癫痫的介绍(中英)

1、 CHAPTER 12Antiepileptic & Anticonvulsive Drugs Section 1 Antiepileptic Drugs 抗癫痫药抗癫痫药 Epilepsy癫痫Epilepsy is a heterogeneous symptom complex, a chronic disorder characterized by sudden, transit and recurrent seizure which is episodes of brain dysfunction resulting from abnormal discharge of foca

2、l cerebral neuron and diffusion to normal neuronal tissues.Somatic, sensory, automatic and psychotic. 癫痫EpilepsyEtiology: incidence 0.5%-1%Primary epilepsy.Secondary epilepsy.Symptoms and EEGhttp:/400-0196-638 Classifications分类1. Partial seizures局限性发作局限性发作(1)Simple partial seizures单纯局限性发作单纯局限性发作（20-

3、60sec)a. Somatic seizures运动性发作运动性发作b. Sensory seizures感觉性发作感觉性发作c. Automatic seizures植物神经性发作植物神经性发作d. Psychotic seizures精神性发作精神性发作Treatment: carbamazepine, phenytoin,phenobarbital, primidone, valproate Classifications分类(2)Complex partial seizures复合性局限性发作复合性局限性发作a. Psychomotic seizures精神运动性发作精神运动性发作(

4、30s-2m)冲动性神经异常，无意识运动，唇抽动，摇头等动作。冲动性神经异常，无意识运动，唇抽动，摇头等动作。b. Partial seizures secondarily generalized 局限性发作继发全身强直局限性发作继发全身强直-阵挛性发作。阵挛性发作。Treatment similar to partial seizures Classifications分类2. Generalized seizures全身性发作全身性发作(1) Absence seizures (petit mal)：失神性发作（小发作）失神性发作（小发作） Treatment: Ethosuximide,

5、 clonazepam, valproate (2)Generalized tonic-clonic seizures (grad mal)：强直强直-阵挛性发作（大发作）阵挛性发作（大发作）Treatment: Carbamazepine, phenobarbital, phenytoin, primidone, valproateStatus epilepticus：癫痫持续状态癫痫持续状态Diazepam iv, or plus lorazepam, or clonazepam, phenytoin and phenobarbital. Classifications分类(3)Tonic

6、 seizures：强直性发作强直性发作(4) Atonic seizures：无强直性发作无强直性发作(5) Clonic and myoclonic seizures：肌阵挛性发作肌阵挛性发作3. Atypical seizures Infantil spasm: 婴儿痉挛婴儿痉挛http:/http:/http:/400-0059-826癫痫的实验模型 History of Antiepileptic Treatment1857 potassium bromide.1912 phenobarbital.19121937 35 analogs of phenobarbital.1938 p

7、henytoin.19381960Development in the past 4 decades: valproate(1964), antiepilepsrin(1975) Carbamazepin(1980), gabapentin(1990)抗癫痫药分类 Action Mechanisms of Antiepileptic Drugs1. To abolish or attenuate the seizure diffusion by modification of ion channel conductance. Inhibitory of Na+ and Ca2+ channel

8、. a. inhibit discharge in focus. b. inhibit diffusion in normal neuron. Action Mechanisms2. To potationate inhibitory system involving GABA-ergic function.a. Enhancement of GABA-ergic transmission: reuptake or metabolism. b. Direct action on the GABA-R chloride channel complex. Action Mechanismsc. D

9、iminution of glutaminergic functionAMPA (-甲基甲基3 3羟基羟基5 5甲基异恶唑甲基异恶唑4 -4 -丙酸丙酸)R blockade.NMDA ( N-甲基甲基D-D-门冬氨酸门冬氨酸) )-R blockade.Part 1The Common Used Antiepileptic Drugs 常用常用抗癫痫药抗癫痫药 Pharmacologicol actions and mechanismsAntiepilepsy, central pain syndrome and arrhythmia. MechanismsInhibit PTP, inhi

10、bit Na+in and Ca2+inPromote the stabilization of the membrane.1. Block Na+in channel (use-dependent effect).2. Block voltage-sensitive Ca2+in channel(L & N), inhibit K+out.3. Inhibit calmodulin kinase, reduce the release of glutamate and to potentiate GABA inhibiting function. 4. Inhibit PTP. Ph

11、armacokinetics1. Absorption pKa8.3, slow and unpredictable after oral administration.F variable, tmax around 3-12hrs, 6-10d Css(10-20g/ml ), stimulation in oral and im use.2. Distribution PPBR 85%-90%, Vd 0.6L/kg. Pharmacokinetics3. Metabolism by hepatomicroenzymes about 60%-70%, 5%unchanged.4. Elim

12、ination is dose-dependent, plasma concentration:10 g/mL, OOK, t1/2 60hrs. 1. EpilepsyDrug choice for generalized tonic-clonic seizures, simple partial seizures, complex partial seizures except absence seizure. Clinical Uses2. Central pain syndrome: trigeminal neuralgia, glossopharyngeal neuralgia an

13、d sciatica.3. Arrhythmia（心律失常）（心律失常） Adverse Reactions1. Toxic reaction related to drug dose plasma concentration: Cmax(E) 10 g/mL; CTox 20 g/mL (1)CNS symptoms 20 g/mL：drowsiness, dizziness(眩晕眩晕), ataxia(共济共济失调失调); 40 g/mL: psychotic; 50 g/mL: coma. Adverse Reactions(2)CVS symptoms: arrhythmia, and

14、 hypotension.(3)Gastrointestinal reactions. Adverse Reactions2. Chronic toxic reactions(1)Gingival hyperplasia (20%) by inhibiting the the induction of collagenase by glucocorticoids (phenytoin induces glucocorticoids metabolism).(2)Blood system: megalblastic(巨幼红细胞性巨幼红细胞性) anemia, aplastic(再生障碍性再生障碍

15、性)anemia: folic acid dysefficacy.(3)Bone system: osteomalacia. Adverse Reactions3. Allergy: rash, leukopenia, thrombocytopenia, agranulocytosis, aplastic anemia, liver necrosis.4. Teratogenesis: Fetal hydantoin syndrome(胎儿妥因综合征胎儿妥因综合征):小头症、小头症、智障及斜视等。智障及斜视等。芬兰芬兰 1980198019981998年，研究人员追踪了一家产科诊所年，研究人员

16、追踪了一家产科诊所中中970970位怀孕的癫痫妇女，其中有位怀孕的癫痫妇女，其中有740740位在怀孕初期位在怀孕初期（前（前3 3个月）服用抗癫痫药物，另外个月）服用抗癫痫药物，另外239239位则无。结果位则无。结果在这些在这些服用抗癫痫药物的怀孕妇女中，共产下服用抗癫痫药物的怀孕妇女中，共产下2828个严个严重畸形儿（重畸形儿（3.8%3.8%），未服用抗癫痫药物组产下），未服用抗癫痫药物组产下2 2个严个严重畸形儿（重畸形儿（0.8%0.8%；P=0.02P=0.02）。）。 Drug InteractionsHepatomicrosomal enzyme inducer:Glucoc

17、orticoids, quinidine, carbamazepine, cyclosporin, L-dopa, contraceptives, vitamin D.PPBR: sulfonamides, BZ, anticoagulantsHepatomicrosomal enzyme inhibitors:Chloramphenicol, isoniazid Phenobarbital苯巴比妥Broad-spectrum and much effective in grad mal and partial seizures, but not drug choice for grad ma

18、l, alternative and iv in the treatment of status epilepticus. Mechanisms1. Potentiate the GABA inhibitory function: post-synaptic BZ-R, increase GABA induced Cl-in.2. Decrease release of neurotransmitter Ca2+ dependent: NA, ACh, Glu.Increase the threshold and inhibit the spread of seizure to normal

19、tissue. Primidone（扑米酮）Effective for all types of epilepsies except absence mal, more effective than phenobarbital in complex partial seizures.Mechanism similar to phenobarbital and Na+in, K+out. Primidone （扑米酮）Primidone is metabolized to phenobarbital and phenylethylmalonamides (PEMA，苯乙基丙二苯乙基丙二酰胺酰胺)

20、 as active metabolites. Adverse Reactions1. CNS depression, ataxia, drowsness,vertigo.2. Blood system: agranulocytosis, thrombocytopenia, megalblastic anemia. Ethosuximide（乙琥胺）The only indication: absence epilepsy, less effective than clonazepam and valproic acid. Mechanism:a. Reducing the T-type Ca

21、2+ current.b. Inhibiting Na+-K+-ATPase.c. GABA aminotransferase. Adverse Reactions(安全)Gastric distress, CNS distress.Blood system: eosinophilia( (嗜酸性粒细胞增多嗜酸性粒细胞增多症症) ) , thrombocytopenia, aplastic anemia. Benzodiazepines1. Diazepam: drug choice for status epilepticus by iv or plus lorazepam.2. Nitra

22、zepam: absence seizure, myoclonic seizure, and infantile spasm akinetic seizures.3. Clonazepam: absence seizure, myoclonic seizure, infantile spasm and status epilepticus. Sodium Valproate（丙戊酸钠）Sodium dipropylacetate (DPA)Broadspectrum antiepileptic agent.Effective for all types of epilepsy, more ef

23、fective than ethosuxide for absence mol, less effective for grad mal and partial mal. Mechanisms作用机制(1)Potentiate GABA function by inhibiting GABA-aminotransferase (GABA-T) and succinic semialdehyde dehydrogenase (SSADH), increase glutamte decarboxylase to GABA.(2)inhibit voltage-dependent Na+ and T

24、-Ca2+ channel. sodium valproate + - GAD GABA-T glutamic acid GABA succinic semialdehyde sodium valproate - SSADH succinic acidGAD：谷氨酸脱羧酶谷氨酸脱羧酶GABA-T：GABA转氨酶转氨酶SSADH：琥珀酸半醛脱氨酶琥珀酸半醛脱氨酶 Sodium Valproate（丙戊酸钠）Adverse Reactions1. Hepatic intoxication2. CNS and blood system：thrombocytopenia3. Teratogenesis

25、 Carbamazepine（卡马西平）Broadspectrum antiepileptic agent.Mechanisms(1)Inhibiting Na+ and Ca2+channel.(2)Potentiate GABA post-synaptic inhibitory function. CarbamazepineActions and Uses1. Antiepileptic effects: grad mal, simple and complex partial seizures, mania.2. Central algesia: trigeminal neuralgia

26、, glossopharyngeal neuralgia more effective than phenytoin.3. diabetes insipidus( (尿崩症）尿崩症） 尿崩症病因：下丘脑病因：下丘脑神经垂体部位的病变神经垂体部位的病变 ADHADH（AVP)AVP)，肾小管重吸收功能障碍，肾小管重吸收功能障碍 多尿、烦渴、多饮与低比重尿多尿、烦渴、多饮与低比重尿AVP(arginine vasopressin):AVP(arginine vasopressin):精氨酸加压素精氨酸加压素ADH(antidiuretic hormone):ADH(antidiuretic hor

27、mone):抗利尿激素抗利尿激素卡马西平：卡马西平：促进促进ADHADH分泌分泌 Pharmacokineticstmax around 2-6 hrs, PPBR 70%, active cyclooxide metabolite, t1/2 35 hrs at beginning, then may shorten by 50% due to enzyme inducer (around 15-20h). Other DrugsFlunarizine（氟桂利嗪）（氟桂利嗪） Strong calcium antagonist, used in the treatment of grad m

28、al and partial. Lamotrigine(拉莫三嗪）Used as an add-on therapy or monotherapy in the treatment of absence or myoclonic seizure in children.The mechanism may related to inhibit voltage-dependent Na+ channel. Topiramate（托吡酯）Used in the treatment of partial seizure with or without generalized tonic-clonic seizures.Part 2 General Principles and Drug Choice for The Therapy of Epilepsy1. Accurate evaluation.2. The drug choice for initial treatment of seizures（单纯型）（单纯型）.(1) grad mal and simple partial seizuresCarbama