This document discusses various anticonvulsant drugs, including their mechanisms of action, metabolism pathways, and side effects. It covers common anticonvulsants like phenytoin, carbamazepine, gabapentin, and lamotrigine. The document also discusses novel broad-spectrum anticonvulsants still under development and proposes that future anticonvulsants should target the genetic mechanisms of epilepsy progression and treatment resistance.

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