AntiepilepticandAnticonvulsantDrugs1SeizureEpilepsyisnotasingleentity;itisafamilyofdifferentrecurrentseizuredisordersthathaveincommonthesudden,excessiveanddisorderlydischargeofcentralneurons.Thisresultsinabnormalmovementorperceptionsthatareofshortdurationbutthattendtorecur.2Localexcitatory

AbnormalhighfrequencydischargingAbnormalspreadingBrainmalfunctionAccompaniedwithabnormalEEG發(fā)病率高；突發(fā)性，不可預(yù)測；不可根治，需終身服藥3Classificationofepilepsy4InternationalClassificationofEpilepticSeizures:

PartialOnsetSeizures（局限性發(fā)作）SimplePartial（單純局限性）ComplexPartial（復(fù)合性局限性）PartialSeizureswithsecondarygeneralization

（局限性發(fā)作繼發(fā)全身強(qiáng)直陣攣性發(fā)作）PartialseizureswithdyscognitivefeaturesPartialseizureswithoutdyscognitivefeatures5InternationalClassificationofEpilepticSeizures:

PrimaryGeneralizedSeizuresAbsence(PetitMal)

（失神性發(fā)作/小發(fā)作）Myoclonic

（肌陣攣性發(fā)作）GeneralizedTonic+Clonic（全身強(qiáng)直陣攣性發(fā)作）http://www.uwo.ca/cns/resident/pocketbook/pictures/3-hz-s-w.jpg6Thepathwaysforseizurepropagationinpartialseizuresandprimarygeneralizedseizures7Originofasurfaceepilepticdischarge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：paroxysmaldepolarizationshift

陣發(fā)性去極化漂移8SodiumInfluxCalciumInfluxChlorideInfluxPDSSurfaceSpikeKeffluxSeizuresaregeneratedbygroupsofneuronswhichdepolarizingsynchronouslyEpilepticneuronsgenerateParoxysmalDepolarizingShift(陣發(fā)性去極化飄移,PDS)DuringaPDS,thereistherepetitiveactivationofkeyionchannels.Theseionchannelsrepresentopportunitiestopreventorterminateseizures.9MechanismsofantiepilepticdrugsElectrophysiologicalInhibitingexcessivedischargesInhibitingspreadofdischargesMolecularPotentiatingGABAneuronalfunctionsInhibitingexcitatoryneuronalfunctionsModulatingNa+,Ca2+,K+,Cl-channelfuctions10Moleculartargetsforanti-seizuredrugsattheexcitatory,glutamatergicsynapse.興奮性11Moleculartargetsforanti-seizuredrugsattheinhibitory,GABAergicsynapse.抑制性12AntiepilepticdrugsFocusformationandepilepticattackFocusshiftRefractoryepilepsyImbalanceofexcitationandinhibitory

Na+、Ca2+、NMDA

、K+、Cl-、GABASpreading13A.

AntiepilepticdrugsSpecialdrugsPhenytoinSodium苯妥英鈉,大侖丁141.Pharmacologicaleffectsandthemechanism

(1)Effects

—Inhibitingspreadof

abnormaldischarges—Notonthehappeningofabnormaldischarge

A.

Antiepilepticdrugs15苯妥英鈉161.Pharmacologicaleffectsandthemechanism

(2)Mechanism—BlockingNa+channelininactivestate—InhibitingL-andN-typeCa2+channel(butnotT-typeCa2+channel)—CalmodulinkinaseactivityNeurotransmitterrelease(NE,5-HT,DAetc.)—Blockposttetanicpotentiation(PTP)formationA.

Antiepilepticdrugs172.Clinicaluses(1)Anti-epilepsyGrandmal,statusepilepticus;Partialseizures(simpleandcomplex);Ineffectiveforpetitmal(absenceseizures)

失身小發(fā)作(2)Trigeminal(三叉神經(jīng)疼)andrelatedneuralgia(神經(jīng)疼)(3)Anti-arrhythmiaA.

Antiepilepticdrugs18Largerdoses:non-linearkinetics（>10g/ml）Halflife=24hoursTherapeuticrange=10-20ug/mlLevelsabove20causeataxia(共濟(jì)失調(diào))andnystagmus（眼球震顫）HepaticmetabolismCYP3AenzymepathwayCYP3AantagonistswillraisephenytoinlevelsNecessarytomonitorplasmaconcentrationsInitiallylinearPsuedofirstorderA.

Antiepilepticdrugs3.ADME19204.Adverseeffects(1)LocalreactionsGIreactions;gingivalhyperplasia(2)CNSreactionsParticularlyinthecerebellumandvestibularsystems:nystagmus(眼球震顫),ataxia(共濟(jì)失調(diào)),etc.Behavioralchanges:confusion,hallucination,coma

(3)HemologicalreactionsMegaloblasticanemia(affectthemetabolismoffolicacid)A.

Antiepilepticdrugs21(4)AllergicreactionsSkinreactions;bloodcellabnormality(includingthrombocytopenia,agranulocytosis);hepatictoxicity;ect.(5)SkeletalreactionsOsteomalacia(骨質(zhì)疏松)byincreasevitaminDmetabolismandcalciumabsorption(inducer)(6)OthersBirthdefects,hirsutism,etc

A.

Antiepilepticdrugs225.Druginteractions（蛋白結(jié)合、代謝）(1)Increasesplasmaconcentrationsofdrugsbydisplacementofplasmaproteinbinding(salicylates)

(2)Drugmetabolizingenzymeinhibitordecreasethemetabolismofphenytoin(isoniazid異煙肼,chloramphenicol氯霉素)(3)Drugmetabolizingenzymeinducerincreasethemetabolismofphenytoin(phenobarbital,carbamazepine)(4)PhenytoinenhancesthemetabolismofcorticosteroidsandvitaminDA.

Antiepilepticdrugs23Phenobarbital苯巴比妥A.

AntiepilepticdrugsSedativeandhypnoticeffectInhibitingbothformationandspreadofdischarges.PostsynapticCl-influxPresynapticCa2+influx

neurotransmitterrelease(NE,ACh,Glu,etc.)

Effectiveforgrandmal,statusepilepticus,partialsimpleseizures.24DrugsactingatthechloridechannelBenzodiazepinesBindstospecificreceptorsPhenobarbitalBindstobarbituratespecificreceptorValproateDecreasesGABAdegradationinpresynapticterminalA.

Antiepilepticdrugs苯巴比妥苯二氮卓類丙戊酸鈉25BlockT-typeCa2+channelBlockNa+-K+-ATPaseInhibitcerebralmetabolismandGABAtransaminase

EffectiveforpeptitmalCombinedwithphenobarbitalEthosuximide乙琥胺A.

Antiepilepticdrugs26Valproatesodium丙戊酸鈉A.

AntiepilepticdrugsBroadspectrumInhibitingspreadofdischargesbutnotformation

IncreasesGABAlevelsviainhibitingGABAtransaminase,

GABAtransport,

GlutamatedecarboxylaseInhibitNa+andL-typeCa2+EnhanceK+?GIsideeffectsTremorHepatitisPancreatitisSeriousneuraltubeandcardiacdefectsinfetusin1%27BlocksNa+andCa2+channelsEnhanceGABAEffectiveagainstpsychomotorseizures,andgrandmalEffectiveformania,depression,andneuralgiaLikephenytoin,metabolizedbyCYP3Apathway(aninducer)Needtitrationup!SafetyandToxicityDosedependence-doublevision,ataxiarash5-10%raremarrowsuppressionrarehepatitisfrequenthyponatremia/Waterintoxication(Dosedependence)fetalmalformationsCarbamazepine卡馬西平A.

Antiepilepticdrugs28OtherantiepilepticdrugsPrimidone撲米酮：analoguesofphenobarbital,usedforphenobarbital-andphenytoin-ineffectivepatientsMephenytoin美芬妥英,Ethotoin乙苯妥英：analoguesofphenytoinDiazepam地西泮:statusepilepticus(i.v.)Nitrozepam硝西泮,Clonazepam氯硝西泮：peptitmalLamotrigine拉莫三嗪A.

Antiepilepticdrugs29OtherantiepilepticdrugsOxarbazepine（奧卡西平）：similarascarbamazepinebutweakerAntiepilepsirine（抗癇靈）:broadspectrum,esp.

grandmalLamotrigine拉莫三嗪：Na+channelantagonist.EffectiveagainstbothpartialandgeneralizedepilepsyFlunarizine

氟桂利嗪:InhibitL-andT-typeCa2+channel.broadspectrumTopiramate托吡酯：BlocksAMPA+kainatereceptorsAlsoblocksNa+andCa2+

channelsA.

Antiepilepticdrugs30卡馬西平苯妥英鈉丙戊酸鈉拉莫三嗪31丙戊酸鈉乙琥胺二甲雙酮32丙戊酸鈉苯二氮卓類巴比妥類33Commontoxicityofantiepilepticdrugs:

CNSreactionsHemologicalreactionsHepatictoxicityTeratogenicity（致畸）A.

Antiepilepticdrugs34TeratogenicityAllAED'scausefetalmalformationsinatleast6%ofinfants.Highestriskwithphenytoin,valproate,phenobarbital,andcarbamazepine(ClassDdrugs)Folatesupplementationpreventsneuraltubedefects.35Principalsofantiepilepticdruguses1.Choiceofdrugs(1)Grandmal/Partial：

Phenytoin,Carbamazepine,Phenobarbital

Primidone,Valproatesodium(2)Peptitmal:

Ethosuximide

Clonazepam,Valproatesodium(3)Psychomotor：Carbamazepine,Phenytoin(4)Statusepilepticus：Diazepan(i.v.)

Phenytoin(i.v.),Phenobrbital(i.m.)A.

Antiepilepticdrugs362.Dosage：

smalllargerdoses;doseindividualization;plasmaconcentrationmonitoringifnecessary3.Usage：

drugcombination4.Withdrawal：graduallyandslowlyA.

Antiepilepticdrugs371.Effects：centraldepression;vasodilatation,BP;relaxingskeletalmuscles2.Uses：convulsion；hypertensioncrisis3.Adverseeffects：depressionofrespiratoryandvasomotorcenters,antagonizedbycalciumpreparations(i.v.)MagnesiumSulfate硫酸鎂B.

Anticonvulsantdrugs38OtheranticovulsantdrugsSedative-hypnoticdrugsB.

Anticonvulsantdrugs39DrugswhichprimarilyaffectK+channelLevetiracetam左乙拉西坦HighPotency->75%reductioninseizuresinover20%ofrefractorypatientsFewsideeffectsexcept:FatigueDepressionandPsychosisleadingtodiscontinuationin7%.

WhiteetalNeurology200340Mechanism-MultipleBlocksAMPA+kainatereceptorsAlsoblockssodiumandCAchannelsPotentiateGABAtransmissionEffectiveagainstbothpartialandgeneralizedepilepsyExcretedprimarilyinurineStartat25mg/day…titrateto300-500/dayBehavioral/CognitiveproblemscommonLowriskofrashCausesweightlossRelativelysafe,ClassCinpregnancyHighPotency>75%reductionsinover20%ofrefractorypatientsDrugswhichaffectKainateandAMPAreceptorsZonisamideTopiramate41Anti-epileptics(AEDs)

Note:Allofthefollowingdrugshavemultiplemechanismsofaction(primarymechanismsincludeblockadeofvoltagegatedNa+channels,enhancementofGABAergicneurotransmission,andinhibitionofglutamatergicneurotransmission)OlderAED’sphenytoinvoltagegated

Na+channelblocker

carbamazepinevoltagegated

Na+channelblocker

valproate/valproicacidGABAmetabolisminhibitorphenobarbitalallostericGABAAagonistNewerAED’soxcarbazepinevoltagegated

Na+channelblocker

lamotriginevoltagegated

Na+channelblocker

topiramateglutamatereceptorantagonist;voltagegated

Na+channelblocker

levetiracetammultipleactionsgabapentinCa2+channelblockerzonisamideglutamatereceptorantagonist;Na+andT-typeCa+2+channelblockerlorazepam(I.V.)forstatusepilepticusallostericGABAAagonistinhibitionisuse-dependent;limitsabilityofneuronstofireathighfrequency..maintainsNa+channelininactivatedstateandslowsrateofrecovery;nochangeinspontaneousactivityorfiringatslowrate)42Anti-EpilepticDrug’sEffectiveas

Monotherapy(SingleAgent)

Partial(LocalizationRelated)OlderAED’sPhenytoin(苯妥英鈉)Carbamazepine（卡馬西平）Valproate（丙戊酸鈉）NewerAED’sOxcarbazepine（奧卡西平）Lamotrigine（拉莫三嗪）Topiramate（托吡酯）FrenchetalNeurology2004Bold=newgenerationAEDGeneralizedValproate

（丙戊酸鈉）(GTCandabsence)Topiramate（托吡酯）(GTC)Lamotrigine（拉莫三嗪）(absence)FrenchetalNeurology200443

NewAED’seffectiveasadjunctivetreatmentforrefractoryepilepsy

Partial

TopiramateLevetiracetamPregabalinZonisamideOxcarbazepineLamotrigineGabapentinTiagabineAboveallhavelevelI,randomizedclinicaltrials,orAorBevidence,AANguidelines2004GeneralizedTopiramateLevetiracetamLamotrigineDatafromrandomizedplacebocontrolledtrialsDrugsinredaregenerallyconsideredhighpotency44IncreasedexpressionofABCtransportinepilepsyTransporters45耐藥癲癇大鼠P-gp表達(dá)增加抗癲癇藥敏感大鼠抗癲癇藥耐藥大鼠Control耐藥癲癇大鼠46P-gp抑制劑增強(qiáng)抗癲癇藥Oxarbazepine（OXC,奧卡西平）作用及延長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47ContributionofCYPstodrugmetabolism48CYPEnzymes(fromGuengerich2003)抑制劑誘導(dǎo)劑底物49AEDsandHepaticCYP450InteractionsValproicacid

CYP2Cinhibitor(inhibitsphenobarbital,phenytoinmetabolism)Phenytoin

CYPinducer(3A4and2C);metabolizedby2C9CarbamazepineCYPinducer(CYPinducer(3A4and2C);metabolizedby3A4...inducesitsownmetabolismPhenobarbitalCYPinducer(3A4and2C)Induction–increaseinamountofenzymeprotein,resultinginanincreaseintherateofmetabolismoftheaffecteddrugInhibition–competitionattheenzymesitethatresultsinadecreaseinmetabolismoftheaffecteddrug50DrugsTreatingParkinsonDiseaseandAlzheimerDisease

51Parkinson’sdisease(PD)RigidityTremorBradykinesiaPosturalinstability(propulsion,retropulsion).52Tremor:oneofthecommonsymptomsofPD53黑質(zhì)-紋狀體通路中腦-邊緣/皮層通路結(jié)節(jié)-漏斗通路Substantianigro-striatumdopaminergicpathway

isinvolvedinPDpathogenesis54ParkinsondiseaseDopaminergicneurondegenerationinsubstantianigroandstriatumNormal5556DopamineAcetylcholineAbnormalbalanceofDA/AChneuronalfunctionsinextrapyramidalsystemofParkinsondiseaseLevodopaMuscarinicantagonists57NormalParkinsondisease(-)injuredrelativelypotentiated(-)58TyrosineTHDOPADopamineDecarboxylaseDopamineDBHNorepinephrineMAO-BmetabolismsMAO-AmetabolismsDAreceptorsTreatmentI:Increasedopamine59Differentapproachesinclude:

I.increasesindopaminesynthesiscapacityII.directactivationofpost-synapticreceptorsIII.inhibitionofdopaminemetabolismIV.alterationoftheinteraction/balancewithotherneurotransmittersV.dopaminereleasersVI.L-DOPAmetabolisminhibitorsWhatisthedesiredgoalofpharmacologicaltherapiesforParkinson’sdisease?Note:Alltherapiestreatthesymptomsofthedisease;noneareneuroprotectiveandnoneslowtheprogressionofthedisease60?

StriataldopaminelevelsarelowinPD.?DopaminedoesnotpassBBBand,hence,hasnotherapeuticeffectinPD.?L-Dopa,anaminoacid,theimmediateprecursortodopamine,istransportedacrossBBBandisaneffectivedrugforPD.

RationaleforL-DopaPrecursorLoading:LevodopaandrelateddrugsDrugsfortreatmentofParkinsondisease(左旋多巴)(多巴胺)L-dopaistransformedtoDA

bydopadecarboxylase(oneofthearomaticL-aminoaciddecarboxylases,AAAD,左旋芳香氨基酸脫羧酶)inboththebrainandperipheralorgans.61L-DOPAperipheralmetabolism62Levodopa1.ADMEPenetratingintothebrain,transformedtoDAorNE(less)Distributedinperipheraltissue(most)2.EffectsandusesParkinsondisease:decreasestherigidity,tremors,andothersymptoms3.AdverseeffectsEarly(1)GI:nausea,vomiting,etc.(2)CVS:hypotension,arrhythmia,etc.-(1)CNS:emotionaldepression/psychosis;abnormalinvoluntary;hallucinations;etc.Late(1)fluctuationofresponse:endofdose/“wearingoff”periods;on/offperiods(suddenlossofsymptomcontrol,akinesia)

.(2)dyskinesia(運(yùn)動(dòng)障礙，afteryearsofchronicL-DOPA,upto80%,Involuntarymovements: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),andtremorDrugsfortreatmentofParkinsondisease63

Carbidopa(卡比多巴)aperipheraldecarboxylaseinhibitorreducesperipheralmetabolismofL-DOPA,increasesL-DOPAbioavailability,cannotcrossBBB;decreasesitsadverseeffectsbyallowinglowerL-DOPAdosagestobeused.ThecombinationofL-DOPA&carbidopa,iscalledSinemet?.(L-DOPAt1/2~1.5h)3-O-methyl-DOPAPeripheryCNSL-DOPAdopamineBBBCOMTAAADL-DOPAdopamineAAADMAOPyridoxal5-phosphate64LevodopaaloneLevodopa+Carbidopa65DopamineSynthesisandStorage66WithoutWithCOMTInhibitorFDOPA-/+COMTInhibitor:

2FDOPAPETStudies-oneindividual

SamedoseofFDOPA,iv;pluscarbidopa,poFDOPAUptakeConclusion:COMTinhibitorincreasedbrainbioavailabilityofFDOPAbyinhibitingperipheralmetabolismofFDOPAto3-O-methylFDOPAFDOPA

fluorodopamineAAADCOMTInperiphery:3-O-methylFDOPAFDOPA

fluorodopamineAAADCOMT67一般情況下，對(duì)L-dopa制劑的反應(yīng)可分為3個(gè)階段：①良好反應(yīng)階段（2～5年），為用藥的最初階段，每6～8小時(shí)或更長時(shí)間服藥1次，可使全部癥狀得到平穩(wěn)的緩解或改善。②中間反應(yīng)階段（2～3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)藥物無作用期，稱為劑末現(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)。③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。68DrugsfortreatmentofParkinsondisease

Otherdrugs1.DAreceptoragonists1stgenerationagonists:(ergotderivatives)bromocriptine*(溴隱亭,D2agonist)(t1/2~12h)

pergolide*(培高利特,

D2/D3agonist)(t1/2~24h)2ndgenerationagonists:

ropinirole

(t1/2~6h)(普拉克索,

D2/D3agonist)pramipexole

(t1/2

~8-12h)

(羅平尼咯,D2agonist)

Canbeusedasmonotherapyformildparkinsonism,orcombinedwithlevodopaforadvanceddisease,permittingthedoseoflevodopatobereducedandsmoothingoutresponsefluctuations.69LowerincidenceofdyskinesiaandresponsefluctuationSomeindividualsdevelopatroublingsleepdisorder,with suddenattacksofsleep(突然昏睡)duringordinarydaytimeactivitiesPosturalhypotensionDose-relatedpsychiatricsideeffects(similartoL-DOPAbutmayoccurmorefrequently,especiallyinelderly)Nauseaorvomiting(drugsactiveatchemotriggerzone(CTZ))themajoradverseeffectsofDAreceptoragonists702.MAO-Binhibitors（Peripheralmetabolismofcatecholamines(mostlyMAO-A)isunaffected.）decreasingDAmetabolismintheCNSSelegiline

司來吉蘭Rasagiline

雷沙吉蘭3.COMTinhibitors(decreasingDAmetabolism)

CNSCOMTinhibitor:

：itecapone

硝替卡朋peripheralCOMTinhibitor:

entacapone恩他卡朋DrugsfortreatmentofParkinsondisease71DrugsfortreatmentofParkinsondisease

4.Amantadine金剛烷胺UsedformildParkinson’sdisease,asanearlymonotherapyMechanismsofactionmayinclude:releaseofdopamine,blockDAreuptake,actionsonglutamatereceptors(asanNMDA-receptorantagonist)Thedoseshouldbereducedwithrenalimpairment.Potentialadverseeffects:-CNSreactions(dizziness,anxiety,impairedcoordination)-hyperkinesias(運(yùn)動(dòng)亢進(jìn))-nausea,vomiting-others72MuscarinicantagonistsTrihexyphenidyl(苯海索，artane,

安坦)Benzatropine(苯扎托品)DecreasingCNScholinergicfunctionsAdjuvantofParkisondiseasetreatmentDrugsfortreatmentofParkinsondisease73DRUGTHERAPY-SummaryMainLineAgents:L-DOPApluscarbidopa(Sinemet?)Dopaminereceptoragonists(ropinirole)?LowerEfficacy/SecondLineorAdjuvantAgents:AnticholinergicsReuptakeInhibitororreleaser(amantadine)COMTInhibitor(entacapone)MAOBInhibitors(rasagiline,selegiline)74?Reserpine,whichdepletesbraincatecholamines,inducesParkinson’sdiseasesymptoms?Antipsychotics(neuroleptics),thatblockDAreceptors,ie,dopaminereceptorantagonists.?N-methyl-4-phenyl-l,2,3,6-tetrahydropyridine(MPTP)isaby-productofillicitsynthesisofisomeperidine.MPTPfirstcametomedicalattentionbecauseitproducedsymptomssimilartoParkinson’sdisease.Drug-InducedParkinsonism75Drugsfortreatmentofdementia(Alzheimerandrelateddiseases)AnticholinesterasedrugsCholinoceptoragonistsNeurotrophicfactor-likedrugs76PathologicalcharacteristicsofADAtrophyofthebra