Antiepileptic Drugs
Types of Seizures
Generalized Seizure
Partial/Focal Seizure
Simple Partial Seizure – conciousness is not
Absence/Petit mal Seizure
impaired
 With motor signs
 With sensory symptoms
 With autonomic symptoms & signs
 With psychic symptoms

Complex Partial/Temporal
lobe/Psychomotor Seizure – loss of
Myoclonic Seizure
conciousness
 Simple partial onset followed concious
impairment
 Concious impairment at the onset
Partial seizures evolving to secondarily
generalized seizures



Simple partial seizures evolving to
generalized seizures
Complex partial seizures evolving to
generalized seizures
Simple partial seizures evolving to complex
partial seizures evolving to generalized
seizures



Involve an interruption to consciousness
where the person experiencing the seizure
seems to become vacant and
unresponsive for a short period of time
(usually up to 30 seconds)
Slight muscle twitching may occur
Involve an extremely brief (< 0.1 second)
muscle contraction
Result in jerky movements of muscles or
muscle groups
Tonic Seizure


Myoclonus that are regularly repeating at
a rate typically of 2-3 per second
In some cases, the length varies.
Tonic-clonic/Gran Mal Seizure


Involve an initial contraction of the muscles
(tonic phase) which may involve
o Tongue biting
o Urinary incontinence
o Absence of breathing
This is followed by rhythmic muscle
contractions (clonic phase)
Atonic Seizures

Involve the loss of muscle tone, causing the
person to fall to the ground
Continous Seizure
Status Epilepticus



Refers to continuous seizure activity with no
recovery between successive seizures
When the seizures are convulsive, it is a lifethreatening
A tonic-clonic seizure lasting longer than 5
minutes is usually considered grounds for
calling the emergency services.
Epilepsia Partialis Continua
Rare type of focal motor seizure (hands
and face)
 Recurs every few seconds or minutes for
extended periods (days or years)
 It is usually due to
o Strokes in adults
o Focal cortical inflammatory processes in
children (Rasmussen's encephalitis)

The major mechanism of actions of antiepileptic drugs are
1. Enhancement of GABAergic inhibitory transmission
2. Inhibition of excitatory (glutamatergic) transmission
3. Modification of ionic conductance
Classification of Antiepileptic drugs
1. Based on Mechanism of Actions
a. Drugs that inhibit Na+ influx by inhibiting Na+ voltage channels
i. Phenytoin
ii. Carbamazepine
iii. Valproic acid
iv. Lamotrigine
v. Lacosamide
b. Drugs that inhibit Glutamatergic receptors
i. Felbamate
c. Drugs that augment the GABAergic inhibitory transmission
i. Phenobarbital
ii. Benzodiazepine
iii. Tiagabine
iv. Vigabatrin
d. T-type Ca2+ channels blockers
i. Ethosuximide
ii. Valproic acid
e. Mixed group
i. Levetiracetam
ii. Topiramate
iii. Valproic acid
iv. Phenobarbital
2. Based on Clinical Usage
a. Drugs used in partial seizures and tonic-clonic generalized seizures
i. Older Generation
1. Cyclic Ureides
a. Phenytoin
b. Primidone
c. Phenobarbital
d. Ethosuximide
2. Carbamazepines
3. Valproic acid
ii. Newer Generation
1. Lamotrigine
2. Levetiracetam
3. Gabapentin
4. Topiramate
5. Vigabatrin
6. Lacosamide
b. Drugs used in generalized seizures
i. Ethosuximide
ii. Valproate acid
Regimen of Antiepileptic Therapy
1. Partial Seizures
a. Carbamazepine (OR)
b. Phenytoin
2. Generalized Seizures
a. Carbamazepine (OR)
b. Phenytoin
3. Secondary Generalized Seizure
a. Carbamazepine
4. Absence Seizures
a. Ethosuximide
5. Myoclonic Seizure
a. Valproate acid
Drugs
Phenytoin

Have narrow therapeutic
index
Elimination Pattern
Dose dependent
Pattern of elimination
o Very low blood level
 Follows first order
elimination
o Therapeutic blood level
 Max capacity of hepatic
metabolism has reached
o Slightly higher level than
that of therapeutic’s
 Follows zero order
elimination
 Slight ↑ in dose may
markedly ↑phenytoin
level
 Half life
o Once followed the zero
order elimination, half life
is unpredictable
(↑disorderly)
o Leads to
 Steady state
concentration cant be
achieved in routine
fashion
 Pts quickly develops
toxicity


Mechanism of
Action
Pharmacokinetics
Absorption
 Readily absorp orally
(depends on formulation)
 Absorption after IM admin
is unpredictable
o Accumulation of
Phenytoin in skeletal
muscle may occur
o Therefore, this route of
admin should be avoided
Distribution
 Highly plasma protein
binding
 Accumulate in
o Brain
o Liver
o Muscle
o Fat
Metabolism
 Undergoes CYP450
hepatic metabolism
 Shows to be CYP450
inducer
Excretion
 Excreted through urine
 Some in unchanged form
Blocks the
activated state of
Na+ voltage
channels
o Leads to the
blockade of
high frequency
firing of neurons
 ↓synaptic release
of Glutamate

Clinical
Indication
1. Generalized

tonic-clonic/
Gran mal seizure
2. Partial seizures

Should not be
given in Absence

seizures
 It may
exacerbate the 
condition
Drug Interactions

o
o
o
o
Adverse Effects
Phenytoin is highly plasma protein
binding
Other highly plasma protein bound
drugs may displace phenytoin
 Phenylbutazone
 Sulfonamides
Displacement of phenytoin may result
in
 ↓total plasma phenytoin level
 ↑free plasma phenytoin
 ↑toxicity
↓plasma protein binding in
 Hypoalbumineamia
 Renal failure
 Hepatic disease
Has affinity to Thyroid Binding Globulin
 May interfere the reading during
thyroid function test
Nystagmus
(involuntary
movement of
eyes)
Diplopia (double
vision)
Ataxia (loss of
coordination and
muscle movement)
Gingivial
hyperplasia
o Happens in poor
oral hygiene
 Hirsutism
 Neuropathy
Contraindication
Pregnancy
 May lead to
o Fetal Hydantoin
Syndrome
 Spina bifida
Drugs
Carbamazepine

Available only in oral form
Contraindication
Pregnancy
Mechanism of
Action
Pharmacokinetics
Absorption
 Readily absorp orally
 Complete absorption in all
pts
 Becomes slower if taken by
food
o Beneficial in pts taking
higher daily dose as to
tolerate side effects
Distribution
 Peak concentration
achieved after 6-8 hours
 Low volume of distribution
 70% bound to plasma
protein
o Other drugs do not show
any displacement of
carbamazepine
Blocks the
inactivated state
of Na+ voltage
channels
o Leads to the
blockade of
high
frequency
firing of
neurons
 ↓synaptic release
of Glutamate

Clinical
Indication


Generalized
tonic-clonic/
Gran mal seizure
Partial seizures
Should not be given
in Absence seizures
 It may
exacerbate the
condition
Drug Interactions
Carbamazepine is a CYP450 enzyme
inducer
 Carbmazepine may induce
metabolism of
o Phenytoin
o Ethosuximide
o Valproic acid
o Clonazepam
Metabolism
 Undergoes CYP450 hepatic  Metabolism of carbamazepine can be
inhibited (leads to ↑serum level) if given
metabolism
with
o Carbamazepine-10,11o Valproic acid
epoxide seems to have
 Metabolism of carbamazepine can be
anticonvulsant activity
induced (leads to ↓serum level) if given
 Shows to be CYP450 inducer
with
o Phenobarbital
Excretion
o Phenytoin
 Excreted through urine
Adverse Effects







Diplopia
Ataxia
GIT upsets
Hyponatreamia
Water
intoxification
Aplastic anemia
Agranulocytosis
Drugs
Valproic Acid
Contraindication
Pregnancy
 May cause
o Spina bifida
o Cardiovascular anomalies
o Orofacial anomalies
o Digital anomalies
Mechanism of
Action
Pharmacokinetics
Absorption
 Readily absorp orally
 Bioavailibility up to 80%
 Will be ionized upon
entering the blood
circulation
Distribution
 Highly plasma protein
binding of up to 90%
 Accumulate in
o Extracellular water cause
couldn’t pass the plasma
membrane
Metabolism
 Undergoes CYP450
hepatic metabolism
Excretion
 Excreted through urine
 Some in unchanged form
Blocks the
inactivated state
of Na+ voltage
channels
o Leads to the
blockade of
high frequency
firing of neurons
 Blocks the NMDA
receptors
 ↑GABA level in
the brain
o ↑activity of
Glutamic Acid
Decarboxylase
(GAD)
o ↑GABAergic
inhibitory
transmission

Clinical
Indication





Generalized
tonic-clonic/
Gran mal seizure
Partial seizures
Generalized
seizures
Absence
seizures
Myoclonic
seizures
Drugs Interaction
Displace phenytoin from plasma
protein
 Inhibits metabolism of
o Phenobarbital
o Phenytoin
o Carbamazepine

Adverse Effects







GIT upset
Fine tremor
Weight gain
Alopecia
Increase in
appetite
Hepatotoxicity
Thrombocytopenia
Drugs
Felbamate
Ethoxusimide
Phenobarbital
Mechanism of
Action
Pharmacokinetics
Absorption
 Readily absorp orally
Metabolism
 Undergoes CYP450
hepatic metabolism
Excretion
 Excreted through urine

Absorption
 Complete absorption
following oral admin
Distribution
 Does not bound to
plasma protein
Metabolism
 Metabolizes through
hydroxylation
 Long half life of 40hours
Excretion
 Excreted through urine

Absorption
 Complete absorption
following oral admin
Distribution
 Does not bound to
plasma protein
Metabolism
 Metabolize though liver
 No active metabolite
Excretion
 Excreted through urine

Clinical
Indication
Block of NMDA

receptors

↑GABAA receptor
responses
↓the lowthreshold current
of Ca2+ T-type
channels
 This channels are
located at the
Thalamus
o Responsible for
generation of
rhythmic
cortical
discharge in
absence seizure
 ↑phasic GABAA
phasic receptor
responses
 ↓excitatory
synaptic
responses






Adverse Effects
Partial seizures

Generalized

seizures
associated with
LennoxGastaut
syndrome in
children
Absence

seizures
o
o
o





Aplastic anemia
Severe hepatitis
Generalized
tonic-clonic/
Gran mal
seizure
Partial seizures
Generalized
seizures
Neonatal
seizures
Status
epilepticus
Sedation
Cognitive
problems
Ataxia
Hyperactivity
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

Gastric distress
Pain
Nausea
Vomitting
Fatigue
Headache
Dizziness
Hiccup
Euphoria
Drugs
Diazepam
Benzodiazepine
Mechanism of
Action
Pharmacokinetics
Absorption
 Readily absorp
orally
 Rectal admin gives
peak
concentration
within 1hour
Distribution
 90% of bioavailibilty
Metabolism
 Metabolize though
liver
 Produce numerous
active metabolites
Excretion
 Excreted through
urine
Absorption
 Readily absorp
orally
Distribution
 80% bioavailibility
Metabolism
 Metabolize though
Clonazepam
liver extensively
 No active
metabolite
Excretion
 Excreted through
urine

↑phasic GABAA
phasic receptor
responses
Clinical Indication

Status epilepticus



Absence seizures
Myoclonic seizure
Infantile spasm
Adverse Effects

Sedation
Drugs
Topiramate
Lamotrigine
Mechanism of
Action
Pharmacokinetics
Absorption
 Readily absorp
orally
Distribution
 Not bound to
plasma protein
Metabolism
 Metabolize though
liver extensively
 No active
metabolite
Excretion
 Excreted through
urine
 40% excreted
unchanged

Absorption
 Readily absorp
orally
Distribution
 Not bound to
plasma protein
Metabolism
 Metabolize though
liver extensively
 No active
metabolite
Excretion
 Excreted through
urine

Clinical Indication
Blocks the
activated state of
Na+ voltage
channels
o Leads to the
blockade of high
frequency firing
of neurons
 ↑GABAA receptor
responses
 ↓excitatory synaptic
responses

Prolong inactivation
of Na+ voltage
channels
Blocks presynaptic
Ca2+ voltage
channels
↓release of
Glutamate











Adverse Effects
Generalized tonicclonic/ Gran mal
seizure
Partial seizures
Generalized
seizures
Absence seizures
Migraine




Sedation
Cognitive slowing
Confusion
Paraesthesia
Generalized tonicclonic/ Gran mal
seizure
Partial seizures
Generalized
seizures
Absence seizures
Myoclonic seizures




Dizziness
Headache
Diplopia
Rash