Antiepileptic drugs

Antiepileptic Antiepileptic DrugsDrugs

SEIZURESSEIZURES

Transient disturbance of cerebral Transient disturbance of cerebral functionfunction

Abnormal paroxysmal neuronal Abnormal paroxysmal neuronal dischargedischarge

It can beIt can be

a. acutea. acute

b. chronicb. chronic

EPILEPSYEPILEPSY

Collective name for group of CNS Collective name for group of CNS disordersdisorders

With repeated occurrence of sudden and With 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

Nature of epilepsyNature of epilepsy

Epilepsy affects about 0.5% of the Epilepsy affects about 0.5% of the population. population.

Seizure and convulsionsSeizure and convulsions Caused by an asynchronous high-frequency Caused by an asynchronous high-frequency

discharge of a group of neuronsdischarge of a group of neurons Partial seizures affect localized brain regionsPartial seizures affect localized brain regions Generalised seizures affect the whole brain. Generalised seizures affect the whole brain.

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 seizure clonic fit (grand mal) and the absence seizure (petit mal). (petit mal).

Animal models Animal models It may be associated It may be associated

with enhanced excitatory amino acid transmissionwith enhanced excitatory amino acid transmission impaired inhibitory transmission impaired inhibitory transmission abnormal electrical properties of the affected cells. abnormal electrical properties of the affected cells. glutamate content in areas surrounding an epileptic glutamate content in areas surrounding an epileptic

focus may be increasedfocus may be increased

CLASSIFFICATION OF CLASSIFFICATION 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

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 entire Clonic 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

MOA OF DRUGSMOA OF DRUGS

1.1. Reduced the spread of excitation from Reduced the spread of excitation from seizure foci to normal neuronsseizure foci to normal neurons

2.2. Enhancement of GABA mediated inhibitory Enhancement of GABA mediated inhibitory transmissiontransmission

3.3. Prevent or reduced excessive discharge of Prevent or reduced excessive discharge of altered neurons of seizure focialtered neurons of seizure foci

4.4. Diminution of glutaminergic excitatory Diminution of glutaminergic excitatory transmissiontransmission

5.5. Modification of ionic conductanceModification of ionic conductance

Where Does Diffusion Where 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

OUT

OUT

IN

IN

IN

IN

Action Potential Action Potential ComponentsComponents

Mem

bran

e P

oten

tial

(m

V)

-50

-70

0

+30

Time (msec)

ThresholdPotential

ThresholdPotential

Resting MembranePotential

Resting MembranePotential

Na+ equilibriumNa+ equilibrium

ActionPotential

ActionPotential

Depolarization!Depolarization!

HyperpolarizedHyperpolarized

Membrane PermeabilityMembrane PermeabilityM

embr

ane

Pot

enti

al (

mV

)

-50

-70

0

+30

Time (msec)

ThresholdPotential

ThresholdPotential

Resting MembranePotential

Resting MembranePotential

Na+

Inf

lux K

+ Efflux

Mem

bran

e P

oten

tial

(m

V)

-50

-70

0

+30

Time (msec)

ThresholdPotential

ThresholdPotential

Resting MembranePotential

Resting MembranePotential

Na+

Inf

lux K

+ Efflux

It getshyperpolarized!

It getshyperpolarized!

What Happens to the Membrane If Cl- Rushes Into the Cell During Repolarization?

Mem

bran

e P

oten

tial

(m

V)

-50

-70

0

+30

Time (msec)

It decreases!

It decreases!

What Happens to the Frequency of Action Potentials If the Membrane Gets Hyperpolarized?

Clinical Correlation

Remember that it is the rate of action potential Remember 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!

Gamma Amino Butyric Gamma Amino Butyric Acid ReceptorsAcid Receptors

GABA Receptor

GABA Receptor

Exterior

Interior

Cl -Cl -

Hyperpolarized!Hyperpolarized!

GABA+Bz ComplexGABA+Bz ComplexBz

Receptor

Bz Receptor

GABA Receptor

GABA Receptor

Exterior

Interior

Cl -Cl -

ProfoundlyHyperpolarized!Profoundly

Hyperpolarized!

Anti-Seizure MedicationsAnti-Seizure Medications

BenzodiazepinesBenzodiazepines diazepam (Valium®)diazepam (Valium®) lorazepam (Ativanlorazepam (Ativan®®))

BarbituratesBarbiturates phenobarbital phenobarbital

(Luminal(Luminal®®))

Ion Channel InhibitorsIon Channel Inhibitors carbamazepine carbamazepine

(Tegretol(Tegretol®®)) phenytoin (Dilantin®)phenytoin (Dilantin®)

Misc. AgentsMisc. Agents valproic acid valproic acid

(Depakote®)(Depakote®)

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

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 epilepticus 4. Status epilepticus - diazepam, lorazepam, phenytoin- diazepam, lorazepam, phenytoin 5. Febrile seizures-5. Febrile seizures- phenobarbital phenobarbital

Adverse effectsAdverse effects

TeratogenicTeratogenic valproic acid- neural tube defectsvalproic acid- neural tube defects Phenytoin- craniofacial abnormalities, spina Phenytoin- craniofacial abnormalities, spina

bifidabifida Phenytoin- fetal hydantoin syndromePhenytoin- fetal hydantoin syndrome

CNS, respiratory depressionCNS, respiratory depression

Adverse effectsAdverse effects

PhenytoinPhenytoin Nystagmus, diplopia, ataxia, gingival Nystagmus, diplopia, ataxia, gingival

hyperplasia, hirsutism, anemia,facial hyperplasia, hirsutism, anemia,facial coarseningcoarsening

CarbamazepineCarbamazepine Diplopia, ataxia, blood dyscrasiaDiplopia, ataxia, blood dyscrasia

Valproic acidValproic acid GI distress, hepatotoxicityGI distress, hepatotoxicity

Gingival hyperplasiaGingival hyperplasia

PharmacokineticsPharmacokinetics

Drug metabolism inducersDrug metabolism inducers Phenytoin, carbamazepinePhenytoin, carbamazepine

Drug metabolism inhibitorsDrug metabolism inhibitors Valproic acidValproic acid

CLASSIFICATION OF CLASSIFICATION OF ANTICONVULSANTSANTICONVULSANTS BARBITURATESBARBITURATESPhenobarbitalPhenobarbitalMephobarbitalMephobarbitalMetharbitalMetharbitalPrimidonePrimidone

BARBITURATESBARBITURATES

Hypnotic –sedativeHypnotic –sedative AnesthesiaAnesthesia Tolerance and addictionTolerance and addiction anticonvulsantanticonvulsant

MOAMOASPECIFICSPECIFIC

- 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

TOXICITYTOXICITY

Morbilliform rashMorbilliform rash HypoprothrombinemiaHypoprothrombinemia Megaloblastic anemiaMegaloblastic anemia OsteomalaciaOsteomalacia

HYDANTOINSHYDANTOINS

Anticonvulsant Anticonvulsant Anti-arrhythmicAnti-arrhythmic

MOAMOA

Prolongs inactivated state of Na Prolongs inactivated state of Na channelchannel

Alters K and Ca conductanceAlters K and Ca conductance

TOXICITYTOXICITY

gingival hyperplasiagingival hyperplasia

megaloblastic anemiamegaloblastic anemia

HYDANTOINSHYDANTOINS

PhenytoinPhenytoin MephenytoinMephenytoin ethotoinethotoin

BENZODIAZEPINESBENZODIAZEPINES

AntianxietyAntianxiety Sedative-hypnoticSedative-hypnotic Muscle relaxantMuscle relaxant PreanestheticPreanesthetic AnticonvulsantAnticonvulsant

CARBAMAZEPINECARBAMAZEPINE

Decrease spread of seizure Decrease spread of seizure activity from an active focusactivity from an active focus

Blocks Na channelsBlocks Na channels

Anti-Epileptic DrugsAnti-Epileptic Drugs

Carbamazepine:Carbamazepine: derivative of tricyclic antidepressants derivative of tricyclic antidepressants Partial and tonic clonic 1Partial and tonic clonic 1st st lineline similar profile of that of phenytoin, but with fewer similar profile of that of phenytoin, but with fewer

unwanted effects unwanted effects effective in most forms of epilepsy (except absence effective in most forms of epilepsy (except absence

seizures); particularly effective in psychomotor seizures); particularly effective in psychomotor epilepsy; also useful in trigenimal neuralgia epilepsy; also useful in trigenimal neuralgia

strong enzyme-inducing agent; therefore, many drug strong enzyme-inducing agent; therefore, many drug interactions interactions

low incidence of unwanted effects; principally low incidence of unwanted effects; principally sedation, ataxia, mental disturbances, water sedation, ataxia, mental disturbances, water retention. retention.

ETHOSUXIMIDEETHOSUXIMIDE

Blocks Ca channelsBlocks Ca channels Inhibits Na and K atpaseInhibits Na and K atpase Inhibits GABA aminotransferaseInhibits GABA aminotransferase

Anti-Epileptic DrugsAnti-Epileptic Drugs

Ethosuximide:Ethosuximide: the main drug used to treat absence the main drug used to treat absence

seizures, may exacerbate other forms seizures, may exacerbate other forms acts by blocking T-type calcium channels acts by blocking T-type calcium channels relatively few unwanted effects, mainly relatively few unwanted effects, mainly

nausea and anorexia.nausea and anorexia. Withdrawal is not a problemWithdrawal is not a problem

VALPROATESVALPROATES

Increase GABA mediated Increase GABA mediated transmissiontransmission

Blocks Na channels at low Blocks Na channels at low concentrationconcentration

Blocks K channels at high Blocks K channels at high concentrationconcentration

Anti-Epileptic DrugsAnti-Epileptic Drugs Valproate:Valproate:

chemically unrelated to other anti-epileptic chemically unrelated to other anti-epileptic drugs drugs

Absence and tonic clonic 1Absence and tonic clonic 1stst line and partial line and partial 22ndnd line line

mechanism of action not clear; weak mechanism of action not clear; weak inhibition of GABA transaminase; some inhibition of GABA transaminase; some effect on sodium channels effect on sodium channels

related few unwanted effects: baldness, related few unwanted effects: baldness, teratogenicity, liver damage (rare, but teratogenicity, liver damage (rare, but serious). serious).

New Anti-Epileptic DrugsNew Anti-Epileptic Drugs

Topiramate: Topiramate: complex actions, not fully understood complex actions, not fully understood Partial and tonic clonic 2Partial and tonic clonic 2ndnd line line similar to phenytoin with fewer side-effects and similar to phenytoin with fewer side-effects and

simpler pharmacokinetics simpler pharmacokinetics Risk of teratogenesisRisk of teratogenesis

Lamotrigine:Lamotrigine: acts by inhibiting sodium channels acts by inhibiting sodium channels broad therapeutic profile broad therapeutic profile main side-effects are hypersensitivity reactions main side-effects are hypersensitivity reactions

(especially skin rashes). (especially skin rashes). Partial 2Partial 2ndnd line line

New Anti-Epileptic drugsNew Anti-Epileptic drugs Felbamate: Felbamate:

mechanisms of action unknown mechanisms of action unknown Partial 3Partial 3rdrd line line use limited to intractable disease because of the use limited to intractable disease because of the

risk of severe hypersensitivity reactionsrisk of severe hypersensitivity reactions. .

Gabapentin: Gabapentin: mechanism of action not known mechanism of action not known Partial and tonic clonic 2Partial and tonic clonic 2ndnd line line saturable absorption; therefore, it is safe in saturable absorption; therefore, it is safe in

overdose overdose relatively free of side-effects.relatively free of side-effects.

Medications by Seizure TypeMedications by Seizure Type(Generalized Seizures)(Generalized Seizures)

Absence (petit mal)Absence (petit mal) brief period of unresponsiveness <30 s brief period of unresponsiveness <30 s 11stst line ethosuximide, valproic acid line ethosuximide, valproic acid 22ndnd line lamotrigine line lamotrigine

Tonic-clonic (grand mal)Tonic-clonic (grand mal) dramatic convulsions and loss of dramatic convulsions and loss of

consciousness consciousness 11stst line valproic acid, line valproic acid,

carbamazepine,phenytoin carbamazepine,phenytoin 22ndnd line lamotrigine, phenobarbital line lamotrigine, phenobarbital

Medications by Seizure TypeMedications by Seizure Type(Partial Seizures)(Partial Seizures) Simple PartialSimple Partial

Sensory seizureSensory seizure 11stst line carbamazepine, phenytoin line carbamazepine, phenytoin 22ndnd line lamotrigine, gabapentin, valproic acid line lamotrigine, gabapentin, valproic acid

Complex Partial Complex Partial Starts at simple partial and generalizesStarts at simple partial and generalizes 11stst line carbamazepine,phenytoin line carbamazepine,phenytoin 22ndnd line lamotrigine, gabapentin line lamotrigine, gabapentin

Unremitting seizure Unremitting seizure respiratory compromise respiratory compromise 11stst line lorazepam, diazepam line lorazepam, diazepam 22ndnd line phenytoin line phenytoin

LIVER- VALPROICLIVER- VALPROIC NA DEC- CARBAMAZEPINENA DEC- CARBAMAZEPINE