1. AntiepilepticAntiepileptic
DrugsDrugs

2. SEIZURESSEIZURES
 Transient disturbance of cerebralTransient disturbance of cerebral
functionfunction
 Abnormal paroxysmal neuronalAbnormal paroxysmal neuronal
dischargedischarge
 It can beIt can be
a. acutea. acute
b. chronicb. chronic

3. EPILEPSYEPILEPSY
 Collective name for group of CNSCollective name for group of CNS
disordersdisorders
 With repeated occurrence of sudden andWith repeated occurrence of sudden and
transitory seizurestransitory seizures
 It can beIt can be
a. primary or idiopathica. primary or idiopathic
b. secondary or symptomaticb. secondary or symptomatic

4. Nature of epilepsyNature of epilepsy
 Epilepsy affects about 0.5% of theEpilepsy affects about 0.5% of the
population.population.
 Seizure and convulsionsSeizure and convulsions
 Caused by an asynchronous high-Caused by an asynchronous high-
frequency discharge of a group offrequency discharge of a group of
neuronsneurons
 Partial seizures affect localized brainPartial seizures affect localized brain
regionsregions
 Generalised seizures affect the wholeGeneralised seizures affect the whole
brain.brain.

5. Nature of epilepsyNature of epilepsy
 Two common forms of epilepsy are the tonic-Two common forms of epilepsy are the tonic-
clonic fit (grand mal) and the absence seizureclonic fit (grand mal) and the absence seizure
(petit mal).(petit mal).
 Animal modelsAnimal models
 It may be associatedIt may be associated
 with enhanced excitatory amino acid transmissionwith enhanced excitatory amino acid transmission
 impaired inhibitory transmissionimpaired inhibitory transmission
 abnormal electrical properties of the affected cells.abnormal electrical properties of the affected cells.
 glutamate content in areas surrounding an epilepticglutamate content in areas surrounding an epileptic
focus may be increasedfocus may be increased

6. CLASSIFFICATION OFCLASSIFFICATION OF
SEIZURESSEIZURES
 Partial SeizurePartial Seizure
 Focal area in the brain is involvedFocal area in the brain is involved
 Types:Types:
a. Simple partiala. Simple partial
 No impairment of consciousnessNo impairment of consciousness
 motor or sensory symptomsmotor or sensory symptoms
 b. complexb. complex
 with impairment of consciousnesswith impairment of consciousness
 with automatismswith automatisms

7.  GeneralizedGeneralized
 Entire brain is involvedEntire brain is involved
 Tonic-clonic/ Grand malTonic-clonic/ Grand mal
 Tonic phase- loss of consciousness, rigidityTonic phase- loss of consciousness, rigidity
 Clonic phase- jerking movements of entireClonic phase- jerking movements of entire
bodybody
 Absence/ Petit malAbsence/ Petit mal
 In childrenIn children
 brief loss of consciousness (10s) blank stare,brief loss of consciousness (10s) blank stare,
blinking, facial twitchingblinking, facial twitching
 MyoclonicMyoclonic
 brief jerksbrief jerks

8. MOA OF DRUGSMOA OF DRUGS
1.1. Reduced the spread of excitation fromReduced the spread of excitation from
seizure foci to normal neuronsseizure foci to normal neurons
2.2. Enhancement of GABA mediated inhibitoryEnhancement of GABA mediated inhibitory
transmissiontransmission
3.3. Prevent or reduced excessive discharge ofPrevent or reduced excessive discharge of
altered neurons of seizure focialtered neurons of seizure foci
4.4. Diminution of glutaminergic excitatoryDiminution of glutaminergic excitatory
transmissiontransmission
5.5. Modification of ionic conductanceModification of ionic conductance

9. Where Does DiffusionWhere Does Diffusion
Take the Ion?Take the Ion?
Exterior
Interior
K+
5 mM
K+
5 mM
Cl-
Low
Cl-
Low
Cl-
High
Cl-
High
K+
150 mM
K+
150 mM
Na+
15 mM
Na+
15 mM
Na+
150 mM
Na+
150 mM
O
U
T
O
U
T
I
N
I
N
I
N
I
N

10. Action PotentialAction Potential
ComponentsComponents
MembranePotential(mV)
-50
-70
0
+30
Time (msec)
Threshold
Potential
Threshold
Potential
Resting Membrane
Potential
Resting Membrane
Potential
Na+
equilibriumNa+
equilibrium
Action
Potential
Action
Potential
Depolarization!Depolarization!
HyperpolarizedHyperpolarized

11. MembraneMembrane
PermeabilityPermeability
MembranePotential(mV)
-50
-70
0
+30
Time (msec)
Threshold
Potential
Threshold
Potential
Resting Membrane
Potential
Resting Membrane
Potential
Na+
Influx
K+Efflux

12. MembranePotential(mV)
-50
-70
0
+30
Time (msec)
Threshold
Potential
Threshold
Potential
Resting Membrane
Potential
Resting Membrane
Potential
Na+
Influx
K+Efflux
It gets
hyperpolarized!
It gets
hyperpolarized!
What Happens to the Membrane If Cl-
Rushes Into the Cell During
Repolarization?

13. MembranePotential(mV)
-50
-70
0
+30
Time (msec)
It
decreases!
It
decreases!
What Happens to the Frequency of
Action Potentials If the Membrane Gets
Hyperpolarized?

14. Clinical Correlation
 Remember that it is the rate of action potentialRemember that it is the rate of action potential
propagation that determines neurologic function.propagation that determines neurologic function.
 Determined by frequency of action potentials.Determined by frequency of action potentials.
What is a seizure?What is a seizure?
What would be the
effect on the membrane
of ⇑ Cl-
influx
during a seizure?
What would be the
effect on the membrane
of ⇑ Cl-
influx
during a seizure?
Hyperpolarization & …
⇓ seizure
activity!

15. Gamma Amino ButyricGamma Amino Butyric
Acid ReceptorsAcid Receptors
GABA
Receptor
GABA
Receptor
Exterior
Interior
Cl -Cl -
Hyperpolarized!Hyperpolarized!

16. GABA+Bz ComplexGABA+Bz Complex
Bz
Receptor
Bz
Receptor
GABA
Receptor
GABA
Receptor
Exterior
Interior
Cl -Cl -
Profoundly
Hyperpolarized!
Profoundly
Hyperpolarized!

17. Anti-SeizureAnti-Seizure
MedicationsMedications
BenzodiazepinesBenzodiazepines
 diazepam (Valium®)diazepam (Valium®)
 lorazepam (Ativanlorazepam (Ativan®®
))
BarbituratesBarbiturates
 phenobarbitalphenobarbital
(Luminal(Luminal®®
))
Ion Channel InhibitorsIon Channel Inhibitors
 carbamazepinecarbamazepine
(Tegretol(Tegretol®®
))
 phenytoin (Dilantin®)phenytoin (Dilantin®)
Misc. AgentsMisc. Agents
 valproic acidvalproic acid
(Depakote®)(Depakote®)

18.  MOAs:MOAs:
 1. Sodium channel blockers1. Sodium channel blockers
 - Phenytoin, carbamazepine, valproic acid- Phenytoin, carbamazepine, valproic acid
 2.Calcium channel blockers2.Calcium channel blockers
 EthosuximideEthosuximide
 3. GABA-mediated3. GABA-mediated
 Benzodiazepines, phenobarbital, gabapentin,Benzodiazepines, phenobarbital, gabapentin,
tiagabinetiagabine

19.  IndicationsIndications
 1. GTC and partial seizures1. GTC and partial seizures
 - valproic acid, carbamazepine, phenytoin- valproic acid, carbamazepine, phenytoin
 2. Absence2. Absence
 - ethosuximide, valproic acid- ethosuximide, valproic acid
 3. Myoclonic3. Myoclonic
 - clonazepam, valproic acid- clonazepam, valproic acid
 4. Status epilepticus4. Status epilepticus
 - diazepam, lorazepam, phenytoin- diazepam, lorazepam, phenytoin
 5. Febrile seizures-5. Febrile seizures- phenobarbitalphenobarbital

20. Adverse effectsAdverse effects
 TeratogenicTeratogenic
 valproic acid- neural tube defectsvalproic acid- neural tube defects
 Phenytoin- craniofacial abnormalities, spinaPhenytoin- craniofacial abnormalities, spina
bifidabifida
 Phenytoin- fetal hydantoin syndromePhenytoin- fetal hydantoin syndrome
 CNS, respiratory depressionCNS, respiratory depression

23. Adverse effectsAdverse effects
 PhenytoinPhenytoin
 Nystagmus, diplopia, ataxia, gingivalNystagmus, diplopia, ataxia, gingival
hyperplasia, hirsutism, anemia,facialhyperplasia, hirsutism, anemia,facial
coarseningcoarsening
 CarbamazepineCarbamazepine
 Diplopia, ataxia, blood dyscrasiaDiplopia, ataxia, blood dyscrasia
 Valproic acidValproic acid
 GI distress, hepatotoxicityGI distress, hepatotoxicity

24. Gingival hyperplasiaGingival hyperplasia

25. PharmacokineticsPharmacokinetics
 Drug metabolism inducersDrug metabolism inducers
 Phenytoin, carbamazepinePhenytoin, carbamazepine
 Drug metabolism inhibitorsDrug metabolism inhibitors
 Valproic acidValproic acid

26. CLASSIFICATION OFCLASSIFICATION OF
ANTICONVULSANTSANTICONVULSANTS
 BARBITURATESBARBITURATES
PhenobarbitalPhenobarbital
MephobarbitalMephobarbital
MetharbitalMetharbital
PrimidonePrimidone

27. BARBITURATESBARBITURATES
 Hypnotic –sedativeHypnotic –sedative
 AnesthesiaAnesthesia
 Tolerance and addictionTolerance and addiction
 anticonvulsantanticonvulsant

28. MOAMOA
SPECIFICSPECIFIC
- enhances GABA receptor mediated- enhances GABA receptor mediated
current by opening chloride channelscurrent by opening chloride channels
- blocks excitatory responses induced by- blocks excitatory responses induced by
glutamateglutamate
- high concentration blocks Na and Ca- high concentration blocks Na and Ca
conductancesconductances

29. TOXICITYTOXICITY
 Morbilliform rashMorbilliform rash
 HypoprothrombinemiaHypoprothrombinemia
 Megaloblastic anemiaMegaloblastic anemia
 OsteomalaciaOsteomalacia

30. HYDANTOINSHYDANTOINS
 AnticonvulsantAnticonvulsant
 Anti-arrhythmicAnti-arrhythmic

31. MOAMOA
 Prolongs inactivated state of NaProlongs inactivated state of Na
channelchannel
 Alters K and Ca conductanceAlters K and Ca conductance
TOXICITYTOXICITY
gingival hyperplasiagingival hyperplasia
megaloblastic anemiamegaloblastic anemia

32. HYDANTOINSHYDANTOINS
 PhenytoinPhenytoin
 MephenytoinMephenytoin
 ethotoinethotoin

33. BENZODIAZEPINESBENZODIAZEPINES
 AntianxietyAntianxiety
 Sedative-hypnoticSedative-hypnotic
 Muscle relaxantMuscle relaxant
 PreanestheticPreanesthetic
 AnticonvulsantAnticonvulsant

34. CARBAMAZEPINECARBAMAZEPINE
 Decrease spread of seizureDecrease spread of seizure
activity from an active focusactivity from an active focus
 Blocks Na channelsBlocks Na channels

35. Anti-Epileptic DrugsAnti-Epileptic Drugs
 Carbamazepine:Carbamazepine:
 derivative of tricyclic antidepressantsderivative of tricyclic antidepressants
 Partial and tonic clonic 1Partial and tonic clonic 1stst
lineline
 similar profile of that of phenytoin, but with fewersimilar profile of that of phenytoin, but with fewer
unwanted effectsunwanted effects
 effective in most forms of epilepsy (except absenceeffective in most forms of epilepsy (except absence
seizures); particularly effective in psychomotorseizures); particularly effective in psychomotor
epilepsy; also useful in trigenimal neuralgiaepilepsy; also useful in trigenimal neuralgia
 strong enzyme-inducing agent; therefore, manystrong enzyme-inducing agent; therefore, many
drug interactionsdrug interactions
 low incidence of unwanted effects; principallylow incidence of unwanted effects; principally
sedation, ataxia, mental disturbances, watersedation, ataxia, mental disturbances, water
retention.retention.

36. ETHOSUXIMIDEETHOSUXIMIDE
 Blocks Ca channelsBlocks Ca channels
 Inhibits Na and K atpaseInhibits Na and K atpase
 Inhibits GABA aminotransferaseInhibits GABA aminotransferase

37. Anti-Epileptic DrugsAnti-Epileptic Drugs
 Ethosuximide:Ethosuximide:
 the main drug used to treat absencethe main drug used to treat absence
seizures, may exacerbate other formsseizures, may exacerbate other forms
 acts by blocking T-type calcium channelsacts by blocking T-type calcium channels
 relatively few unwanted effects, mainlyrelatively few unwanted effects, mainly
nausea and anorexia.nausea and anorexia.
 Withdrawal is not a problemWithdrawal is not a problem

38. VALPROATESVALPROATES
 Increase GABA mediatedIncrease GABA mediated
transmissiontransmission
 Blocks Na channels at lowBlocks Na channels at low
concentrationconcentration
 Blocks K channels at highBlocks K channels at high
concentrationconcentration

39. Anti-Epileptic DrugsAnti-Epileptic Drugs
 Valproate:Valproate:
 chemically unrelated to other anti-epilepticchemically unrelated to other anti-epileptic
drugsdrugs
 Absence and tonic clonic 1Absence and tonic clonic 1stst
line and partialline and partial
22ndnd
lineline
 mechanism of action not clear; weakmechanism of action not clear; weak
inhibition of GABA transaminase; someinhibition of GABA transaminase; some
effect on sodium channelseffect on sodium channels
 related few unwanted effects: baldness,related few unwanted effects: baldness,
teratogenicity, liver damage (rare, butteratogenicity, liver damage (rare, but
serious).serious).

40. New Anti-Epileptic DrugsNew Anti-Epileptic Drugs
 Topiramate:Topiramate:
 complex actions, not fully understoodcomplex actions, not fully understood
 Partial and tonic clonic 2Partial and tonic clonic 2ndnd
lineline
 similar to phenytoin with fewer side-effects andsimilar to phenytoin with fewer side-effects and
simpler pharmacokineticssimpler pharmacokinetics
 Risk of teratogenesisRisk of teratogenesis
 Lamotrigine:Lamotrigine:
 acts by inhibiting sodium channelsacts by inhibiting sodium channels
 broad therapeutic profilebroad therapeutic profile
 main side-effects are hypersensitivity reactionsmain side-effects are hypersensitivity reactions
(especially skin rashes).(especially skin rashes).
 Partial 2Partial 2ndnd
lineline

41. New Anti-Epileptic drugsNew Anti-Epileptic drugs
 Felbamate:Felbamate:
 mechanisms of action unknownmechanisms of action unknown
 Partial 3Partial 3rdrd
lineline
 use limited to intractable disease because of theuse limited to intractable disease because of the
risk of severe hypersensitivity reactionsrisk of severe hypersensitivity reactions..
 Gabapentin:Gabapentin:
 mechanism of action not knownmechanism of action not known
 Partial and tonic clonic 2Partial and tonic clonic 2ndnd
lineline
 saturable absorption; therefore, it is safe insaturable absorption; therefore, it is safe in
overdoseoverdose
 relatively free of side-effects.relatively free of side-effects.

42. Medications by SeizureMedications by Seizure
TypeType
(Generalized Seizures)(Generalized Seizures)
 Absence (petit mal)Absence (petit mal)
 brief period of unresponsiveness <30 sbrief period of unresponsiveness <30 s
 11stst
line ethosuximide, valproic acidline ethosuximide, valproic acid
 22ndnd
line lamotrigineline lamotrigine
 Tonic-clonic (grand mal)Tonic-clonic (grand mal)
 dramatic convulsions and loss ofdramatic convulsions and loss of
consciousnessconsciousness
 11stst
line valproic acid,line valproic acid,
carbamazepine,phenytoincarbamazepine,phenytoin
 22ndnd
line lamotrigine, phenobarbitalline lamotrigine, phenobarbital

43. Medications by SeizureMedications by Seizure
TypeType
(Partial Seizures)(Partial Seizures) Simple PartialSimple Partial
 Sensory seizureSensory seizure
 11stst
line carbamazepine, phenytoinline carbamazepine, phenytoin
 22ndnd
line lamotrigine, gabapentin, valproic acidline lamotrigine, gabapentin, valproic acid
 Complex PartialComplex Partial
 Starts at simple partial and generalizesStarts at simple partial and generalizes
 11stst
line carbamazepine,phenytoinline carbamazepine,phenytoin
 22ndnd
line lamotrigine, gabapentinline lamotrigine, gabapentin
 Unremitting seizureUnremitting seizure  respiratory compromiserespiratory compromise
 11stst
line lorazepam, diazepamline lorazepam, diazepam
 22ndnd
line phenytoinline phenytoin

44.  LIVER- VALPROICLIVER- VALPROIC
 NA DEC- CARBAMAZEPINENA DEC- CARBAMAZEPINE