MicrosoftPowerPoint-抗癫痫药-20

1Chapter14Chapter14AntiepilepticandAntiepilepticandanticonvulsivedrugsanticonvulsivedrugs抗癫痫药和抗惊厥药抗癫痫药和抗惊厥药北京大学医学部药理学系李卫东2009年9月§§11抗癫痫药抗癫痫药AntiepilepticdrugsAntiepilepticdrugs癫痫癫痫EpilepsyEpilepsy是大脑神经元突发性异常放电导致短暂的是大脑神经元突发性异常放电导致短暂的大脑功能障碍的一种慢性疾病大脑功能障碍的一种慢性疾病Adisordercharacterizedbyrecurrentepisodesofparoxysmal(阵发的）阵发的）braindysfunctionduetoasudden,disorderly,andexcessiveneuraldischarge癫痫的两个基本特征——反复性和发作性IncidenceIncidence„„30to60per100,000personshaveepilepsy30to60per100,000personshaveepilepsy„„CommoninveryyoungchildrenCommoninveryyoungchildren„„60percentcompletelycontrollable;2560percentcompletelycontrollable;25percentcanreduceseveritypercentcanreduceseverity„„PatientswithepilepsyinChinaareaboutasPatientswithepilepsyinChinaareaboutasmanyas8millionmanyas8millionCausesofEpilepsyCausesofEpilepsy„„HeadTraumaHeadTrauma„„FeverFever„„InfectionInfection„„TumorTumorinbrain„Parasitesinbrain„Brainvascularmalformations„„MetabolicdisorderMetabolicdisorder„„Toxins(leadpoisoningToxins(leadpoisoning……))„„MedicationsMedications癫痫发病特点癫痫发病特点1.1.发作时，脑灰质神经元群发作时，脑灰质神经元群过度放电过度放电。局部。局部病灶神经元同时去极化，发生高频病灶神经元同时去极化，发生高频、阵发、、阵发、同步同步、、爆发式放电爆发式放电2.2.病灶的异常放电向周围正常组织病灶的异常放电向周围正常组织扩散扩散，致，致更广泛的脑组织兴奋，引起癫痫发作的临更广泛的脑组织兴奋，引起癫痫发作的临床表现，床表现，出现惊厥症状3.3.有运动、感觉、有运动、感觉、植物神经功能植物神经功能和精神方面和精神方面异常异常2（一）原发性癫痫：又称真性或特发性或隐原性癫痫。其真正的原因不明。虽经现代各种诊查手段检查仍不能明确（二）继发性癫痫：又称症状性癫痫。指能找到病因的癫痫。见上述常见病因根据发作情况可分为大发作、小发作、精神运动性发作、局限性发作和复杂部分性发作癫痫的分类GeneralizedTonicGeneralizedTonic--ClonicClonicSeizuresSeizures全身性强直－阵挛性发作全身性强直－阵挛性发作„„Personstiffens,falls,andconvulses,Personstiffens,falls,andconvulses,losingconsciousnesslosingconsciousness„„EEGabnormalinmorethan2/3ofEEGabnormalinmorethan2/3ofcasescases„„CauseinyoungchildrenduetoCauseinyoungchildrenduetoinfection,metabolicdisorderortraumainfection,metabolicdisorderortrauma„„Inolderindividuals,usuallyduetoInolderindividuals,usuallyduetotraumaortumortraumaortumorgrandmalandstatusepilepticsgrandmalandstatusepileptics癫痫持续状态癫痫持续状态大发作反复发生，间歇期甚短，持续抽搐和昏迷AbsenceSeizures失神发作（小发作）„„TemporarylapseofconsciousnessthatstartsTemporarylapseofconsciousnessthatstartsandendsabruptlyandendsabruptly„„Usualageofonsetis3to12yearsoldUsualageofonsetis3to12yearsold„„HighgeneticpredispositionHighgeneticpredisposition„„Over50percentgointoremissionafterOver50percentgointoremissionafteradolescenceadolescenceSimplepartialseizures单纯性部分发作„„LocalizedseizuredisorderwhichlastsafewLocalizedseizuredisorderwhichlastsafewminutesandischaracterizedbymotororminutesandischaracterizedbymotororsensoryphenomenainahand,armorbodysensoryphenomenainahand,armorbodypartpart„„SeizuremovessequentiallyfromoneareatoSeizuremovessequentiallyfromoneareatoanotheronthesamesideofthebodyanotheronthesamesideofthebody„„Mostfrequentbetween5Mostfrequentbetween5--15yearsofage15yearsofage3Complexpartialseizures复杂性部分发作„„AlsocalledpsychomotorortemporallobeAlsocalledpsychomotorortemporallobeseizuresseizures„„IndividuallosesawarenessIndividuallosesawareness„„RepetitivemotorbehaviorsoccurRepetitivemotorbehaviorsoccur„„Last1toafewminutesLast1toafewminutes„„Symptomsincludesconfusion,irritabilitySymptomsincludesconfusion,irritability„„Causes:Geneticpredisposition,prenatalCauses:Geneticpredisposition,prenataltrauma,brainlesionstrauma,brainlesionsPartialwithSecondarilyGeneralizedPartialwithSecondarilyGeneralizedTonicTonic--clonicclonicSeizuresSeizures继发强直阵挛性部分性发作„„SometimespartialseizuresdevelopintofullSometimespartialseizuresdevelopintofullbodyseizuresbodyseizures„„UsuallythisiswhentheyareuncontrollableUsuallythisiswhentheyareuncontrollableThereasonsforfallingsickness向脑内注射谷氨酸可诱发异常高频放电；向脑内注射GABAA受体拮抗剂可诱发异常高频放电提示：提示：癫痫发作与脑内谷氨酸（兴奋性氨基酸）和GABA（抑制性氨基酸）失平衡有关Historyofantiepilepticdrugs19121912年发现苯巴比妥年发现苯巴比妥19381938年发现苯妥英。两种传统药物一年发现苯妥英。两种传统药物一直应用至今直应用至今19641964年发现了丙戊酸钠年发现了丙戊酸钠近近2020余年，合成很多新药物，但仍停余年，合成很多新药物，但仍停留在对症治疗水平留在对症治疗水平AntiepilepticdrugsAntiepilepticdrugs11、、mannerofactionmannerofaction11、、InhibitInhibitlocaldischargelocaldischarge22、、InhibitInhibitfiringfiringarounddiffusearounddiffuse♦♦直接抑制病灶神经元过度放电直接抑制病灶神经元过度放电((特别是抑制特别是抑制持久高频反复放电持久高频反复放电sustainedhighsustainedhighfrequencefrequencerepetitivefiring,SHRFrepetitivefiring,SHRF))♦♦提高正常脑组织的兴奋阈，减弱病灶兴奋提高正常脑组织的兴奋阈，减弱病灶兴奋的扩散，防止癫痫复发的扩散，防止癫痫复发ActionmechanismsofActionmechanismsofantiepilepticdrugsantiepilepticdrugs11、、IncreasingfunctionofGABAIncreasingfunctionofGABA22、、InterfereNaInterfereNa++、、KK++、、CaCa2+2+channelchannel♦♦增强增强GABAGABA介导的抑制性突触传递功能介导的抑制性突触传递功能♦♦阻滞离子通道：阻滞离子通道：NaNa++、、CaCa2+2+、、KK++4PHARMACOKINETICSPHARMACOKINETICS„„11．口服吸收良好，肌内注射吸收不规则，起效．口服吸收良好，肌内注射吸收不规则，起效慢慢„„22．有效血药浓度．有效血药浓度1010－－2020μμg/mlg/ml„„3.3.被肝微粒体酶代谢，剂量过大可使酶饱和，被肝微粒体酶代谢，剂量过大可使酶饱和，t1/2t1/2延长延长苯妥英苯妥英((phenytoinphenytoin)大仑丁DilantinCCNCNHOONa11．．抗癫痫：抗癫痫：抗大发作抗大发作,,精神运动型发作精神运动型发作————首选，部首选，部分性发作次之，分性发作次之，iviv治疗癫痫持续状态。治疗癫痫持续状态。但对小发作无效，甚增加发作次数22．治疗中枢性疼痛综合征．治疗中枢性疼痛综合征及外周神经痛及外周神经痛((三叉神经、三叉神经、坐骨神经、舌咽神经痛）坐骨神经、舌咽神经痛）33．抗心律失常．抗心律失常::室性，特别是强心苷中毒（首选）室性，特别是强心苷中毒（首选）CLINICALUSE作用特点作用特点11、、起效慢。一次给药后约起效慢。一次给药后约1212小时血浆达峰浓度，连小时血浆达峰浓度，连续服用的治疗量续服用的治疗量66--1010天达稳态血浓天达稳态血浓22、个体差异大，制剂生物利用度显著不同、个体差异大，制剂生物利用度显著不同((硫酸钙－硫酸钙－乳糖事件）。有条件最好