Pharmacoogy Chapter 16颜光美药理学 抗癫痫药

1、table 16-1 (1) table 16-1 (1) types of epilepsy and anti-epileptic drugstypes of epilepsy and anti-epileptic drugstypes of types of epilepsy epilepsy clinical features clinical features anti-epileptic drugs anti-epileptic drugs ( (* *preferred)preferred) partial seizurespartial seizures 1. simple 1.

2、 simple partial partial seizures seizures involuntary muscle involuntary muscle contraction and contraction and abnormal sensory abnormal sensory experience without loss experience without loss of consciousness, of consciousness, seizures lasting for seizures lasting for 2060 sec; 2060 sec; carbamaz

3、epinecarbamazepine* *, , valproatevalproate, clonazepam, clonazepam, , phenytoin, phenytoin, phenobarbitalphenobarbital, , primidoneprimidone, , antiepilepsirineantiepilepsirine, , lamotriginelamotrigine; ; 2. complex 2. complex partial partial seizures seizures (p(psychomotorsychomotor epilepsy) ep

4、ilepsy) conscious disturbance conscious disturbance and psychiatric symptom and psychiatric symptom with with often involuntary often involuntary movement, such as movement, such as shake shake head, lasting for head, lasting for 0.52min; 0.52min; the same drugs mentioned the same drugs mentioned ab

5、ove;above; table 16-1 (2)table 16-1 (2)types of epilepsy and anti-epileptic drugstypes of epilepsy and anti-epileptic drugstypes of types of epilepsy epilepsy clinical features clinical features anti-epileptic drugs anti-epileptic drugs ( (* *preferred)preferred) 3. partial 3. partial seizures with

6、seizures with followingfollowing tonic-clonictonic-clonic seizures seizures partial seizures is partial seizures is followed byfollowed by tonic- tonic-clonicclonic seizures without seizures without loss of consciousness, loss of consciousness, lasting for 12min; lasting for 12min; the same drugs me

7、ntioned the same drugs mentioned above;above; generalized seizures generalized seizures 1. tonic-1. tonic-clonicclonic seizures seizures (grandmal(grandmal) ) and status and status epilepticus epilepticus immediate loss of immediate loss of consciousness with consciousness with generalized tonic-gen

8、eralized tonic-clonicclonic convulsion, convulsion, lasting for a few lasting for a few minutes. seizures minutes. seizures lasting for longer time lasting for longer time is termed as status is termed as status epilepticusepilepticus; ; carbamazepinecarbamazepine* *, , phenytoin, valproatephenytoin

9、, valproate, , phenobarbitalphenobarbital, , primidoneprimidone, , vigabatrinvigabatrin, , lamotriginelamotrigine, , antiepilepsirineantiepilepsirine; ; status epilepticusstatus epilepticus: : diazepamdiazepam* * ( (i.v.); i.v.); table 16-1 (3)table 16-1 (3)types of epilepsy and anti-epileptic types

10、 of epilepsy and anti-epileptic drugsdrugstypes of types of epilepsy epilepsy clinical features clinical features anti-epileptic drugs anti-epileptic drugs ( (* *preferred)preferred) 2.absence 2.absence seizures seizures (petit mal) (petit mal) patient abruptly patient abruptly ceases whatever he or

11、 ceases whatever he or she is doing, and she is doing, and stares vacantly for a stares vacantly for a few seconds, with few seconds, with unaware of unaware of surroundings; surroundings; ethosuximideethosuximide* *, , clonazepamclonazepam, valproate, valproate, , nitrazepamnitrazepam, clobazam, cl

12、obazam; ; 3. atypical 3. atypical absence absence seizures seizures this seizures occurs this seizures occurs and recovers more and recovers more slowly than absence slowly than absence seizures; seizures; ethosuximideethosuximide* *, , clonazepamclonazepam, valproate, valproate, , nitrazepamnitraze

13、pam, clobazam, clobazam; ; table 16-1 (4)table 16-1 (4)types of epilepsy and anti-epileptic drugstypes of epilepsy and anti-epileptic drugs types of types of epilepsy epilepsy clinical features clinical features anti-epileptic drugs anti-epileptic drugs ( (* *preferred)preferred) 4.myoclonic 4.myocl

14、onic seizures seizures local myoclonialocal myoclonia lasts for a few lasts for a few seconds; seconds; valproatevalproate, , clonazepamclonazepam, clobazam, clobazam; ; 5. infant 5. infant myoclonicmyoclonic seizures seizures generalized rhythmic generalized rhythmic myocloniamyoclonia with with un

15、consciousness in unconsciousness in infant. infant. clonazepamclonazepam, , valproatevalproate, clobazam, clobazam, , glucocorticoid glucocorticoid cconcohhnnnoooh5c2hh ethosuximide carbamazepine valproate sodium phenytoin phenobarbital primidone fig. 16-1 molecular structures of antiepileptic drugs

16、nnooh5c2hhcnccooh5c2h3cch2hnonh2chch2ch2coonach2ch2ch3ch3 抑制癫抑制癫病灶神经元的过度放电，或作用于病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用的基础与其增强gaba介导的突触抑制作用有关介导的突触抑制作用有关，如如: 1. 苯二氮苯二氮类类(benzodiazepines)和苯巴比妥和苯巴比妥(phenobarbital)激动激动gabaa受体、促进受体、促进gaba介导介导的氯的氯通道开放。通道开放。2. 噻加宾噻加宾(tiagabine

17、)抑制抑制gaba的摄取、增加突触的摄取、增加突触后膜的后膜的gaba的浓度。的浓度。3. 氨己烯酸氨己烯酸(vigabatrin)抑制抑制gaba转氨酶活性、减转氨酶活性、减少少gaba的灭活。的灭活。 【抗癫抗癫药物的作用机制药物的作用机制】4. 一些药物的作用与阻滞离子通道有关，如一些药物的作用与阻滞离子通道有关，如phenytoin，carbamazepine，valproate和和lamotrigine可通过阻滞细胞膜电压依赖性钠可通过阻滞细胞膜电压依赖性钠通道通道(valtage-dependent na+ channels)，抑制，抑制na+的内流而降低膜的兴奋性。的内流而降低膜

18、的兴奋性。5. 某些药物如某些药物如氟桂利嗪氟桂利嗪(flunarizine)，phenytoin和和ethosuximide的效应可能还与阻的效应可能还与阻滞滞t型钙通道有关型钙通道有关6. 抗痫灵抗痫灵(antiepilepsirine)与增加脑内与增加脑内5-ht含含量有关量有关(表表16-2)。【抗癫抗癫药物的作用机制药物的作用机制】 【体内过程【体内过程】1. 口服吸收慢而不规则口服吸收慢而不规则，连续服用治疗量连续服用治疗量需经需经610天才能达到有效血药浓度。因此天才能达到有效血药浓度。因此，常先用，常先用phenobarbital等作用较快的药物等作用较快的药物控制发作，在改用

19、控制发作，在改用phenytoin的同时，一般的同时，一般将本药与前用的药合用将本药与前用的药合用710天。天。2. 治疗癫治疗癫持续状态时宜静脉注射。持续状态时宜静脉注射。其其血血浆蛋白结合率约为浆蛋白结合率约为90，大部分经肝药酶，大部分经肝药酶代谢为无活性的羟基苯妥英代谢为无活性的羟基苯妥英。3. 血药浓度的个体差异较大，因而临床用血药浓度的个体差异较大，因而临床用量应注意个体化。量应注意个体化。苯妥英钠苯妥英钠 (phenytoin, 大仑丁大仑丁dilantin) 1. 对高频对高频异常放电神经元的钠通道具有显著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，从而能抑的

20、阻滞作用，降低细胞膜的兴奋性，从而能抑制癫制癫病灶神经元的病灶神经元的高频高频异常放电及其放电的异常放电及其放电的扩散。扩散。此外，此外，还与阻滞神经元的还与阻滞神经元的t型钙型钙通道通道, 抑抑制制ca2+的内流有关的内流有关。 2. 高浓度时也高浓度时也能抑制神经末梢对能抑制神经末梢对gaba的摄的摄取和诱导取和诱导gabaa受体增多，从而增强受体增多，从而增强gaba介介导的导的突触后抑制作用。这些作用与其抑制癫突触后抑制作用。这些作用与其抑制癫病灶神经元病灶神经元高频高频放电的产生及其扩散有关。放电的产生及其扩散有关。【药理作用【药理作用】1. 抗癫抗癫 是常用的抗癫是常用的抗癫药，对

21、癫药，对癫大发大发作、单纯部分性发作和对精神运动性发作作、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。疗效较好，但对小发作无效或甚至加重。 2. 治疗外周神经痛治疗外周神经痛 用于治疗三叉神经、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，使疼痛明显减轻对三叉神经痛疗效较好，使疼痛明显减轻，发作次数减少。，发作次数减少。 3. 抗心律失常。抗心律失常。【临床应用【临床应用】1局部刺激局部刺激 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齿龈增生齿龈增生 多见于儿童和青少年，发生率约20

22、，一般停药36个月后可自行消退。3神经系统反应：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【不良反应】4血液系统反应血液系统反应 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【不良反应】 butazolidin

23、、sulfanilamides和和salicylates可与可与phenytoin竞争血浆蛋白竞争血浆蛋白的结合部位。的结合部位。 phenytoin诱导肝药酶而诱导肝药酶而加速多种药物如避孕药的代谢和降低加速多种药物如避孕药的代谢和降低其药效。其药效。chloromycetin等通过抑制肝等通过抑制肝药酶而提高药酶而提高phenytoin的血药浓度的血药浓度。phenobarbital诱导肝药酶而加速诱导肝药酶而加速phenytoin的代谢。的代谢。【药物相互作用【药物相互作用】 药物药物 应用应用 不良反应不良反应p phenobarbithenobarbital al 大发作、癫大发作、

24、癫持续状态、持续状态、单纯部分性发作、精神运单纯部分性发作、精神运动性发作动性发作 见镇静催眠药见镇静催眠药primidone primidone 对大发作疗效优于对大发作疗效优于phenobarbitalphenobarbital，但对部，但对部分性发作疗效不及分性发作疗效不及phenytoinphenytoin和和carbamazepine carbamazepine 嗜睡、共济失调、巨嗜睡、共济失调、巨幼红细胞性贫血、白幼红细胞性贫血、白细胞和血小板减少细胞和血小板减少 mephenytoinmephenytoin 主要用于癫主要用于癫大发作，由大发作，由于不良反应较重，仅用于于不良反应

25、较重，仅用于其他药物不能控制的患者其他药物不能控制的患者 多形性红斑、高热、多形性红斑、高热、黄疸、中毒性肝炎、黄疸、中毒性肝炎、精神症状精神症状 ethotoinethotoin 对大发作和复杂部分性发对大发作和复杂部分性发作有效。由于作用弱，只作有效。由于作用弱，只作辅助药物与其他药合用作辅助药物与其他药合用 不良反应少见不良反应少见 常用抗癫常用抗癫药的比较药的比较(1)(1)常用抗癫常用抗癫药的比较药的比较(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

26、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；对小发作疗效优于ethosuximide常见有恶心、呕吐等，cns反应少，约25%的患者有肝毒性carbamaze-pine 对各类型癫有效，其中对精神运动性发作和大发作疗效较好 眩晕、恶心、呕吐，少数可有粒细胞和血小板减

27、少。1. 合理选择药物和剂量合理选择药物和剂量 单纯型癫单纯型癫一般选一般选用一种有效药物，先从小剂量开始，逐量增用一种有效药物，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。患者，常需联合用药。2. 合理疗程合理疗程 在治疗过程中不宜随便更换药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

28、要维持治疗停用原药。症状完全控制后，还要维持治疗23年再逐渐停药，以防复发。年再逐渐停药，以防复发。3. 注意不良反应注意不良反应 因为癫因为癫需长期甚至终生需长期甚至终生用药。用药。抗癫抗癫药的合理应用药的合理应用table 16-2 (1)table 16-2 (1)summary of summary of charateristicscharateristics of some newly developed of some newly developed anti-epileptic drugsanti-epileptic drugsdrugsdrugs cellular cellu

29、lar mechanismsmechanisms main usesmain uses mainly mainly unwanted unwanted effectseffects antiepilepsantiepilepsirine irine increaseincrease in in content of content of 5-5-serotonin; serotonin; broad therapeutic broad therapeutic profileprofile; ; relatively free relatively free of side-of side-ef

30、fects, effects, drowsiness etc.drowsiness etc. vigabatrin vigabatrin inhibition of inhibition of gaba gaba transaminasetransaminase; ; effective in effective in patients patients unresponsive to unresponsive to conventional conventional drugsdrugs; ; drowsiness, drowsiness, behaviour and behaviour a

31、nd mood changesmood changes lamotrigine lamotrigine inhibition of inhibition of nana+ + channels channels; ; broad therapeutic broad therapeutic profileprofile; ; hypersensitivithypersensitivity reactions y reactions (especially (especially skin rashes)skin rashes) table 16-2 (2)table 16-2 (2)summar

32、y of summary of charateristicscharateristics of some newly developed of some newly developed anti-epileptic drugsanti-epileptic drugsdrugsdrugs cellular cellular mechanismsmechanisms main usesmain uses mainly unwanted mainly unwanted effectseffects felbamatefelbamate unknownunknown; ; broad broad th

33、erapeutic therapeutic profileprofile; ; use limited to use limited to intractable disease, intractable disease, owing to risk of owing to risk of hypersensitivity hypersensitivity reactions resulting reactions resulting in in aplasticaplastic anemiaanemia gabapentigabapentin n unknownunknown; ; part

34、ial partial seizures; seizures; safe in overdose. safe in overdose. relatively free of relatively free of side-effectsside-effects table 16-2 (3)table 16-2 (3)summary of summary of charateristicscharateristics of some newly developed of some newly developed anti-epileptic drugsanti-epileptic drugsdrugsdrugs cellular cellular mechanismsmechanisms main usesmain uses mainly unwanted mainly unwanted effectseffects tiagabinetiagabine gaba uptake gaba uptake inhibitorinhibitor; ; partial partial seizures in seizures in adults; adul