1.11 Anti-Seizure Epilepsy (Seizures) Drugs - Rani Qasem 2015-2016

5/15/2016
Dr. Rani Qasem/ Dr. Faisal Alamri
Antiepileptic (Anti-seizures)
Drugs
Dr. Faisal Alamri
Objectives
At the end of the lecture, the students should be able
to:
1. Should know the Classification of Epileptic
Seizures
2. Should know the Drug Choice for Different Epileptic
Seizures 3. Should know the important Side Effects
4. Should know the Important Drug-drug
Interactions
EMMS Program - LECTURE: Antiepileptic Drugs

Dr. Rani Qasem
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Introduction to Epilepsy
• The 2nd most common neurologic disorder after stroke.
• Epilepsy is a chronic disorder caused by recurrent seizures and
manifested by a heterogeneous complex of symptoms….
– Questions: Are there incidental seizures that are temporary in
nature?! What do you think!
• Seizures: Finite episodes of abnormal electrical discharge of
cerebral neurons.
• Causes of seizures: MANY- include: hereditary, Infection,
neoplasms, developmental defects and head injury.
• Hereditary defects: single gene defects in autosomal
dominant genes encoding voltage-gated ion channels or
GABA A receptors are common hereditary factors that
lead to seizures.
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Dr. Rani Qasem
Classification of Seizures
• Seizures are divided
into two groups: Partial
& Generalized.
• The type of medication
used for epilepsy
depends on the empiric
nature of the seizure.
– Drugs used for partial
seizures are more or less
the same for all subtypes
of partial seizures.
– Drugs used for
generalized seizures are
determined by the
individual seizure
subtype. EMMS Program - LECTURE: Antiepileptic Drugs 4
Dr. Rani Qasem
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A. Partial (focal) Seizures

• Involve only a portion of the brain, typically part of one lobe of
one hemisphere.
• Symptoms depend on the site of neuronal discharge and extent
of spread to other neurons in the brain.
• Consciousness is usually
preserved.
• Simple
– Confined to a single locus in the brain and does not spread.
partial:
– May spread to become complex and then spread to become
a secondary generalized
convulsion.
• Complex
– Exhibit complex sensory hallucinations and mental
partial:
distortion. – Consciousness is usually altered.
EMMS Program - LECTURE: Antiepileptic 5
Drugs Dr. Rani Qasem
B. Generalized Seizures
• Begin locally and spread throughout both hemispheres of the brain.
• Primary generalized seizures may be convulsive or nonconvulsive - usually with
immediate loss of consciousness.
• Types include:
1. Tonic-clonic: Result in loss of consciousness, followed by tonic (continuous
contraction) and clonic (rapid contraction and relaxation) phases- followed by
confusion and exhaustion due to the depletion of glucose and energy stores.
2. Absence: Involve a brief, abrupt, and self-limiting loss of consciousness. The
patient stares and exhibits rapid eye-blinking, which lasts for 3 to 5 seconds.
3. Myoclonic: Consist of short episodes of muscle contractions- jerks, that may
recur for several minutes- usually at morning after the patients wakes up.
4. Febrile seizures: Accompanied by high fever and consist of generalized tonic-
clonic convulsions of short duration.
5. Status epilepticus: Two or more seizures occur without recovery to full
consciousness in between. Life-threatening & requires emergency treatment.
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Why use antiepileptic drugs?

• Seizures can be dangerous and life threatening.
• Seizures alter life - driving, education, employment. •
Seizures may interfere with brain functions - memory,
endocrine.
 Only about 70% of patients can have seizures well
controlled and many will experience side effects.
 Surgery can help some patients with focal seizures.

Treatment goals
 Prevent seizures.
 Prevent or reduce.
 Drug side effects.
 Drug interactions.
 Worsening of current medical
problems.  Improve the quality of life.
 Provide simple, cost-effective clinical
care.
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EMMS Program - LECTURE: Antiepileptic

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Characteristics of an ideal
seizures drug?
• Effective against the seizure type in question - broad spectrum
drugs are even better!
• Little or no acute CNS toxicity - cognitive, sedation, behavior!
• Little or no systemic toxicity - liver, bone marrow, rashes!
• Active orally.
• Long half life - once per day dosing.
• No drug interactions - especially important in the elderly.
• No effect on brain development and development in general.

BASIC PHARMACOLOGY OF ANTISEIZURE DRUGS-

General Chemistry
Older generation of Antiepileptics:
• Barbiturates
Have in common a heterocyclic ring
• Hydantoins structure with a variety of
substituents!
• Oxazolidinediones
• Succinimides
• Acetylureas
• Carbamazepine
• Valproic acid Structurally dissimilar!
• Benzodiazepines
• Newer antiepileptic's marketed since 1990:
Eslicarbazepine, felbamate, gabapentin, lacosamide, lamotrigine,
levetiracetam, oxcarbazepine, pregabalin, retigabine, rufinamide, stiripentol,
tiagabine, topiramate, vigabatrin, and zonisamide- all structurally dissimilar!
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Dr. Rani Qasem
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Pharmacokinetic Properties of
Antiseizure Drugs
• Antiseizure drugs exhibit many similar pharmacokinetic properties;
Why? – Most have been selected for oral activity and all must reach the
CNS. drugs are only slightly soluble, but absorption is usually good –
• Many
(80–100% of the dose reaches the circulation).
• Most antiseizure drugs (except phenytoin, tiagabine, and valproic acid)
are not highly bound to plasma proteins.
• Antiseizure drugs are chiefly cleared by hepatic mechanisms, although
they have low extraction ratios
• Many antiseizure drugs are converted to active metabolites that are also
cleared by the liver.
• Plasma clearance is relatively slow; many antiseizure drugs are therefore
considered to be medium to long acting.
• Many of the older antiseizure drugs are potent inducers of hepatic
microsomal enzyme activity.
EMMS Program - LECTURE: Antiepileptic Drugs 11
Dr. Rani Qasem
Mechanisms of Action of
Antiepileptic Drugs
• Block voltage-dependent Na+ channels.
• Enhance GABA inhibition;
– Potentiate GABA action
– Prevent degradation of GABA
– Enhance the release of GABA
• Block voltage-dependent Ca++ channels.
• Bind to synaptic vesicle protein (SV2A).
• Antagonize glutamate actions - Block Kainate, NMDA &
AMPA receptors and enhance GABA release.
Dr. Rani Qasem
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Molecular targets of antiseizure drugs at excitatory

glutamatergic synapses
Presynaptic targets diminishing glutamate
release include:
• +
Voltage-gated (VG) Na channels
(phenytoin, carbamazepine,
lamotrigine lacosamide).
2+
• VG-Ca channels (ethosuximide, lamotrigine,
gabapentin, and pregabalin).
• K + channels (retigabine).
• Synaptic vesicle proteins (SV2A)
(levetiracetam).
• CRMP-2, collapsin-response mediator
protein-2 (lacosamide).
Postsynaptic targets
include:
• AMPA receptors (blocked by phenobarbital,
topiramate, and lamotrigine).
• NMDA receptors (blocked by felbamate).
• EAAT, excitatory amino acid transporter.
• Red dots represent glutamate. EMMS Program - LECTURE: Antiepileptic Drugs 13

Dr. Rani Qasem
Molecular targets of antiseizure drugs

at inhibitory GABAergic synapse
These include “specific” targets:
• GABA transporters (especially
GAT-1, tiagabine).
• GABA-transaminase (GABA-T,
Vigabatrin).
• GABA A receptors
(benzodiazepines).
• Potentially, GABA B receptors.
• Synaptic vesicular proteins
(SVA2).
• Effects may also be mediated
by “nonspecific” targets such
as by voltage-gated (VG) ion
channels and synaptic proteins.
IPSP, inhibitory postsynaptic
potential.
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Blue dots represent GABA. EMMS Program - LECTURE: Antiepileptic
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DRUGS USED IN PARTIAL SEIZURES & GENERALIZED

TONIC-CLONIC SEIZURES
1. Phenytoin (and congeners)
2. Carbamazepine
3. Valproate
4. Barbiturates
5. Others that are less common, but used.

Dr. Rani Qasem
PHENYTOIN
• The oldest nonsedative antiseizure drug .
• Known for decades as diphenylhydantoin.
• Chemistry- is a diphenyl-substituted hydantoin .
• Has much lower sedative properties than compounds with alkyl substituents
at the 5 position.
• Fosphenytoin- A phosphate ester, more soluble prodrug of phenytoin that is
available for parenteral use- rapidly converted to phenytoin in the plasma.
• Mephenytoin, Ethotoin, & Phenacemide are Phenytoin congeners-
Phenacemide was withdrawn from the marker.
Fosphenytoin
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Phenytoin

Drugs
Dr. Rani Qasem
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Mechanism of Action
of Phenytoin
• Blocks sustained high-frequency repetitive firing of action potentials - How!
• Sodium channels exist in three main conformations: the resting state, the
open state, and the inactive state.

Mechanism of Action of
Phenytoin …
• At therapeutic concentrations, the major action of phenytoin is to block
continued
Na+ channels and inhibit generation of rapid repetitive action potentials.
• Phenytoin preferentially binds and prolongs the inactivation state of Na +
channels-
– The drug dissociates very slowly causing a time dependent block of the
channel .
– The fraction of inactive channels is increased by membrane
depolarization and repetitive firing.
– Phenytoin binding produces voltage-dependent, use-dependent &
time-dependent block of Na+ -dependent action potentials .
• Phenytoin causes excitation in some cerebral neurons by reducing Ca +2
permeability- This explains why phenytoin inhibits Ca +2 induced secretory
processes like release of hormones and neurotransmitters.
• Phenytoin decreases the synaptic release of glutamate and enhances the
release of GABA .
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Effects of three antiseizure drugs on

sustained high-frequency action
potentials!
• Intracellular recordings were made from neurons while depolarizing current pulses,
approximately 0.75 s in duration, were applied (on-off step changes indicated by arrows).
• In drug absence, a series of high-frequency repetitive action potentials filled the entire
duration of the current pulse.
• At therapeutic concentrations, phenytoin, carbamazepine, and sodium valproate
markedly reduced the number of action potentials elicited by the current pulses.
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Pharmacokinetics of Phenytoin
… continued
• Absorption highly dependent on the
formulation of the dosage form.
• Absorption is complete, but time to peak
conc. may range from 3 to 12 hours!
• Phenytoin is 90% bound to plasma
albumin.
• Phenytoin is metabolized to inactive
metabolites excreted in urine. Conc. dependent
First order
• The elimination of phenytoin is dose- elimination
dependent- exhibits saturable enzyme
metabolism!- what does that mean?!
Conc. independent
• Phenytoin sodium should not be given IM Zero order
elimination
because of its low solubility and tendency
to precipitate causing tissue damage &
necrosis.
• Fosphenytoin is given IM and IV.
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Phenytoin Toxicity
• Nystagmus, diplopia & ataxia are the most
common dose-related adverse effects. Diplopia
• Sedation & slurred speech occur at
considerably higher plasma levels.
• Gingival hyperplasia and hirsutism occur to Cleft lip and palate
some degree in most patients.
• Long-term use causes coarse facial
features, mild peripheral neuropathy and
abnormalities in vitamin D metabolism
leading to osteomalacia.
• When given during pregnancy, high Ataxia
incidents of cleft lip & palate occurred in
newborns.
• Idiosyncratic reactions to phenytoin are
relatively rare.
• Abrupt discontinuation can precipitate
Gingival hyperplasia
status epilepticus.
CARBAMAZEPINE
 Tricyclic compound effective in treatment
of bipolar depression- closely related to
imipramine.
 Initially marketed for the treatment
of trigeminal neuralgia.
 Became the drug of choice for both partial
seizures and generalized tonic-clonic seizures
• Mechanism of Action of Carbamazepine:
 Acts presynaptically to decrease synaptic
transmission by;
 Inhibiting high-frequency repetitive
+ Na
firing in neurons by blocking
channels. +
 Potentiating voltage-gated K currents .

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Pharmacokinetics of
Carbamazepine
• Carbamazepine is erratically & slowly absorbed following oral
administration- but almost complete absorption occurs.
• The drug is approximately 70% bound to plasma proteins
– No clinically significant protein-binding interactions have been
reported!
• It induces its own drug metabolism and has an active anticonvulsant
metabolite-
– Initial half-life of 36 hrs decreases to 8 –12 hrs after continuous therapy.
• Carbamazepine is an inducer of several isozyme families - CYP1A2,
CYP2C, and CYP3A- and UGT enzymes- can alter the clearance of
other drugs.
– Not well tolerated by the elderly. …. Why?!
Toxicity -
Carbamazepine
• Most common are diplopia and ataxia.
• Mild gastrointestinal upsets, unsteadiness, and at much
higher doses, drowsiness.
• Occasional hyponatremia and water intoxication!
• Most common idiosyncratic reaction is erythematous skin
rash…. Significance!
• Other idiosyncratic reactions include blood dyscrasias,
including fatal cases of aplastic anemia and agranulocytosis-
– Especially in the elderly - a justification to stop the drug.

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Carbamazepine Congeners
• Oxcarbazepine - closely related to • Eslicarbazepine acetate (ESL) - a

carbamazepine and used for the prodrug rapidly converted to S(+)
same seizure types. eslicarbazepine compared to
• Has an improved toxicity profile but oxcarbazepine.
less effective than carbamazepine. • Both, oxcarbazepine and
• Half life is ≈ 2 hours. eslicarbazepine have the same
• Activity attributed to its metabolite- metabolites as active product.
the 10-hydroxy metabolite
(especially the S(+) enantiomer
eslicarbazepine).
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Carbamazepine Congeners
• The mechanism of
action of
carbamazepine,
≈25% of the oral dose
oxcarbazepine, and
ESL appears to be the
same- blocking
voltage-gated Na +
channels.
• The possible
advantage of ESL is
its once-daily dosing
Mono-hydroxy derivative (MHD)
regimen.
(ESL) EMMS Program - LECTURE: Antiepileptic

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PHENOBARBITAL
• The oldest of the currently available antiseizure drugs.
• Although considered one of the safest antiseizure drugs, the use of other
medications with milder sedative effects has been urged.
• Many consider barbiturates the drugs of choice for seizures in infants.
CHEMISTRY
• The four derivatives of barbituric acid clinically useful as antiseizure
drugs are phenobarbital, mephobarbital, metharbital, and primidone.
Phenobarbital Mephobarbital Metharbital Primidone

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Mechanism of Action of
PHENOBARBITAL
• Phenobarbital binds to an allosteric regulatory site on
the GABA A receptor and enhances the GABA receptor-
mediated current by prolonging the openings of Cl−
channels.
• Phenobarbital also decreases excitatory responses-
decreasing glutamate release.
• Phenobarbital also suppresses high-frequency
repetitive firing in neurons by acting on Na+
conductance, but only at high concentrations.
– At high concentrations, barbiturates block some Ca2+
currents (L-type and N-type).
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PRIMIDONE
• Primidone- metabolized to
phenobarbital and
phenylethylmalonamide (PEMA).
• All three compounds are active
anticonvulsants.
• Given orally- completely
absorbed.
• During chronic therapy,
phenobarbital levels derived from
primidone are usually two to three
times higher than primidone
levels…. Significance?!
• The dose-related adverse
effects
of primidone are similar to those
of its metabolite, phenobarbital. 29

FELBAMATE
• Reserved for refractory seizures because of its
side effects.
• Effective against partial seizures and seizures that
occur in “Lennox-Gastaut syndrome.”
• Causes aplastic anemia and severe hepatitis
(hepatic failure) at high rates and has been
relegated to the status of a third-line drug for
refractory cases.
• Has multiple mechanisms of action:
1. Use-dependent block of glutamate NMDA receptor.
2. Barbiturate-like potentiation of GABAA receptor.
• Felbamate inhibits CYP2C19 required for the metabolism of several
medications.
• Felbamate interacts with antiepileptics – increases plasma
phenytoin & valproate, and decreases plasma carbamazepine.
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GABAPENTIN & PREGABALIN

• Gabapentin & Pregabalin are GABA analogs- effective against partial seizures.
• Pregabalin used for neuropathic pain- diabetic neuropathy & postherpetic
neuralgia.
• Mechanism of Actions:
1. Do NOT act directly on GABA receptors but modify synaptic or
nonsynaptic release of GABA resulting in an increase in brain GABA
concentration.
2. Decrease Ca2+ entry by binding N-type voltage-gated Ca 2+ channels on
presynaptic glutaminergic neurons decreasing glutamate release.
• Both are not metabolized- do not induce hepatic enzymes- not bound to plasma
proteins- drug-drug interactions are negligible- elimination is renal- and excreted
unchanged. ….. In which patient population are these drugs preferred?!

LACOSAMIDE- formerly
known as Erlosamide
• An amino acid-related compound studied in pain syndromes & partial
seizures.
• Mechanism of Action
1. Enhances slow inactivation of voltage-gated Na + channels.
2. Binds collapsin-response mediator protein, CRMP-2 blocking the
effect of neurotrophic factors on axonal and dendritic growth. …
prevent formation of abnormal neuronal connections in the brain.
• Approved as adjunctive therapy in the treatment of partial-onset
seizures with or without secondary generalization.
• Produce altered mood; false & unusual sense of well-being…. Classified
schedule V.
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LAMOTRIGINE
• Mechanism of Action
1. Suppresses sustained rapid firing of neurons and produces a
voltage- and use-dependent blockade of Na + channels.
2. Inhibits voltage-gated Ca 2+ channels, particularly the N- and P/Q-
type channels.
3. Decreases synaptic release of glutamate.
• Effective against partial seizures, absence and myoclonic seizures and the
Lennox-Gastaut syndrome.
• Effective for bipolar disorder.
• Metabolized primarily to the N-2 glucuronide through the UGT pathway.
• Potentially life-threatening dermatitis develops in 1 –2% of pediatric
patients.
• The half-life of lamotrigine is decreased by enzyme-inducing drugs
(carbamazepine and phenytoin) and increased by greater than 50 percent
with the addition of valproate.
• Lamotrigine is well tolerated by the elderly population.
LEVETIRACETAM
• Binds selectively to the synaptic vesicular protein SV2A modifying
synaptic release of glutamate and GABA through an action on vesicular
function.
• Used as adjunctive treatment of partial seizures, myoclonic seizures, and
primary generalized tonic-clonic seizures in adults and children.
RETIGABINE (EZOGABINE in the US)

• A potassium-channel facilitator!!
• Adjunctive treatment of partial-onset seizures in adults.

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Rufinamide
• Rufinamide is a triazole derivative.
• Decreases sustained high-frequency firing of neurons and
prolongs the inactive state of the Na+ channel.
• Used as adjunctive treatment of seizures associated with the
Lennox-Gastaut syndrome.
• Birth control tablets are less effective when concomitantly
used with rufinamide.
Triazole ring

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TIAGABINE
• An inhibitor of GABA uptake, and
increases extracellular GABA levels
prolonging its inhibitory effects.
• Indicated for the adjunctive treatment of
partial seizures
TIAGABINE
ZONISAMIDE
• A sulfonamide derivative.
• Acts on Na+ and T-type voltage-gated Ca2+
channels.
• Effective against partial and generalized
tonic-clonic seizures and useful against
infantile spasms and certain myoclonias. ZONISAMIDE
• Adverse effects: drowsiness, cognitive
impairment, and serious skin rashes.
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TOPIRAMATE
• A substituted monosaccharide effective in partial and primary
generalized epilepsy and treatment of migraine.
• Mechanism of Action:
– Like phenytoin and carbamazepine, the drug blocks
repetitive firing of voltage-gated
+ Na channels.
– Reduces high-voltage activated (L-type) Ca channels.
2+
– Potentiates the inhibitory effect of GABA- bind a different site from

the benzodiazepines or barbiturates.
– Depresses the excitatory effects of kainate on glutamate receptors.
• • Coadministration of topiramate reduces ethinyl estradiol levels-
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VIGABATRIN
• Vigabatrin produces a sustained increase in the extracellular
concentration of GABA in the brain.
– The drug is an irreversible inhibitor of GABA
aminotransferase (GABA-T), the enzyme responsible for
degradation of GABA.
• In 30% or more of patients, the drug has been associated with
adverse effects resulting in visual field loss ranging from mild
to severe.
• Vigabatrin is reserved for infantile spasms or complex partial
seizures refractory to other treatments.

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DRUGS USED IN
GENERALIZED SEIZURES
• ETHOSUXIMIDE
• PHENSUXIMIDE & METHSUXIMIDE
• VALPROIC ACID & SODIUM VALPROATE
• OXAZOLIDINEDIONES- Trimethadione. •
Others………

Ethosuximide
• One of three antiseizure succinimides - ethosuximide, phensuximide,
and methsuximide.
• Methsuximide and phensuximide have phenyl substituents, whereas
ethosuximide is 2-ethyl-2-methylsuccinimide.
Mechanism of Action
• Has an important effect on Ca 2+ currents, reducing the low-threshold (T-
type) current.
• Has a very narrow spectrum of clinical activity- particularly effective
against absence seizures.
Succinimide Ethosuximide Phensuximide methsuximide

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VALPROIC ACID & SODIUM VALPROATE

• Valproic acid is a fatty carboxylic acid with antiseizure activity- greatest for
carbon chain lengths of five to eight atoms.
• Fully ionized at body pH- valproate ions probably the active form of the drug.
Mechanism of Action-
• Blocks sustained high-frequency repetitive firing of neurons.
• Blockade of NMDA receptor-mediated excitation.
• Increase GABA brain levels:
– Facilitates synthesis of glutamic acid decarboxylase, the enzyme responsible for
GABA synthesis.
– Inhibits GABA transporter GAT-1.
– Inhibits GABA transaminase at high concentrations blocking GABA degradation. •
Valproate is very effective against absence seizures, can control certain types
of myoclonic seizures & effective against tonic-clonic seizures.
• IV formulations occasionally used to treat status epilepticus.
• Used in the management of bipolar disorder and migraine prophylaxis.
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VALPROIC ACID & SODIUM VALPROATE

………….. continued
•
Divalproex Na+ : Enteric-coated tablet containing a 1:1 combination of
valproic acid and sodium valproate- absorbed slowly and is preferred by
many patients.
Drug Interactions:
– Displaces phenytoin from plasma proteins.
– Inhibits metabolism of several drugs- phenobarbital, phenytoin, and carbamazepine.
– Dramatically decreases lamotrigine clearance- used to adjust lamotrigine plasma levels.
Toxicity:
• Common dose-related adverse effects: nausea, vomiting & GI
complaints.
• Sedation uncommon and a fine tremor is frequently seen at high levels.
• Reversible adverse effects, seen in a small number of patients, include
weight gain, increased appetite, and hair loss.
• Idiosyncratic toxicities of valproate include hepatotoxicity (may be severe &
life- threatening) and thrombocytopenia.
• May substantially increase the incidence of spina bifida in offspring of
women who took valproate during pregnancy- in addition to increased 42
incidence of cardiovascular, orofacial, and digital abnormalities.
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OXAZOLIDINEDIONES
• Trimethadione- was the drug of choice for absence seizures
until the introduction of succinimides in the 1950s.
• Uses— trimethadione, paramethadione, and dimethadione
— is now very limited.
• Have the same effect on thalamic Ca 2+ currents as
ethosuximide (reducing the T-type Ca2+ current).
• The most common dose-related adverse effect of the
oxazolidinediones is sedation.
• Trimethadione has been associated with many other toxic
adverse effects, some of which are severe.
• These drugs should not be used during pregnancy

OTHER DRUGS USED IN

MANAGEMENT OF EPILEPSY
• BENZODIAZEPINES
• ACETAZOLAMIDE

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BENZODIAZEPINES
Six benzodiazepines play prominent roles in the therapy of epilepsy;
1. Diazepam- highly effective in stopping continuous seizure activity-
generalized tonic-clonic status epilepticus.
2. Lorazepam – some studies suggest it to be safer and more effective than
longer acting diazepam in the treatment of pediatric status epilepticus.
3. Clonazepam –
– Long-acting drug with documented efficacy against absence seizures;
– It is one of the most potent antiseizure agent on a milligram basis.
– Effective in some cases of myoclonic seizures and infantile spasms.
4. Nitrazepam used for infantile spasms and myoclonic seizures but is less
potent than clonazepam.
5. Clorazepate for complex partial seizures in adults.
6. Clobazam used in a variety of seizure types

Limitations of Benzodiazepines
in Treating Epilepsy
Two prominent aspects of benzodiazepines limit their
usefulness.
• Pronounced sedative effect.
• Tolerance, in which seizures may respond initially but recur
within a few months.

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ACETAZOLAMIDE
• A diuretic whose main action is the inhibition of carbonic
anhydrase.
• Mechanism of Action:
– Either the mild acidosis in the brain may be the mechanism by which the
drug exerts its antiseizure activity.
– Alternatively, the depolarizing action of bicarbonate ions moving out of
neurons may be diminished by carbonic anhydrase inhibition.
• Acetazolamide has been used for all types of seizures but is
severely limited by the rapid development of tolerance-
seizures return usually within a few weeks.
• The drug may have a special role in epileptic women who
experience seizure exacerbations at the time of menses.

SPECIAL ASPECTS OF THE

TOXICOLOGY OF ANTISEIZURE DRUGS
• TERATOGENICITY - CONTROVERSIAL – it appears that children born to
mothers taking antiseizure drugs have an increased risk, perhaps
twofold, to congenital malformations.
– Phenytoin - implicated in a specific syndrome called fetal hydantoin
syndrome-
• Similar syndrome has been detected following the administration of
phenobarbital & carbamazepine.
– Valproate has been implicated in a specific malformation, spina bifida.
– Topiramate shows some teratogenicity in animal testing.
• CONLUSIVE STATEMENT: Epileptologists agree that although it is
important to minimize exposure to antiseizure drugs, both in numbers &
dosages, it is also important not to allow maternal seizures to go
unchecked.
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• WITHDRAWAL - Withdrawal of antiseizure drugs, whether by accident
or by design, can cause increased seizure frequency & severity.
• Because of the heterogeneity of epilepsy, complete discontinuance of
antiseizure drug administration is an especially difficult problem.
• Some drugs are more easily withdrawn than others.
• In general, withdrawal of anti-absence drugs is easier than withdrawal
of drugs needed for partial or generalized tonic-clonic seizures.
• Barbiturates and benzodiazepines are the most difficult to discontinue.
• If a patient is seizure-free for 3 or 4 years, a trial of gradual
discontinuance is often warranted.
• Note: Abrupt discontinuance of antiseizure drugs ordinarily does not
cause seizures in nonepileptic patients.


TOXICOLOGY OF ANTISEIZURE DRUGS •
OVERDOSE- Antiseizure drugs are central nervous system
depressants but are rarely lethal.
• Very high blood levels are usually necessary before overdoses
can be considered life-threatening.
• The most dangerous effect of antiseizure drugs after large
overdoses is respiratory depression, which may be
potentiated by other agents, such as alcohol.
• Treatment of antiseizure drug overdose is supportive;
stimulants should not be used.
– Efforts to hasten removal of antiseizure drugs, such as alkalinization of
the urine with weak acids like phenytoin are usually ineffective & lack
enough evidence for any benefit.

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• SUICIDALITY- FDA analysis of suicidal behavior during clinical
trials of antiseizure drugs was carried out in 2008.
– Suicidal behavior or suicidal ideation was 0.37% in patients
taking active drugs and 0.24% in patients taking placebo.
• Although the entire class of antiseziure drugs may receive some
changes in labeling, it is noteworthy that the odds ratios for
carbamazepine and for valproate were less than 1, and no data
were available for phenytoin.
• Whether suicide attempts are a real impact of drug therapy or
inextricably associated with this serious, debilitating disorder —
with its inherently high rate of suicidality —is unclear to date!
Summary

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1.11 Anti-Seizure Epilepsy (Seizures) Drugs - Rani Qasem 2015-2016

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1.11 Anti-Seizure Epilepsy (Seizures) Drugs - Rani Qasem 2015-2016

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5/15/2016

Dr. Rani Qasem/ Dr. Faisal Alamri

EMMS Program - LECTURE: Antiepileptic Drugs

A. Partial (focal) Seizures

Why use antiepileptic drugs?

EMMS Program - LECTURE: Antiepileptic 7

EMMS Program - LECTURE: Antiepileptic

EMMS Program - LECTURE: Antiepileptic 9

BASIC PHARMACOLOGY OF ANTISEIZURE DRUGS-

Molecular targets of antiseizure drugs at excitatory

• Red dots represent glutamate. EMMS Program - LECTURE: Antiepileptic Drugs 13

Molecular targets of antiseizure drugs

DRUGS USED IN PARTIAL SEIZURES & GENERALIZED

EMMS Program - LECTURE: Antiepileptic Drugs 15

EMMS Program - LECTURE: Antiepileptic 16

EMMS Program - LECTURE: Antiepileptic 17

Effects of three antiseizure drugs on

 Potentiating voltage-gated K currents .

EMMS Program - LECTURE: Antiepileptic

EMMS Program - LECTURE: Antiepileptic

• Oxcarbazepine - closely related to • Eslicarbazepine acetate (ESL) - a

(ESL) EMMS Program - LECTURE: Antiepileptic

Phenobarbital Mephobarbital Metharbital Primidone

EMMS Program - LECTURE: Antiepileptic

EMMS Program - LECTURE: Antiepileptic

GABAPENTIN & PREGABALIN

EMMS Program - LECTURE: Antiepileptic 31

RETIGABINE (EZOGABINE in the US)

EMMS Program - LECTURE: Antiepileptic

EMMS Program - LECTURE: Antiepileptic

– Potentiates the inhibitory effect of GABA- bind a different site from

EMMS Program - LECTURE: Antiepileptic 38

EMMS Program - LECTURE: Antiepileptic 39

Succinimide Ethosuximide Phensuximide methsuximide

VALPROIC ACID & SODIUM VALPROATE

VALPROIC ACID & SODIUM VALPROATE

EMMS Program - LECTURE: Antiepileptic 43

OTHER DRUGS USED IN

EMMS Program - LECTURE: Antiepileptic 44

EMMS Program - LECTURE: Antiepileptic 45

EMMS Program - LECTURE: Antiepileptic 46

EMMS Program - LECTURE: Antiepileptic 47

SPECIAL ASPECTS OF THE

SPECIAL ASPECTS OF THE

EMMS Program - LECTURE: Antiepileptic 49

SPECIAL ASPECTS OF THE

EMMS Program - LECTURE: Antiepileptic 50

SPECIAL ASPECTS OF THE

EMMS Program - LECTURE: Antiepileptic 52

EMMS Program - LECTURE: Antiepileptic 53

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