抗帕金森病药课件

Anti-ParkinsonDrugs

抗帕金森病药物1Anti-ParkinsonDrugs

抗帕金森病药物1ThenervousdisordercharacterizedbyDr.JamesParkinson（1817）Restingtremor

(静止性震颤)Rigidity(肌强直)Bradykinesia(运动迟缓)Dementia(痴呆)Excessivesalivation2Parkinson’sdisease

(帕金森病，PD)Thenervousdisordercharacter多巴胺（DA）缺失假设PD患者黑质病变，DA合成减少，使纹状体内DA含量降低，导致黑质-纹状体通路DA能神经功能减弱，胆碱能神经功能占优势，引起肌张力增高等症状3发病机制依据：左旋多巴或DA激动剂可显著缓解PA症状；破坏黑质-纹状体DA神经元的神经毒素和长期使用DA阻断剂可PA。致PA。多巴胺（DA）缺失假设3发病机制依据：PathogenesisProgressivedegenerationofDA-producingneuronsinthesubstantianigra(黑质)ImbalanceinDAandAChactiononneuronsofthecorpusstriatum(纹状体)4PathogenesisProgressivedegene黑质纹状体侧脑室5黑质纹状体侧脑室566PathologicalHallmarkAbnormalaccumulationofthe-synucleinprotein（-突触核蛋白）inthebrain.-突触核蛋白Lewybody

7PathologicalHallmarkAbnormalTherapeuticStrategiesIncrease

DAactivityorreduce

AChactivity,restoretheirbalanceinthecorpusstriatumAtpresent,thereisnocureforPD,butmedications,surgeryandmultidisciplinary

managementcanproviderelieffromthesymptoms.8TherapeuticStrategiesIncreaseLevodopa

(左旋多巴,L-dopa)Hasbeenthemostwidelyusedtreatmentforover30years.L-dopaistransformedintoDAinthedopaminergicneuronsbydopa-decarboxylase(多巴脱羧酶)torestoreDAactivityinthecorpusstriatum.9Levodopa(左旋多巴,L-dopa)HasbeeIsabsorbedrapidlyfromtheintestineandentertheCNStobecomeDA>95%在外周被脱羧酶脱羧DA仅1-3%的原形药物可到达脑内外周脱羧酶抑制药显著增加原形药物透过BBBIsusuallyadministeredwithperipheraldopadecarboxylaseinhibitors10PharmacokineticsIsabsorbedrapidlyfromtheiReducerequireddosageandtoxicitySinemet

(心宁美)：

carbidopa(卡比多巴)/L-dopa=1:10Madopar

(美多巴)：

benserazide(苄丝肼)/L-dopa=1:411L-dopa+peripheraldopadecarboxylaseinhibitorsReducerequireddosageandtox12FateoforallyadministeredL-dopaandtheeffectofcarbidopa.12FateoforallyadministeredTherapeuticEffectsAmelioratesallPDsymptomsafterseveralweeksoftreatmentandimproveslifequalityIsparticularlyeffectiveinrelievingbradykinesia(运动迟缓)Incombinationwithcarbidopatoreducedosageandtoxicity13TherapeuticEffectsAmelioratesAdverseEffects

大多由生成的DA所致GIeffects早期出现厌食、恶心、呕吐偶见溃疡出血aremuchlessfrequentwhenusedincombinationwithcarbidopa(<20%)14AdverseEffects大多由生成的DA所致1CardiovascularEffects:arrhythmias,Posturalhypotension(体位性低血压)3.异常不随意运动(1)约一半病人在治疗2-4m内出现异常不随意运动(2)面舌抽搐，怪相，摇头，双臂腿或躯干不自主出现各种各样的摇摆运动15CardiovascularEffects:arrh(3)“开-关”现象（On/offphenomenon

）病人突然多动不安，而后出现肌强直运动不能，两者交替出现，严重妨碍患者日常活动长期服用L-dopa产生耐受所致(4)精神障碍幻觉、妄想、躁狂、失眠、焦虑、恶梦等16(3)“开-关”现象（On/offphenomenonVitaminB6(多巴脱羧酶辅酶)enhances

theperipheralactivityoflevodopaandmaythereforeworsenitsadverseeffectsAntipsychoticdrugs(抗精神病药)blockDAreceptorsandthereforereducethetherapeuticeffectofL-dopa17DrugInteractionsVitaminB6(多巴脱羧酶辅酶)enhancesDopamineReceptorAgonistsDopamineagonistsinthebrainhaveasimilareffecttoL-dopasincetheybindtodopaminergicpost-synapticreceptors.Theyarenowmainlyusedasaninitialtherapyformotorsymptoms.WhenusedinlatePDtheyareusefulatreducingtheoffperiods.Bromocriptine(溴隐亭)Pramipexole(普拉克索)18DopamineReceptorAgonistsDopaPharmacologicPropertiesDonotrequireenzymaticconversiontoanactivemetaboliteReadilypassBBBHavenopotentiallytoxicmetabolitesSelectivelyactoncertainDAreceptorsHavefeweradverseeffectsthanL-dopa治疗初期可与Sinemet合用（心宁美:卡比多巴+左旋多巴）；也可用于L-dopa治疗后产生运动障碍和“开-关”现象的患者，以及对L-dopa耐受的患者19PharmacologicPropertiesDonotBromocriptine(溴隐亭)

Anergot(麦角)derivativeA

selectiveD2agonist：垂体（小剂量）黑质-纹状体（大剂量）OftengivenincombinationwithSinemetCanbeusedtotreathyperprolactinemia(高泌乳素血症)andacromegaly(肢端肥大症)20Bromocriptine(溴隐亭)Anergot(MAOInhibitorsSelegiline(司来吉兰):selectivelyinhibitsMAO-B(存在于CNS).可增强L-dopa的作用，减少其剂量和毒性.21MAOInhibitorsSelegiline(司来吉兰COMTInhibitorsEntacapone(恩他卡朋):

抑制外周COMT,减少L-dopa代谢为3-氧-甲基多巴(3-OMD),使脑内可利用的L-dopa增加。可增加L-dopa的生物利用度，延长其半衰期。PD辅助药物22COMTInhibitorsEntacapone(恩他卡谢谢23谢谢23Anti-ParkinsonDrugs

抗帕金森病药物24Anti-ParkinsonDrugs

抗帕金森病药物1ThenervousdisordercharacterizedbyDr.JamesParkinson（1817）Restingtremor

(静止性震颤)Rigidity(肌强直)Bradykinesia(运动迟缓)Dementia(痴呆)Excessivesalivation25Parkinson’sdisease

(帕金森病，PD)Thenervousdisordercharacter多巴胺（DA）缺失假设PD患者黑质病变，DA合成减少，使纹状体内DA含量降低，导致黑质-纹状体通路DA能神经功能减弱，胆碱能神经功能占优势，引起肌张力增高等症状26发病机制依据：左旋多巴或DA激动剂可显著缓解PA症状；破坏黑质-纹状体DA神经元的神经毒素和长期使用DA阻断剂可PA。致PA。多巴胺（DA）缺失假设3发病机制依据：PathogenesisProgressivedegenerationofDA-producingneuronsinthesubstantianigra(黑质)ImbalanceinDAandAChactiononneuronsofthecorpusstriatum(纹状体)27PathogenesisProgressivedegene黑质纹状体侧脑室28黑质纹状体侧脑室5296PathologicalHallmarkAbnormalaccumulationofthe-synucleinprotein（-突触核蛋白）inthebrain.-突触核蛋白Lewybody

30PathologicalHallmarkAbnormalTherapeuticStrategiesIncrease

DAactivityorreduce

AChactivity,restoretheirbalanceinthecorpusstriatumAtpresent,thereisnocureforPD,butmedications,surgeryandmultidisciplinary

managementcanproviderelieffromthesymptoms.31TherapeuticStrategiesIncreaseLevodopa

(左旋多巴,L-dopa)Hasbeenthemostwidelyusedtreatmentforover30years.L-dopaistransformedintoDAinthedopaminergicneuronsbydopa-decarboxylase(多巴脱羧酶)torestoreDAactivityinthecorpusstriatum.32Levodopa(左旋多巴,L-dopa)HasbeeIsabsorbedrapidlyfromtheintestineandentertheCNStobecomeDA>95%在外周被脱羧酶脱羧DA仅1-3%的原形药物可到达脑内外周脱羧酶抑制药显著增加原形药物透过BBBIsusuallyadministeredwithperipheraldopadecarboxylaseinhibitors33PharmacokineticsIsabsorbedrapidlyfromtheiReducerequireddosageandtoxicitySinemet

(心宁美)：

carbidopa(卡比多巴)/L-dopa=1:10Madopar

(美多巴)：

benserazide(苄丝肼)/L-dopa=1:434L-dopa+peripheraldopadecarboxylaseinhibitorsReducerequireddosageandtox35FateoforallyadministeredL-dopaandtheeffectofcarbidopa.12FateoforallyadministeredTherapeuticEffectsAmelioratesallPDsymptomsafterseveralweeksoftreatmentandimproveslifequalityIsparticularlyeffectiveinrelievingbradykinesia(运动迟缓)Incombinationwithcarbidopatoreducedosageandtoxicity36TherapeuticEffectsAmelioratesAdverseEffects

大多由生成的DA所致GIeffects早期出现厌食、恶心、呕吐偶见溃疡出血aremuchlessfrequentwhenusedincombinationwithcarbidopa(<20%)37AdverseEffects大多由生成的DA所致1CardiovascularEffects:arrhythmias,Posturalhypotension(体位性低血压)3.异常不随意运动(1)约一半病人在治疗2-4m内出现异常不随意运动(2)面舌抽搐，怪相，摇头，双臂腿或躯干不自主出现各种各样的摇摆运动38CardiovascularEffects:arrh(3)“开-关”现象（On/offphenomenon

）病人突然多动不安，而后出现肌强直运动不能，两者交替出现，严重妨碍患者日常活动长期服用L-dopa产生耐受所致(4)精神障碍幻觉、妄想、躁狂、失眠、焦虑、恶梦等39(3)“开-关”现象（On/offphenomenonVitaminB6(多巴脱羧酶辅酶)enhances

theperipheralactivityoflevodopaandmaythereforeworsenitsadverseeffectsAntipsychoticdrugs(抗精神病药)blockDAreceptorsandthereforereducethetherapeuticeffectofL-dopa40DrugInteractionsVitaminB6(多巴脱羧酶辅酶)enhancesDopamineReceptorAgonistsDopamineagonistsinthebrainhaveasimilareffecttoL-dopasincetheybindtodopaminergicpost-synapticreceptors.Theyarenowmainlyusedasaninitialtherapyformotorsymptoms.WhenusedinlatePDtheyareusefulatreducingtheoffperiods.Bromocriptine(溴隐亭)Pramipexole(普拉克索)41DopamineReceptorAgonistsDopaPharmacologicPropertiesDonotrequireenzymatic