课件：临床药理学癫痫.ppt

癫痫是一类脑部的慢性疾病，是由自发性的，反复发作的不正常脑部高频放电，并向周围扩散而致抽搐。发作时伴有EEG异常。病因多种多样，可为脑外伤，脑肿瘤，中毒等，也有不少原因不明。 癫痫不是单一种疾病，是许多疾病的集合。癫痫综合征(Epileptic syndromes )。 发病率约1%，青少年多。,癫痫（epilepsy）,癫痫发作分型,全面性发作 (Generalized-onset seizures ) 均有意识障碍及双例大脑半球同时受累，脑电固呈双侧同步对称异常电活动。 (1)失神发作：典型失神发作：非典型失神发作； (2)肌阵挛发作 (3)阵挛发作 (4)强直发作 (5)强直-阵挛发作(典型大发作) (6)失张力发作 部分性发作(局灶性发作, Partial-onset seizures ) (1)单纯部分性发作：无意识障碍 (2)复杂部分性发作：有意识障碍 (3)部分发作发展到全身强直一阵挛发作,大发作(Tonic-Clonic Seizures)：突然意识丧失，倒地抽搐，面色青紫，口吐白沫，经数分钟后深睡1小时左右后苏醒。 如大发作频繁，间隔甚短，持续昏迷，称癫痫持续状态(Status epilepticus)。 小发作(Absence Seizures)：突然意知消失，动作中断，目瞪直视，不倒地抽搐。小孩多见每天可发作数十数百次。,精神运动性发作(Complex partial seizures 的一种)：阵发性精神失常，伴有无意识动作，持续时立数分钟至数日不等。EEG为每秒4周的高幅方形波。 局限性发作(Simple partial seizures )：细胞放电局限于一侧大脑半球，表现为一侧面部，或肢体肌肉抽搐，或感觉异常。发作前常有幻听，幻嗅等。特点为保持意识。 如抽搐发展到期对侧，则意识消失，发展为大发作。,2癫痫发作机制： 仍不甚明了。可能与膜离子通道不正常，Na-K-ATP酶功能下降，造成膜静止电位降低，GABA的抑制功能降低。GABA和谷氨酸（GA）广泛存在于CNS，GABA为抑制性递质，GA为兴奋性递质。当GABA操纵的离子通道减弱，GA操纵的通道增强，而使一群神经元同步放电，而后向周围传播，造成癫痫发作。即兴奋性力量超过了抑制性力量导致神经网络的突然兴奋。,Mechanisms (leading to decreased inhibition ) Defective GABA-A inhibition :coupled to chloride channels inducing an IPSP . They are one of the main targets modulated by the anticonvulsants that are currently available. Defective GABA-B inhibition :coupled to potassium channels, inhibiting the release of excitatory neurotransmitter in the presynaptic afferent projection . Defective activation of GABA neurons Defective intracellular buffering of calcium : interneuron loss,Mechanisms (leading to increased excitation ) Increased activation of NMDA receptors Increased synchrony between neurons T-calcium channels (absence seizures) GABA-B receptor antagonists suppress absence seizures . valproic acid and ethosuximide suppress the T-calcium current, blocking its channels. some anticonvulsants that increase GABA levels, such as gabapentin, tiagabine, and vigabatrin, are associated with exacerbation of absence seizures.,3药物制止癫痫发作的方式和机制： 作用方式 作用于病灶神经元，减少其过度放电。 作用于病灶周围正常组织，防止异常放电的扩散。目前常用的药物大多数通过这种方式发挥作用。 作用机制 抑制钠通道，膜稳定作用 抑制钙通道 增强GABA功能，促进释放，减少降解,特定病人,特发性全身性发作 82% 原因不明的局限性发作 45% 症状性局限性发作 35% 颞叶外局限性发作 36% 头部损伤 30% 脑发育不良 24% 颞叶癫痫 20% 海马硬化症 11% 海马硬化症加其它病变 3%,2200例不同病因患者治疗后癫痫发作控制达一年以上的百分率,常用抗癫痫药 苯妥英钠 药理作用和应用： A抗癫痫：除小发作外，对各类型癫痫发作均有效，大发作疗效最好。 不能消除发作前的先兆症状，EEG不能完全恢复，表明主要抑制异常放电扩散，而不是抑制病灶放电。 作用机制；阻断电压依赖性钠通道。增强GABA的抑制功能，促进Cl-通道开放。 B抗心律失常 C治疗外周神经痛（如三叉神经痛）。,药动学： 口服吸收慢而不规则，需6-10天才达到稳态血浓（10-20 ug/ml）。血浓过高时转达入零级动力学。血浓个体差异大，应测定血浓，调整剂量，使用权用药个体化。 不良反应： A局部刺激：胃肠反应或静脉炎等。刺激性大，不宜肌注。 B神经中毒症状：眼球震颤，共济失调，眩晕，复视，昏迷。 长期服用如血浓过高，可引起不易觉察的不良反应，影剧院响儿童的智力发育。 C其它：过敏反应，牙龈增生，白细胞下降，巨幼细胞性贫血，女性多毛，男性乳房发育。 D致畸,丙戌酸钠（Sodium Valproate） 对各类癫痫发作均有效。小对作效好，精神运动性发作疗效近于卡马西平，大发作不如苯妥英和苯巴比妥。 现为大发作和不明类型首选药。 机制：不很清楚 抑制GABA的降解酶（转氨酶），使GABA上升。 抑制GABA的再摄取，增高突触间隙中GABA浓度。 降低兴奋性氨基酸（天冬氨酸、谷氨酸）的浓度。 直接增强GABA受体而使神经元的抑制加强。 直接作用于神经元膜，影响钾的流动。 不良反应：消化道症状，嗜睡，共济失调，肝损害，可致畸。 最近发现可能影响幼儿智力发育，不宜用于妊娠和婴儿。,卡马西平（酰胺咪嗪，Carbamazine） 除小发作外的所有类型 ，作用机制与苯妥英相似，主要通过阻断Na+通道起作用。 对精神运动性发作好，大发作也较有效。 小发作疗效差甚至加重,苯巴比妥 明显改善EEG，消除发作前兆，有时可恢复正常。同时降低病灶和其周围脑组织的兴奋阈值。 苯巴比妥与GABAA受体复合物结合，增强GABA介导的抑制作用；延长氯离子通道开放时间，易化GABA的抑制作用；尚有钠离子通道的阻滞作用。可以抑制癫痫灶的发放。 除小发作外都有效，主要用于5岁以下的小儿大发作，新生儿发作及高热惊厥。,苯巴比妥可以导致认知功能障碍，影响儿童学习，所以在儿童应慎用。因其具有明显的镇静作用及多种不良反应，在临床上正逐渐为其它抗癫痫药所代替。长期应用突然停用可出现戒断症状出现焦虑，失眠，震颤，甚至意识模糊及惊厥发作。,安定、氯硝安定 静脉注射治疗癫痫状态，肌阵挛性发作，精神运动性发作。 乙琥胺： 只用于小发作，不良反应发生较少。,近年新药,拉莫三嗪 lamotrigine 奥卡西平 oxcarbazepine 加巴喷丁 gabapentin 托吡酯 topiramate 噻加宾 tiagabine 左乙拉西坦 levetiracetam 唑尼沙胺 zonisamide /cgi/content/full/62/8/1252 非氨酯 felbamate (可致肝损害，再障，不作为第一线药。),与老一代的主要抗癫痫药物（丙戊酸，卡马西平，苯妥因）相比，这些新一代药物的抗癫痫作用并没有更强，但不良反应和药动学相互作用等发生较少。,* Decrease in lamotrigine serum concentrations by oral contraceptives,2019/8/25,22,可编辑,Question 1: How does the efficacy and tolerability of the new AEDs compare with that of older AEDs in patients with newly diagnosed epilepsy? Summary ： Efficacy in newly diagnosed patients. Gabapentin is effective in the treatment of newly diagnosed partial epilepsy. Lamotrigine, topiramate, and oxcarbazepine are effective in a mixed population of newly diagnosed partial and generalized tonic-clonic seizures. There are insufficient data to make a recommendation for the syndromes individually. At present, there is insufficient evidence to determine effectiveness in newly diagnosed patients for tiagabine, zonisamide, or levetiracetam.,Comparison to standard AED. Oxcarbazepine is equivalent to carbamazepine and phenytoin in efficacy, but superior in dose-related tolerability, at individually determined doses. Oxcarbazepine is equivalent in efficacy and tolerability to valproic acid. Topiramate at doses of 100 and 200 mg/day was equivalent in efficacy and safety to 600 mg fixed dose carbamazepine and 1,250 mg/day valproic acid, both in children aged 6 years and older and adults.,Lamotrigine is equivalent in efficacy to carbamazepine and phenytoin and superior in tolerability to carbamazepine, both in adults and elderly individuals. Topiramate at 100 mg and 200 mg is equivalent in efficacy and safety to 600 mg of fixed-dose, immediate-release carbamazepine administered in a BID regimen for partial seizures and to 1,250 mg of fixed-dose valproic acid for idiopathic generalized seizures.,Gabapentin is effective in monotherapy at 900 and 1,800 mg and is equivalent in efficacy to a 600 mg fixed dose of carbamazepine. Nine hundred milligrams of gabapentin is better tolerated than 600 mg fixed-dose, short-acting carbamazepine administered in a BID schedule.,Recommendation. 1. Patients with newly diagnosed epilepsy who require treatment can be initiated on standard AEDs such as carbamazepine, phenytoin, valproic acid, phenobarbital, or on the new AEDs lamotrigine, gabapentin, oxcarbazepine, or topiramate. Choice of AED will depend on individual patient characteristics (Level A).,Question 2: What is the evidence that the new AEDs are effective in adults or children with primary or secondary generalized epilepsy? Conclusions. Lamotrigine is effective in children with newly diagnosed absence seizures. Summary of findings. Lamotrigine is effective in the treatment of children with newly diagnosed absence seizures. At present, there is insufficient evidence to determine effectiveness in newly diagnosed primary or secondary generalized epilepsy for topiramate, oxcarbazepine, tiagabine, zonisamide, or levetiracetam.,Recommendation. 1. Lamotrigine can be included in the options for children with newly diagnosed absence seizures (Level B). 文献来源： /cgi/content/full/62/8/1252 /cgi/content/full/62/8/1261,Table 6 Summary of AAN evidence-based guidelines level A or B recommendation for use,新诊断EP病人新型AEDS的选择,TGB为噻加宾；代表有I或II级循证医学依据，代表尚无I或II级循证医学依据,难治性EP病人新型AEDS的选择,TGB为噻加宾；代表有I或II级循证医学依据，代表尚无I或II级循证医学依据,药物相互作用,抗癫痫药，特别是传统的抗癫痫药大都具有药酶诱导作用或高血浆蛋白结合率，加上药物本身的不良反应较多，易因药物作用产生不良反应。 发生相互影响，有的有抵消作用，有的有增强作用。 酶诱导：苯妥因钠、苯巴比妥、卡马西平 高血浆蛋白结合：丙戊酸钠(酶抑制剂),Carbamazepine Increased by erythromycin, clarithromycin, propoxyphene, fluoxetine, and grapefruit juice Decreased by phenytoin, and phenobarbital Phenytoin Increased by cimetidine, and if levels are high, topiramate and oxcarbazepine Decreased by phenobarbital,Common Antiepileptic Drug Interactions: Effect on Serum Levels of a Second Drug,Common Antiepileptic Drug Interactions: Effect on Serum Levels of a Second Drug,Valproate Increased by lamotrigine Decreased by carbamazepine, phenobarbital, an