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1、抗癫痫药AntiepilepticDrugsStillwatersrundeep.流静水深流静水深,人静心深人静心深Wherethereislife,thereishope。有生命必有希望。有生命必有希望Definitions in epilepsy:Definitions in epilepsy:nEpilepsy Epilepsy comprises comprises recurrent recurrent episodes episodes of of abnormal abnormal cerebral cerebral neuronal neuronal discharge. di
2、scharge. The The resulting resulting seizures seizures are are usually usually clinically clinically obvious obvious and and vary vary in in pattern pattern according according to to which which parts parts of of the the brain brain are affected.are affected.nEpilepsy Epilepsy can can be be caused c
3、aused by by many many neurological neurological diseases, diseases, including including infection, infection, trauma, trauma, infarction infarction and and neoplasia.neoplasia.nHeredity Heredity has has an an important important role role (especially (especially in in the the idiopathic idiopathic g
4、eneralised epilepsies).generalised epilepsies).Normal brain cellNormal brain cellAbnormal high-Abnormal high-frequency frequency dischargedischargeFocusFocusDrug actionDrug actionInhibit dischargeInhibit dischargeStabilize membrane, inhibit the Stabilize membrane, inhibit the diffusion of discharge
5、(primary)diffusion of discharge (primary)Common seizure types of Common seizure types of Epilepsy:Epilepsy:nGeneralised seizures.Generalised seizures.nAbsence (petit mal).Absence (petit mal).nTonic/clonic (grand mal). Tonic/clonic (grand mal). nPartial seizures.Partial seizures.nSimple partial seizu
6、res.Simple partial seizures.nComplex Complex partial partial seizures seizures (temporal lobe epilepsy).(temporal lobe epilepsy). Generalised seizures:Generalised seizures:nAbsence Absence (petit (petit mal): mal): These These seizures seizures have have abrupt abrupt onset onset and and cessation,
7、cessation, with with impaired impaired consciousness, consciousness, but but with with normal normal posture posture often often retained. retained. The The EEG EEG shows shows a a typical spike and wave pattern.typical spike and wave pattern.nTonic/clonic Tonic/clonic (grand (grand mal):mal): Consc
8、iousness Consciousness is is impaired impaired and and the the patient patient usually usually falls falls to to the the floor. floor. A A phase phase of of muscle muscle contraction contraction (tonic) (tonic) is is followed followed by by irregular irregular muscle muscle clonus clonus and and the
9、n then by by sleep. Injury may occur.sleep. Injury may occur.Partial seizures:Partial seizures:nSimple Simple partial partial seizures:seizures: features features depend depend on on the the part part of of the the brain brain affected, affected, result result from from discharge discharge in in the
10、 the precentral precentral gyrus. gyrus. Consciousness Consciousness is unimpaired.is unimpaired.nComplex Complex partial partial seizures seizures (temporal (temporal lobe lobe epilepsy):epilepsy): Consciousness Consciousness is is impaired impaired with with complex, complex, often often repetitiv
11、e, action.repetitive, action.The EEG in The EEG in seizure of Epilepsyseizure of Epilepsy 3 Hz Paradoxical discharge3 Hz Paradoxical dischargeSpike waveSpike waveEpilepsyEpilepsy Pathogenesis:nThe The neuron neuron in in brain brain lesion lesion depolarizes depolarizes together together suddenly, s
12、uddenly, and and then then product product high-frequency high-frequency ,out-break ,out-break discharge. discharge. The The discharge discharge can can diffuse diffuse to to surrounding surrounding normal normal tissue tissue extensive extensive excitation excitation the the brain brain function fu
13、nction transient aberration.transient aberration.Normal brain cellNormal brain cellAbnormal high-Abnormal high-frequency frequency dischargedischargeFocusFocusDrug actionDrug actionInhibit dischargeInhibit dischargeStabilize membrane, inhibit the Stabilize membrane, inhibit the diffusion of discharg
14、e (primary)diffusion of discharge (primary)EpilepsyEpilepsyTherapeutic principle:nChange the permeability of NaChange the permeability of Na+ +, , CaCa2+2+and Kand K+ + in nerve cell membrane, in nerve cell membrane, degrade excitement stage, extend degrade excitement stage, extend refractory phase.
15、refractory phase.nDirectly or indirectly increase CNS Directly or indirectly increase CNS levels of GABA.levels of GABA.The The primaryprimary animal animal modelsmodels used used in in anti-anti-epilepticepileptic drugs drugs researchresearchMaximal electroshock seizure (MES )Maximal electroshock s
16、eizure (MES )Maximal electroshock seizure (MES )Maximal electroshock seizure (MES ) modelmodelmodelmodel：screen the drugs which used in screen the drugs which used in screen the drugs which used in screen the drugs which used in grand mal.grand mal. Pentetrazole (PTZ) induced Pentetrazole (PTZ) indu
17、ced Pentetrazole (PTZ) induced Pentetrazole (PTZ) induced convulsion model:convulsion model: screen the drugs which used in screen the drugs which used in screen the drugs which used in screen the drugs which used in petit mal.petit mal. Kindling seizure model:Kindling seizure model:Kindling seizure
18、 model:Kindling seizure model:screen the drugs which used in screen the drugs which used in grand mal. S Spontaneously epileptic rat (SER) modelpontaneously epileptic rat (SER) model： used in anti-used in anti-epileptic drugs research. drugs research.memo:将震颤大鼠与Zitter基因变异大鼠交配，于1986年培育出SER鼠。它也具有震颤，脑海
19、绵状变性等特点。是tm基因与Zitter（zi）基因共同突变的结果。除了具有TRM大鼠的重度失神发作之外，SER鼠还表现为高频率的强直性自发痉挛。在SER鼠的大脑皮质及海马用慢性记录电极作自发的脑电波检查发现，当SER失神发作时，出现与TRM鼠同样的57Hz的多波峰波群放电；在其出现强直性痉挛时，出现两个部位一致的低振幅快速波。中枢神经系统病理检查结果显示，SER除具有TRM鼠的重度脑海绵状变性外，还出现了神经细胞低形成或形成异常，生殖器萎缩，不育，胡须和体毛屈曲，视觉障碍，听觉障碍，高级运动障碍等。Classification of Antiepileptic Classification
20、of Antiepileptic DrugsDrugsnHydantoinsHydantoins：SodiumSodium PhenytoinPhenytoinnBarbituratesBarbiturates：Phenobarbital, Phenobarbital, PrimidonePrimidonenSuccinimideSuccinimide：EthosuximideEthosuximidenBenzodiazepine: Benzodiazepine: Diazepam, Diazepam, NitrazepamNitrazepamnOthers: Others: Sodium V
21、alproateSodium ValproateSodium Phenytoin (Sodium Phenytoin (苯妥英钠苯妥英钠) ) 【Physiological dispositionPhysiological disposition】nSodium Phenytoin is absorbed slowly Sodium Phenytoin is absorbed slowly after oral administration.After after oral administration.After 6-10 days, its plasma concentration 6-1
22、0 days, its plasma concentration can achieve effect levels. This can achieve effect levels. This drug has variable interpatient drug has variable interpatient plasma concentration.plasma concentration. Sodium Phenytoin Sodium PhenytoinMechanism of action:Mechanism of action:It can block sodium chann
23、els (voltage-It can block sodium channels (voltage-,frequency-,and time dependent fashion) ,frequency-,and time dependent fashion) and inhibit the generation of action and inhibit the generation of action potentials.potentials.It can increase the function of It can increase the function of inhibitor
24、y transmitter GABA, inhibit inhibitory transmitter GABA, inhibit nerve terminal to uptake GABA and induce nerve terminal to uptake GABA and induce the increasing of GABA receptor, thereby the increasing of GABA receptor, thereby enhance GABA-mediated postsynaptic enhance GABA-mediated postsynaptic i
25、nhibition.inhibition.Sodium PhenytoinSodium Phenytoin【Pharmacologic properties and clinical Pharmacologic properties and clinical applicationapplication】nAnti-epilepticAnti-epileptic：It can be used for It can be used for partial seizures and tonic/clonic partial seizures and tonic/clonic seizures, b
26、ut not for other generalised seizures, but not for other generalised seizure types.seizure types.nPeripheral neuralgiaPeripheral neuralgia：cranial nerve, cranial nerve, ischiadic nerve and cranial nerve.ischiadic nerve and cranial nerve. nArrhythmia :Arrhythmia : membrane-stabilizing membrane-stabil
27、izing action.action.Sodium PhenytoinSodium PhenytoinnDigestive system Digestive system nGingival hyperplasiaGingival hyperplasianNervous systemNervous systemnHematological systemHematological systemnSkeletal systemSkeletal systemnAllergic responseAllergic responsenOthersOthers【Adverse effectsAdverse
28、 effects】Sodium PhenytoinSodium Phenytoin【Adverse effects】nDigestive system:Digestive system: anorexia, nausea, anorexia, nausea, vomiting and abdominal pain (recommend to vomiting and abdominal pain (recommend to take it after meal). It may cause phlebitis take it after meal). It may cause phlebiti
29、s after IV. after IV. nGingival hyperplasia:Gingival hyperplasia: It common occurs in It common occurs in children and teenagers after long term use, children and teenagers after long term use, the incidence rate is about 20%. Generally, the incidence rate is about 20%. Generally, this effect can re
30、solve after drug withdraw this effect can resolve after drug withdraw 3 to 6 months.3 to 6 months.Sodium PhenytoinSodium Phenytoin【Adverse effects】 nNervous system: Nervous system: nystagmus, diplopia, nystagmus, diplopia, vertigo, ataxia (usually only at very vertigo, ataxia (usually only at very h
31、igh concentration). Severe patient high concentration). Severe patient occurs language disorder, mental occurs language disorder, mental confusion and cataphora.confusion and cataphora.nHematological Hematological system: system: Because Because it it can can inhibit inhibit the the absorption absor
32、ption of of folinic folinic acid acid and and accelerate accelerate its its metabolism. metabolism. This This drug drug also also can can inhibit inhibit folic folic acid acid reductase. reductase. So So it it may may cause cause megaloblastic megaloblastic anemia anemia after after long-term long-t
33、erm use use (recommend (recommend to to pretreat pretreat with with folinic acid).folinic acid).Sodium PhenytoinSodium Phenytoin【Adverse effects】 nSkeletal system:Skeletal system: It can enhance vitamin D It can enhance vitamin D metabolism, so Phenytoin may increase the metabolism, so Phenytoin may
34、 increase the risk of hypocalcemia, rickets and risk of hypocalcemia, rickets and osteomalacia after long-term osteomalacia after long-term treatment(pretreat with vitamin D if treatment(pretreat with vitamin D if necessary).necessary).nAllergic response:Allergic response: rash,rash, thrombocytopeni
35、a thrombocytopenia, agranulocytosis and aplastic anemia., agranulocytosis and aplastic anemia.nOthers:Others: rarely appear rarely appear male male barymastia, barymastia, female hirsutism and lymphadenectasis. female hirsutism and lymphadenectasis. Phenobarbital (Phenobarbital (苯巴比妥苯巴比妥) )Mechanism
36、 of action:Mechanism of action:nPhenobarbital Phenobarbital can can inhibit inhibit the the paradoxical paradoxical discharge discharge of of epilepsy epilepsy focus focus selectively, selectively, enhance enhance stimulation stimulation of of surrounding surrounding tissues tissues and and block di
37、scharge diffuse to normal tissues.block discharge diffuse to normal tissues.nPhenobarbital facilitate GABA-mediated Phenobarbital facilitate GABA-mediated inhibition of neuronal activity.inhibition of neuronal activity.PhenobarbitalPhenobarbitalPharmacologic properties:Pharmacologic properties:nPhen
38、obarbital can be used for all Phenobarbital can be used for all types of epilepsy. The effects by types of epilepsy. The effects by turns are: grand mal and status turns are: grand mal and status epilepticsepilepticslocal psychomotor local psychomotor seizureseizurepetit mal.petit mal.nTake effect r
39、apidlyTake effect rapidly（1 12 hr), the 2 hr), the first choice of grand mal.first choice of grand mal.nPrevent convulsive and eliminate Prevent convulsive and eliminate precursory symptom.precursory symptom. PhenobarbitalPhenobarbital【Adverse effects】nSomnolenceSomnolence、depression.depression.nTol
40、erance develops after long-term Tolerance develops after long-term treatment.treatment.Primidone(Primidone(去氧苯比妥去氧苯比妥) ) Primidone(Primidone(扑米酮扑米酮) )nPharmacologic properties:Pharmacologic properties: Absorption Absorption after after oral oral administration administration is is rapid, rapid, and
41、and the the plasma plasma peak peak concentration concentration is is approximately approximately 3 3 hours hours at at therapeutic therapeutic doses. doses. It It can can be be used used for for all all types types of of epilepsy epilepsy except except petit petit mal. mal. Its Its better better to
42、 to use use this this drug drug with with sodium sodium phenytoin. phenytoin. With With regard regard to to grand grand mal, mal, the the effect effect of of primidone primidone is is better better than than phenobarbital,this phenobarbital,this drug drug is is useless useless to to petit mal.petit
43、mal.Primidone (Primidone (Primidone)Primidone)【Adverse effects】nCommon:Common: somnolence, vertigo, nausea somnolence, vertigo, nausea and vomiting.and vomiting.n Rare: Rare: megaloblastic anemia, megaloblastic anemia, leucopenia and thrombocytopenia.leucopenia and thrombocytopenia.Ethosuximide (Eth
44、osuximide (乙琥胺乙琥胺 ) )nPetit Petit mal mal (first (first choice), choice), useless useless to to other types of other types of seizure.seizure. Common adverse effect Common adverse effectnGastrointestinal tract:Gastrointestinal tract: anorexia, anorexia, nausea, vomiting.nausea, vomiting.nCNS:CNS: he
45、adache, headache, dizziness and dizziness and somnolence.somnolence.nRarely appear Rarely appear agranulemia and agranulemia and aplastic anemia.aplastic anemia. Diazepem(Diazepem(安定安定) & ) & Nitrazepem(Nitrazepem(硝基安定硝基安定) )DiazepemDiazepem ：nDiazepem Diazepem is is indicated indicated for for stat
46、us status epilepticus.epilepticus.NitrazepemNitrazepem : :nIts Its highly highly effective effective in in controlling controlling petit mal and myoclonus epilepsy.petit mal and myoclonus epilepsy.nSudden Sudden withdrawal withdrawal of of nitrazepem nitrazepem is is likely likely to to aggravate ag
47、gravate seizure seizure and and induced induced symptom. symptom. Sodium Valproate (丙戊酸钠丙戊酸钠 )Pharmacologic propertiesPharmacologic properties: nEnhance Enhance the the enzymatic enzymatic activity activity of of glutamate glutamate decarboxylase.GABAdecarboxylase.GABAnInhibit Inhibit GABA GABA reup
48、take reuptake and and synapse synapse inactivationsynapse inactivationsynapse frontal frontal membrane membrane GABA GABA enhance GABA postsynaptic inhibitionenhance GABA postsynaptic inhibitionnBroad Broad spectrum spectrum antiepileptic antiepileptic drug, drug, use use to to all all types of epil
49、epsy.types of epilepsy.nCNS:CNS: somnolence, somnolence, disequilibrium, disequilibrium, acratia acratia and and tremor.tremor.nHepatic lesionHepatic lesion (20% patients). (20% patients). nGastrointestinal Gastrointestinal tract: tract: nausea, nausea, vomiting vomiting and and anorexia.anorexia.Ca
50、rbamzepine (Carbamzepine (卡马西平卡马西平) )Pharmacologic propertiesPharmacologic properties: nCarbamazepine can block sodium channel, inhibit paradoxical discharge and discharge diffusion. It may relate to the postsynaptic inhibition of postsynaptic inhibition of GABA.GABA.nBroad Broad spectrum spectrum a
51、ntiepileptic antiepileptic drug, drug, use use to to all types of epilepsy.all types of epilepsy. nTrigeminal neuralgia (therapeutic effect is good).nAntidiuresisdiabetes insipidus.Carbamzepine Carbamzepine 【Adverse effectsAdverse effects】nCNS:CNS: somnolence, disequilibrium somnolence, disequilibri
52、umnGastrointestinal tract: Gastrointestinal tract: nausea, vomiting nausea, vomiting and anorexia.and anorexia.nRashRash，leucopenia leucopenia ，thrombocytopeniathrombocytopenia，aplastic anemia and hepatic lesion.aplastic anemia and hepatic lesion. Principle of MedicationPrinciple of Medication n1 12
53、 times/year2 times/year，no drugs are neededno drugs are needednGrand pit (first choice): Grand pit (first choice): Sodium Sodium p phenytoin or phenobarbital, henytoin or phenobarbital, carbamzepine, carbamzepine, Primidone.Primidone.nPetit mal (first choice): Petit mal (first choice): Ethosuximide,
54、 Ethosuximide, clonazepam and sodium valproate.clonazepam and sodium valproate.nStatus epilepticus:Status epilepticus:Diazepam or sodium Diazepam or sodium phenytoin (IV), phenobarbital, diazepam, phenytoin (IV), phenobarbital, diazepam, clonazepam.clonazepam.nPsychomotor:Psychomotor: Sodium phenyto
55、in or combine Sodium phenytoin or combine with desoxybarbital or carbamazepine.with desoxybarbital or carbamazepine.Principle of Medication (I)Principle of Medication (I)nThe dose can be gradually increased from The dose can be gradually increased from a low starting dose until reach the best a low
56、starting dose until reach the best effect.effect.nIn the initial stage, the patients In the initial stage, the patients should only be treated with a single should only be treated with a single antiepileptic drug, if the drug is antiepileptic drug, if the drug is useless, then it can be changed. Whe
57、n useless, then it can be changed. When drug changing is necessary, it should be drug changing is necessary, it should be gradually withdrawn after the effect of gradually withdrawn after the effect of new drug occurs. new drug occurs. nAfter the symptom is fully controlled, After the symptom is ful
58、ly controlled, the patients should the patients should continuing be continuing be treated for 2 or 3 years. Sudden treated for 2 or 3 years. Sudden withdrawal of drugs are likely to withdrawal of drugs are likely to precipitate relapse. precipitate relapse. Principle of Medication Principle of Medi
59、cation (II)(II)nEnhance therapeutic effect: dosing Enhance therapeutic effect: dosing individually, monitoring drug individually, monitoring drug plasma concentration, plasma concentration, examining examining regularly. regularly. nEvaluating efficacy and safety.Evaluating efficacy and safety.nAdju
60、sting drug dosage: the Adjusting drug dosage: the therapeutic index of antiepileptic therapeutic index of antiepileptic drug is loweasy to be poisoning drug is loweasy to be poisoning Therapeutic dose is get close to Therapeutic dose is get close to toxic dose. toxic dose. Anticonvulsant DrugsAntico
61、nvulsant DrugsnConvulsions are involuntary skeletal Convulsions are involuntary skeletal muscular contractions. Convulsions can muscular contractions. Convulsions can arise from pathological processes within arise from pathological processes within or outside the brain, toxins, drug or outside the b
62、rain, toxins, drug overdose, or withdrawal from drug overdose, or withdrawal from drug dependence. dependence. nCommonly used anticonvulsant drugs are Commonly used anticonvulsant drugs are sedative and hypnotic drugs. Magnesium sedative and hypnotic drugs. Magnesium Sulfate is also used on this disease.Sulfate is also used on this disease.Thanks!
