ)充了紋狀體中DA的不足，提高中樞DA神經(jīng)功能，抑制膽堿能神經(jīng)功能，產(chǎn)生抗震顫麻痹的作用?？怪袠型诵行约膊∷?/p>

體內(nèi)過(guò)程

口服后主要在小腸經(jīng)主動(dòng)轉(zhuǎn)運(yùn)系統(tǒng)而迅速吸收。進(jìn)入中樞量不到1%，99%在外周經(jīng)脫羧換化為DA是引起不良反應(yīng)的主要原因。因此，提出與外周多巴脫羧酶抑制劑合用達(dá)到增效，減少不良反應(yīng)，還可減少左旋多巴的用量?？怪袠型诵行约膊∷幣R床應(yīng)用1.帕金森病治療廣泛用于各種類型PD病人，運(yùn)動(dòng)障礙癥狀不明顯者一般不用。對(duì)抗精神病藥物所致錐體外系癥狀無(wú)效。病人長(zhǎng)期用藥效果有較大個(gè)體差異。服藥6年后，約半數(shù)病人失效。2．肝昏迷輔助治療肝昏迷病人，由于肝功能障礙，血中苯乙胺、酪胺升高，在神經(jīng)細(xì)胞內(nèi)經(jīng)β-羥化酶作用生成苯乙醇胺和章胺（偽遞質(zhì)）妨礙正常神經(jīng)功能。用左旋多巴后，轉(zhuǎn)化為NA恢復(fù)正常神經(jīng)功能，病人逐漸轉(zhuǎn)為清醒。魚抗中樞退行性疾病藥不良反應(yīng)

大多是由于左旋多巴在體內(nèi)生成DA所致。1．胃腸道反應(yīng)厭食、惡心、嘔吐、腹部不適。是由于DA興奮延腦催吐化學(xué)感受區(qū)所致。繼續(xù)治療，由于產(chǎn)生耐受性，胃腸道反應(yīng)可減輕。2．心血管反應(yīng)部分病人出現(xiàn)體位性低血壓反應(yīng)，表現(xiàn)頭暈，偶見暈厥。少數(shù)病人心律失常(DA興奮心臟β1受體)。3．不自主異常運(yùn)動(dòng)如咬牙、吐舌、點(diǎn)頭、做怪相及舞蹈樣動(dòng)作，發(fā)生率約40~80%，多在長(zhǎng)期用藥后出現(xiàn)，主要是由于DA補(bǔ)充過(guò)度，須減量。少數(shù)病人長(zhǎng)期用藥后，可出現(xiàn)“開關(guān)現(xiàn)象”，表現(xiàn)為突然多動(dòng)不安(開)，轉(zhuǎn)為全身產(chǎn)生強(qiáng)直不動(dòng)(關(guān))，二者交替出現(xiàn)，機(jī)制尚無(wú)完滿解釋。4．精神障礙與DA過(guò)度興奮中腦一邊緣系統(tǒng)DA受體有關(guān)?？怪袠型诵行约膊∷?.外周多巴脫羧酶抑制劑卡比多巴（Carbidopa）、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，可增加血和腦內(nèi)L-dopa達(dá)3~4倍。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）抗中樞退行性疾病藥聯(lián)合用藥主要優(yōu)點(diǎn)1、提高左旋多巴療效（增效）2、減少外周副作用（減毒）3、減少左旋多巴用量（70~80%）抗中樞退行性疾病藥3.COMT抑制劑

L-dopa代謝有兩條途徑：L-dopaDA3-OMD（3-O-甲基多巴）而3-OMD又可與L-dopa競(jìng)爭(zhēng)轉(zhuǎn)運(yùn)載體而影響L-dopa的吸收和進(jìn)入腦組織（生物利用度降低）-co2COMT抗中樞退行性疾病藥

硝替卡朋（nitecapone）托卡朋（tocapone）安托卡朋（entocapone）可增加紋狀體中L-dopa和DA。當(dāng)與卡比多巴合用時(shí)，只抑制外周COMT，增加L-dopa生物利用度，而不影響腦內(nèi)COMT（不易通過(guò)血腦屏障）?？怪袠型诵行约膊∷幙估夏晷园V呆藥

DownsizedTarget

AtinyproteincalledADDLcouldbethekeytoAlzheimer's

ScientificAmerican2004抗中樞退行性疾病藥ScientistshavelongsuspectedthattheproteinclumpsandtanglesidentifiedbyAloisAlzheimerin1907somehowcausethediseasethatbearshisname,probablybykillingneurons.Nowsomeresearchersareblamingamuchsmallerformofprotein,onethatapparentlyproducesmemorydeficitsmerelybybindingtoneuronsanddisruptingtheirabilitytotransmitsignals.Thesearchhasbegunforanantibodythatwoulddestroythesetinyproteins--orADDLs--therebypreventingtheonsetofAlzheimer'sdiseaseandpossiblyevenreversingtheearlysymptoms.

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

KleindevelopedanantibodythatrevealedhowADDLsattachtodendritesinthehippocampus,therebydisruptingsignalsneededtoproduceshort-termmemories.AndlastsummerKlein,Krafft,