10.抗癫痫和抗惊厥药——山东大学药理学英文课件

1、Welcome to Pharmacology Chapter 18 Antiepileptic & Anticonvulsive DrugsSection 1 Antiepileptic DrugsEpilepsy Epilepsy is a heterogeneous symptom complex, a chronic disorder characterized by sudden, transit and recurrent seizures which are episodes of brain dysfunction resulting from abnormal dischar

2、ge of focal cerebral neuron and diffusion to normal neuronal tissues.Somatic, sensory, automatic and psychoticEpilepsyEtiology incidence:0.5%1% Primary epilepsy Secondary epilepsyClassificationsPartial seizures (1)Simple partial seizures 单纯局限性发作 (2)Complex partial seizures 复合性局限性发作Generalized seizur

3、es (1)Absence seizures(petit mal) 失神发作小发作 (2)Myoclonic seizures 肌阵挛性发作 (3)Generalized tonic-clonic seizures (grad mal) 强直-阵挛性发作大发作 (4)Status epilepticus 癫痫持续状态(1) Grand mal epilepsy Loss of consciousness and myotonia-myoclonus for a few minutes. Continuous episodes with sustained loss of consciousne

4、ss is called epilepticism. (2) AbsenceInvolve a brief, sudden and self-limiting loss of consciousness.The patient stare and exhibits rapid eye-blinking, which lasts for 3 to 5 seconds without any motor disorder.(3) Myoclonic Consist of short episode of local muscle contractions that may reoccur for

5、several minutes.PartialSimple partial Do not lose conciousness and often exhibit abnomal activity of a single limb or muscle group.PartialComplex partial Exhibit motor dysfuntion and loss of conciousness.Experimental Models1. Electric stimulate(maximal electroshock seizure, MES): grad mal2. Pentylen

6、etetrazol(PTZ): absence seizure3. Spontaneously epileptic rat(SER)4. Kindling response: Complex partial seizures 5. GlutamateHistory of Antiepileptic Drugs1857 potassium bromide(溴化钾)1912 phenobarbital19121937 35 analogs of phenobarbital1938 phenytoin19381960valproate(64), Antiepilepsrin(75) Carbamaz

7、epin(80), gabapentin(90)The ClassificationsHydantoinsAnticonvulsive barbituratesBenzodiazepinesSuccinimidesNew drugsElectrophysiology of antiepilepsy drugs a. inhibit discharge in focus b. inhibit diffusion in normal neuronMechanisms of action of antiepilepsy drugsTo affect inhibitory system involvi

8、ng GABAergic function a. Enhancement of GABAergic transmission: reuptake or metabolism b. Direct action on the GABA-R chloride channel complex Mechanisms2.Modification of ion channel conductance Inhibitory of Na+ and/or Ca2+ channel N-typeCa2+ channel L-type T-type absence seizures Mechanisms c. Dim

9、inution of glutaminergic function AMPA-R blockade NMDA-R blockade Phenytoin Sodium 苯妥英钠, Dilantin, 大仑丁Mechanisms 1.inhibit diffusion in normal neuron by inhibiting post tetanic potentiation(PTP)Post tetanic potentiation (PTP) :Increase in amplitude of EPSP after neuron has received tetanic stimulus,

10、 in neurons refers to any high frequency burst of stimulationMechanisms2.Promote the stablization of the membrane a.block voltage-sensitive (use-dependent effect) Na+ channel b.block voltage-sensitive Ca2+ channel c. inhibit K+ outMechanisms3.inhibit the activity of camudulin kinase4. Potentiate GAB

11、A inhibiting functionClinical uses1.Epilepsy: generalized tonic-clonic seizures simple partial seizures complex partial seizures first choice except absence seizure Pay attention to childrenClinical uses2. Central pain syndrome: neuralgias trigeminal neuralgia et al3. Arrhythmia心律失常PharmacokineticsA

12、bsorption pKa8.3, slow and unpredictable after oral administration Css 5-7d stimulation by oral and im(pH=10.4)2. Distribution Pharmacokinetics3. Metabolism : by hepatomicroenzymes about 60%-70%, 5% unchanged 相互作用4. Elimination : dose-dependent plasma concentration less than 10g/ml, FOK, t1/2 6-24hr

13、s more than 10 g/ml, OOK, t1/2 20-60hrsAdverse Reactions Cmax(E) 10g/ml; CTox 20g/mlGastrointestinal reactionGingival hyperplasia by increasing the the induction of collagenaseAdverse Reactions3. CNS symptoms 20g/ml：drowsiness, dizziness, ataxia, 40g/ml: psychotic, 50g/ml: coma4. Blood system: folic

14、 acid dysefficacyAdverse Reactions4. Allergy leukopenia白细胞减少, agranulocytosis粒细胞缺乏, thrombocytopenia血小板减少, aplastic anemia再生障碍性贫血5. Bone system hypocalcemia,osteomalacia, rachitis reason：vitamin D Adverse Reactions6.心血管反响 arrhythmia hypotensionAdverse Reactions7.Others:a.Teratogenesis fetal hydantoi

15、n syndrome (胎儿妥因综合征b.peripheral neuritis 芬兰 19801998年，研究人员追踪了一家产科诊所中970位怀孕的癫痫妇女，其中有740位在怀孕初期前3个月服用抗癫痫药物，另外239位那么无。结果在这些服用抗癫痫药物的怀孕妇女中，共产下28个严重畸形儿3.8%，未服用抗癫痫药物组仅产下2个严重畸形儿0.8%；P=0.02 Drug InteractionsHepatomicrosomal enzyme inducerHepatomicrosomal enzyme inhibiterPPBRCarbamazepine卡马西平Broadspectrum anti

16、epileptic agent Mechanisms inhibit Na+ channel potentiat GABA inhibitory functionCarbamazepine Actions and UsesAntiepileptic effects grad mal, partial seizures with complex symptomatology first choiceCentral algesia: trigeminal neuralgia more effective than phenytoinmania躁狂症and depression尿崩症Pharmaco

17、kineticsslow and unpredictable after oral administration2. PPBR 80%3. Active metabolite： cyclooxide 4. t1/2 35 hrs at beginning, then may shorten by 50% due to enzyme inductionAdverse Reactions 1. Gastrointestinal reaction 2. CNS reactions: drowsness, vertigo, nausea, vomit, ataxia 3. Blood system:

18、leukopenia白细胞减少, agranulocytosis粒细胞缺乏, thrombocytopenia血小板减少, aplastic anemia再生障碍性贫血 4. Hepatic intoxicationPhenobarbital Broad-spectrum and much effective in grad mal and partial seizures, but not drug choice for grad mal, alternative and iv in the treatment of status epilepticusMechanismsPotentiat

19、e the GABA inhibitory function: pre-synaptic GABA-R Ca2+ NeurotransmitterInhibitory of Na+ and Ca2+ channelPrimidone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+outPrimidone

20、扑米酮Primidone is metabolized to phenobarbital and phenylethylmalonamides(PEMA, 苯乙基丙二酰胺) as active metabolitesEthosuximide乙琥胺The only indication: absence epilepsy Mechanisms: reducing the T-type Ca2+ current inhibiting GABA aminotransferase(转氨酶)，Na+-K+-ATPAdverse Reactions(safe)Gastric distressCNS dis

21、tressBlood system ： agranulocytosis, thrombocytopenia, aplastic anemia4. SLESodium Valproate丙戊酸钠 Broadspectrum antiepileptic agentMechanisms: 1.potentiate GABA function inhibit GABA-T increase the activity of GAD 2.inhibit Na+ channel 3.inhibit L-Ca2+ channel inhibit T-Ca2+ channeluses Effective for

22、 all types of epilepsy, more effective than ethosuxide, less effective for grad mal and partial mal grad mal combine with absence seizures first choiceAdverse Reactions1. Hepatic intoxication2. CNS and blood system thrombocytopenia3. TeratogenesisBenzodiazepines 1. Diazepam :first choice for status

23、epilepticus by iv 2. Nitrazepam硝西泮: myoclonic seizure, atypical absence seizure and infantile spasm 3. Clonazepam: absence seizure, atonic and akinetic seizuresOther New DrugsFlunarizine(氟桂利嗪)Nonselective calcium channel-blocking drugsEffective for all types of epilepsy, more effective for grad mal

24、and partial mal3. inhibit Na+ channel inhibit L-Ca2+ channel inhibit T-Ca2+ channelAntiepilepsirin抗痫灵Broadspectrum antiepileptic agent 5-HTSafe Lamotrigine(拉莫三嗪Used as an add-on therapy or monotherapy in the treatment of absence or myoclonic seizure2. The mechanism may related to inhibit voltage-dep

25、endent Na+ channelTopiramate托吡酯Used in the treatment of partial seizure with or without generalized tonic-clonic seizuresinhibit Na+ channel potentiat GABA inhibitory functionDiminution of glutaminergic functionTherapy for EpilepsyGeneral Principles and Drug Choice for The Therapy of EpilepsyAccurate evaluationThe drug choice for initial treatment of seizures Therapy for Epilepsy(1) grad mal and simple partial seizures: Carbamazepine, phenytoin Phenobarbital, primidone and valproic acid as alternativeTherapy for E