1、Antiepileptic and Anticonvulsant Drugs,Seizure,Epilepsy is not a single entity; it is a family of different recurrent seizure disorders that have in common the sudden, excessive and disorderly discharge of central neurons. This results in abnormal movement or perceptions that are of short duration b

2、ut that tend to recur.,Local excitatory ,Abnormal high frequency discharging,Abnormal spreading,Brain malfunction Accompanied with abnormal EEG,發(fā)病率高； 突發(fā)性，不可預(yù)測(cè)； 不可根治，需終身服藥,Classification of epilepsy,International Classification of Epileptic Seizures:Partial Onset Seizures（局限性發(fā)作）,Simple Partial（單純局限性）

3、 Complex Partial （復(fù)合性局限性） Partial Seizures with secondary generalization （局限性發(fā)作繼發(fā)全身強(qiáng)直陣攣性發(fā)作）,Partial seizures with dyscognitive features Partial seizures without dyscognitive features,International Classification of Epileptic Seizures: Primary Generalized Seizures,Absence (Petit Mal) （失神性發(fā)作/小發(fā)作） Myoc

4、lonic （肌陣攣性發(fā)作） Generalized Tonic+Clonic （全身強(qiáng)直陣攣性發(fā)作）,http:/www.uwo.ca/cns/resident/pocketbook/pictures/3-hz-s-w.jpg,The pathways for seizure propagation in partial seizures and primary generalized seizures,Origin of a surface epileptic discharge,強(qiáng)直性發(fā)作,陣攣性發(fā)作,發(fā)作后抑制,表面腦電圖,細(xì)胞外記錄,細(xì)胞內(nèi)記錄,PDS：paroxysmal depo

5、larization shift 陣發(fā)性去極化漂移,Sodium Influx,Calcium Influx,Chloride Influx,PDS,Surface Spike,K efflux,Seizures are generated by groups of neurons which depolarizing synchronously Epileptic neurons generate Paroxysmal Depolarizing Shift (陣發(fā)性去極化飄移, PDS) During a PDS, there is the repetitive activation of

6、key ion channels. These ion channels represent opportunities to prevent or terminate seizures.,Mechanisms of antiepileptic drugs,Electrophysiological Inhibiting excessive discharges Inhibiting spread of discharges Molecular Potentiating GABA neuronal functions Inhibiting excitatory neuronal function

7、s Modulating Na+, Ca2+, K+, Cl- channel fuctions,Molecular targets for anti-seizure drugs at the excitatory, glutamatergic synapse.,興奮性,Molecular targets for anti-seizure drugs at the inhibitory, GABAergic synapse.,抑制性,Antiepileptic drugs,Focus formation and epileptic attack,Focus shift,Refractory e

8、pilepsy,Imbalance of excitation and inhibitory Na+、Ca2+、NMDA 、K+ 、Cl-、GABA,Spreading,A. Antiepileptic drugs,Special drugs,Phenytoin Sodium 苯妥英鈉, 大侖丁,1. Pharmacological effects and the mechanism (1) Effects Inhibiting spread of abnormal discharges Not on the happening of abnormal discharge,A. Antiepi

9、leptic drugs,苯妥英鈉,1. Pharmacological effects and the mechanism (2) Mechanism Blocking Na+ channel in inactive state Inhibiting L- and N-type Ca2+ channel (but not T-type Ca2+ channel ) Calmodulin kinase activity Neurotransmitter release (NE, 5-HT, DA etc.) Block posttetanic potentiation (PTP) format

10、ion,A. Antiepileptic drugs,2. Clinical uses (1) Anti-epilepsy Grand mal, status epilepticus; Partial seizures (simple and complex); Ineffective for petit mal (absence seizures) 失身小發(fā)作 (2) Trigeminal (三叉神經(jīng)疼) and related neuralgia (神經(jīng)疼) (3) Anti-arrhythmia,A. Antiepileptic drugs,Larger doses: non-linea

11、r kinetics（ 10 g/ml） Half life = 24 hours Therapeutic range = 10-20 ug/ml Levels above 20 cause ataxia (共濟(jì)失調(diào)) and nystagmus（眼球震顫） Hepatic metabolism CYP3A enzyme pathway CYP3A antagonists will raise phenytoin levels Necessary to monitor plasma concentrations,Initially linear Psuedo first order,A. An

12、tiepileptic drugs,3. ADME,4. Adverse effects (1) Local reactions GI reactions; gingival hyperplasia (2) CNS reactions Particularly in the cerebellum and vestibular systems: nystagmus (眼球震顫), ataxia (共濟(jì)失調(diào)), etc. Behavioral changes: confusion, hallucination, coma (3) Hemological reactions Megaloblasti

13、c anemia (affect the metabolism of folic acid),A. Antiepileptic drugs,(4) Allergic reactions Skin reactions; blood cell abnormality (including thrombocytopenia, agranulocytosis); hepatic toxicity; ect. (5) Skeletal reactions Osteomalacia (骨質(zhì)疏松) by increase vitamin D metabolism and calcium absorption

14、 (inducer) (6) Others Birth defects, hirsutism, etc,A. Antiepileptic drugs,5. Drug interactions（蛋白結(jié)合、代謝） (1) Increases plasma concentrations of drugs by displacement of plasma protein binding (salicylates) (2) Drug metabolizing enzyme inhibitor decrease the metabolism of phenytoin (isoniazid異煙肼, chl

15、oramphenicol氯霉素) (3) Drug metabolizing enzyme inducer increase the metabolism of phenytoin (phenobarbital, carbamazepine) (4) Phenytoin enhances the metabolism of corticosteroids and vitamin D,A. Antiepileptic drugs,Phenobarbital 苯巴比妥,A. Antiepileptic drugs,Sedative and hypnotic effect Inhibiting bo

16、th formation and spread of discharges. Postsynaptic Cl- influx Presynaptic Ca2+ influx neurotransmitter release (NE, ACh, Glu, etc.) Effective for grand mal , status epilepticus, partial simple seizures.,Drugs acting at the chloride channel,Benzodiazepines Binds to specific receptors Phenobarbital B

17、inds to barbiturate specific receptor Valproate Decreases GABA degradation in presynaptic terminal,A. Antiepileptic drugs,苯巴比妥,苯二氮卓類,丙戊酸鈉,Block T-type Ca2+ channel Block Na+-K+-ATPase Inhibit cerebral metabolism and GABA transaminase Effective for peptit mal Combined with phenobarbital,Ethosuximide

18、乙琥胺,A. Antiepileptic drugs,Valproate sodium 丙戊酸鈉,A. Antiepileptic drugs,Broad spectrum Inhibiting spread of discharges but not formation Increases GABA levels via inhibiting GABA transaminase, GABA transport, Glutamate decarboxylase Inhibit Na+ and L-type Ca2+ Enhance K+ ?,GI side effects Tremor Hep

19、atitis Pancreatitis Serious neural tube and cardiac defects in fetus in 1%,Blocks Na+ and Ca2+ channels Enhance GABA Effective against psychomotor seizures, and grand mal Effective for mania, depression, and neuralgia Like phenytoin, metabolized by CYP3A pathway (an inducer) Need titration up!,Safet

20、y and Toxicity Dose dependence-double vision, ataxia rash 5-10% rare marrow suppression rare hepatitis frequent hyponatremia/Water intoxication (Dose dependence) fetal malformations,Carbamazepine 卡馬西平,A. Antiepileptic drugs,Other antiepileptic drugs Primidone 撲米酮：analogues of phenobarbital, used for

21、 phenobarbital- and phenytoin-ineffective patients Mephenytoin 美芬妥英, Ethotoin 乙苯妥英： analogues of phenytoin Diazepam 地西泮: status epilepticus (i.v.) Nitrozepam 硝西泮, Clonazepam 氯硝西泮：peptit mal Lamotrigine 拉莫三嗪,A. Antiepileptic drugs,Other antiepileptic drugs Oxarbazepine（奧卡西平）：similar as carbamazepine

22、but weaker Antiepilepsirine（抗癇靈）: broad spectrum, esp. grand mal Lamotrigine 拉莫三嗪： Na+ channel antagonist. Effective against both partial and generalized epilepsy Flunarizine 氟桂利嗪: Inhibit L- and T-type Ca2+ channel. broad spectrum Topiramate托吡酯： Blocks AMPA+kainate receptors Also blocks Na+ and Ca2

23、+ channels,A. Antiepileptic drugs,卡馬西平,苯妥英鈉,丙戊酸鈉,拉莫三嗪,丙戊酸鈉,乙琥胺,二甲雙酮,丙戊酸鈉,苯二氮卓類,巴比妥類,Common toxicity of antiepileptic drugs: CNS reactions Hemological reactions Hepatic toxicity Teratogenicity（致畸）,A. Antiepileptic drugs,Teratogenicity,All AEDs cause fetal malformations in at least 6% of infants. High

24、est risk with phenytoin, valproate, phenobarbital, and carbamazepine (Class D drugs) Folate supplementation prevents neural tube defects.,Principals of antiepileptic drug uses 1. Choice of drugs (1) Grand mal / Partial： Phenytoin, Carbamazepine, Phenobarbital Primidone, Valproate sodium (2) Peptit m

25、al: Ethosuximide Clonazepam, Valproate sodium (3) Psychomotor：Carbamazepine, Phenytoin (4) Status epilepticus：Diazepan (i.v.) Phenytoin (i.v.), Phenobrbital (i.m.),A. Antiepileptic drugs,2. Dosage： small larger doses; dose individualization; plasma concentration monitoring if necessary 3. Usage： dru

26、g combination 4. Withdrawal：gradually and slowly,A. Antiepileptic drugs,1. Effects：central depression; vasodilatation, BP ; relaxing skeletal muscles 2. Uses：convulsion；hypertension crisis 3. Adverse effects： depression of respiratory and vasomotor centers, antagonized by calcium preparations (i.v.)

27、,Magnesium Sulfate 硫酸鎂,B. Anticonvulsant drugs,Other anticovulsant drugs Sedative-hypnotic drugs,B. Anticonvulsant drugs,Drugs which primarily affect K+ channel,Levetiracetam 左乙拉西坦 High Potency-75% reduction in seizures in over 20% of refractory patients,Few side effects except: Fatigue Depression a

28、nd Psychosis leading to discontinuation in 7%. White et al Neurology 2003,Mechanism -Multiple Blocks AMPA+kainate receptors Also blocks sodium and CA channels Potentiate GABA transmission Effective against both partial and generalized epilepsy Excreted primarily in urine Start at 25 mg/daytitrate to

29、 300-500/day,Behavioral /Cognitive problems common Low risk of rash Causes weight loss Relatively safe, Class C in pregnancy High Potency 75% reductions in over 20% of refractory patients,Drugs which affect Kainate and AMPA receptors,Zonisamide,Topiramate,Anti-epileptics (AEDs) Note: All of the foll

30、owing drugs have multiple mechanisms of action (primary mechanisms include blockade of voltage gated Na+ channels, enhancement of GABAergic neurotransmission, and inhibition of glutamatergic neurotransmission) Older AEDs phenytoin voltage gated Na+ channel blocker carbamazepine voltage gated Na+ cha

31、nnel blocker valproate/valproic acid GABA metabolism inhibitor phenobarbital allosteric GABA A agonist Newer AEDs oxcarbazepine voltage gated Na+ channel blocker lamotrigine voltage gated Na+ channel blocker topiramate glutamate receptor antagonist; voltage gated Na+ channel blocker levetiracetam mu

32、ltiple actions gabapentin Ca2+ channel blocker zonisamide glutamate receptor antagonist; Na+ and T-type Ca+2+ channel blocker lorazepam (I.V.) for status epilepticus allosteric GABA A agonist,inhibition is use-dependent; limits ability of neurons to fire at high frequency. . maintains Na+ channel in

33、 inactivated state and slows rate of recovery; no change in spontaneous activity or firing at slow rate),Anti-Epileptic Drugs Effective as Monotherapy (Single Agent),Partial (Localization Related) Older AEDs Phenytoin (苯妥英鈉) Carbamazepine （卡馬西平） Valproate （丙戊酸鈉） Newer AEDs Oxcarbazepine （奧卡西平） Lamot

34、rigine（拉莫三嗪） Topiramate（托吡酯） French et al Neurology 2004 Bold= new generation AED,Generalized Valproate （丙戊酸鈉） (GTC and absence) Topiramate（托吡酯） (GTC) Lamotrigine （拉莫三嗪） (absence) French et al Neurology 2004,New AEDs effective as adjunctive treatment for refractory epilepsy,Partial Topiramate Leveti

35、racetam Pregabalin Zonisamide Oxcarbazepine Lamotrigine Gabapentin Tiagabine Above all have level I, randomized clinical trials, or A or B evidence, AAN guidelines 2004,Generalized Topiramate Levetiracetam Lamotrigine Data from randomized placebo controlled trials Drugs in red are generally consider

36、ed high potency,Increased expression of ABC transport in epilepsy,Transporters,P-gp抑制劑增強(qiáng)抗癲癇藥Oxarbazepine（OXC, 奧卡西平）作用及延長(zhǎng)癲癇病人入院間隔時(shí)間,P-gp基因敲除及其抑制劑增加腦內(nèi)抗癲癇藥濃度,Contribution of CYPs to drug metabolism,CYP Enzymes,(from Guengerich 2003),抑制劑,誘導(dǎo)劑,底物,AEDs and Hepatic CYP450 Interactions,Valproic acid CYP2C in

37、hibitor (inhibits phenobarbital, phenytoin metabolism) Phenytoin CYP inducer (3A4 and 2C); metabolized by 2C9 Carbamazepine CYP inducer (CYP inducer (3A4 and 2C); metabolized by 3A4. . . induces its own metabolism Phenobarbital CYP inducer (3A4 and 2C),Induction increase in amount of enzyme protein,

38、 resulting in an increase in the rate of metabolism of the affected drug Inhibition competition at the enzyme site that results in a decrease in metabolism of the affected drug,Drugs Treating Parkinson Disease and Alzheimer Disease,Parkinsons disease (PD),Rigidity Tremor Bradykinesia Postural instab

39、ility (propulsion, retropulsion).,Tremor: one of the common symptoms of PD,黑質(zhì)-紋狀體通路,中腦-邊緣/皮層通路,結(jié)節(jié)-漏斗通路,Substantia nigro -striatum dopaminergic pathway is involved in PD pathogenesis,Parkinson disease Dopaminergic neuron degeneration in substantia nigro and striatum,Normal,Dopamine,Acetylcholine,Abno

40、rmal balance of DA/ACh neuronal functions in extrapyramidal system of Parkinson disease,Levodopa,Muscarinic antagonists,Normal,Parkinson disease,(-),injured,relatively potentiated,(-) ,Tyrosine,TH,DOPA,Dopamine Decarboxylase,Dopamine,DBH,Norepinephrine,MAO-B,metabolisms,MAO-A,metabolisms,DA receptor

41、s,Treatment I: Increase dopamine,Different approaches include: I. increases in dopamine synthesis capacity II. direct activation of post-synaptic receptors III. inhibition of dopamine metabolism IV. alteration of the interaction/balance with other neurotransmitters V. dopamine releasers VI. L-DOPA m

42、etabolism inhibitors,What is the desired goal of pharmacological therapies for Parkinsons disease?,Note: All therapies treat the symptoms of the disease; none are neuroprotective and none slow the progression of the disease, Striatal dopamine levels are low in PD. Dopamine does not pass BBB and, hen

43、ce, has no therapeutic effect in PD. L-Dopa, an amino acid, the immediate precursor to dopamine, is transported across BBB and is an effective drug for PD.,Rationale for L-Dopa Precursor Loading:,Levodopa and related drugs,Drugs for treatment of Parkinson disease,(左旋多巴),(多巴胺),L-dopa is transformed t

44、o DA by dopa decarboxylase (one of the aromatic L-amino acid decarboxylases, AAAD, 左旋芳香氨基酸脫羧酶) in both the brain and peripheral organs.,L-DOPA peripheral metabolism,Levodopa 1. ADME Penetrating into the brain, transformed to DA or NE (less) Distributed in peripheral tissue (most) 2. Effects and uses

45、 Parkinson disease: decreases the rigidity, tremors, and other symptoms 3. Adverse effects Early (1) GI: nausea, vomiting, etc.(2) CVS: hypotension, arrhythmia, etc. -(1) CNS: emotional depression/ psychosis; abnormal involuntary; hallucinations; etc. Late (1) fluctuation of response: end of dose/“w

46、earing off” periods; on/off periods (sudden loss of symptom control, akinesia) .(2) dyskinesia (運(yùn)動(dòng)障礙，after years of chronic L-DOPA, up to 80%, Involuntary movements: chorea(舞蹈癥), ballismus(投擲癥), athetosis(手足徐動(dòng)癥), dystonia(肌張力失常), myoclonus(肌陣攣), and tremor,Drugs for treatment of Parkinson disease,Ca

47、rbidopa (卡比多巴) a peripheral decarboxylase inhibitor reduces peripheral metabolism of L-DOPA, increases L-DOPA bioavailability, can not cross BBB; decreases its adverse effects by allowing lower L-DOPA dosages to be used. The combination of L-DOPA plus carbidopa, po,FDOPA Uptake,Conclusion: COMT inhi

48、bitor increased brain bioavailability of FDOPA by inhibiting peripheral metabolism of FDOPA to 3-O-methyl FDOPA,FDOPA,fluorodopamine,AAAD,COMT,In periphery:,一般情況下，對(duì)L-dopa制劑的反應(yīng)可分為3個(gè)階段： 良好反應(yīng)階段（25年），為用藥的最初階段，每68小時(shí)或更長(zhǎng)時(shí)間服藥1次，可使全部癥狀得到平穩(wěn)的緩解或改善。 中間反應(yīng)階段（23年），此階段中每次服藥僅可引起短時(shí)間的癥狀改善，每個(gè)劑量的后期與下一個(gè)劑量前，有1個(gè)藥物無(wú)作用期，稱為劑末

49、現(xiàn)象，此外，還可出現(xiàn)開關(guān)現(xiàn)象和反常性運(yùn)動(dòng)不能；這種療效下降與黑質(zhì)DA能神經(jīng)元逐漸衰退，DA合成、貯存進(jìn)一步下降，及DA受體反應(yīng)能力降低有關(guān)。 反應(yīng)衰退階段，對(duì)L-dopa制劑反應(yīng)明顯下降或根本不起反應(yīng)；運(yùn)動(dòng)困難與致殘程度更為嚴(yán)重；同時(shí)治療中的一些不良反應(yīng)更為明顯。,Drugs for treatment of Parkinson disease,Other drugs 1. DA receptor agonists 1st generation agonists: (ergot derivatives) bromocriptine* (溴隱亭, D2 agonist) (t1/2 12 h)

50、pergolide* (培高利特, D2/D3 agonist)(t1/2 24 h) 2nd generation agonists: ropinirole (t1/2 6 h) (普拉克索, D2/D3 agonist) pramipexole (t1/2 8 -12 h) (羅平尼咯, D2 agonist) Can be used as monotherapy for mild parkinsonism, or combined with levodopa for advanced disease, permitting the dose of levodopa to be reduc

51、ed and smoothing out response fluctuations.,Lower incidence of dyskinesia and response fluctuation Some individuals develop a troubling sleep disorder, with sudden attacks of sleep (突然昏睡) during ordinary daytime activities Postural hypotension Dose-related psychiatric side effects (similar to L-DOPA

52、 but may occur more frequently, especially in elderly) Nausea or vomiting (drugs active at chemotrigger zone (CTZ) ),the major adverse effects of DA receptor agonists,2. MAO-B inhibitors （ Peripheral metabolism of catecholamines (mostly MAO-A) is unaffected.） decreasing DA metabolism in the CNS Sele

53、giline 司來(lái)吉蘭 Rasagiline 雷沙吉蘭 3. COMT inhibitors (decreasing DA metabolism) CNS COMT inhibitor: ：itecapone 硝替卡朋 peripheral COMT inhibitor: entacapone恩他卡朋,Drugs for treatment of Parkinson disease,Drugs for treatment of Parkinson disease 4. Amantadine 金剛烷胺,Used for mild Parkinsons disease, as an early m

54、onotherapy Mechanisms of action may include: release of dopamine, block DA reuptake, actions on glutamate receptors (as an NMDA-receptor antagonist) The dose should be reduced with renal impairment. Potential adverse effects: - CNS reactions (dizziness, anxiety, impaired coordination) - hyperkinesia

55、s(運(yùn)動(dòng)亢進(jìn)) - nausea, vomiting - others,Muscarinic antagonists Trihexyphenidyl (苯海索，artane, 安坦) Benzatropine (苯扎托品) Decreasing CNS cholinergic functions Adjuvant of Parkison disease treatment,Drugs for treatment of Parkinson disease,DRUG THERAPY - Summary,Main Line Agents: L-DOPA plus carbidopa (Sinemet

56、) Dopamine receptor agonists (ropinirole) Lower Efficacy/Second Line or Adjuvant Agents: Anticholinergics Reuptake Inhibitor or releaser (amantadine) COMT Inhibitor (entacapone) MAO B Inhibitors (rasagiline, selegiline), Reserpine, which depletes brain catecholamines, induces Parkinsons disease symp

57、toms Antipsychotics (neuroleptics), that block DA receptors, ie, dopamine receptor antagonists. N-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) is a by-product of illicit synthesis of isomeperidine. MPTP first came to medical attention because it produced symptoms similar to Parkinsons disease.,Drug-Induced Parkinsonism,Drugs for treatment of dementia (Alzheimer and related diseases) Anticholinesterase drugs Cholinoceptor agonists Neurotrophic factor-like drugs,Pathological characteristics of AD,Atr