1. Welcome to Pharmacology

2. Chapter 18 Antiepileptic & Anticonvulsive Drugs

3. Section 1 Antiepileptic Drugs

4. Epilepsy 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 discharge of focal cerebral neuron and diffusion to normal neuronal tissues. Somatic, sensory, automatic and psychotic

6. Epilepsy Etiology incidence:0.5 % ~1 %  Primary epilepsy  Secondary epilepsy

7. Classifications 1. Partial seizures (1)Simple partial seizures 单纯局限性发作 (2)Complex partial seizures 复合性局限性发作 2. Generalized seizures (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

8. (1) Grand mal epilepsy Loss of consciousness and myotonia- myoclonus for a few minutes. Continuous episodes with sustained loss of consciousness is called epilepticism.

9. (2) Absence Involve 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.

10. (3) Myoclonic Consist of short episode of local muscle contractions that may reoccur for several minutes.

11. Partial Simple partial Do not lose conciousness and often exhibit abnomal activity of a single limb or muscle group.

12. Partial Complex partial Exhibit motor dysfuntion and loss of conciousness.

13. Experimental Models 1. Electric stimulate(maximal electroshock seizure, MES): grad mal 2. Pentylenetetrazol(PTZ): absence seizure 3. Spontaneously epileptic rat(SER) 4. Kindling response: Complex partial seizures 5. Glutamate

14. History of Antiepileptic Drugs 1857 potassium bromide( 溴化钾 ) 1912 phenobarbital 1912~1937 35 analogs of phenobarbital 1938 phenytoin 1938~1960 valproate(64), Antiepilepsrin(75) Carbamazepin(80), gabapentin(90)

15. The Classifications Hydantoins Anticonvulsive barbiturates Benzodiazepines Succinimides New drugs

16. Electrophysiology of antiepilepsy drugs a. inhibit discharge in focus b. inhibit diffusion in normal neuron

17. Mechanisms of action of antiepilepsy drugs 1. To affect inhibitory system involving GABAergic function a. Enhancement of GABAergic transmission: reuptake or metabolism b. Direct action on the GABA-R chloride channel complex

18. Mechanisms 2.Modification of ion channel conductance Inhibitory of Na + and/or Ca 2+ channel N-type Ca 2+ channel L-type T-type absence seizures

19. Mechanisms c. Diminution of glutaminergic function AMPA-R blockade NMDA-R blockade

20. Phenytoin Sodium （苯妥英钠, Dilantin, 大仑丁）

21. Mechanisms 1.inhibit diffusion in normal neuron by inhibiting post tetanic potentiation(PTP)

22. Post tetanic potentiation (PTP) :Increase in amplitude of EPSP after neuron has received tetanic stimulus, in neurons refers to any high frequency burst of stimulation

23. Mechanisms 2.Promote the stablization of the membrane a.block voltage-sensitive (use- dependent effect) Na + channel b.block voltage-sensitive Ca 2+ channel c. inhibit K + out

24. Mechanisms 3.inhibit the activity of camudulin kinase 4. Potentiate GABA inhibiting function

25. Clinical uses 1.Epilepsy: generalized tonic-clonic seizures simple partial seizures complex partial seizures first choice except absence seizure Pay attention to children

26. Clinical uses 2. Central pain syndrome: neuralgias trigeminal neuralgia et al 3. Arrhythmia （心律失常）

27. Pharmacokinetics 1. Absorption pK a 8.3, slow and unpredictable after oral administration C ss 5-7d stimulation by oral and im(pH=10.4) 2. Distribution PPBR about 90%,Vd 0.6-0.7L/kg

28. Pharmacokinetics 3. Metabolism : by hepatomicroenzymes about 60%-70%, 5% unchanged 相互作用 4. Elimination : dose-dependent plasma concentration less than 10  g/ml, FOK, t 1/2 6-24hrs more than 10  g/ml, OOK, t 1/2 20-60hrs

29. Adverse Reactions C max (E) 10  g/ml; C Tox 20  g/ml 1. Gastrointestinal reaction 2. Gingival hyperplasia by increasing the the induction of collagenase

30. Adverse Reactions 3. CNS symptoms  20  g/ml ： drowsiness, dizziness, ataxia, ﹥ 40  g/ml: psychotic, ﹥ 50  g/ml: coma 4. Blood system: folic acid dysefficacy

31. Adverse Reactions 4. 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

32. Adverse Reactions 6. 心血管反应 arrhythmia hypotension

33. Adverse Reactions 7.Others: a.Teratogenesis fetal hydantoin syndrome ( 胎儿妥因综合征） b.peripheral neuritis

34. 芬兰 1980 ～ 1998 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 位则无。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 ）

35. Drug Interactions 1. Hepatomicrosomal enzyme inducer 2. Hepatomicrosomal enzyme inhibiter 3. PPBR

36. Carbamazepine （卡马西平 ） Broad–spectrum antiepileptic agent Mechanisms inhibit Na + channel potentiat GABA inhibitory function

37. Carbamazepine Actions and Uses 1. Antiepileptic effects grad mal, partial seizures with complex symptomatology first choice 2. Central algesia: trigeminal neuralgia more effective than phenytoin 3. mania （躁狂症） and depression 4. 尿崩症

38. Pharmacokinetics 1. slow and unpredictable after oral administration 2. PPBR 80% 3. Active metabolite ： cyclooxide 4. t 1/2 35 hrs at beginning, then may shorten by 50% due to enzyme induction

39. Adverse Reactions 1. Gastrointestinal reaction 2. CNS reactions: drowsness, vertigo, nausea, vomit, ataxia 3. Blood system: 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 intoxication

40. Phenobarbital 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 epilepticus

41. Mechanisms 1. Potentiate the GABA inhibitory function: pre-synaptic GABA-R 2. Ca 2+ Neurotransmitter 3. Inhibitory of Na + and Ca 2+ channel

42. 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

43. Primidone （扑米酮） Primidone is metabolized to phenobarbital and phenylethylmalonamides(PEMA, 苯乙基丙二酰胺 ) as active metabolites

44. Ethosuximide （乙琥胺） The only indication: absence epilepsy Mechanisms: 1. reducing the T-type Ca 2+ current 2. inhibiting GABA aminotransferase ( 转 氨酶 ) ， Na + -K + -ATP

45. Adverse Reactions(safe) 1. Gastric distress 2. CNS distress 3. Blood system ： agranulocytosis, thrombocytopenia, aplastic anemia 4. SLE

46. Sodium Valproate （丙戊酸钠） Broad–spectrum antiepileptic agent  Mechanisms: 1.potentiate GABA function inhibit GABA-T increase the activity of GAD 2.inhibit Na + channel 3.inhibit L-Ca 2+ channel inhibit T-Ca 2+ channel

47. uses Effective for all types of epilepsy, more effective than ethosuxide, less effective for grad mal and partial mal grad mal combine with absence seizures first choice

48. Adverse Reactions 1. Hepatic intoxication 2. CNS and blood system thrombocytopenia 3. Teratogenesis

49. Benzodiazepines 1. Diazepam :first choice for status epilepticus by iv 2. Nitrazepam （硝西泮） : myoclonic seizure, atypical absence seizure and infantile spasm 3. Clonazepam: absence seizure, atonic and akinetic seizures

50. Other New Drugs Flunarizine ( 氟桂利嗪 ) 1. Nonselective calcium channel-blocking drugs 2. Effective for all types of epilepsy, more effective for grad mal and partial mal 3. inhibit Na + channel inhibit L-Ca 2+ channel inhibit T-Ca 2+ channel

51. Antiepilepsirin （抗痫灵） 1. Broad–spectrum antiepileptic agent 2. 5-HT 3. Safe

52. Lamotrigine ( 拉莫三嗪） 1. Used as an add-on therapy or monotherapy in the treatment of absence or myoclonic seizure 2. The mechanism may related to inhibit voltage-dependent Na + channel

53. Topiramate （托吡酯） Used in the treatment of partial seizure with or without generalized tonic-clonic seizures inhibit Na + channel potentiat GABA inhibitory function Diminution of glutaminergic function

54. Therapy for Epilepsy General Principles and Drug Choice for The Therapy of Epilepsy 1. Accurate evaluation 2. The drug choice for initial treatment of seizures

55. Therapy for Epilepsy (1) grad mal and simple partial seizures: Carbamazepine, phenytoin Carbamazepine, phenytoin Phenobarbital, primidone and valproic acid as alternative Phenobarbital, primidone and valproic acid as alternative

56. Therapy for Epilepsy (2)Absence seizure: ethosuxide valproic acid, clonazepam (3)Complex partial seizures: Carbamazepine Phenytoin ， primidone, valproic acid

57. Therapy for Epilepsy （ 4 ） Status epilepticus Diazepam iv, or clonazepam, phenytoin and phenobarbital (5)Tonic seizure: valproic acid (6)Myoclonic seizure: Glucocorticoids, clonazepam

58. Therapy for Epilepsy 3. Increase dose gradually 4. Withdrawn or discontinue ---- gradually (half year) 5. Change drug or add a second drug and/or combination 6. Monitoring the serum drug level 7. Adverse reactions teratogenesis

59. Section 2 Anticonvulsants  Convulsion  Barbiturates  Benzodiazepines  Chloral hydrate  Magnesium Sulfate

60. Magnesium Sulfate 1. 给药途径不同，药理作用不同 2. Relaxant of skeletal muscle and CNS depression by iv or im 3. Mechanism : calcium antagonism 4. Used in convulsion caused by eclampsia ， 高血压危象 5. respiratory inhibition and hypotension when overdose.

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