Epilepsy

Epilepsy is a central nervous system disorder

(neurological disorder) in which nerve cell
activity in the brain becomes disrupted,
causing seizures or periods of unusual
behavior, sensations and sometimes loss of
consciousness.
 Epilepsy
 Epilepsy is a disorder characterized by
recurring seizures (also known as “seizure
disorder”)

 A seizure is a brief, temporary disturbance in

the electrical activity of the brain
 Epilepsy
All brain functions -- including feeling, seeing,
thinking, and moving muscles -- depend on
electrical signals passed between nerve cells
in the brain

A seizure occurs when too many nerve cells in

the brain “fire” too quickly causing an
“electrical storm”
 Focal (Partial)seizures
 When seizures appear to result from abnormal activity in just one area of
brain, they're called focal (partial) seizures.

 Partial seizures without loss of consciousness (simple partial seizures).

Don't cause a loss of consciousness.
Alter emotions or change the way things look, smell, feel, taste or sound. result in
involuntary jerking of a body part, such as an arm or leg, and spontaneous sensory
symptoms such as tingling, dizziness and flashing lights.

 Focal dyscognitive seizures (complex partial seizures)

change or loss of consciousness or awareness. (1-2 min long)
stare into space and not respond normally to our environment or
perform repetitive movements, such as hand rubbing, chewing, swallowing or
walking in circles. (Purposeless movement)
 Generalized seizures

• Seizures that appear to involve all areas of the brain are called generalized
seizures.

• Absence seizures/Petit mal seizures,

often occur in children and are characterized by staring into space or subtle
body movements such as eye blinking or lip smacking. These seizures may
occur in clusters and cause a brief loss of awareness. (few Seconds)
without loss of postural control
occurs 100 of times per day

Tonic seizures. Tonic seizures cause stiffening of muscles. These seizures

usually affect muscles in back, arms and legs and may cause us to fall to the
ground.
Atonic seizures. Akinetic/Atonic seizures, also known as
drop seizures, cause a loss of muscle control, which
may cause to suddenly collapse or fall down
Consciousness is briefly impaired
Relaxation of all muscles

Clonic seizures. Clonic seizures are associated with

repeated or rhythmic, jerking muscle movements.
These seizures usually affect the neck, face and arms.
Myoclonic seizures. Myoclonic seizures usually appear as
sudden brief jerks or twitches of our arms and legs.
Shock-like momentary contraction of muscles of a limb or
the whole body
Sudden and brief contraction of muscle

Tonic-clonic seizures. grand mal seizures, are the most

dramatic type of epileptic seizure and can cause an abrupt
loss of consciousness, body stiffening and shaking, and
sometimes loss of bladder control or biting tongue
Status epilepticus. A state of continuous
seizure activity lasting more than five minutes,
or having frequent recurrent seizures without
regaining full consciousness in between them.

People with status epilepticus have an

increased risk of permanent brain damage and
death
HISTORY of Antiepileptic Drugs

• Bromides (1857)
• Phenobarbital (1912)
• Phenytoin (1938)
• Ethosiximide, Carbmazepine
• New anticonvulsants
vigabatrin, gabapentin, lamotrigine, topiramate,
oxcarbazepine, levetiracetam, pregabalin etc.
 1. Carboxamides (enzyme inductors – CYP450):
Carbamazepine (+ neuropathic pain – n. trigeminus,
postherpetic pain, etc.), Oxcarbazepine
2. Hydantoins: Phenytoin (enzyme inductor)
ANTISEIZURE DRUGS

3. Barbiturates (Phenobarbital – enzyme inductors) and their

analogues (Primidone – prodrug)
4. Succinimides: Ethosuximide
5. Valproates (enzyme inhibitors): Sodium valproate
6. Benzodiazepines: Clonazepam, Lorazepam, Nitrazepam
7. GABA analogues: Gabapentin, Tiagabine
8. Hetereogenic anticonvulsants: Lamotrigine, Levetiracetam,
Pregabalin (partial seizures, peripheral neuropathic pain),
Topiramate, Vigabatrin
MECHANISM OF ACTION OF ANTIEPILEPTIC DRUGS
Antiepileptics inhibit the neuronal discharge or its spread in one or
more of the following ways:
(1) Enhancing GABA synaptic transmission: barbiturates, benzo-
diazepines, gabapentin, levetiracetam, tiagabine, vigabatrin, topira-
mate, valproate; the result is increased permeability to chloride ion,
which reduces neuronal excitability. Valproate and topiramate block
GABA transaminase and tiagabine blocks reuptake of GABA.
(2) Reducing cell membrane permeability to voltage-dependent
sodium channels: carbamazepine, lamotrigine, oxcarbazepine,
phenytoin, topiramate, valproate.
(3) Reducing cell membrane permeability to calcium T-channels:
valproate, ethosuximide; the result is diminishing of the generation
of action potential.
(4) Inhibiting excitory neurotransmitter glutamate: lamotrigine.
 GABA
Barbiturates
Benzodiazepines
Gabapentin
Levetiracetam
Tiagabine
Topiramate
Valproate
Vigabatrin

Na+ Ca2+
Carbamazepine
Ethosuximide
Lamotrigine
Levetiracetam
Oxcarbazepine
Pregabalin
Phenytoin
Valproate
Topiramate
Valproate
Antiseizure drugs
enhanced
GABA
synaptic
transmission
Antiseizure drugs, enhanced Na+ channel inactivation
 Na Channels
• Voltage- gated sodium channels are critical for action potential (AP)
generation and propagation .
• The sodium channel exists in three principal conformational states:

1. the channel is in the resting closed state;

2. the channel opens and permits the conduction of sodium ions;

3. the channel then enters a nonconducting, inactivated state.

Phenytoin, lamotrigine, oxcarbazepine, and car- bamazepine bind to

and stabilize the inactivated state of the sodium channel
 Calcium channels
 Calcium channels are also targets for AEDs, as they regulate not
only neuronal excitability but also neurotransmitter release

 The voltage-gated calcium channels expressed in the brain can

be subdivi- ded into four main classes, L-, P/Q-, N-, and T- type
channels

 N- and P/Q-type channels-Gabapentin, Pregabalin

 T- type –ethosuximide, zonisamide and valproate

• GABAergic system Gamma amino butyric acid
(GABA) is the major inhibitory
neurotransmitter in the brain.
Antiseizure drugs, induced reduction of
current through T-type Ca2+ channels.
 Mechanism of action

 The exact mechanism by which levetiracetam

acts to treat epilepsy is unknown.
 However, the drug binds to a synaptic vesicle
glycoprotein, SV2A, and inhibits presynaptic
calcium channels reducing neurotransmitter
release and acting as a neuromodulator.
 This is believed to impede impulse conduction
across synapses
 Partial Onset Seizures

Adults 16 Years and Older

 Treatment should be initiated with a daily dose of 1000 mg/day,
given as twice-daily dosing (500 mg twice daily).

 Additional dosing increments may be given (1000 mg/day additional

every 2 weeks) to a maximum recommended daily dose of 3000 mg

Pediatric Patients
• 1 Month to < 6 Months
• Treatment should be initiated with a daily dose of 14 mg/kg in 2
divided doses (7 mg/kg twice daily). The daily dose should be
increased every 2 weeks by increments of 14 mg/kg to the
recommended daily dose of 42 mg/kg (21 mg/kg twice daily).
 Primary Generalized Tonic-Clonic Seizures

Adults 16 Years and Older

 Treatment should be initiated with a dose of 1000 mg/day, given as
twice-daily dosing (500 mg twice daily).

 Dosage should be increased by 1000 mg/day every 2 weeks to the

recommended daily dose of 3000 mg.

Pediatric Patients Ages 6 to <16 Years

 Treatment should be initiated with a daily dose of 20 mg/kg in 2
divided doses (10 mg/kg twice daily). The daily dose should be
increased every 2 weeks by increments of 20 mg/kg to the
recommended daily dose of 60 mg/kg (30 mg/kg twice daily).
• Overall, LEV was well tolerated by all patient
groups. The favorable adverse event profile
suggests that LEV might be suitable for use by
elderly patients.
 Sodium Valproate
• Current evidence suggests that women taking
valproate in the first trimester run the highest
risk for congenital malformations, an effect that
is probably dose-related

• there is a substantial risk of major

malformations including spina bifida when
valproate is used as monotherapy or with other
drugs.
 Carbamazepine
 For almost 20 years reports have associated
carbamazepine with an increased risk of
structural birth defects including spina bifida.

Phenytoin
 Phenytoin is now used less frequently in women
with epilepsy. It has been reported to produce an
increase in major malformations.
 Juvenile Myoclonic Epilepsy
 Temporal Lobe Epilepsy
 Complex Partial Seizures
 Myoclonic Seizures
 Refractory Seizures
 Secondarily Generalized Seizures
 Simple Partial Seizures
 Tonic-clonic Seizures
 The most severe side effects
• According to the FDA’s Alert, among the
patients with epilepsy in these drug studies, 1
out of 1000 people taking the placebo
(inactive substance) showed suicidality
compared to approximately 3.5 out of 1000
people who took an AED
 Levetiracetam- Common Side Effects

• Patients treated with Levetiracetam should be

monitored for the emergence or worsening of
depression, suicidal thoughts or behaviour,
and/or any unusual changes in mood or
behaviour.
 Levetiracetam-Common
Side Effects
• somnolence

• Pharyngitis

• Headache
 Side-effects
• fatigue,coordination difficulties,behavioral
abnormalities.Mood or mental changes,
including agitation, anxiety,apathy,
depersonalisation, and depression,

• Abnormal behaviour, aggression, anger,

confusion,hallucinations, irritability and
psychotic disorders
• Absorption of levetiracetam is rapid, with peak plasma
concentrations occurring in about an hour following
oral administration in fasted subjects.

• The oral bioavailability of levetiracetam tablets is 100%

.

• Food does not affect the extent of absorption of

levetiracetam but it decreases Cmax by 20% and delays
Tmax by 1.5 hours
• Levetiracetam and its major metabolite are
less than 10% bound to plasma proteins;
clinically significant interactions with other
drugs through competition for protein binding
sites are therefore unlikely
• Levetiracetam plasma half-life in adults is 7 ± 1
hour and is unaffected by either dose or
repeated administration.

• Levetiracetam is eliminated from the systemic

circulation by renal excretion as unchanged
drug which represents 66% of administered
dose.
 Special Population

 Pregnanacy: GROUP-C
 There are no adequate and well-controlled studies in pregnant
women.
 Levetiracetam should be used during pregnancy only if the
potential benefit justifies the potential risk to the fetus.

Nursing Mothers
 Levetiracetam is excreted in breast milk. Because of the potential
for serious adverse reactions in nursing infants from Levetiracetam,
a decision should be made whether to discontinue nursing or
discontinue the drug, taking into account the importance of the
drug to the mother.
 Geriatric Use :Levetiracetam is known to be substantially excreted by the kidney,
and the risk of adverse reactions to this drug may be greater in patients with
impaired renal function.

 Because elderly patients are more likely to have decreased renal function, care
should be taken in dose selection, and it may be useful to monitor renal function.

 Use In Patients With Impaired Renal Function Clearance of levetiracetam is

decreased in patients with renal impairment and is correlated with creatinine
clearance. Caution should be taken in dosing patients with moderate and severe
renal impairment and in patients undergoing hemodialysis.

 Hepatic Impairment:No dose adjustment is needed for patients with hepatic

impairment.
•  Levetiracetam has a novel structure and unique mechanisms of action.
Unlike other AEDs, the mechanisms of action of levetiracetam appear to
involve neuronal binding to synaptic vesicle protein 2A,
• inhibiting calcium release from intraneuronal stores, opposing the activity of
negative modulators of GABA- and glycin-gated currents and inhibiting
excessive synchronized activity between neurons.
• In addition, levetiracetam inhibits N-type calcium channels.
• Levetiracetam is associated with rapid and complete absorption, high oral
bioavailability, minimal metabolism that consists of hydrolysis of the
acetamide group, and primarily renal elimination.

• It lacks cytochrome P450 isoenzyme-inducing potential and is not associated

with clinically significant pharmacokinetic interactions with other drugs,
including other AEDs.