ANTIEPILEPTIC

DRUGS
Dr. Hiwa K. Saaed
Department of Pharmacology & Toxicology
College of Pharmacy
University of Sulaimani 2014-15
 Antiepileptic drugs (AEDs)
 Definitions and Terminology
 Historical overview
 Classification of AEDs
 Etiologies and risk factors
 Classifications of seizures
 Management of epilepsy
 Principles of treatment
 Classification of Antiepileptic
 Mechanism of Antiepileptic drug
 Special cases: pregnancy
 Vagal nerve stimulation and deep brain stimulation
 Epilepsy:
Epilepsy: is a disorder of cerebral cortex characterized by
recurrent (periodic and unpredictable) seizures. often
accompanied by episodes of unconsciousness and/or
amnesia.
Globally, epilepsy is the third most common neurologic
disorder after cerebrovascular and Alzheimer’s disease.
Epilepsy is not a single entity but an assortment of different
seizure types and syndromes originating from several
mechanisms that have in common the sudden, excessive,
and synchronous discharge of cerebral neurons.
Seizures
Seizures are sudden, transitory, and uncontrolled episodes
of brain dysfunction, resulting from abnormal electrical
discharge in cerebral neuronal cells, associated with
prolonged depolarisation of cerebral neurons result in
motor, sensory or behavioral changes.
• The site of origin of the abnormal neuronal firing determines the
symptoms that are produced. For example,
 if the motor cortex is involved, the patient may experience
abnormal movements or a generalized convulsion.
 Seizures originating in the parietal or occipital lobe may include
visual, auditory, and olfactory hallucinations.
Seizures may
 Remain localised (focal epilepsy)
 Spread (generalised epilepsy)
 ETIOLOGY OF SEIZURES
• Idiopathic: In most cases, epilepsy has no identifiable cause.
• changes in physiologic factors, such as an alteration in
 blood gases, pH (extreme acidosis or alkalosis), electrolytes
(hyponatrmia, hypocalcemia), and blood glucose (hypglycemia)
• changes in environmental factors, such as
 sleep deprivation, alcohol intake (rapid withdrawal from
depressants), and stress.
• Epilepsy can be due to an underlying
 Genetic (heredity),
 Structural; CNS infection i) meningeal infection ii) tumors
 or metabolic defects
 High Fever
 or an unknown cause.
Classification of Epileptic Seizures
 I. Partial (Focal) Seizures
1. Partial (focal) seizures (60%): they start locally in a
certain site, its divided into:
A. Simple partial: may occur at any age, without loss of
consciousness,
1. Jacksonian motor epilepsy: convulsion in single group of muscles or
limb.
2. Jacksonian sensory epilepsy or paraesthesia in some localized
region.

B. Complex partial (psychomotor or temporal lobe):

 it is associated with loss of consciousness for about 30 seconds
to 2 minutes.
 Disturbances of cognitive, affective, and psychomotor (chewing
movement, diarrhoea, urination) or sensory hallucinations (smell
or taste).
 80% of individuals experience their initial seizures before 20 years of age
 II. Generalized Seizures
 begin locally, rapidly spread,
 affect the whole brain, both hemispheres
 may be convulsive or non convulsive,
 immediate loss of consciousness.
It is divided into:
1. Tonic-clonic (grand-mal)
2. Absence (petit-mal)
3. Myoclonic
4. Febrile seizures
5. Status epilepticus
 II. Generalized Seizures
1) Tonic-clonic. Patient fall in convulsion & may bite his
tongue & may lose control of his bladder or bowel.
2) Tonic. Some patients, after dropping unconscious
experience only the tonic or clonic phase of seizure.
3) Atonic ( akinetic). Starts between the ages 2-5 yrs. The
pt’s legs simply give under him & drops down.
4) Absence: Loss of consciousness without involving
motor area. Most common in children ( 4-12 yrs ).
 II. Generalized Seizures
5) Myoclonic: rare, occur at any age
Sudden, brief shock like contraction which may involve
the entire body or be confined to the face, trunk or
extremities. May reoccur for several minutes
6) Febrile Seizures: young children (3M-5 years) with
illness accompanied by high fever. Consist of generalized
tonic-clonic convulsion with short duration.
7) Status epilepticus (reoccurring seizure): Continuous (a
series of rapid recurrent seizures) tonic-clonic without
intervening return of consciousness. It is life-threatening
emergency.
 First aid for seizures

Do
• Remove harmful objects nearby
• Cushion their head
• aid breathing by gently placing them
in recovery position
Don’t
• Restrain the person movement
• Put anything in the person’s mouth
• Give them anything to eat and drink
until they are fully recovered
 Management of Epilepsy
Therapy is symptomatic in that the majority of drugs
prevent seizures, but neither effective prophylaxis or cure
is available.
The goal of the therapy is to improve the patient’s quality
of life through:
1. maximize the seizure control
2. minimize drug side effects
In general, seizures can be controlled with one
medication in approximately 75% of patients.
Patients may require more than one medication in order
to optimize seizure control, and some patients may never
obtain total seizure control.
 Management of Epilepsy

Antiepileptics are indicated when there is two or more

seizures occurred in short interval (6m-1year)
Drug choice is based on:
1. Classification of seizures.
2. Patient’s age & health state
3. Data on efficacy, tolerability, safety and
pharmacokinetics
 Starting Treatment
start low, go slow

• Rx should always be started with a single

drug at a small dose
• All common side-effects must be discussed
• teratogenicity and contraception if applicable
• Importance of compliance should be stressed
• Careful titration is a must
- start low, go slow
 Historical overview
• Modern treatment of seizures started in 1850 with the
introduction of bromides, which was based on the
theory that epilepsy was caused by an excessive sex
drive.
• In 1910, phenobarbital , became the drug of choice for
many years.
• A number of medications similar to Phenobarbital were
developed, including primidone.
• In 1940, phenytoin has become a major first-line
antiepileptic drug (AED) in the treatment of partial and
secondarily generalized seizures.
 Historical overview
• In 1968, carbamazepine (CBZ) was approved, initially
for the treatment of trigeminal neuralgia; later, in 1974, it
was approved for partial seizures.
• Ethosuximide has been used since 1958
• Valproate (VPA) was licensed in Europe in 1960 and in
the United States in 1978, and now is widely available
throughout the world.
 Classification of Anticonvulsants
Classical Newer after 1990
before 1990 Felbatol (felbamate) 1993
Phenytoin Neurontin (gabapentin) 1994
Phenobarbital Lamictal (lamotrigine) 1995

Primidone Topamax (topiramate) 1996

Gabitril (tiagabine) 1998
Carbamazepine
Keppra (levetiracetam) 1999
Ethosuximide
Trileptal (oxcarbazepine) 2000
Valproic Acid
Zonegran (zonisamide) 2000
Benzodiazepines
Lyrica (pregabalin) 2005
Potiga (Ezogabine)
Aptiom (Eslicarbazepine)
Banzel (Rufinamide), VIMPAT (Lacosamide), other
 Anti-epileptic drugs (AEDs)

AEDS act by:

I. Block the initiation of the electrical discharge from the
focal area
II. Prevent the spread of abnormal electrical discharge to
adjacent brain area
AEDs prevent depolarisation of neurones by:
 Modification of ion conductance (direct membrane
stabilisation)
 inhibition of excitatory (glutamergic) activity
 stimulation of inhibitory (GABAergic) transmission.
 They do their actions by:

-↓ axonal conduction by preventing Na+ influx through fast

Na+ channels

Example:
Carbamazepine, oxcarbamazepine, phenytoin, also at
high doses barbiturates and valproate. Lamotrigine,
felbamate, topiramate

-↓ presynaptic Ca+2 influx through type T channels in

thalamic neurons

Example:
Ethosuximide, valproic acids, lamotrigine
 Effects of three antiepileptic drugs on high
frequency discharge of cultured neurons

Block of sustained high frequency repetitive firing of

action potentials.
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 They do their actions by:

-↑ inhibitory tone through

1. facilitation of GABA-mediated hyperpolarization (Barbs,
BZs),
2. inhibiting GABA metabolism valproic acid and vigabatrin
3. or action on the reuptake of GABA (as with tiagabine)
-↓ excitatory effects of glutamic acid
1. lamotrigine, topiramate (block AMPA receptors);
2. Felbamate, Phenobarbital (blocks NMDA receptors)
Mechanism of action of AEDs
 Classification of AEDs

Ion Channels# Enhance Inhibitory aa # Inhibit

Na+: Benzodiazepines Excitatory aa
Phenytoin, (diazepam, clonazepam) Felbamate
Carbamazepine, Barbiturates (phenobarbital) Topiramate
Lamotrigine Valproic acid
Topiramate Gabapentin
Valproic acid Vigabatrin
# For general tonic-clonic Topiramate
and partial seizures
Felbamate
Ca++ #:
# Most effective in myoclonic but also in
Ethosuximide tonic-clonic and partial
Valproic acid Clonazepam: for Absence
Zonisamide
# For Absence seizures
 TREATMENT OF SEIZURES
Seizure disorder Drugs
Tonic-clonic (Grand mal) Carbamazepine or
Drug of Choice Valproate or
Phenytoin or
Phenobarbital
Alternatives: Topiramte
Lamotrigine (as adjunct or alone)
Gabapentin (as adjunct)

Partial (simple or complex) Carbamazepine or Topiramte or

Drug of choice Phenytoin or Valproate

Alternatives: Phenobarbital
Lamotringine (as adjunct or alone)
Gabapentin (as adjunct )
 Treatment
TREATMENT contd cont,d
OF SEIZURES
Absence ( petit mal) DOC* Ethosuximide or Valproate

Alternatives: Clonazepam
Lamotrigine
Myoclonic, Atonic DOC Valproate

Alternatives: Clonazepam

Status Epilepticus DOC Diazepam, i.v.

or Phenytoin, i.v. or Vaproate
Alternatives: Phenobarbital, i.v
Febrile Seizures Diazepam, rectal**, I.V
Valproate
* DOC = Drug of choice Corticotropin (IM) or prednisolone
** Preferred
 AEDs pharmacokinetics

Most classical antiepileptic drugs exhibit similar

pharmacokinetic properties.
• Good absorption (although most are sparingly soluble).
• Low plasma protein binding (except for phenytoin, BDZs,
valproate, and tiagabine).
• Conversion to active metabolites (carbamazepine,
primidone, fosphenytoin).
 PHENYTOIN Adverse effects

• Ataxia and nystagmus.

• Cognitive impairment.
• Hirsutism
• Gingival hyperplasia, Coarsening of facial features.
• folate dependent megaloblastic anaemia,
• Osteomalacia,
• Inhibition of ADH,
• inhibition of insulin secretion→hyperglycemia and
glycosuria
• Hypoprothrominemia—coagulopathy
• Exacerbates absence seizures.
PHENYTOIN TERATOGENICITY

Fetal hydantoin syndrome

include:
• cleft lip, cleft palate
• congenital heart disease
• slowed growth
• mental deficiency
 CARBAMAZEPINE Pharmacokinetics

• Absorbed slowly, enters brain rapidly

• Potent inducer of hepatic drug metabolising enzymes
• own half life reduces over 2-3 weeks
• increases metabolism of theophylline, warfarin and
various hormones
• complex drug interactions with other anticonvulsant
agents
 CARBAMAZEPINE Adverse effects

• Stupor, coma,
• respiratory depression,
• drowsiness, dizziness,
• vertigo, ataxia,
• blurred vision, diplopia,
• bradycardia,
• skin rashes,
• GI upsets.
• Hyponatremia in elderly
• The 10,11-epoxide metabolite →blood dyscrasias
(leukopenia and aplastic anaemia), and serious
liver toxicity.
 OXCARBAZEPINE (Trileptal)

• 10-KETO DERIVATIVE OF CARBAMAZEPINE

• With improved toxicity profile.
• Less potent than carbamazepine.
• Active metabolite.

Mechanism of action, similar to carbamazepine

Adverse effects:
 Hyponatremia,
 Less hypersensitivity, and induction of hepatic
enzymes than with carbamazepine.

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 Eslicarbazepine

• Eslicarbazepine acetate is a prodrug that is converted to

the active metabolite eslicarbazepine (S-licarbazepine) by
hydrolysis.
• S-licarbazepine is the active metabolite of oxcarbazepine
• It is a voltage-gated sodium channel blocker
• and is approved for partial-onset seizures in adults.
• Eslicarbazepine exhibits linear pharmacokinetics and is
eliminated via glucuronidation.
• The side effect profile includes dizziness, somnolence, diplopia, and
headache. Serious adverse reactions such as rash, psychiatric side
effects, and hyponatremia occur rarely.
 SODIUM VALPROATE

inhibits P450 system

Adverse effects:
 Elevated liver enzymes including own.
 Tremor, hair loss, changes in hair growth
 increased appetite Weight gain.
 coagulopathy (inhibition of platelet aggregation),
 Idiosyncratic hepatotoxicity.
 Negative interactions with other antiepileptics.
 Teratogen: spina bifida
 FELBAMATE (Felbatrol)

• Effective against partial seizures but has severe side

effects.
• Thus, used only for refractory cases.

• One of the metabolites; α,β-unsaturated aldehyde, 2-

phenylpropenal is chemically reactive, like acrolein
covalently linking proteins as well as DNA, it can cause
liver and bone marrow toxicity

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 GABAPENTIN (Neurontin)
• Used as an adjunct in partial and generalized
tonic-clonic seizures. Adverse effects:

• Does not induce liver enzymes.  Somnolence.

• not bound to plasma proteins. • Dizziness.

• drug-drug interactions are negligible. • Ataxia.

• Low potency. • Headache.

• An a.a.. Analog of GABA that does not act on • Tremor.

GABA receptors, it may however alter its
metabolism, non-synaptic release and transport.
• Alleviate both diabetic neuropathies pain and post
herpetic pain

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 VIGABATRIN

• RX of Partial Seizures
• Inhibit GABA transaminase
ADVERSE EFFECTS:
• Depression,
• psychosis,
• visual dysfunction
 LAMOTRIGINE (Lamictal)

• Presently use as add-on therapy with Adverse effects:

valproic acid. • Dizziness
• Almost completely absorbed • Headache
• T1/2 = 24 hrs
• Diplopia
• Low plasma protein binding
• Nausea
• Blocks sodium channels, & high voltage
Ca+2 channel • Somnolence
• thus its effective in partial, generalized, • Rash
myoclonic, absence seizures & Lennox-
Gastaut syndrome (LGS).
• Approved for use in bipolar disorder

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 LEVETIRACETAM (Keppra)

• Adjunct Rx of refractory Partial Seizure

• Unknown mechanism of action but binds to presynaptic
vesicle protein
ADVERSE EFFECT
Dizziness, sleep disturbances, headache, and asthenia
(LACK OF ENERGY)
 TIAGABINE (Gabatril)
• 100% bioavailable, Adverse effects:
• highly protein bound. •Dizziness
•Nervousness
• T1/2 = 5 -8 hrs •Tremor
• Effective against partial and •Difficulty
generalized tonic-clonic seizures. concentrating
•Depression
• GABA uptake inhibitor GAT-1. •Asthenia
•Emotional
•Psychosis
•Skin rash

10-Nov-14 39
 EZOGABINE

• Ezogabine is thought to open voltage-gated M-type

potassium channels leading to stabilization of the
resting membrane potential.
• Ezogabine exhibits linear pharmacokinetics and no
drug interactions at lower doses.
• Possible unique side effects are
 urinary retention,
 QT interval prolongation,
 blue skin discoloration,
 retinal abnormalities.
 TOPIRAMATE (Topamax)

• Broad spectrum antiseizure activity, also used in

migraine Adverse effects:
• Rapidly absorbed, bioav. is > 80%, has no • Somnolence
active metabolites, excreted in urine.T1/2 = 20-30 • Fatigue
hrs
• Dizziness
• blocking of voltage-dependent sodium channels
• Cognitive
• Additionally ↑ the frequency of Cl- channel slowing
opening by binding to GABA receptor.
• Paresthesias
• High-voltage calcium currents (L-type) are • Nervousness
reduced
• Confusion
• Depresses excitatory action of kainate on AMPA • Urolithiasis
receptors.
• Carbonic anhydrase inhibiter effect
• Weight loss
• Teratogenic in animal models.
10-Nov-14 41
 PERAMPANEL

• is a selective α-amino-3-hydroxy-5-methyl-4-
isoxazolepropionic acid antagonist resulting in reduced
excitatory activity.
• Perampanel has a long half-life enabling once-daily
dosing.
• It is approved for adjunctive treatment of partial-onset
seizures in patients 12 years or older.
 RUFINAMIDE

acts at sodium channels. It is approved for the adjunctive

treatment of seizures associated with Lennox-Gastaut
syndrome in children over age 4 years and in adults.
Adverse effects
include the potential for shortened QT intervals. Patients
with familial short QT syndrome should not be treated
with rufinamide.
 ZONISAMIDE

• Sulfonamide derivative
• Orally active half-life 50-60 hrs
• Both focal and generalized
MECHANISM OF ACTION
• Blocks voltage-gated Na+ channels and T-type Ca+2 current,
• enhancement of GABA-receptor function
ADVERSE EFFECTS:
 somnolence, Ataxia,
 Oligohidrosis has been reported, and patients should be monitored for
increased body temperature and decreased sweating. hyperthermia
(children)
 Kidney stone
 STATUS EPILEPTICUS

Status epilepticus is life threatening and requires

emergency treatment usually consisting of
administration of a fast-acting medication such
as a benzodiazepine, followed by a slower-
acting medication such as phenytoin.
 Special Cases: Pregnancy

• Seizure very harmful for pregnant women.

• Antiepileptic drugs associated with increased (2-3 fold)
incidence of birth defects (cleft lip/palate and cardiac
defects)
• Significant risk of neural tube defects, folic acid is
recommended to be given for every pregnant women
with epilepsy
• Phenytoin, sodium valproate are absolutely
contraindicated and oxcarbamazepine is better than
carbamazepine.
 Special Cases: Pregnancy

• Monotherapy usually better than drugs combination.

• Experience with new anticonvulsants still not reliable
• Newborns of mothers receiving phenobarbitone, or
phenytoin may develop hypoprothrominemia,
heamorrhage prevented by Vit. K
• Drugs are secreted in small quantities into breast milk
but not usually sufficient to prevent breast feeding
(phenobarbitone significantly)
 ANTISEIZURE DRUG INTERACTIONS

With other drugs:

antibiotics  phenytoin, phenobarb, carb.
anticoagulants phenytoin and phenobarb
metabolism.
cimetidine displaces pheny, v.a. and BDZs
isoniazid  toxicity of phenytoin
oral contraceptives antiepileptics  metabolism.
salicylates displaces phenytoin and v.a.
theophyline carb and phenytoin may
effect.
 VAGAL NERVE STIMULATION (VNS)

VNS requires surgical implant of a small pulse generator with a

battery and a lead wire for stimulus. The device is implanted and its
lead wires wrapped around the patient’s vagal nerve.
This treatment was approved in 1997. The device is also approved
for treatment of depression. The mechanism of action is unknown.
VNS has been effective in treatment of partial onset seizures and has
enabled reduction of drug therapy in some cases.
It is an alternative for patients whose conditions have been refractory
to multiple drugs and in those who are sensitive to the many adverse
effects of antiseizure drugs and those who have difficulty adhering to
medication schedules. However, VNS is a costly and invasive
procedure.
 DEEP BRAIN STIMULATION (DBS)

DBS therapy uses a pacemaker-like device to deliver targeted

electrical stimulation to the anterior nucleus of the thalamus.
The therapy is FDA approved with conditions for adjunctive
treatment for partial-onset seizures in adults with medically
refractory epilepsy.
DBS is also FDA approved for treatment of advanced Parkinson
disease and essential tremor.