ANTISEIZURE DRUGS
NMDA receptors (blocked by felbamate)
- Anticonvulsants
- Antiepileptics
- Commonly used for long periods of time
(avoid toxicity and drug interaction)
- Well absorbed orally
- Good bioavailability
- Most drugs metabolized by hepatic
enzymes active metabolites
- DRUG INTERACTIONS are common
1. Drugs that inhibit antiseizure drug
metabolism or displace anticonvulsant
from plasma protein bindings sites
toxic levels of plasma concentration
2. Drugs that induce hepatic drug-
metabolizing enzymes (e.g., rifampicin)
inadequate levels of plasma concentration
Presynaptic targets diminishing glutamate
release
1. Voltage-gated (VG) Na + channels (phenytoin,
carbamazepine, lamotrigine, and
lacosamide)
2. VG-Ca 2+ channels
(ethosuximide, lamotrigine, gabapentin, and
pregabalin)
3. K + channels (retigabine)
4. synaptic vesicle proteins SV 2 A
(levetiracetam)
5. CRMP-2, collapsin-response mediator protein-
2 (lacosamide)
Postsynaptic targets
6. AMPA receptors (blocked by phenobarbital,
topiramate, and lamotrigine)
7.
EAAT, excitatory amino acid transporter. Red
dots represent
Glutamate
DRUGS USED IN PARTIAL SEIZURES AND
GENERALIZED TONIC CLONIC SEIZURES
PHENYTOIN
- Diphenylhydantoin
- OLDEST non sedative antiseizure drug
- Non-sedating
- Blocks sodium channels
- Oral bioavailability is variable
o Individual differences in first-pass
metabolism
- Diphenyl-substituted hydantoin
- Much less sedative effect (no alkyl
substitution at carbon 5 position)
- Intramuscular absorption is unpredictable
- Binds extensively to plasma proteins (97-
98%)
- Metabolism is nonlinear
o Elimination shifts from first-order to
zero- order kinetics at moderate to
high dose levels
o High doses toxic effects
- Mechansim of action
1. It alters Na+, K+, and Ca2+
conductance, membrane potentials,
and the concentrations of amino
acids and the neurotransmitters
norepinephrine, acetylcholine, and -
aminobutyric acid (GABA).
2. Causes excitation in some cerebral
neurons
o A reduction of calcium
permeability, with inhibition of
calcium influx across the cell
membrane
- Therapeutic concentration (TC) 10-20
mg/ml
o 5-7 days to reach steady state at
low blood concentration
o 4-6 weeks to reach steady state at
high blood concentration
- Fosphenytoin is a water-soluble prodrug
form that is used parenterally
- The half-life of phenytoin varies from 12 to
36 hours, with an average of 24 hours
Much longer half-lives are observed at
higher concentrations.
- Free (unbound) levels in plasma is
increased transiently by drugs that
compete for binding
o Sulfonamides
o Valproic acid
- Metabolism is enhanced in the presence
of inducers of liver metabolism
o Phenobarbital
o Rifampicin
- Metabolism is inhibited by other drugs
o Cimetidine
o Isoniazid
- Phenytoin is highly bound to plasma
proteins.
- Drug concentration in cerebrospinal fluid
is proportionate to the free plasma level.
- Phenytoin accumulates in brain, liver,
muscle, and fat.
- Toxic effects
o Diplopia
o Ataxia
o Hirsutism
o Gingival hyperplasia
o Idiosyncratic reactions like rashes
o Hematologic complications
- Congeners of Phenytoin
- Phenacemide already withdrawn
- Mephenytoin and Ethotoin
- Mephenytoin
o metabolized to 5,5-
ethylphenylhydantoin via
demethylation
o Nirvanol, contributes most of the
antiseizure activity of mephenytoin
o Hydroxylated and undergo
subsequent conjugation and
excretion.
o Therapeutic levels for mephenytoin
range from 5 mcg/mL to 16
mcg/mL, and levels above 20
mcg/mL are considered toxic
o Therapeutic blood levels of
nirvanol are between 25 and 40
mcg/mL
o A therapeutic range for ethotoin
has not been established.
CARBAMAZEPINE
- Tricyclic
- Closely related to IMIPRAMINE
- Treatment for Trigeminal Neuralgia
- Non-sedating
- Blocks sodium channels
- Absorbed orally
- Bound to plasma proteins (70%)
- TC=4-8 microgram/ml
- Mechanism of Action
1. Blocks sodium channels at therapeutic
concentrations and inhibits high-frequency
repetitive firing in neurons
2. Acts presynaptically to decrease synaptic
transmission
- Induces formation of liver drug-
metabolizing enzyme
o Increases the metabolism of the
drug itself
o May increase the clearance of
many other anticonvulsant drugs
o Enzyme inducer
- Metabolism may be inhibited by other
drugs
o Propoxyphene
o Valproic acid
o Results to increased levels of the
drug
- Therapeutic level
- In adults, daily doses of 1 g or even 2 g
- In children, in whom a dosage of 15–25
mg/kg/d
- Therapeutic level is usually 4–8 mcg/mL.
o Many patients complain of diplopia
at drug levels above 7 mcg/mL,
others can tolerate levels above 10
 mcg/mL, especially with
monotherapy.
- Toxic effects
o Diplopia
o Ataxia
o Rashes
o Idiosyncratic blood dyscrasia
OXCARBAZEPINE
- Oxcarbazepine has a half-life of only 1–2
hours.
- Its activity resides almost exclusively in
the 10-hydroxy metabolite
- 10-hydroxy metabolite similar half life
with Carbamazepine ie, 8–12 hours
- The drug is mostly excreted as the
glucuronide of the 10-hydroxy metabolite.
ELSICARBAZINE acetate
- PRODRUG used in Europe
- Adjuntive therapy for patients with Partial
Onset Seizure
- More rapidly converted to S(+)licarbazine
than oxcarbazepine
- MOA: blocks Na-channels
- Administered at 400-1200 mg/day
- Maximal Effect if coadministered with
other anti-seizure
PHENOBARBITAL
- Barbiturate
- Phenobarbital, Mephobarbital,
Metharbital, are very similar
- Primidone
o When metabolize yields
Phenobarbital
o Sedating effect
o For infants
PRIMIDONE
- Desoxyphenobarbitalwas first marketed in
the early 1950s
- It was later reported that primidone was
metabolized to phenobarbital and
phenylethylmalonamide (PEMA)
- All three compounds are active
anticonvulsants.
PRIMIDONE
- MOA: Similar to Phenytoin
- Completely absorbed, usually reaching
peak concentrations about 3 hours after
oral administration
- It is not highly bound to plasma proteins;
approximately 70% circulates as unbound
drug.
- Primidone has a larger clearance than
most other antiseizure drugs (2 L/kg/d),
corresponding to a half-life of 6–8 hours.
- PEMA clearance is approximately half
that of primidone, but phenobarbital has a
very low clearance.
- Phenobarbital therefore accumulates very
slowly but eventually reaches therapeutic
concentrations
- Chronic therapy, phenobarbital levels
derived from primidone are usually two to
three times higher than primidone levels.
- Therapeutic range of 8–12 mcg/mL.
- Phenobarbital, at steady state usually
vary from 15 mcg/mL to 30 mcg/mL.
- Remember that the parent drug reaches
steady state rapidly (30–40 hours), but the
active metabolites phenobarbital (20
days) and PEMA (3–4 days) reach steady
state much more slowly.
VIGABATRIN
- MOA:
1. Irreversible inhibitor of GABA
aminotransferase (GABA-T), the
enzyme responsible for the
degradation of GABA
 2. Also inhibit the vesicular GABA
transporter
3. Sustained increase in the
extracellular concentration of GABA
in the brain leads to some
desensitization of synaptic GABAA
receptors but prolonged activation of
nonsynaptic GABAA receptors that
provide tonic inhibition
- Half-life is approximately 6–8 hours
- Adults, vigabatrin should be started at an
oral dosage of 500 mg twice daily; a total
of 2–3 g (rarely more) daily may be
required for full effectiveness.
- Typical toxicities include drowsiness,
dizziness, and weight gain.
- Clinical Indication
o Partial seizures and West's
syndrome
LAMOTRIGINE
- MOA:
1. Suppresses sustained rapid firing of
neurons and produces a voltage- and
use-dependent inactivation of sodium
channels thus effective in focal epilepsy
2. Inhibits voltage-gated Ca2+ channels,
particularly the N- and P/Q-type channels,
which would account for its efficacy in
primary generalized seizures in
childhood, including absence attacks
3. Lamotrigine also decreases the synaptic
release of glutamate
- Clinical Indication
1. Effective as monotherapy for partial
seizures
2. Bipolar disorder
- Toxicity
o Dizziness
o headache,
o diplopia
o nausea
o somnolence
o skin rash that is considered a
typical hypersensitivity reaction
FELBAMATE
- MOA:
1. Use-dependent block of the NMDA
receptor, with selectivity for the NR1-2B
sub-type
2. Potentiates GABAA receptor responses
- Felbamate has a half-life of 20 hours
- Metabolized by hydroxylation and
conjugation
- Significant percentage of the drug is
excreted unchanged in the urine
- Clinical Indication
o partial seizures
o Lennox-Gastaut syndrome
GABAPENTIN AND PREGABALIN
- MOA: Bind avidly to the 2 subunit of
voltage-gated Ca2+ channels
- Decreases Ca2+ entry, with a predominant
effect on presynaptic N-type channels
- Act presynaptically to decrease the release of
glutamate
ANTI-EPILEPTIC ACTIVITY
- Gabapentin is not metabolized and does
not induce hepatic enzymes
- Not bound to plasma proteins.
- Drug-drug interactions are negligible.
- Elimination is via renal mechanisms; the
drug is excreted unchanged.
- Half-life is relatively short, ranging from 5
to 8 hours
- Administered two or three times per day.
- Pregabalin not metabolized and is almost
entirely excreted unchanged in the urine
- It is not bound to plasma proteins and has
virtually no drug-drug interactions
- Half-life of pregabalin ranges from about
4.5 hours to 7.0 hours
- More than once per day dosing
LACOSAMIDE TOPIMARATE
- Amino acid-related compound that has - Topiramate is a substituted
been studied in both pain syndromes and monosaccharide
partial seizures - MOA:
- MOA: 1. involve blocking of voltage-gated sodium
1. Enhances slow inactivation of
voltage-gated Na+ channels ZONISAMIDE RUFINAMIDE
2. Binds to the collapsin-response MOA - Acts sodium Acts on
mediator protein, CRMP-2, thereby channel sodium
blocking the effect of neurotrophic - Act on voltage- channel
factors such as BDNF and NT3 on gated calcium
axonal and dendritic growth. channels
- Lacosamide is approved as adjunctive CLINICAL - partial and Lennox-
therapy in the treatment of partial-onset INDICATION generalized tonic- Gastaut
seizures with or without secondary clonic seizures syndrome
generalization in patients with epilepsy - infantile spasms Recalcitrant
16 years and older - myoclonias seizure
- Oral lacosamide is rapidly and completely ADVERSE Drowsiness,
absorbed in adults, with no food effect EFFECTS cognitive
- Peak concentrations occur from 1 to 4 impairment, and
hours after oral dosing, with an elimination potentially
half-life of 13 hours serious skin
rashes
TIAGABINE channels
- Derivative of nipecotic acid and was 2. appears to potentiate the inhibitory effect
"rationally designed" as an inhibitor of of GABA, acting at a site different from the
GABA uptake benzodiazepine or barbiturate sites
- MOA: 3. depresses the excitatory action of kainate
o Inhibitor of GABA uptake in both on glutamate receptors
neurons and glia - Clinical Indications:
o Inhibits the transporter isoform 1 o Lennox-Gastaut syndrome
(GAT-1) rather than GAT-2 or o West's syndrome
GAT-3 o Absence seizures
o Increases extracellular GABA - Rapidly absorbed (about 2 hours) and is
levels in the forebrain and 80% bioavailable
hippocampus - No food effect on absorption
o Prolongs the inhibitory action of - half-life is 20–30 hours
synaptically released GABA, but its - Birth control pills may be less effective in
most significant effect may be the presence of topiramate, and higher
potentiation of tonic inhibition estrogen doses may be required
- 90–100% bioavailability
- highly protein-bound
- half-life is 5–8 hours and decreases in the
presence of enzyme-inducing drugs
- Food decreases the peak plasma
concentration
DRUGS USED IN GENERALIZED SEIZURES
ETHOSUXIMIDE
- Phenosuximide, Ethosuximide, and
Methsuximide
- MOA:
o Inhibits calcium channels, reducing
the low threshold to the T-type
current
o Effect is on the thalamic neurons
- Clinical Indication: Absence seizures
- Absorption is complete following
administration of the oral dosage forms.
- Peak levels are observed 3–7 hours after
oral administration of the capsules.
- Ethosuximide is not protein-bound
- Interaction with Valproic acid causes:
o decrease in ethosuximide
clearance
o higher steady-state concentrations
owing to inhibition of metabolism
- Toxic effects
o Gastric and hematological
abnormalities
o Skin rashes
PHENSUXIMIDE & METHSUXIMIDE
- Phenylsuccinimides
- Methsuximide is generally considered
more toxic, and phensuximide less
effective, than ethosuximide.
- Some activity against maximal
electroshock seizures
- Methsuximide has been used for partial
seizures by some investigators.
VALPROIC ACID AND Na VALPROATE
- Carboxylic acid derivative
- MOA:
1. Blocks sustained high-frequency repetitive
firing of neurons in culture at
therapeutically relevant concentrations.
2. Its action against partial seizures may be
a consequence of this effect on Na+
currents.
3. Blockade of NMDA receptor-mediated
excitation may also be important.
4. Facilitate glutamic acid decarboxylase
(GAD), the enzyme responsible for GABA
synthesis.
- Valproate is well absorbed after an oral
dose, with bioavailability greater than
80%.
- Peak blood levels are observed within 2
hours.
- Food may delay absorption, and
decreased toxicity may result if the drug is
given after meals
- Competes for phenytoin plasma protein
binding sites
- Inhibits metabolism
o Phenytoin
o Phenobarbital
o Lamotrigine
- Toxicity
o Nausea, vomiting, and other
gastrointestinal complaints such as
abdominal pain and heartburn
o Reversible adverse effects, seen in
a small number of patients, include
weight gain, increased appetite,
and hair loss
VALPROIC ACID
- Better control than ethosuximide for tonic-
clonic seizure
- Hepatotoxic especially in children below 2
y/o
- Hepatic biotransformation
o Formation of a toxic metabolite
o Implicated in the hepatotoxicity of
the drug
OXAZOLIDINEDIONES
- TRIMETHADIONE
o remained the drug of choice for
absence seizures until the
introduction of succinimides in the
1950s
- Clinical Indication:
o Pentylenetetrazol-induced seizures
 - MOA: §TONIC PHASE
o Trimethadione raises the threshold §Less than 1 minute
for seizure discharges after §Abrupt loss of
repetitive thalamic stimulation consciousness
o Has the same effect on thalamic § Muscle rigidity
Ca2+ currents as ethosuximide § Respiratory arrest
(reducing the T-type calcium § CLONIC PHASE
current) § 2-3 minutes
- Trimethadione is rapidly absorbed peaks § Jerking of body muscles
within 1 hour after drug administration § Lip or tongue biting
- Not bound to plasma proteins § Fecal and urinary
- Trimethadione is completely metabolized incontinence
in the liver by demethylation to o Formerly called grand mal
dimethadione
- Dimethadione has an extremely long half- - ABSENCE SEIZURE, GENERALIZED
life (240 hours) and may exert the major o Impaired consciousness
antiseizure activity. o Often abrupt onset and brief
o Sometimes with automatism
CLINICAL USES o Loss of postural tone
- Drug choice is made on basis of o Enuresis
1. Established efficacy in the specific seizure o Begin in childhood and usually
state that has been diagnosed cease by the age of 20
3. Prior responsiveness of the patient o Formerly petit mal
2. Anticipated toxicity of the drug
- MYOCLONIC SEIZURES
- PARTIAL SEIZURES o Single or multiple myoclonic
SIMPLE muscle jerks
o Consciousness preserved
o Manifested variously
§ Convulsive jerking - STATUS EPILEPTICUS
§ Paresthesias o Series of seizures
§ Psychic symptoms (altered o Usually tonic-clonic
sensory perception, o Without recovery of consciousness
illusions, hallucinations, between attacks
affect changes) o Life-threatening emergency
§ Autonomic dysfunction
TOXICITY
- PARTIAL SEIZURES - Chronic therapy is associated with toxic
COMPLEX effects
o Impaired consciousness (Table on Adverse effects and complications of
o Preceded, accompanied, or the
followed by psychological use of antiepileptic drugs)
symptoms A. TERATOGENICITY
- Increased risk for congenital abnormalities
- TONIC-CLONIC SEIZURES, - Phenytoin
GENERALIZED o Fetal hydantoin syndrome
o 2 phases - Valproic acid
 o Neural tube defect (spina bifida) § Dependent on the
B. OVERDOSAGE TOXICITY frequency of neuronal
- Commonly used drugs are CNS discharge
depressants - Prolongation of the inactivated state of
o Respiratory depression Na+ channel and the refractory period of
o Management is supportive the neuron
o Flumazenil maybe used for - Phenobarbital and valproic acid
benzodiazepine overdose o May exert similar effects at higher
C. LIFE-THREATENING TOXICITY doses
- Valproic acid and patients taking multiple B. GABA-RELATED TARGETS
anticonvulsant drugs - Benzodiazepines
o Fatal hepatotoxicity has occurred o Interact with specific GABAA
with greatest risk to children receptor-chloride ion channel
younger than 2 years macromolecular complex
- Lamotrigine o Frequency of Cl- ion channel
o Skin rashes and life-threatening opening is increased
Steven-Johnson syndrome o Facilitates the inhibitory effects of
- Zonisamide GABA
o Severe skin reactions - Phenobarbital and other barbiturates
- Felbamate o Enhance the inhibitory actions of
o Aplastic anemia GABA
o Acute hepatic failure o Interact with different receptor site
D. WITHDRAWAL on Cl-
- Accomplished gradually to avoid increase ion channel
seizure frequency and severity o Increased duration of Cl- ion
- Withdrawal from anti-absence seizure channel
drugs is easier than in drugs used for opening
partial or generalized tonic-clonic seizure - GABA transaminase
states o An important enzyme in the
termination
MECHANISM OF ACTION of action of GABA
- General effect o Vigabatrin
o Suppress repetitive action § Irreversibly inactivates the
potentials in epileptic foci in the enzyme at therapeutic
brain plasma levels
o Different mechanisms are involved - GABA transaminase
in achieving this effect o Valproic acid
o In some cases, multiple § Inhibits the enzyme by at
mechanisms may contribute to very high concentrations
antiseizure activity o Tiagabine
§ Inhibits reuptake of GABA
A. SODIUM CHANNEL BLOCKADE transporters in neurons and
- Phenytoin, carbamazepine and glia
lamotrigine o Gabapentin
o Block voltage-gated sodium § Structural analogue of
channels GABA
o Rate dependent
 § Does not activate the
receptors - Gabapentin
§ Mechanism of action is o Used adjunctively in refractory
unclear cases
- Topiramate
C. CALCIUM CHANNEL BLOCKADE o Adjunctive drug
- Ethosuximide - Vigabatrin
o Inhibits low-threshold (T type) Ca2+ o Back-up drug
currents - Levetiracetam, tiagabine, zonisamide
o Pacemakers to generate rhythmic o Newer agents for partial seizures
cortical discharge
o Valproic acid has similar action B. ABSENCE SEIZURES
- Ethosuximide and valproic acid
D. OTHER MECHANISMS o Preferred drugs because of
- Valproic acid minimal sedation
o Neuronal membrane - Ethosuximide
hyperpolarization enhancing K+ o Uncomplicated absence seizures if
channel permeability patients can tolerate its GI side
- Phenobarbital effects
o Antagonist at some glutamate - Valproic acid
receptors o Patients with concomitant
- Felbamate generalized tonic clonic or
o Blocks glutamate NMDA receptors myoclonic seizures
- Topiramate - Clonazepam
o Blocks sodium channels o Alternative drug
o Potentiates the action of GABA o Causes sedation and tolerance
o May also block glutamate - Lamotrigine and topiramate
receptors o Also approved for use

CLINICAL USES C. MYOCLONIC SEIZURES

- Diagnosis of specific type of seizure is - Valproic acid
important for prescribing the most o Treatment of choice
appropriate drug or combination of drugs - Clonazepam
A. GENERALIZED TONIC-CLONIC AND o Can be effective
PARTIAL SEIZURES o High doses required cause
- Drug of choice drowsiness
o Valproic acid - Levetiracetam, lamotrigine and
o Carbamazepine zonisamide
o Phenytoin o Back up drugs
- Phenobarbital - Felbamate
o Primidone o Adjunct drug
o Alternative agent in adults o Hematotoxic and hepatotoxic
o Primary drug in infants
- Lamotrigine D. STATUS EPILEPTICUS
o Alternative - IV diazepam or lorazepam
o Usefulness is limited by its toxic o Effective in terminating attacks
potential o Short-term control
- IV phenytoin
o For prolonged therapy
o Highly effective
o Less sedating
o May cause cardiotoxicity (solvent
propylene glycol)
o Fosphenytoin (water soluble) is
safer
- Phenobarbital
o Can be used especially in children
- General anesthesia
o Very severe status epilepticus
o For patients who do not respond to
these measures

E. INFANTILE SPASMS
- Corticotropin and corticosteroids
o Commonly used
o Cushingoid side effect
- Benzodiazepines and other
anticonvulsants
o May also be used
o Efficacy is limited

F. OTHER CLINICAL USES

- Valproic acid, carbamazepine, phenytoin
and gabapentin
o Effective for bipolar disorders
- Gabapentin
o Drug of choice for trigeminal
neuralgia
- Phenytoin
o Migraine