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1、1Chapter 14 Anti-epilepsy drugs (AEDs) and Anti-convulsion drugs Liu YinghuaDepartment of pharmacologyWhat is Epilepsyn n Recurrent attackn n Excessive dischargen n Usually seizure without warning and causen n Affecting muscle, speech, vision, and awarenessn n More severe if not treated 3Classificat
2、ionSimple Partial complexPartial seizureGeneralized seizureAbsence seizure(小小发作发作发作发作)Generalized tonic-clonic seizure(grand mal,大发作大发作)Myoclonic seizure Status epilepticusMechanisms ofAnti-epileptic drugsuuImbalance of Glutamate and GABA due to the defective GABA receptoruuIon channel mutationuuImm
3、unologic mechanism5Individual drugsPhenytoin sodium /Dilantin 苯妥英钠苯妥英钠苯妥英钠苯妥英钠/ /大仑丁大仑丁大仑丁大仑丁Carbamazepine 卡马西平卡马西平Ethosuximide 乙琥胺乙琥胺Sodium valproate 丙戊酸钠丙戊酸钠Benzodiazepines and barbiturates6Mechanisms of action:1.PTP(posttitanic 1.PTP(posttitanic potentiation)2. Membrane stabilization. Phenytoin b
4、locks sodium channel and therefore prevents sodium-dependent action potential (AP) blocks L-type calcium channelCaMK7Antiepileptic effects and clinical applications: Generalized tonic-clonic (grand mal) Partial seizure (local attack of epilepsy) Central pain (trigeminal neuralgia三叉神经痛) Anti-arrhythm
5、ia (membrane stability)Phenytoin sodium / Dilantin 8Pharmacokinetics:Absorbance: not musle injection. oral intake，intravenous injection（IV）Distribution: 85-90% bound to plasma proteinMetabolism: inactivated in liver by P-450Bioavailability:95% approximatelyDrug interactions: highly protein-bound; me
6、tabolized by hepatic enzyme as a inducer.Phenytoin sodium / Dilantin 苯妥英钠苯妥英钠9Adverse effects and toxicity:Adverse effects and toxicity:Dose-dependent toxicity : nausea, dizzy, ataxia(共济失调共济失调), insanity(精神错乱精神错乱), coma（昏迷）（昏迷）Chronic toxicity: teeth, hypocalcemiaAllergyMalformation 牙龈增生牙龈增生Phenytoi
7、n sodium / Dilantin 苯妥英钠苯妥英钠10Carbamazepine 卡马西平卡马西平Effects and applications: Broad spectrum AEDs, preferred for grand mal and simply partial seizure.Mechanism: block sodium channelAdverse effects: dose-dependent. Dizzy, nausea, ataxia, blurred vision, myelosuppression (bone marrow suppression) 11Ph
8、enobarbital 苯巴比妥苯巴比妥Effects and applications: grand mal and status epileptics.Mechanism: binds to GABA-A receptor and prolongs chloride channel openingAdverse effects: sedation particularly at the beginning of therapy12Ethosuximide 乙琥胺乙琥胺Effects and applications: Particularly effective on absence se
9、izuresMechanisms: Reduce T-type calcium currents in thalamic neurons which is responsible for generating the discharge of an absence attack.13Sodium Valproate 丙戊酸钠丙戊酸钠Broad-spectrum AEDs, effective in all types of epilepsy. It should be avoided in patients with liver disease due to its hepatotoxicit
10、y. 14Benzodiazepines 苯二氮卓类苯二氮卓类Diazepam: The preferred AED for status epilepticus. IVNitrazepam: absence seizureClonazepam: broad spectrum. Effective for generalized convulsions and, to a lesser extent , in partial epilepsies. Effective for status epileptics iv. 15大发作大发作 小发作小发作 部分部分 癫痫持续癫痫持续苯妥英钠苯妥英钠
11、 首选首选 +首首 iv苯巴比妥苯巴比妥 + + iv乙琥胺乙琥胺 +首首 地西泮地西泮 + + iv首首氯硝西泮氯硝西泮 + + iv丙戊酸钠丙戊酸钠 + + + 卡马西平卡马西平 +首首 +首首 （复杂性）（复杂性）抗癫痫药物的比较抗癫痫药物的比较16Anti-convulsion Drugs 抗惊厥药抗惊厥药Convulsion: symptoms of over-excited, strong involuntary muscle contraction of the bodyMagnesium sulfate (硫酸镁硫酸镁): anti-Ca2+ , muscle relexati
12、on and anti-hypertension. Therapeutical uses: Convulsion, hypertension crisis17Anti-convulsion Drugs 抗惊厥药抗惊厥药adverse effects: Low TI, respiratory suppression, hypotension and cardiac arrest. Prevention: tendon jerk (腱反射腱反射) and BP Treatment: artificial respiration and Ca2+18要要 求求【掌握掌握】治疗大发作、小发作、癫痫持治
13、疗大发作、小发作、癫痫持续状态的药物；苯妥英钠，卡马西平，续状态的药物；苯妥英钠，卡马西平，乙琥胺、丙戊酸钠的药理作用、临床乙琥胺、丙戊酸钠的药理作用、临床应用。应用。【熟悉熟悉】抗癫痫药物长期使用的不良反抗癫痫药物长期使用的不良反应；抗惊厥药，硫酸镁的作用、应用应；抗惊厥药，硫酸镁的作用、应用及氯化钙对抗作用。及氯化钙对抗作用。【了解了解】癫病的分型，抗癫痫药作用机癫病的分型，抗癫痫药作用机制。制。 19Chapter 15 Treatment of neurodegenerative disease20CNSDegenerativeDiseaseHuntington disease 亨廷顿
14、舞蹈病亨廷顿舞蹈病Parkinsons disease 帕金森病帕金森病Alzheimers disease 阿尔茨海默病阿尔茨海默病Parkinsons desease?Features: uStatic tremors 静止性震颤静止性震颤umuscular rigidity 肌强直肌强直uBradykinesia 运动迟缓运动迟缓uAtaxia 共济失调共济失调 （Postural and gait abnormalities 姿势步态异常）姿势步态异常）22PD 症状症状静止震颤静止震颤肌肉强直肌肉强直运动迟缓运动迟缓共济失调共济失调23Etiology:uReduction of t
15、he activity of dopaminergic neurons in the substantia nigra and corpus striatum results in an imbalance between the excitatory cholinergic neurons and inhibitory dopaminergic nerons. 24丘脑丘脑第三脑室第三脑室尾核尾核尾核尾核侧脑室侧脑室黑质黑质苍白球苍白球苍白球苍白球壳核壳核壳核壳核黑质黑质纹状体多纹状体多巴胺能神经通路巴胺能神经通路纹纹状状体体AchDA多巴胺学说多巴胺学说脊髓前角运脊髓前角运动神神经元元抑抑
16、制制兴奋 胆碱能胆碱能通路通路2526Carlsson (left) receives the Nobel prize for his work on dopamine from the Swedish king in 200027多巴胺学说多巴胺学说DAAChACh抑制抑制兴奋兴奋兴奋兴奋正常正常帕金森病帕金森病DA抑制抑制28Drugs used in PD2.Anti-cholinergicsDopamineAcetylcholine1.Dopaminergic agents29多巴胺多巴胺(Dopamine, DA)的的“来去来去”L-dopaL-TyrNA脱羧酶脱羧酶(AADC)(A
17、ADC)羟化酶羟化酶羟羟化化酶酶COMTMAODADR30 一、拟多巴胺类药一、拟多巴胺类药1.多巴胺的前体药多巴胺的前体药 左旋多巴左旋多巴2.左旋多巴的增效药左旋多巴的增效药.氨基酸脱羧酶氨基酸脱羧酶(AADC)抑制药抑制药-卡比多巴卡比多巴.MAO-B抑制药抑制药-司来吉兰司来吉兰.COMT抑制药抑制药-硝替卡朋、托卡朋硝替卡朋、托卡朋3.DA 受体激动药受体激动药 溴隐亭溴隐亭 4.促多巴胺释放药促多巴胺释放药 金刚烷胺金刚烷胺二、抗胆碱药二、抗胆碱药 苯海索、苯扎托品苯海索、苯扎托品抗帕金森病药分类抗帕金森病药分类31uuMechanism of action: Precursor
18、of dopamine, 1% could cross the BBB and is converted to DopamineuuPharmacokinetics: A: rapid oral absorption, D: 1% in CNS, 99% to cause adverse effects, M: Presynaptic uptake mechanism or MAO and COMT L-dopa 左旋多巴左旋多巴 32L-dopaL-dopa1%1%brainperiphery DADAAADCAADC补充纹状体中补充纹状体中DADA的不足的不足, ,并使并使DADA和和Ac
19、hAch浓度平衡。浓度平衡。ADRADRPharmacological effects of L-dopa Decarboxylated to dopamine in the brain, to make up the diminished dopamine in the striatum.33L-dopauApplications 1.anti-Parkinsonsdisease:anti-Parkinsonsdisease: (1)youngormildpatientswithgood(1)youngormildpatientswithgoodeffect.effect.(2)effect
20、iveformusclestiffness(2)effectiveformusclestiffnessandmovementdifficulties.andmovementdifficulties.(3)slowandsustained(3)slowandsustained 2. hepatic coma: L-dopaNA34uAdverse effects: Peripheral effects: GI 80% (nausea, vomit), CVS 30%(hypotension) CNS effects: Hyperkinesia, On-off response 50% Psych
21、iatric symptomL-dopa 左旋多巴左旋多巴 36卡比多巴卡比多巴 carbidopa外周外周中枢中枢L-dopa口服口服多巴胺：发挥疗效多巴胺：发挥疗效多巴胺：产生不良反多巴胺：产生不良反应应AADCAADC抑制外周抑制外周AADC：卡比多巴：卡比多巴37Selegiline 司来吉兰司来吉兰uu Mechanism : Decreasing metabolism of levodopa to improve efficacy of L-DOPAMAO-B inhibitors38MAO-B inhibitorsPeripheralCNSL-dopaP.O.P.O.DADAMA
22、O-AMAO-BSelegiline 司来吉兰司来吉兰Metabolism Metabolism 39D2R agonistu One of the first choice uSide effects similar to L-dopa, but lower incidence of on-off response Bromocriptine 溴隐亭溴隐亭40CommonlyuseddrugsforPDDopamine代谢产物代谢产物L-DOPAAADCCOMTL-DOPA代谢产物代谢产物DopamineAADC代谢产物代谢产物代谢产物代谢产物COMTMAO-B血脑屏障血脑屏障Selegil
23、ineDRcarbidopa外周外周脑脑DR溴隐亭溴隐亭41Amantadine 金刚烷胺金刚烷胺 uMechanism: Complex: dopamine synthesis and release, dopamine reuptake; also may be related to block excitatory amino acid receptor (NMDA)uEffects: better than anticholinergics, less than L-dopa. quickly and shortly42uuM receptor antagonist in CNSuuG
24、ood at anti-tremor and mainly used in early phase of PD or Parkinson syndrome by drugsuuSide effects similar to AtropineBenzhexol 苯海索苯海索( (安坦安坦) )Anticholinergics43阿尔茨海默病阿尔茨海默病(AD)发病趋势发病趋势ADDrugs on Alzheimer disease44 -amyloid(A 40/42)Senile Plaques, SPsNeurofibrillary Tangles, NFTsHyperphosphoryla
25、ted TauImpairmentCognition Memory BehaviorOther changesACh deficiencyInflammationMitochondrial dysfunctionHallmark Alterations in AD Brain45vPrimary dementia：age，progressive cognitive disorder，memory dificiency，different from the normal aging. (CHD, tumor, AD, Stroke, DM)vpathology：brain atrophy， -a
26、myloid aggregation，neurofibrilay tangles vBasis of disfunction：transmission disturbance of ，neurodegeneration，neuron lossDrugs on Alzheimer disease46Drugs on Alzheimer disease多奈哌齐多奈哌齐donepezil 首选首选加加兰他敏兰他敏galantaminegalantamine美金刚美金刚memantinememantine石杉碱石杉碱甲甲 huperzine huperzine 中药提取中药提取他克林他克林 tacri
27、ne 毒性大毒性大 停用停用vTherapy：enhance the action of central cholinergic nerve 47要要 求求【掌握掌握】左旋多巴的体内过程及作用机制临左旋多巴的体内过程及作用机制临床应用及不良反应，与多巴脱羧酶抑制药床应用及不良反应，与多巴脱羧酶抑制药合用依据。合用依据。【熟悉熟悉】金刚烷胺和溴隐亭在治疗帕金森病金刚烷胺和溴隐亭在治疗帕金森病的作用。胆碱受体阻药苯海索治疗帕金森的作用。胆碱受体阻药苯海索治疗帕金森病的应用与特点。病的应用与特点。【了解了解】帕金森病的黑质纹状体的多巴胺缺帕金森病的黑质纹状体的多巴胺缺乏学说。左旋多巴与药物相互作用。胆碱乏学说。左旋多巴与药物相互作用。胆碱酯酶抑制药治疗老年性痴呆症药理学机制。酯酶抑制药治疗老年性痴呆症药理学机制。
