Pharmacology of Antiepileptic Drugs

Pharmacology of Antiepileptic Drugs
Melanie K. Tallent, Ph.D.
tallent@drexel.edu

Basic Mechanisms Underlying
Seizures and Epilepsy
Seizure: the clinical manifestation of an
abnormal and excessive excitation and
synchronization of a population of cortical
neurons
Epilepsy: a disease characterized by
spontaneous recurrent seizures
Epileptogenesis: sequence of events that
converts a normal neuronal network into an
epileptic network

Simple
Complex
Partial Seizures
localized onset can be determined
Secondary generalized

Simple Partial Seizure
• Focal with minimal spread of abnormal
discharge
• normal consciousness and awareness are
maintained

Complex Partial Seizures
Local onset, then spreads
Impaired consciousness
Clinical manifestations vary with site of
origin and degree of spread
– Presence and nature of aura
– Automatisms
– Other motor activity
Temporal lobe epilepsy
most common

Secondarily Generalized Seizures
Begins focally, with or without focal neurological
symptoms
Variable symmetry, intensity, and duration of tonic
(stiffening) and clonic (jerking) phases
Typical duration up to 1-2 minutes
Postictal confusion and somnolence

In generalized seizures,
both hemispheres are
widely involved from
the outset.
Manifestations of the
seizure are
determined by the
cortical site at which
the seizure arises.
Present in 40% of all
epileptic Syndromes.
Generalized Seizures

Generalized seizures
• Absence seizures (Petit mal): sudden onset and
abrupt cessation; brief duration, consciousness is
altered; attack may be associated with mild clonic
jerking of the eyelids or extremities, postural tone
changes, autonomic phenomena and automatisms
(difficult diagnosis from partial); characteristic 2.5-3.5
Hz spike-and wave pattern
• Myoclonic seizures: myoclonic jerking is seen in a
wide variety of seizures but when this is the major
seizure type it is treated differently to some extent from
partial leading to generalized

Generalized Seizures (cont)
• Atonic seizures: sudden loss of postural tone;
most often in children but may be seen in adults
• Tonic-clonic seizures (grand mal): major
convulsions with rigidity (tonic) and jerking
(clonic), this slows over 60-120 sec followed by
stuporous state (post-ictal depression)

Generalized Tonic-Clonic Tonic Clonic Seizures
• Recruitment of neurons throughout the cortex
• Major convulsions, usually with two phases:
• 1) Tonic phase: muscles will suddenly tense up, causing the
person to fall to the ground if they are standing.
• 2) Clonic phase: muscles will start to contract
• and relax rapidly, causing convulsions
• Convulsions:
− motor manifestations
− may or may not be present during seizures
− excessive neuronal discharge
• Convulsions appear in Simple Partial and Complex Partial
Seizures if the focal neuronal discharge includes motor centers;
they occur in all Generalized Tonic-Clonic Seizures regardless of
the site of origin.
• Atonic and absence Seizures are non-convulsive
•

Video
http://www.youtube.com/watch?v=frWcJJkXQFM

Status Epilepticus
• More than 30 minutes of continuous seizure
activity
• Two or more sequential seizures spanning
this period without full recovery between
seizures
• Medical emergency

Antiepileptic Drug
A drug which decreases the frequency and/or
severity of seizures in people with epilepsy
Treats the symptom of seizures, not the
underlying epileptic condition
Goal—maximize quality of life by minimizing
seizures and adverse drug effects
Currently no “anti-epileptogenic” drugs
available

Therapy Has Improved Significantly
• “Give the sick person some blood from a
pregnant donkey to drink; or steep linen in it, dry
it, pour alcohol onto it and administer this”.
– Formey, Versuch einer medizinischen Topographie
von Berlin 1796, p. 193

Current Pharmacotherapy
• Just under 60% of all people with epilepsy can
become seizure free with drug therapy
• In another 20% the seizures can be drastically
reduced
• ~ 20% epileptic patients, seizures are refractory
to currently available AEDs

Choosing Antiepileptic Drugs
Seizure type
Epilepsy syndrome
Pharmacokinetic profile
Interactions/other medical conditions
Efficacy
Expected adverse effects
Cost

General Facts About AEDs
• Good oral absorption and bioavailability
• Most metabolized in liver but some excreted
unchanged in kidneys
• Classic AEDs generally have more severe CNS
sedation than newer drugs (except
ethosuximide)
• Because of overlapping mechanisms of action,
best drug can be chosen based on minimizing
side effects in addition to efficacy

Classification of AEDs
Classical
• Phenytoin
• Phenobarbital
• Primidone
• Carbamazepine
• Ethosuximide
• Valproate (valproic acid)
• Trimethadione (not currently
in use)
Newer
• Lamotrigine
• Felbamate
• Topiramate
• Gabapentin/Pregabalin
• Tiagabine
• Vigabatrin
• Oxycarbazepine
• Levetiracetam
• Fosphenytoin

Side effect issues
• Sedation - especially with barbiturates
• Cosmetic - phenytoin
• Weight gain – valproic acid, gabapentin
• Weight loss - topiramate
• Reproductive function – valproic acid
• Cognitive - topiramate
• Behavioral – felbamate, leviteracetam
• Allergic - many

Cellular Mechanisms of
Seizure Generation
emedicine.com

Targets for AEDs
• Increase inhibitory neurotransmitter system—
GABA
• Decrease excitatory neurotransmitter system—
glutamate
• Block voltage-gated inward positive currents—
Na + or Ca ++
• Increase outward positive current—K +
• Many AEDs pleiotropic—act via multiple
mechanisms

Epilepsy—Glutamate
Epilepsy Glutamate
The brain’s major excitatory neurotransmitter
Two groups of glutamate receptors
– Ionotropic—fast synaptic transmission
• NMDA, AMPA, kainate
• Gated Ca ++ and Gated Na+ channels
– Metabotropic—slow synaptic transmission
• Regulation of second messengers (cAMP and
Inositol)
• Modulation of synaptic activity
Modulation of glutamate receptors
– Glycine, polyamine sites, Zinc, redox site

Epilepsy—Glutamate
Epilepsy Glutamate

Glutamate Receptors as AED Targets
• NMDA receptor sites as targets
– Ketamine, phencyclidine, dizocilpine block channel
and have anticonvulsant properties but also
dissociative and/or hallucinogenic properties; open
channel blockers.
• AMPA receptor sites as targets
– Since it is the “workhorse” receptor can anticipate
major sedative effects

Felbamate
• Antagonizes the glycine site on the NMDA
receptor and blocks Na+ channels*
• Very potent AED lacking sedative effect (unlike
nearly all other AEDs)
• Associated with rare but fatal aplastic anemia,
hence is restricted for use only in extreme
refractory epilepsy

Topiramate
• Acts on AMPA receptors, blocking the glutamate binding
site, but also blocks kainate receptors and Na+
channels, and enhances GABA currents (highly
pleiotropic*)
• Used for partial seizures, as an adjunct for absence and
tonic-clonic seizures (add-on or alternative to phenytoin)
• Very long half-life (20h)

Epilepsy—GABA
Epilepsy GABA
Major inhibitory neurotransmitter in the
CNS
Two types of receptors
– GABAA —post-synaptic, specific
recognition sites, CI- channel
– GABAB —presynaptic autoreceptors,
also postsynaptic, mediated by K +
currents

GABA Receptor
A

Clonazapam
• -Benzodiazepine used for absence seizures
(and sometimes myoclonic): “fourth-line AED”
• -Most specific AED among benzodiazepines,
appearing to be selective for GABAA activation
in the reticular formation leading to inactivation
of T-type Ca2+ channels, hence its useful for
absence seizures
• -Sedating; May lose effectiveness due to
development of tolerance (≤6 months)

Lorazapam and Diazepam
• Benzodiazepines used as first-line treatment for
status epilepticus (delivered IV – fast acting)
• Sedating

Phenobarbital
– Barbiturate used for partial seizures, especially in
neonates. Oldest of the currently used AEDs
– Very strong sedation; Cognitive impairment;
Behavioral changes
– Very long half-life (up to ~5days); #Induces P450
– Tolerance may arise; Risk of dependence
– Primidone, another barbiturate metabolized to
Phenobarbital, and Phenobarbital are now seldom
used in initial therapy, owing to side-effects

AEDs That Act Primarily on GABA
Tiagabine
– Interferes with GABA re-uptake
Vigabatrin (not currently available in US)
– elevates GABA levels by irreversibly inhibiting
its main catabolic enzyme, GABAtransaminase

Na+ Channels as AED Targets
• Neurons fire at high frequencies during seizures
• Action potential generation is dependent on Na+
channels
• Use-dependent or time-dependent Na+ channel
blockers reduce high frequency firing without
affecting physiological firing

Na +
A = activation gate
I = inactivation gate
Anticonvulsants:
Mechanisms of Action
Voltage-gated sodium channel
I
Open Inactivated
Carbamazepine
Phenytoin
McNamara JO. Goodman & Gilman’s. 9th ed. 1996:461-486.
Na +
X
Na + Na +
I
Lamotrigine
Valproate

AEDs That Act Primarily on Na+
Phenytoin, Carbamazepine
– Block voltage-dependent sodium channels at high firing
frequencies—use dependent
Oxcarbazepine
– Blocks voltage-dependent sodium channels at high
firing frequencies
– Also effects K+ channels
Zonisamide
Channels
– Blocks voltage-dependent sodium channels and T-type
calcium channels

Phenytoin
• First-line for partial seizures; some use for tonicclonic
seizures
• Highly bound to plasma proteins – displaced by
Valproate; #Induces P450 resulting in increase
in its own metabolism, but its metabolism is also
increased by alcohol, diazepam
• Sedating
• Fosphenytoin: Prodrug for Phenytoin, used for
IM injection

Carbamazapine
• A tricyclic antidepressant used for partial
seizures; some use in tonic-clonic seizures
• #Induces P450 resulting in increase in its own
metabolism;
• Sedating; Agranulocytosis and Aplastic anemia
(elderly); Leukopenia (10% of patients);
Hyponatremia; Nausea and visual disturbances

Oxcarbazapine
• Newer drug, closely related to Carbamazapine,
approved for monotherapy, or add-on therapy in
partial seizures
• May also augment K+ channels*
• Some #induction of P450 but much less than
that seen with Carbamazapine
• Sedating but otherwise less toxic than
Carbamazapine

Zonisamide
• Used as add-on therapy for partial and
generalized seizures
• -Also blocks T-type Ca2+ channels*
• -Very long half-life (1-3days)

Lamotrigine
• Add-on therapy, or monotherapy for refractory
partial seizures
• Also inhibits glutamate release and (perhaps)
Ca2+ channels (=pleiotropic*)
• Metabolism affected by Valproate,
Carbamazapine, Phenobarbital, Phenytoin
• Less sedating than other AEDs; (Severe
dermatitis in 1-2% of pediatric patients)

Ca 2+ Channels as Targets
• General Ca2+ channel blockers have not proven
to be effective AEDs.
• Absence seizures are caused by oscillations
between thalamus and cortex that are generated
in thalamus by T-type (transient) Ca 2+ currents

Ethosuximide
• Acts specifically on T-type channels in thalamus,
and is very effective against absence seizures.
• Long half-life (~40h)
• Causes GI disturbances; Less sedating than
other AEDs

Gabapentin and its second generation
derivative Pregabalin
• -Act specifically on calcium channel subunits
called α2δ1. It is unclear how this action leads to
their antiepileptic effects, but inhibition of
neurotransmitter release may be one
mechanism
• -Used in add-on therapy for partial seizures and
tonic-clonic seizures
• -Less sedating than classic AEDs

What about K+ channels?
• K+ channels have important inhibitory control over
neuronal firing in CNS—repolarizes membrane to
end action potentials
• K+ channel agonists would decrease
hyperexcitability in brain
• So far, the only AED with known actions on K+
channels is valproate
• Retiagabine is a novel AED in clinical trials that
acts on a specific type of voltage-dependent K+
channel (M-channel)

Valproate (Valproic Acid)
• First-line for generalized seizures, also used for
partial seizures
• Also blocks Na+ channels and enhances
GABAergic transmission (highly pleiotropic*)
• Highly bound to plasma proteins; #Inhibits P450
• CNS depressant; GI disturbances; hair loss;
weight gain; teratogenic; (rare: hepatotoxic)

Regulation of Neurotransmitter release
• Several AED have actions that result in the
regulation of neurotransmitter release from the
presynaptic terminal, such as lamotrigine, in
addition to their noted action on ion channels or
receptors.
• Levetiracetam appears to have as its primary
action the regulation of neurotransmitter release
by binding to the synaptic vesicle protein SV2A:

Levetiracetam
• -Add-on therapy for partial seizures
• -Short half-life (6-8h)
• -CNS depression

Pleiotropic AEDs
• Many AEDs act on multiple targets, increasing
their efficacy
• Felbamate, lamotrigine, topirmate, valproate

Drug Interactions
• Many AEDs are notable inducers of cytochrome
P450 enzymes and a few are inhibitors.
• Of the classic AEDs, phenytoin, carbamazipine,
phenobarbital, and primidone are all strong
inducers of cytochrome P450 enzymes. They
are autoinducers, in other words they increase
their own metabolism.
• Valproate inhibits cytochrome P450 enzymes.

Pharmacokinetic Considerations
• Most AEDs undergo complete or nearly complete absorption when
given orally.
• Fosphenytoin (prodrug) may be administered intramuscularly if
intravenous access cannot be established in cases of frequent
repetitive seizures
• Diazepam (available as a rectal gel) has been shown to terminate
repetitive seizures and can be administered by family members at
home.
• Phenytoin, fosphenytoin, phenobarbital, diazepam, lorazepam and
valproate are available as IV preparations for emergency use.
• Most AEDs are metabolized in the liver (P450) by hydroxylation or
conjugation. These metabolites are then excreted by the kidney.
Gabapentin undergoes no metabolism and is excreted unchanged
by the kidney.

Treatment of Epilepsy
• First consideration is efficacy in stopping
seizures
• Because many AEDs have overlapping,
pleiotropic actions, the most appropriate drug
can often be chosen to reduce side effects.
Newer drugs tend to have less CNS
depressant effects.
• Potential of long-term side effects,
pharmokinetics, and cost are other
considerations

Treatment of Epilepsy
• Monotherapy is preferred: better patient
compliance, less adverse effects
• Add-on therapy is often necessary to
eliminate “break-through” or refractory
seizures

Partial seizures
Simple
Complex
Secondary
Generalized
AED Treatment Options
Primary generalized seizures
Tonic-
Clonic
Tonic
phenytoin, carbamazepine, phenobarbital,
gabapentin, oxcarbazepine, pregabalin
Myoclonic
valproic acid, lamotrigine, topiramate,
(levetiracetam, zonisamide)
Atonic Absence
Ethosuximide
Check notes

Status Epilepticus
• More than 30 minutes of continuous seizure
activity
• Two or more sequential seizures spanning
this period without full recovery between
seizures
• Medical emergency

• Treatment
Status Epilepticus
– Diazepam, lorazapam IV (fast, short acting)
– Followed by phenytoin, fosphenytoin, or
phenobarbital (longer acting) when control is
established

Alternative Uses for AEDs
• Gabapentin/pregabalin, carbamazepine—neuropathic
pain
• Lamotrogine, carbamazepine—bipolar disorder
• Leviteracitam, valproate, topirimate, gabapentin—
migraine

Questions?