antiepileptic drugs
TRANSCRIPT
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