单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,第16章,抗癫药及抗惊厥药,Chapter,16 Antiepileptic and Anticonvulsant,广西医科大学 黄仁彬,The characteristic event of epilepsy is the,seizure(often associated with a convulsion),which is caused by abnormal high-frequency discharge of some group of neurons,starting locally and spreading to a varying extent to affect other part of the brain.Current drug therapy is effective in 70%80%of patients.,第一节,抗癫药,Epilepsy,多种病因引起的,长期反复发作性的大脑功能失调。,其,特征,为发作时大脑局部病灶神经元突发性的异常高频放电并向周围组织扩散，出现短暂的大脑功能失调,。,表现,为突然发作,性的短暂的运动、感觉、意识和植物神经功能异常,可伴有脑电图改变。癫的,治疗,应长期用药，以减少或防止发作，但不能根治。,癫,Table 16-1(1),Types of Epilepsy and,Anti-epileptic Drugs,types of epilepsy,clinical features,anti-epileptic drugs(*preferred),partial seizures,1.simple partial seizures,involuntary muscle contraction and abnormal sensory experience without loss of consciousness,seizures lasting for 2060 sec;,carbamazepine*,valproate,clonazepam,phenytoin,phenobarbital,primidone,antiepilepsirine,lamotrigine;,plex partial seizures(,psychomotor epilepsy),conscious disturbance and psychiatric symptom,with often involuntary movement,such as shake head,lasting for 0.52min;,t,he same drugs mentioned above;,Table 16-1 (2),Types of Epilepsy and,Anti-epileptic Drugs,types of epilepsy,clinical features,anti-epileptic drugs(*preferred),3.partial seizures with,following tonic-clonic seizures,partial seizures is,followed by tonic-clonic seizures without loss of consciousness,lasting for 12min;,t,he same drugs mentioned above;,generalized seizures,1.tonic-clonic seizures(,grandmal)and status epilepticus,immediate loss of consciousness with generalized tonic-clonic convulsion,lasting for a few minutes.Seizures lasting for longer time is termed as status epilepticus;,carbamazepine*,phenytoin,valproate,phenobarbital,primidone,vigabatrin,lamotrigine,antiepilepsirine;,status epilepticus:diazepam*(i.v.);,Table 16-1 (3),Types of Epilepsy and,Anti-epileptic Drugs,types of epilepsy,clinical features,anti-epileptic drugs(*preferred),2.,absence seizures,(petit mal),patient abruptly ceases whatever he or she is doing,and stares vacantly for a few seconds,with unaware of surroundings;,ethosuximide*,clonazepam,valproate,nitrazepam,clobazam;,3.atypical,absence seizures,This seizures occurs and recovers more slowly than absence seizures;,ethosuximide*,clonazepam,valproate,nitrazepam,clobazam;,Table 16-1 (4),Types of Epilepsy and,Anti-epileptic Drugs,types of epilepsy,clinical features,anti-epileptic drugs(*preferred),4.myoclonic seizures,local myoclonia lasts for a few seconds;,valproate,clonazepam,clobazam;,5.infant myoclonic seizures,generalized rhythmic myoclonia with unconsciousness in infant.,clonazepam,valproate,clobazam,glucocorticoid,ethosuximide,carbamazepine valproate sodium,phenytoin phenobarbital primidone,Fig.16-1 Molecular structures of antiepileptic drugs,抑制癫病灶神经元的过度放电，或作用于病灶周围正常神经元，抑制异常放电的扩散。这些作用的基础与其增强GABA介导的突触抑制作用有关，如:1.,苯二氮类,(benzodiazepines,)和苯巴比妥,(phenobarbital,),激动GABA,A,受体、促进GABA介导的氯,通道开放。2.,噻加宾(tiagabine,),抑制GABA的摄取、增加突触后膜的GABA的浓度。,3.,氨己烯酸,(vigabatrin,),抑制GABA转氨酶活性、减少GABA的灭活。,【抗癫药物的作用机制】,4.一些药物的作用与阻滞离子通道有关，如,phenytoin，carbamazepine，valproate,和,lamotrigine,可通过阻滞细胞膜电压依赖性钠通道,(,valtage-dependent Na,+,channels)，抑制Na,+,的内流而降低膜的兴奋性。5.某些药物如,氟桂利嗪,(flunarizine,)，phenytoin,和,ethosuximide,的效应可能还与阻滞T型钙通道有关,6.,抗痫灵,(antiepilepsirine,),与增加脑内5-HT含量有关,(表16-2)。,【抗癫药物的作用机制】,【体内过程】,1.口服吸收慢而不规则，连续服用治疗量需经610天才能达到有效血药浓度。因此，常先用phenobarbital等作用较快的药物控制发作，在改用,phenytoin的同时，一般将本药与前用的药合用710天。,2.治疗癫持续状态时宜静脉注射。其血浆蛋白结合率约为90，大部分经肝药酶代谢为无活性的羟基苯妥英。3.血药浓度的个体差异较大，因而临床用量应注意个体化。,苯妥英钠,(Phenytoin,大仑丁dilantin),1.,对,高频异常放电神经元的钠通道具有显著的阻滞作用，降低细胞膜的兴奋性，从而能抑制癫病灶神经元的高频异常放电及其放电的扩散。此外，还与阻滞神经元的T型钙通道,抑制,Ca,2+,的内流有关,。2.高浓度时也能抑制神经末梢对,GABA,的摄取和诱导,GABA,A,受体增多，从而增强,GABA,介导的突触后抑制作用。这些作用与其抑制癫病灶神经元高频放电的产生及其扩散有关。,【药理作用】,1.抗癫,是常用的抗癫药，对癫大发作、单纯部分性发作和对精神运动性发作疗效较好，但对小发作无效或甚至加重。,2.治疗外周神经痛,用于治疗三叉神经、舌咽神经和坐骨神经等神经性疼痛。其中对三叉神经痛疗效较好，使疼痛明显减轻，发作次数减少。,3.抗心律失常。,【临床应用】,1局部刺激,口服可引起厌食、恶心、呕吐和腹痛等症状,；静脉注射可发生静脉炎。,2齿龈增生,多见于儿童和青少年，发生率约20，一般停药36个月后可自行消退。,3神经系统反应：,量中毒出现为眩晕、共济失调、精神错乱或昏迷等。,【不良反应】,4血液系统反应,抑制folinic acid的吸收并加速其代谢，以及抑制二氢叶酸还原酶活性，长期用药可致巨幼红细胞性贫血。,5骨骼系统反应,诱导肝药酶而加速,Vit.D代谢，可致低钙血症、佝偻病样改变和骨软化症。,6过敏反应,可发生皮疹、血小板减少、粒细胞缺乏、再生障碍性贫血。,7其他反应,偶见男性乳房增大、女性多毛症等。偶致畸胎，故孕妇慎用。久服骤停可使癫发作加剧，甚至诱发癫持续状态。,【不良反应】,Butazolidin、Sulfanilamide,s,和,salicylates,可与,phenytoin,竞争血浆蛋白的结合部位。,Phenytoin,诱导肝药酶而加速多种药物如避孕药的代谢和降低其药效。,Chloromycetin,等通过抑制肝药酶而提高,phenytoin,的血药浓度,。,Phenobarbital,诱导肝药酶而加速,phenytoin,的代谢。,【药物相互作用】,药物,应用,不良反应,Phenobarbital,大发作、癫持续状态、单纯部分性发作、精神运动性发作,见镇静催眠药,Primidone,对大发作疗效优于phenobarbital，但对部分性发作疗效不及phenytoin和carbamazepine,嗜睡、共济失调、巨幼红细胞性贫血、白细胞和血小板减少,Mephenytoin,主要用于癫大发作，由于不良反应较重，仅用于其他药物不能控制的患者,多形性红斑、高热、黄疸、中毒性肝炎、精神症状,Ethotoin,对大发作和复杂部分性发作有效。由于作用弱，只作辅助药物与其他药合用,不良反应少见,常用抗癫药的比较,(1),常用抗癫药的比较,(2),药物,应用,不良反应,Ethosuximide,对小发作不及氯硝西泮,(clonazepam,)，但副作用及耐受性较少，故仍为防治小发作的首选药,常见为胃肠道反应，其次为中枢神经系统症状如头痛，偶见粒细胞缺乏症和再障,Benzodiaze-pine,diazepam是癫持续状态的首选药，nitrazepam主要用于小发作和非典型失神性发作，clonazepam和clobazam对各型癫有效,diazepam静过快可致呼吸抑制，故应缓慢静脉注射。其他见镇静催眠药,Valproate,对各型癫均有效。对大发作不及phenytoin和phenobarbital；对