Antiepileptics Suggested Reading:

*CH 24: Antiseizure Drugs

Katzung 12th edition (online)

Epilepsy affects 2.5 million individuals in

the United States and it is the 3 rd most
common neurologic disorder after stroke.
Learning Objectives
Distinguish among the different seizure classifications and
the drugs available for each classification.
Identify the mechanisms of action for antiseizure drugs at
the levels of specific ion channels and neurotransmitter
systems.
Describe main pharmacokinetic (PK) features for
carbamazepine, phenytoin, and valproic acid for short-term
and long-term use.
 Antiepileptics Drug List
Older Newer
Antiepileptics Antiepileptics
Carbamazepine Felbamate
Clonazepam Gabapentin
Clorazepate Lamotrigine
Diazepam Lacosamide
Ethosuximide Levetiracetam
Lorazepam Tiagabine
Oxcarbazepine Topiramate
Phenobarbital Zonisamide
Phenytoin Retigabine (new)
Primidone
Valproate (valproic acid)
Cellular Basis for Mechanism of
Action of Antiseizure Drugs

Cellular Depolarization Versus

Hyperpolarization
Physiology Review: Depolarization

Na+ or Ca++
+++++
-------- Na+ or Ca++ channel
+ 0

Membrane Potential
+ Change in
Depolarization Depolarization

-70
Physiology Review: Hyperpolarization

K+
+++++
-------- K+ Channel
_

Membrane Potential
_ K+
Hyperpolarization
Change in

Hyperpolarization
 Neurotransmitter Basis for Mechanism
of Action of Antiseizure Drugs
Neurotransmitter GABA GLUTAMATE
(-aminobutyric acid (glutamic acid)

Structure

Physiology Principal Inhibitory Principal Excitatory

Brain Neurotransmitter Brain Neurotransmitter

Hyperpolarizing Effect Depolarizing Effect

on Brain Circuitry on Brain Circuitry

Seizure Threshold
 Therapeutic Strategy:
GABA Enhancement and
Glutamate Inhibition
GLUTAMATE > GABA

++
SEIZURE
PROBABILITY
--

GLUTAMATE < GABA

Pharmacological approaches that shift balance toward greater

GABA activity and less glutamate activity are efficacious in
reducing seizure probability (elevating seizure threshhold).
Overall Mechanistic Strategy
to Increase Seizure Threshold
Voltage-gated Ion Channel Antagonists/
Agonists
(Na+, Ca++, K+)
Receptor Antagonists/ Agonists
Reuptake Modulators

GABA Glutamate
Transmission Transmission

Seizure
Threshold
 3 Main Mechanisms of Antiseizure
Drug Action
1 Block state-dependent ion channels
*Prolong inactivation state of Na+ channels
resulting in longer refractory period.
*Inhibit low-threshold Ca2+ currents (esp. in
thalamic neurons) to dampen
glutamatergic hyperexcitability.

MECHANISM
2 Enhance inhibitory effects of GABA

3 Block excitatory effects of glutamate

Na+ and Ca++ Channel
Blockers
Different States of Ion Channel
Channel Blockers: State-dependence

WATER

Ion OPEN and CLOSED and

RESTING ACTIVATED INACTIVATED
Channels
 State-Dependence (Use-Dependence)
State-Dependent Blockade by Channel Blockers
An ideal channel blocker that is used to treat epilepsy should
target abnormal, diseased tissue more selectively than normal
tissue. The epileptic tissue will display greater neuronal
excitability than normal tissue. For any given time period, the
epileptic tissue will have a greater fraction of sodium (or
calcium) channels in their active (open) and inactive states
than in their resting states. The best and most clinically
effective channel blocker is the one that has greater selectivity
for the active and inactive states versus the resting state. This
quality enables the blocker to antagonize the diseased tissue,
and suppress seizure activity, without significantly affecting
normal tissue.
Clinically useful Na+ channel blockers that display use
dependence are carbamazepine, lamotrigine, phenytoin,
and lacosamide.
Clinically useful Ca++ channel blocker that displays use
dependence is ethosuximide.
 Mechanism 1: Na+ Channel Block
State-dependent block of voltage-gated Na+ channels prolongs
inactivated state of Na+ channel. Drugs selectively target
inactivated state. Refractory period is lengthened which restricts
firing of additional action potentials and reduces neuronal
excitability.

Block At therapeutic concentrations:

Carbamazepine
Lamotrigine
Phenytoin
Lacosamide
 Na+ Channel Blockers: Lacosamide
Versus Classical Antiepileptics
LACOSAMIDE
(more selective)
Enhances rate at which voltage-
gated Na+ channels inactivate. This
stabilizes hyperactive neuronal
membranes and inhibits repetitive
neuronal firing without exhibiting
effects on physiological excitability.
Inhibits Action
Potential Firing
CARBAMAZEPINE
PHENYTOIN
(less selective)
Prolongs duration of time that
voltage-gated Na+ channels
remain in their inactive state and
this prolongs the refractory
period of the action potential.
This reduces the ability of
neurons to fire action potentials.

Carbamazepine (Tegretol )
Mechanism:
Blocks use-dependent voltage-gated Na+ channels
Adverse Effects:
Dangerous or even fatal skin reactions (StevensJohnson syndrome
and toxic epidermal necrolysis) can be caused by carbamazepine
therapy. These reactions are significantly more common in patients
with a particular human leukocyte antigen (HLA) allele, HLA-
B*1502. This allele occurs almost exclusively in patients with
ancestry across broad areas of Asia, including South Asian Indians.
In Europeans a large proportion of sensitivity is associated with
HLA-B58. Researchers have also identified another genetic
variant, HLA-A*3101 which has been shown to be a strong
predictor of both mild and severe adverse reactions to
carbamazepine among Japanese and Europeans.
Hepatotoxicity
 Mechanism 1: Ca Channel Block ++

Relevant Ca++ Channel Subtypes

Type
T (transient)- N (neuronal)- L (long-lasting)-
type Type type

Neurons with Presynaptic Smooth and

Location pacemaker activity Neurons Cardiac Muscle
and post-synaptic Cells

Regulation of Neurotransmitter Heart Rate, blood

Function
cortical activity release pressure
 Mechanism 1: Ca Channel Block
2+

Reduction of Ca2+ flux through T-

type channels (especially in
thalamus). These pacemaker
neurons generate rhythmic
cortical discharge.

T-type Ca++
*Ethosuximide channel block

Lamotrigine T-type Ca++ Primary mechanism:

channel block Na+ channel block

Valproate T-type and N-type Primary mechanism:

Ca++ channel block Reduce GABA
catabolism
Gabapentin T-type and N-type
Pregabalin Ca++ channel block
 Hyperactive T-type Ca++ Channels Cause
Increased Corticothalamic Glutamate Release
Ca++
T-type
+++++
Ca++ channel
-------- No ethosuxmide on board: T-type Ca++
+ channels act as pacemaker cells in the
+ corticothalamic pathway and are hyperactive.
Depolarization
This hyperactivity leads to increased glutamate
release in the cortex that lowers seizure threshold
and makes a seizure more likely.

GLU
Tha
la moc
or tical
Cortex Ca++ T-type
Ca++ channel
Seizure
Threshold
GLU neuron
Thalamus
Ethosuximide Mechanism: Antagonism of T-type Ca+
+
channels decreases corticothalamic activity
Ca++
+++++ ETHOSUXIMIDE
-------------- T-type Ca++ channel
Ethosuxmide on board: T-type Ca++
channels in the thalamus are blocked leading to a
Hyperpolarization hyperpolarized state. This leads to reduced activity
in corticothalamic pathway and less glutamate release
in cortex and increased seizure threshold.

GLU ETHOSUXIMIDE
Tha
la moc
or tical
Cortex Ca++ T-type
Ca++ channel
Seizure
Threshold
GLU neuron
Thalamus
 Ethosuximide

Mechanism:
Reduces low threshold T-type Ca++ currents in thalamus.
This inhibition reduces glutamatergic hyperactivity in
thalamocortical circuitry that underlie absence seizures.
Indication:
Absence seizures in children. Very efficacious and safe.
Pharmacokinetics:
long half-life of ~40 h results in good patient compliance
Adverse effects:
Well tolerated
Typical CNS depressant effects
 Drugs that Increase
GABA Transmission
Increased Decreased
GABA receptor GABA Synthesis GABA Catabolism Blockade of
Activation Cellular GABA
+ Reuptake

GABA GABA GABA

GABA Synthesis in Brain Entirely
Dependent on Glutamate
GABA GLUTAMATE
 GABA Receptors are Inhibitory
GABA

GABAA GABAB GABAC

Inotropic Metabotropic Inotropic

Cl- K+ Cl-

------- ------- -------

Cl- K+ Cl-

Cellular Hyperpolarization

Inhibitory Effects
GABA Drug Targets and Mechanisms
GABAA receptor activation
Phenobarbital
Benzodiazepines

GABA GABA reuptake inhibition

Activity Tiagabine

GABA-transaminase inhibition
Vigabatrin
Valproate
 GABA Synapse and
Mechanisms
Vigabatrin
Valproate

Tiagabine

Benzodiazepines
Phenobarbital
+
Tiagabine
Ethosuximide
GABAA Receptor Complex:
Multiple Binding Sites
Allosteric agonism
Pentameric transmembrane
receptor consisting of 5
subunits surrounding a
central pore that conducts
chloride.
Binds GABA at the
interface between and
subunits.
Multiple isoforms
 GABAA Receptor Complex:
Site of Allosteric Modulation
Allosteric Effect: Endogenous substance or
drug binds to a site on a receptor that is
distinct from that of the primary agonist
(e.g. GABA) and changes the affinity of the
receptor for the primary agonist.
Allosteric agonist: Affinity of the receptor for
the primary agonist is increased when the
allosteric agonist binds. Benzodiazepines and
phenobarbital act through this mechanism.
 GABAA Receptor: Phenobarbital and
Benzodiazepine Mechanism of Action
Presynaptic Benzodiazepines bind to subunit on
GABA GABAA receptor (allosteric site). The site
Terminal is distinct from binding site of
endogenous GABA molecules released
from presynaptic terminals.
GABAA receptor activation reduces
Cl -
neuronal activity.
BENZODIAZEPINE Benzodiazepines do not bind to the same
site as GABA. The GABA and diazepam
GABAA GABA +
recognition sites on GABAA receptor are
Site
Receptor distinct. Benzodiazepines enhance
inhibitory effects of GABA by causing an
Complex increased opening of the chloride ion
channel when GABA binds to its site on
GABAA receptor, leading to more
chloride ions entering the neuron, which
in turn leads to hyperpolarization and
Cl- reduced transmission of action potentials.
Increase in seizure threshold and
Hyperpolarization reduction in seizure probability
GABA-transaminase (GABA-T) inhibition:
Valproate and Vigabatrin Mechanism
Valproate (Reversible Antagonism)
Vigabatrin (Irreversible Antagonism)

GABA-T
GABA + 2-oxoglutarate Glutamate + succinic semialdehyde
GABA Glutamate

Seizure
Threshold
 Drugs that Decrease
Glutamate Transmission
Glutamate Receptors are Excitatory

GLUTAMATE

NMDA AMPA
(inotropic) (inotropic)

Calcium Calcium (Ca++)

(Ca++) Influx and Sodium (Na+)
Influx
Depolarization

Seizure Threshold
NMDA = N-methyl-D-aspartate
AMPA = 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid
Glutamate Drug Targets and Mechanisms
Na+ channel inhibition Glutamate Ca++ channel inhibition
Carbamazepine Ethosuximide
Lamotrigine Activity Lamotrigine
Valproate Gabapentin
Phenytoin Pregabalin
Valproate

Synaptic vesicle AMPA receptor

glycoprotein inhibition
2A (SV2A) inhibition Phenobarbital
Levetiracetam Topiramate

CRMP-2 (Collapsin
response mediator NMDA receptor
protein modulation) inhibition
Lacosamide Felbamate
 Carbamazepine
Glutamate Synapse and Lamotrigine
Mechanisms Valproate
Phenytoin

Levetiracetam Gabapentin
Pregabalin

Lacosamide

Phenobarbital
Felbamate Topiramate

Ethosuximide
Lamotrigine
Gabapentin
Pregabalin
Valproate
 Levetiracetam: Synaptic Vesicle
Glycoprotein 2A (SV2A):
SV2A: Intracellular protein that helps
regulate Ca++-dependent exocytosis of
glutamate from presynaptic terminals.
Levetiracetam interacts with SV2A which
diminishes presynaptic activity and
exocytosis of glutamate that is dependent
on Ca++ channel activity.

Ca++ channel Presynaptic Increased

SV2A Glutamate Seizure
activity
Release Activity
LEVETIRACETAM
 Adverse Effects of
Antiepileptic Drugs

In general, adverse effects are similar for antiepileptic

drugs and are CNS-related due to their high degree of
lipophilicity and brain penetrability.
*CNS depression (ataxia [lack of voluntary coordination of muscle
movements], drowsiness, dizziness, sedation)
*Metabolic disturbances
*Gastrointestinal Effects (constipation, nausea, emesis)
*Visual disturbances (nystagmus)
*Hepatotoxicity (carbamezpine, valproate)
 Miscellaneous Antiepileptic Drugs
GABAPENTIN
RETIGABINE TOPIRAMATE
PREGABALIN
 Retigabine: Activates Voltage-gated
Potassium (Kv7) Channels
NO DRUG + RETIGABINE
Presynaptic Presynaptic
Neuron
RETIGABINE Neuron
K+
----
+
++++ GLU
GLU
K+

+ +

GLU RECEPTOR GLU RECEPTOR

Postsynaptic Postsynaptic
Neuron Neuron

Excitation Excitation
Seizure Threshold Seizure Threshold
 Retigabine
Mechanism:
Activation of voltage-gated class of K+ channels in the Kv7 or
KCNQ class.
Increases K+ efflux out of the cell that leads to cellular
hyperpolarization and decreases exocytosis of glutamate
in the extracellular compartment.
Only approved medication for epilepsy that produces its anti-
seizure effects through potassium channel activation.
Indication:
Adjunctive treatment for partial epilepsy
Adverse Effects:
Schedule V drug by Drug Enforcement Agency (approved
medication with very low abuse liability)
CNS depression typical of antiepileptic drugs
Gabapentin and Pregabalin
 Gabapentin and Pregabalin
Mechanism: + GABAA Receptor
Looks like the neurotransmitter
GABA but acts through a GABA
different mechanism. GABA
activates GABA receptors + GABAB Receptor
(GABAA and GABAB).
Gabapentin and pregabalin are _ Ca++ channels
primarily channel blockers and (T- and N-type)
produce their anti-seizure effects
through blockade of T-type and Gabapentin
N-type Ca++ channels and do not Pregabalin
exert their effects through
GABA receptor activation. Glutamamic Acid
Indications: + Decarboxylase
Epilepsy (GAD)
Gabapentin also treatment for
neuropathic pain resulting from
diabetic neuropathy and
neuralgia.
 Topiramate: Mechanism of Action
GLU
GABA
Neuron
Na+ GLU Neuron

GABA
1
TOPIRAMATE
Na+
3
2 + + GABAA
AMPA
Receptor
Receptor
Postsynaptic
Postsynaptic Neuron
Neuron
Inhibition of voltage-gated Na+ and Ca++ channels leads to cellular
1 hyperpolarization that decreases release of glutamate into the extracellular space.

2 Inhibition of AMPA receptors reduces excitatory effects of glutamate.

3 Activation of GABAA receptors.

 Topiramate Therapeutic
Indications and Adverse Effects
Approved Therapeutic Indications
Epilepsy (adults and Lennox-Gastaut syndrome in children)
Weight loss (in combination with Phentermine)
Migraine
Potential Therapeutic Indications
Drug addiction
Post-traumatic stress disorder (PTSD)
Adverse Effects (due to carbonic anhydrase inhibition)
Metabolic Acidosis
Kidney Stones (calcium oxalate stones)
 Special Considerations for Women
Antiepileptic drugs increase risk for
contraception failure
Potentially due to induction of hepatic
enzymes such as CYP3A4.
Pregnancy (teratogenicity)
Birth defects are higher in mothers taking
antiepileptics [4-8% compared to 2-4%]
Some drugs display greater teratogenicity
(e.g., phenytoin)
Levetiracetam and Lamotrigine safest anti-
epileptic drugs but still carry some risk (both
are Pregnancy Category C)
 Special considerations for children
Infantile spasms (West Syndrome)
this is associated with neurological
problems during birth perhaps
reduction in GABA activity.
Vigabatrin (irreversible inhibition of
GABA-transaminase) approved by
FDA in August 2009 (black box warning:
progressive loss in peripheral vision with
Therapeutic decrease in visual acuity).
Options
Adrenocorticotropic hormone
(ACTH) was approved (Oct 2010) as
monotherapy for infantile spasms in
kids younger than 2.
FDA warning: risk for
suicidal thoughts
FDA (2008) Added black box warnings about
suicidal risk for antidepressants.