Anticonvulsant notes

notes for medicinal chemistry second year B. Pharm

1. ANTICONVULSANT/
ANTIEPILEPTICS
MRS.REKHA AMIT BHALERAO
ASSISTANT PROFESSOR
PHARMACEUTICAL CHEMISTRY
PES MODERN COLLEGE OF PHARMACY, FOR LADIES

2. INTRODUCTION
Theepilepsyisagroupofdisorders
characterizedbychronic,recurrent,paroxysmal
changesinneuralgicfunctioncausedby
abnormalitiesinelectricalactivityofthebrain.
Theyareoneofthecommonneuralgic
disorders,estimatedtoaffect0.52%ofthe
populationandcanoccuratanyage.The
termsconvulsionandseizureareoftenused
interchangeablyandbasicallyhavethesame
meaning.

3. TYPES OFEPILEPSY
Therearefourtypesofepilepsy.
a)Grand Mal
b)Petit Mal
c)Jacksonian(Focal)
d)Psychomotor

4. ❖Certainsignsandsymptomsoftypeofepilepsy:
(a)GrandMal:GrandMalisthemostcommontype
ofepilepsy.Inthistypeofepilepsy,thepersonoften
experiencesanaura(thiscanconsistofcertain
sounds,feardiscomfort)immediatelybeforea
seizure.Thenthepatientlossconsciousnessandhas
tonic-clonicconvulsions.Theseizuresgenerallylast
from2to5minutes.
(b)PetitMal:Thistypeofepilepsyismostfrequently
foundinchildren.Briefperiodsofblankspellsorloss
ofspeechcharacterizespetitmal.Duringtheseizures,
whichusuallylastfrom1to30seconds,theperson
stopswhatheisdoingandaftertheseizureresumes
whathewasdoingbeforetheseizure.Manypersons
arenotawarethattheyhavehadaseizure.

5. (c)Jacksonian(Focal):Thistypeofepilepsyis
rare.Itisusuallyassociatedwithlesionofacertain
partofthebrain(cerebralcortex).Jacksonianepilepsy
ischaracterizedbyfocalorlocalclonictype
convulsionsoflocalizedmusclegroups(forexample,
thumb,bigtoe,andsoforth).Theseizuresnormally
lastfrom1to2minutes.
(d)Psychomotor:Psychomotorepilepsyisrare.It
ischaracterizedbyperiodsofabnormaltypesof
behavior(forexample,extensivechewingor
swallowing).Psychomotorseizuresoccurmostoftenin
children3yearsofagethroughadolescence.The
individualmayexperienceanaurawithperceptual
alterations,suchashallucinationsorastrongsenseof
fear.The localizedseizuresmayadvanceto
generalizedconvulsionswithresultantlossof
consciousness.

6. Classificationof Anticonvulsant
1.Barbiturates: Phenobarbital,Mephobarbital
2.Hydantoins: Phenytoinsodium, ethotoin,
mephenytoin
3.Oxazolidinediones: Trimetghadione,
Paramethadione
4.Succinimides: Phensuximide, methsuximide,
ethosuximide
5.Urea and monoacylureas: Phenacemide,
Carbamazepine
6.Benzodiazepines: Clonazepam, Diazepam
7.New generation of antiepileptics:
Levetiracetam, Gabapentin, Felbamateand
Valproicacid

7. MECHANISM OF ACTION
Seizuresarecausedbyabnormalstimulationofnerves
inthebrainbyothernerves.Generally,anticonvulsants
reducetheexcitabilityoftheneurons(nervecells)of
thebrain.Whenneuronexcitabilityisdecreased,
seizuresaretheoreticallyreducedinintensityand
frequencyofoccurrenceorinsomeinstances,are
virtuallyeliminated.Forsomepatients,onlypartial
controloftheseizuredisordermaybeobtainedwith
anticonvulsantdrugtherapy.
Themodeandthesiteofactionofanticonvulsantsare
notknownforsure.However,itisbelievedthatthe
anticonvulsantssuppressseizuresbydepressingthe
cerebral(motor)cortexofthebrain,therebyraising
thethresholdofthecentralnervoussystem(CNS)to
convulsivestimuli.Therefore,thepersonislesslikely
toundergoseizures.

8. SPECIFICANTICONVULSANT DRUGS
PHENOBARBITAL
Chemistry.Phenobarbitalis5-ethyl-5-phenyl-1H,3H,5H-
pyrimidine-2,4,6-trione.
Properties.Phenobarbitaloccursasawhite,crystalline
powderorcolourlesscrystals,veryslightlysolubleinwater,
freelysolubleinalcohol,solubleinether.Itformswater-soluble
compoundswithalkalihydroxides,carbonatesandwith
ammonia.Phenobarbitalsodiumoccursasawhite,crystalline
powder,hygroscopic,freelysolubleincarbondioxide-freewater,
solubleinalcohol,practicallyinsolubleinmethylenechloride
andinether.

9. Clinicaluses.Mechanismislikelyrelatedto
thepotentiationofGABAinhibitionintheCNS.
Barbituratesalsoantagonizeglutamateexcitation.
1.Phenobarbitalisorallyadministeredinthe
treatmentofgrandmalepilepsy.
2.Itislesseffectiveinthetreatmentofpetitmal
andpsychomotorepilepsies.Theinjectablefromof
thedrugisusedtotreatothertypesofconvulsions.
Adverseeffects.Themostcommonadverse
effectsassociatedwithphenobarbitalaresedation,
dizziness,drowsiness,ataxia(lackofmuscular
coordination),andnystagmus(arapidinvoluntary
movementoftheeyeball).

10. Mephobarbital
Chemistry: Methylphenobarbitoneor Mephobarbitalis
5-ethyl-1-methyl-5-phenylbarbituric acid
Properties: Mephobarbitalis white crystalline, water
insoluble powder. It is soluble in aqueous solutions of
alkali hydroxides and carbonates.

11. HYDANTOINS
1.Hydantoinsarecyclicmonoacylureas.They
possessimidazoline-2,4-dioneheterocyclic
system.Hydantoinsarestructurallyrelatedto
barbiturates,differinginlackingthe6-oxo
moiety.
2.Hydantoinsareweaklyacidicthanbarbiturates.
Thusaqueoussolutionofsodiumsaltsprovide
stronglyalkalinesolutions.
3.Aclinicallyusefulhydantoinpossessanaryl
substituentatthe5-position.
4.Hydantoinderivativespossessingofloweralkyl
substituentshaveantiabsenceactivity.
5.HydantoinsactivateNa
+
-K
+
-dependentandCa
++
-
dependentATPaseandincreaseNa
+
transport.

12. PHENYTOIN
Chemistry.Phenytoinoccursasphenytoin
sodium,chemicallyphenytoinis5,5-
diphenylhydantoin.
Mechanismofaction.Phenytoinactsby
maintainingthedeactivationofvoltage-
sensitivesodiumchannels,therebyblocking
therepetitivefiringofneurons.

13. Clinical Uses of Phenytoin:
1.Phenytoinis used alone or in combination with
phenobarbitalin the treatment of grand mal and
psychomotorepilepsy.
2.It is also used in the treatment of other types of
convulsions.
Adverse effects. Adverse effects associated with
phenytoininclude ataxia, nystagmusand slurred
speech.

14. MEPHENYTOIN
Chemistry.Mephenytoinisahydantoin
derivative.Chemicallyitis5-ethyl-3-methyl5-
phenylhydantoin.
Clinicaluses
1.Mephenytoinisusedtocontrolseizuresin
combinationwithphenytoin
2.Itisusedasareservedrug(onlywhenphenytoin
hasfailed),becausethemetabolicproduct(5-
ethyl-5-phenylhydantoin)ofmephenytoinis
highlytoxic.

15. OXAZOLIDINEDIONES
Oxazolidinedioneswere introduced as
anticonvulsantsin1948.Theypossessthefollowing
heterocyclicsystem:
Oxazolidine-2,4-dioneisanalogoustohydantoin
differsinhavingofoxygenatomatposition1instead
ofNH.
Ex:Trimethadione,paramethadione.
Trimethadione
paramethadione

16. TRIMETHADIONE (Troxidone)
Chemistry. Trimethadioneis an oxazolidinedione
derivative. Chemically it is 3, 5, 5-
trimethyloxazolidine-2,4-dione
Properties. Trimethadioneis colourless or almost
colourless crystals, soluble in water, verysolublein
alcoholandinether.Itshouldbeprotectedfromlight.
Clinical uses. Troxidoneis used in the treatment of
absenceseizures

17. PARAMETHADIONE
Chemistry.Paramethadioneis5-ethyl-3,5-
dimethyloxazolidine-2,4-dione.
Properties.Paramethadioneisavailableas
clear,colourlessliquid.Itispartiallymisciblewith
water.Itshouldbestoredinawell-closed
container.
ClinicalUses
Paramethadioneisusedinthetreatmentof
absenceseizures.

18. SUCCINIMIDES
Oxazolidinedionesaretoxichenceto
replacethemwithlesstoxicdrugs
succinimideswereintroducedin1951as
antiepileptics.Theprecisemechanismof
actionofsuccinimidesisunknown.Ithas
beenpostulatedthatsuccinimides
enhancesinhibitoryprocessesinthebrain,
bysomeeffectonspecificinhibitory
neurotransmittersystems.

20. PHENSUXIMIDE
Chemistry: Phensuximideis a 2,5-pyrrolidinedione
derivative. Chemically it is N-me-thyl-2-
phenylsuccinimide.
Properties:Phensuximideiswhitetooff-white,
crystalline,slightlywater-solublecompound.Itisfreely
solubleinmethanolandethanol.Aqueoussolutionsof
phensuximidearefairlystableatpH2-8.
Clinicaluses.Phensuximideisasuccinimide
antiepilepticagentusedtotreatconvulsionsbutitis
reportedtobelesseffective.

21. ETHOSUXIMIDE
Chemistry: Ethosuximide is 2-ethyl-2-
methylsuccinimide.
Ethosuximidehashydrogenontheimidenitrogen.
Itisthemostacidicandhasaciditycomparableto
thatofsuccinimide(pK
a
;11).Theimideanionis
stabilizedbyresonanceinteractionwiththecarbonyl
groupsoneithersideofit.
Properties:Ethosuximideoccursasawhite
colored,odorlesspowderorwaxysolidhavingbitter
taste.Itisfreelysolubleinwater.

22. Urea and monoacylureas:
Phenacemide,carbamazepine
Phenacemide:
Phenacemideis phenylacetylurea

23. Carbamazepine
• Adverse effects: Dose related neurotoxicity—
sedation, dizziness,
vertigo, and ataxia.
–Hypersensitivity reactions:rashes, photosensitivity,
–Water retention and hyponatremiaas it enhances
ADH action.
–Teratogenic
Uses
• It is the most effective drug for CPS
• Manic depressive illness and acute mania –as an
alternative to lithium

24. Benzodiazepines: Diazepam, Clonazepam
Mechanism of Action:
Increases the frequency of GABAA-activated Cl-channel opening.
Only clonazepam& clorazepateapproved for long-term treatment.,
Clonazepamused for treatment of Lennox-GastautSyndrome,
myoclonic, atonic, and absence seizures, Tolerance develops
after about 6 months
Diazepam and lorazepamare used in treatment of status epileticus.
Diazepam is painful to inject; lorazepamis more commonly used in
acute treatment.
Diazepam
Intermittent use for control of seizure clusters
Diazepam frequently combined with phenytoin.

25. New generation of antiepileptics: Levetiracetam,
Gabapentin, Valproicacid,
Levetiracetam
Gabapentin
Valproicacid
Felbamate

26. SAR of anticonvulsants:
Following is a basic ring structure for
consideration of SAR of anticonvulsants.

27. SAR of Anticonvulsants
1)IfRandR’areloweralkylsthedrugwill
activeagainstAbsenceseizure(Petit-mal)
andthedrugnotactiveagainstgeneralized
tonic-clonic(grand-mal)orpartialseizure.
2)IfoneRisarylthendrugisactiveagainst
generalizedtonic-clonic(grand-mal)or
partialseizure.
3)Onlyphenobarbitalandmephobarbital
showsanticonvulsantselectivity.Both
thesedrugareactiveagainstgeneralized
tonic-clonic(grand-mal)orpartialseizure.

28. THANK YOU