1. ANTICONVULSANTS
by: JhonFredA.Ralisay
HypersensitivitytoPhenytoin (IdiosyncraticToxicity)
-hypersensitivity isbelievedtobe a resultof reactionsof reactive intermediates suchasarene oxide,catechol,or
ο- quinone withhepaticenzymesorothercellularproteins formingcovalentlybondedhaptens.
Haptensare moleculesthattriggersimmune responseandthese moleculesare the onesthatcause
hypersensitivityof individualstophenytoinandotherAEDs
 Arene oxide
-deactivatedbyeitherepoxidehydrolase todihydrodiol (majorurinarymetabolite) orbyGSH and
glutathione transferase
-mediatesteratogenecityof phenytoin
Epoxide hydrolase
-use as biomarkerfordeterminationof riskfetal hydantoinsyndrome
 Catechol
-reducedby normal amountof COMT inlivermakingit easilyoxidizedintoο-quinone
Because of thisCOMT there islesscatechol thatmay act withphenytoinintermmediatesforming
phenytoin-inducedtoxicities
Must remember:
Phenytoinisapotentenzyme inducerspecificallyCYP450isozymesCYP1A2,CYP2C9/19, CYP3A4 as well as
epoxide hydrolaseandUDP-glucuronyl transferase.
Explanation: Thus patientstakingmultipledrugs,plasmaconcentrationof drugsmetabolizedbythese
enzymeswillbe greatlyaffected.
PHENOBARBITAL AND PRIMIDONE
A. Phenobarbital
-onlysedative-hypnoticbarbituratesthatdisplaysenoughanticonvulsantselectivityforuse as
antiepileptic
-a metabolite of Primidone byhepaticenyzme CYP2C9/19
-MOA: = enhancesGABAergictransmission

2. (enhancementof GABAergictransmissionis byprolongingdurationof chloridechannel openings. This
will resulttohyperpolarizationwhichisopposite todepolarizationandinhibitactionpotential.)
B. Primidone (Mysoline)
-metabolizedbyCYP2C9/19 intophenobarbitalandphenylethylmalonamide
-anticonvulsantactionisdue toits minormetabolitewhichisphenobarbital
CARBAMAZEPINE AND OXCARBAZEPINE
A. Carbamazepine(Tegretol)
-5H dibenz[b,f]lazepine 5carboxamide
-an iminostilbenederivative of tricyclicantidepressants (becausetheyhave three ringsof atoms)
-useful forgeneralizedtonic-clonicandpartial seizures
-metabolized intostablemetabolite; 10,11-carbamazepine epoxide byCYP3A4thenfurthermetabolized
by epoxidehydrolasetoinactive form;10,11-carabamazepine-diolwhichisexcretedasglucuronides
-epoxidemetabolite issuspectedforidiosyncraticreactionssuchasaplasticanaemia
MOA: PotentiatesGABA receptor
B. Oxcarbamazepine(Trileptal)
-hasthe same MOA to carabamazepine
-notan enzyme inducer
-metabolizedbyalcohol dehydrogenaseto carbamazepine-ol asο-glucuronide andfurthermetabolized
to 10,11-carbamazepine-diol
-hasmuch hepaticandidiosyncraticside effectsthan carabamazepine
-weakinducerof CYP3A4 andUDP-glucuronyl transferase
-inhibitsCYP2C19

3. GABAPENTINAND PREGABALIN
A. Gabapentin (Neurontin)
-(S)-3-isobutyl-GABA
-broad-spectrumanticonvulsants (meanscantreatany type of epilepsy)
-similarstructure toL-Leucine
-hasmultiple MOA: = modulationof calciuminflux
(meansitregulatesinflux of calciumthusreleasingof neurotransmitteratthe presynapticterminalbe
controlled)
= stimulationof GABA biosynthesis
(helpsinproductionof GABA neurotransmitters)
= compete forbiosynthesisof L-glutamicacid
(glutamicacidsaltisglutamate whichisa an excitatory neurotransmitteriscompetedbyGabapentinin
biosynthesis)
-more than95% isexcretedunchangedinkidney
-has60% bioavailabilityif givenatlow dose
B. Pregabalin (Lyrica)
-analogousinstructure withGabapentin
-has98% bioavailabilitydue toitssimilarstructure withL-Leucine whichhelpsinintestinal absorptionby
saturable small-neutralL-aminoacidtransporter.
FELBAMATE AND FLUROFELBAMATE
A. Felbamate (Felbatol)
-hasbroad spectrumaction
-carbamate esterof 2-phenyl-1,3-propanediol
-hassevere side effectssuchasaplastic anaemia,idiosyncraticreactions,andhepaticfailures
-metabolizedbyCYP450 mediatedhydroxylationswithmetabolitesρ-hydroxyfelbamateand2-
hydroxyfelbamate

4. -alsoundergoesesterase-catalyzedhydrolysisresultingintotwominormetabolites2-phenyl-1,3- propandiol
monocarbamate and3-carbamoyl-2-phenylpropionicacid(CPPA)
-CPPA undergoesoxidative reductionresultingintotoxicreactivemetabolite whichis2-phenylpropanal
(atropaldehyde)
B. Fluorofelbamate
-a productof placementof fluorine atomatthe C-2 positionof FBM
-a verypotentanticonvulsant
-still underphase 2clinical trials
NOVEL BROAD-SPECTRUM ANTCONVULSANTS
A. Lamotrigine (Lamictal)
-antiepilepticdrugs of phenyltriazineclass (hasphenyl groupandtriazine groupinchemical structure)
-effective forrefractorypartial seizures
-MOA: = blockade of sodiumchannels
(blockade of sodiumchannelsdisablessodiumtogetintoneurontoproduce actionpotential)
= Inhibitsthe high-thresholdcalciumchannels
(preventsordecrease release of neurotransmitters)
-metabolizedbyglucuronidation
-metabolitesare2-N-glucuronide(76%) and5-N-glucuronide (10%)
-co-administrationwithvalproate may increaseidiosyncraticreaction
B. Topiramate (Topamax)
-a sulphamate substitutedmonosaccharide
-derivativeof naturallyoccurringsugarD-fructose
-exhibitsbroadandpotent antiepilepticdrugactionsat glutamate andGABA receptors
-oral bioavailabilityof 85%and 95% because of itssimilarstructure toD-glucose whichwillbe easilytransported
to bloodstreamthroughD-glucosetransporterinbrain(rememberthatD-glucose andD-fructose have identical
stereochemistryatmanyof theirchiral centers)

5. -only20% iseliminatedbyCYP2C19 and the remainingdrugisexcretedunchanged
-MOA: = inhibition glutamate release
(release of glutamate anexcitatoryneurotransmitterisblock)
= antagonize glutamate kainicacid/AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionicacid)
receptors
(AMPA receptorisa receptorfor glutamate)
= increase GABAergictransmissionbybindingonthe same sitesof GABA receptorswhere
benzodiazepinesandbarbituratesbind
C. Zonisamide (Zonegram, Excegram)
-sulfonamide type anticonvulsant
-use as adjunctive forpartial seizuresinadultswithepilepsy
-metabolizedby reductive ringcleavage from1,2-benzisoxazoleringto2-sulfamoyl-acetyl-phenol this
biotransformationiscarriedoutbyintestinal bacteria
-because of sulphonamidemoietywiththisdrugpatientwhohave allergicreactionwithsulphonamidesmust
have precautions
D. Levetiracetam (Keppra)
-analogof nootropicagentpiracetam
-doesnothave affinitytoAMPA receptortherebyhasnonootropicactivityfortreatmentof Alzheimer’sdisease
-have noaffinitytoGABA receptors,BZD receptors, variousexcitatory aminoacidrelatedreceptors,orthe
voltage-gatedionchannels
-MOA: = modulate kainite/AMPA inducedexcitatorysynapticcurrents
(AMPA a receptorfor glutamate andexcitatoryneuron)
-antiepilepticactionismediatedbyparentdrugratherthan itsmetabolite whichis(S)-α-ethyl-2-oxo-1-
pyrrolidiniaceticacidviahydrolysisof amide group

6. ANTICONVULSANTSACTS ON A SELECTIVE MOLECULAR TARGET
A. Tiagabine (Gabitril)
-an uptake inhibitor
-MOA: = blocksGABA reuptake atGABA transporter-1increase extracellularGABA concentrationinthe
hippocampus,striatumandcortex therebyprolongingthe inhibitoryactionof GABA
-use forpartial seizures
-inhisstructure nipecoticacida potentinhibitorof GABA reuptake butfailstocross blood-brainbarrier
followingsystemicadministrationbecauseof itshighdegree of ionization
-marketedasR( ̶ )-enantiomerapotentGAT-1 inhibitorwhichisstructurallyrelatedtonipecotic acidhasthe
abilitytocross blood-brainbarrierandmetabolizedbyCYP3A4to 5-oxo-tiagabine
-90% of tiagabine ismetabolizedbyCYP3A4whichaffectsthe thiophenrings
B. Ethosuximide(Zarontin)
-prototypical anticonvulsantforpatientswithabsence seizures
-MOA: = block thresholdT-type calciumchannels
(therebyreducinghyperexcitabilityof thalamicneurons)
C.Methsuximide (Celontin)
-N-dealkylatedactive metaboliteof ethosuximide
-MOA: = block thresholdT-type calciumchannels
(therebyreducing hyperexcitabilityof thalamicneurons)
D. Vigabatrin (Sabril)
-a 4-vinyl analogof GABA
-MOA: = irreversibly blockingGABA catabolismcatalysedbyGABA-T
(meansitblocksthe breakdownof GABA neurotransmitter)
-treatmentforpartial seizures

7. E. Benzodiazepines
Clonazepam(Klonopin) -useful forabsence seizuresandmyoclonicseizures
-tolerance maydevelopquickly
-metabolizedbyhydroxylationatC-3positionfollowedbyglucuronidationandnitro
groupreductionandacetylation
-MOA: = enhancesGABAergictransmissionbybindingtobenzodiazepinessite atGABA
receptors
Diazepam(ValiumandDiastat) -Valiumis givenorallyandDiastatis givenrectally
-adjunctive treatmentforgeneralizedtonic-clonicstatusepilepticus orpatients
withrefractoryepilepsy
-MOA: = enhancesGABAergictransmissionbybindingtobenzodiazepinessite
at GABA receptors
FUTURE DEVELOPMENT OF ANTIEPILEPTIC DRUGS
-all AEDsworkedonlyas prophylaxisagainstsymptomsof epilepsytheydonot preventprogressionof disease
intorefractoryepilepsy
-future directionof developmentsof AEDsmustcome frombetterunderstandingof epileptogenesisespecially
the geneticmechanismsthatunderlie disease progression orthe developmentof resistance afterprolonged
pharmacotherapyof froman innovative designstrategythatproduce new AEDswithuniquemechanism