课件：药理学第二章.ppt

抗癫药及抗惊厥药,Antiepileptic and Anticonvulsant,第一节抗癫痫药,1、癫痫：大脑局部病灶N元兴奋性过高，产生阵发性高频放电，并向周围扩布，导致大脑功能失调综合征。 是一种慢性、反复性、突然发作性大脑功能失调性疾病。 2、类型: 根据临床表现和脑电图（EEG）特点，将癫痫发作分为：部分性发作、强直阵挛性发作（大发作） 、失神性发作（小发作）、精神运动性发作、癫痫持续状态。,3、抗癫痫药物的分类 :按药物作用方式分,（1）作用于神经细胞膜，干扰Na+、Ca2+的内流，降低神经细胞膜的通透性。如苯妥英钠、苯巴比妥。,（2）增强GABA介导的抑制性突触的传递功能，提高突触前或突触后抑制。如丙戊酸钠、硝西泮。,ethosuximide carbamazepine valproate sodium,phenytoin phenobarbital primidone,Fig. 16-1 Molecular structures of antiepileptic drugs,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Ca2+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GABAA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】,【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、Sulfanilamides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】,常用抗癫药的比较(1),常用抗癫药的比较(2),癫痫类型 抗癫痫药 典型大发作 苯妥英钠、卡马西平（酰胺咪嗪） 丙戊酸钠 小发作 乙琥胺、丙戊酸钠、苯二氮卓类 精神运动性发作 卡马西平、苯妥英钠、苯巴比妥 丙戊酸钠 部分性发作 苯妥英钠、扑米酮 癫病持续状态 地西泮、异戊巴比妥、 苯巴比妥、苯妥英钠,1. 合理选择药物和剂量 单纯型癫一般选用一种有效药物，先从小剂量开始，逐量增加至获得理想疗效而不产生严重不良反应的有效剂量。若一种药难以奏效或治疗混合型患者，常需联合用药。 2. 合理疗程 在治疗过程中不宜随便更换药物，必要时采用过渡用药方法，即在原药的基础上加用新药，待新药发挥疗效后再逐渐停用原药。症状完全控制后，还要维持治疗23年再逐渐停药，以防复发。 3. 注意不良反应 因为癫需长期甚至终生用药。,抗癫药的合理应用,惊厥是由于中枢神经系统过度兴奋而引起的全身骨骼肌呈强直性或阵挛性抽搐，常见于高热、破伤风、子痫和中枢兴奋药中毒等引起的惊厥。常用的抗惊厥药有苯二氮类如diazepam、巴比妥类如phenobarbital、magnesium sulfate和水合氯醛(chloral hydrate)。,第二节 抗惊厥药,【药理作用】 给药途径不同而产生不同的药理效应。口服有泻下和利胆作用，注射给药具有抗惊厥和降压作用。 1. 抗惊厥 阻断神经肌肉接头的传递。因为 Mg2+与Ca2+化学性质相似，它竞争性地与Ca2+受点结合，抑制Ca2+内流，从而使运动神经末梢ACh释放减少，产生肌肉松弛作用。当Mg2+过量中毒时同理可用Ca2+来解救。 2. 降压 可使血管扩张和血压下降。 3. 中枢抑制 大剂量时由于中枢神经系统抑制而出现感觉和意识障碍。,硫酸镁(Magnesium sulfate),【临床应用】 本药主要用于治疗子痫、破伤风等惊厥，也用于高血压危象的救治。常以肌内注射、静脉注射或滴注给药。 【不良反应】 本药过量中毒可引起呼吸抑制、血压剧降和心脏骤停。肌腱反射消失是中毒的先兆表现，因此在用药过程中应注意检查腱反射，且宜缓慢静脉注射给药。中毒时立即进行人工呼吸，并缓慢静脉注射氯化钙或葡萄糖酸钙抢救。,Antiepileptic and anticonvulsant drugs suppress the abnormal high-frequency discharge of neurons. Primary drugs mainly include phenytoin, carbamazepine, valproate and ethosuximide. Secondary drugs include diazepam and phenobarbital which are used intravenously in the treatment of status epilepticus.,Anti - epileptic drugs are thought to act principally, by two mechanisms: reducing electrical excitability of neuron membranes, possibly through use - dependent block of Na+ channels, and enhancing GABA -mediated synaptic inhibition, which may result from an enhanced postsynaptic action of GABA, or inhibition of GAGA transaminase or GABA uptake, or direct stimulation of GABA receptors. A few drugs also appear to act by other mechanisms, namely, through inhibition of T-type Ca2+ channels or of glutamate receptors.,Primary anticonvulsants include diazepam, phenobarbital and magnesium sulfate. The latter also exerts muscle relaxation by blocking Ca2+ influx in presynaptic nerve terminals.,Neurodegenerative diseases, such as Parkinsonism, Huntingtons disease and Alzheimers disease, are all associated with progressive loss of neurons and their functions.,If properly managed, drugs do not cure but greatly improve the quality of life in this progressive disease. The strategy of treatment of Parkinsons disease is aimed at restoring dopaminergic/cholinergic balance by one of a number of ways as follows:,1. Reducing cholinergic activity with antimuscarinic (anticholinergic) drugs; this approach is most effective in the acute treatment of rigidity (including iatrogenic, caused by dopamine receptor antagonists);,2. Enhancing dopaminergic activity with dopaminergic drugs by prolonging the action of dopamine through selective inhibition of its metabolism ( selegiline ), activating dopamine receptors ( bromocriptine, lysuride, apomorphine), and modulating the release of dopamine from stores and the reuptake of dopamine (amantadine). This approach is most effective against hypokinesia and rigidity, and less effective in the treatment of tremor. 3. Replenishing neuronal synthesis of dopamine by supplying levodopa, its natural precursor; administration of dopamine itself is ineffective as it does not pass into the brain from the blood.,Alzheimers disease (AD) is a kind of dementia associated with a progressive decrease of cholinergic function in CNS. The tangle of neurofilments, deposition of amyloid protein, and super-phosphorylation of Tau protein are the three main characteristics of AD. A major approach to the pharmacotherapy of AD is aimed at augmenting cholinergic function in the brain. One strategy is to use inhibitors of acetylcholinesterase ( AChE) , the hydrolytic enzyme for acetylcholine. These inhibitors include physostigmine, tacrine, donepezil and galantamine.,Other drugs currently used for treatment of AD include muscarinic agonists, nerve growth factor, enhancers of nerve growth factor, and some metabolic activators. In order to optimize therapeutic results, drugs acting through different mechanisms should be used in combination in the treatment of AD.,Two balanced systems are important in the extrapyramidal control of motor activity at the level of the corpus striatum and substantia nigra：on