ANTIEPILEPTIC DRUGS

EPILEPSY
• It is a Chronic medical condition produced by sudden changes in the electrical
function of the brain.
• It is a condition characterized by recurrent episodes of seizures.

• Seizure- a paroxysmal abnormal discharge at high frequency from neurons in

cerebral cortex.

• Convulsions- involuntary, violent, spasmodic contractions of skeletal muscles.

• Approximately 10% of the population will have at least one seizure in their lifetime.
• Globally, epilepsy is the third most common neurologic disorder after
cerebrovascular and Alzheimer’s disease

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 EPILEPSY

 Medications are the most widely used mode of treatment

for patients with epilepsy.
 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

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 BACKGROUND
• Epilepsy: Neurological disorder affecting the CNS.
– Approximately 2.5 million people in the U.S. (~1% general pop)
– Cost per patient ranges from $4,272 for persons with remission
after initial diagnosis and treatment to $138,602 for persons with
intractable and frequent seizures.

• Causes:
– Genetic (autosomal dominant genes)
– Congenital defects
– Severe head trauma
– Ischemic injury, tumor
– Drug abuse
– Unknown
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http://www.med.uc.edu/neurology/images/
 Etiology
• Congenital defects, Head Injuries, trauma, hypoxia
• Infection ( bacteria or virus ) e.g. meningitis, brain abscess,
viral encephalitis.
• Concussion, Depressed Skull, fractures.
• Brain tumors (including tuberculoma), vascular occlusion,
stroke.
• Drug withdrawal, e.g. CNS depressants,alcohol or drug
abuse or drug overdose, e.g. penicillin.
• A poison, like lead
• Fever in children (febrile convulsion).
• Hypoglycemia
• PKU( phenylalanine Phenylalanine hydroxylase tyrosine )
• Photo epilepsy

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 NERVE CELL COMMUNICATION
• Neurons communicate between themselves using small molecules called
neurotransmitters.

• These neurotransmitters modulate and regulate the electrical activity of a given

neuron, and tell it when to fire an action potential or when not to.
- Glutamate = excitatory (tells the neuron to fire)
- GABA = inhibitory (dampens the neuron firing rate)
• The action potential is an electrical signal that travels down the axon, and is
created using sodium ions (Na+), and inhibited by potassium ions (K+).

• Usually these processes work synergistically to produce normal behavior and

activity.

• When dysfunctional, abnormal electrical activity occurs and can produce

seizures. 6
 Sodium Ions/Channels

Potassium Ions/Channels

Action Potential

Neurotransmitters
(Glutamate, GABA)

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 Drugs and other substances that can cause seizures
Drugs of abuse Psychotropics
• Amphetamine • Antidepressants
• Cocaine • Antipsychotics
• Phencyclidine • Li
• Methylphenidate
Anesthetics and analgesics Sedative-hypnotic drug
• Meperidine withdrawal
• Tramadol • Alcohol
• Local anesthetics • Barbiturates
• Benzodiazepines
Triggers:
Fatigue, Stress, Poor Nutrition, Alcohol And Sleep
Deprivation. 9
TYPES OF SEIZURES

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 Types of

)focal( Primary

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 PARTIAL (FOCAL) SEIZURES

• Excessive electrical activity in one cerebral hemisphere. -Affects only

part of the body. 

• Simple Partial: Person may experience a range of strange or unusual

sensations.
– Motor
– Sensory
– Autonomic
– Key feature: preservation of consciousness.

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 PARTIAL (FOCAL) SEIZURES

• Complex Partial:
– Loss of awareness at seizure onset. Person seems dazed
or confused and exhibits meaningless behaviors.
– Typically originate in frontal or temporal lobes (e.g.
Temporal lobe epilepsy)

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 GENERALIZED SEIZURES

• Excessive electrical activity in both cerebral hemispheres.

• Usually originates in the thalamus or brainstem.
• Affects the whole body.
• Loss of consciousness is common.

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 GENERALIZED SEIZURES
• Myoclonic: Brief shock-like muscle jerks generalized or restricted to part of one extremity.
• These seizures consist of short episodes of muscle contractions that may recur for several
minutes. Myoclonic seizures occur at any age but usually begin around puberty or early
adulthood

Atonic: These seizures are also known as drop attacks and are characterized by a sudden loss of
muscle tone

• Tonic Seizures: sudden stiffening of the body, arms, or legs. These seizures involve increased
tone in the extension muscles and are generally less than 60 seconds long

• Clonic Seizures: Rhythmic jerking movements of the arms and legs without a tonic component

• Tonic-clonic (grand mal): These seizures result in loss of consciousness, followed by

tonic (continuous contraction) and clonic (rapid contraction and relaxation) phases. The
seizure may be followed by a period of confusion and exhaustion due to the depletion of
glucose and energy stores. Tonic phase followed by clonic phase

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 TONIC-CLONIC SEIZURE

Can last from one to several minutes

Therapeutic intervention = lorazepam injection
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 GENERALIZED SEIZURES
• Absence (petit mal): Person appears to “blank out” - “Daydreaming”
– Simple Absence (primarily effects consciousness only)
– Complex Absence
– Atypical Absence (Includes physical symptoms like eye blinking or lip
movements)
– The onset generally occurs in patients at 3 to 5 years of age and lasts
until puberty or beyond. The patient stares and exhibits rapid eye-
blinking, which lasts for 3 to 5 seconds
• Lenox-Glastaut Syndrome. is a severe form of epilepsy that typically becomes
apparent during infancy or early childhood
– Atypical absence, atonic and myclonic
• Status Epilepticus: A seizure lasting longer than 30 min, or 3 seizures without a
normal period in between
– May be fatal
– Emergency intervention required
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 ABSENCE SEIZURE

Can last from a second to several minutes

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PRIMARY GENERALIZED TONIC-CLONIC (GRAND MAL)
SEIZURES

• Drugs of Choice: •Alternatives

• Phenytoin •Lamotrigine
• Carbamazepine •Topiramate
• Oxcarbazepine •Zonisamide
• Valproate •Levetiracetam

•Primidone

•Phenobarbital

•Diazepam
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 Partial, including secondarily generalized seizures

• Drugs of Choice: •Alternatives

• Phenytoin •Lamotrigine
•Topiramate
• Carbamazepine
•Zonisamide
• Oxcarbazepine •Levetiracetam
• Valproate •Primidone
•Phenobarbital
•Gabapentin
•Pregabalin
•Tiagabine

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 Absence (Petit Mal)

• Drugs of Choice: •Alternatives

• Ethosuximide •Clonazepam
•Zonisamide
• Valproate

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 ATYPICAL ABSENCE, MYOCLONIC,
ATONIC SEIZURES

• Drug of Choice: •Alternatives

•Clonazepam
• Valproate •Topiramate
•Zonisamide
•Levetiracetam

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INCIDENCE OF SEIZURE TYPES

Mayo Clinic Proceedings 1996; 71:576-568

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 EPILEPSY – INVESTIGATION
 The concern of the clinician is that epilepsy may be symptomatic of a treatable
cerebral lesion.

 Routine investigation: Haematology, biochemistry (electrolytes, urea and calcium),

chest X-ray, Electroencephalogram (EEG). Neuroimaging (CT/MRI) should be
performed in all persons aged 25 or more presenting with first seizure and in those
pts. with focal epilepsy irrespective of age.

 Specialised neurophysiological investigations: Sleep deprived EEG, video-EEG

monitoring.

 Advanced investigations (in pts. with intractable focal epilepsy where surgery is
considered): Neuropsychology, Semi-invasive or invasive EEG recordings, MR
Spectroscopy, Positron emission tomography (PET) and ictal Single photon
emission computed tomography (SPECT) 25
Prolongation of N a+ Channel FACILITATION OF GABA MEDIATED
inactivation
Cl Channel opening
• Phenytoin
• Carbamazepine
• Valproate • Barbiturate (Barb.)
• Lamotrigine • Benzodiazepine (Bzd.)
• Topiramate • Vigabatrin (Viga.)
• Zonisamide • Valproate (Valpr.)
• Gabapentin (Gabp.)
INHIBITION OF 'T' TYPE Ca2+
CURRENT • Tiagabine (Tiag.)
• Ethosuximide
• Trimethadione
• Valproate
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 MECHANISMS OF ACTION

• 3 main categories of therapeutics:

1.Inhibition of voltage-gated Na+ channels to slow neuron

firing.

2.Enhancement of the inhibitory effects of the

neurotransmitter GABA.

3.Inhibition of calcium channels.

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 TREATMENT

• Try to find a cause. (e.g. fever, head trauma, drug abuse)

– Recurrent seizures that cannot be attributed to any

cause are seen in patients with epilepsy.
• Therapy is aimed at control

– drugs do not cure.

• The type of seizure determines the choice of drug!

• More than 80% of patients with epilepsy can have can

have their seizures controlled with medications.

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 TREATMENT

• Monotherapy with anticonvulsant

– Increase dose gradually until seizures are controlled
or adverse effects become unacceptable.
– Multiple-drug therapy may be required.
• Achieve steady-state kinetics
• Monitor plasma drug levels
• Avoid sudden withdrawal

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 Pharmacokinetics
• Most classical antiepileptic drugs exhibit similar pharmacokinetic
properties.
• Good absorption.

• Low plasma protein binding (except for phenytoin, BDZs,

valproate, and tiagabine).
• Conversion to active metabolites (carbamazepine, primidone,
fosphenytoin).

• Cleared by the liver but with low extraction ratios.

• Distributed in total body water.

• Plasma clearance is slow.

• At high concentrations phenytoin exhibits zero order kinetics. 36

Therapeutic Range

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 There Are Many Adverse Effects Of Therapeutics!!!!

• CNS Effects: •GI Effects

– Drowsiness, sedation, somnolence –Dry Mouth
– Depression –Nausea
– Dizziness –Vomiting
– Slurred speech –Anorexia
– Ataxia –Diarrhea
– Nystagmus
– Diploplia •Rash
– Vertigo •Fetal Abnormalities and
– Headache birth defects
– Confusion
– Tremor
– Interference with cognitive functions
in learning situations
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 NA+ CHANNEL DRUGS

Phenytoin (Dilantin, Phenytek)

Cabamazepine (Tegretol, Carbatrol)
Valproic Acid (Depakene, Depakote)
Lamotrigine (Lamictal)
Topiramate (Topamax)
Zonisamide (Zonegran)
Lidocaine

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 Phenytoin
Pharmacokinetics
• Well absorbed when given orally, however, it is also available as iv.
(for emergency)
• 80-90% protein bound
• Induces liver enzymes (Very Important)
• Metabolized by the liver to inactive metabolite
• Metabolism shows saturation kinetics and hence t ½ increases as the
dose increased
• Excreted in urine as glucuronide conjugate
• Plasma t ½ approx. 20 hours
• Therapeutic plasma concentration 10-20 µg/ml (narrow)
• Dose 200-400 mg/day
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 Phenytoin ( Cont. )
Mechanism of Action:
Membrane stabilization by blocking Na & Ca influx into the neuronal
axon. or inhibits the release of excitatory amino acids via inhibition of
Ca influx
Clinical Uses:
Used for partial Seizures & generalized tonic-clonic seizures. But not
effective for absence Seizures .Also can be used for Rx of ventricular
fibrillation.

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 SIDE EFFECTS:

Dose Related:
• G.I.T upset
• Neurological like headache, vertigo, ataxia,
diplopia, nystagmus ( Involuntary movements of the eyeballs)
• Sedation
• Intimal damage & thrombosis of vein-
So rate of injection s/b < 50mg/min
S/B: small bowel (see small intestine)

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 Side Effects Of Phenytoin
Non-dose related:
• Hyperplasia of Gingival (is an overgrowth of gum tissue around the teeth)
• Hirsutism
• Hypersensitivity reactions (mainly skin rashes and lesions, mouth
ulcer)
• Hepatitis –rare
• Hydantoin syndrome- Fetal malformations- esp. cleft plate,
hypoplastic phalanges, microcephaly)
• Bleeding disorders (infants)
• Osteomalacia due to abnormalities in vit D metabolism
• Megaloblastic anaemia

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• Side effects of phenytoin

• Pharmacokinetic Interactions

– Inhibitors of liver enzymes elevate its plasma levels e.g.

Chloramphenicol, INH (Isoniazid),etc.

– Inducers of liver enzymes reduce its plasma levels e.g.

Carbamazipine; Rifampicin.

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 Sodium Valproate or Valproic Acid
• Valproate (VPA), primarily used to treat epilepsy and bipolar disorder
and to prevent migraine headaches.
• They are useful for the prevention of seizures in those with absence
seizures, partial seizures, and generalized seizures.They can be given
intravenously or by mouth. Long and short acting formulations of
tablets exist
• Pharmacokinetics :
• Available as capsule, Syrup, I.V
• Metabolized by the liver ( inactive )
• High oral bioavailability
• Inhibits metabolism of several drugs such as Carbamazepine;
phenytoin, Topiramate and phenobarbital.
• Excreted in urine ( glucuronide )
• Plasma t1/2 approx. 15 hrs 45
 Sodium valproate
Mode of action (by all possible methods)
• Increase in GABA content of the brain (inhibits GABA –
transaminase and succinic semialdehyde dehydrogenase)

• Clinical Use:
– Very effective against absence, myoclonic seizures.
– Also, effective in gen. tonic-clonic siezures (primarly
Gen)
– Less effective as compared to carbamazepine for partial
seizures
– Like Carbamazepine also can be used for Rx of mania 46
 Sodium valproate

• Side Effects of Sod. valproate:

• Nausea, vomiting and GIT disturbances (Start with low doses)
• Increased appetite & weight gain
• Transient hair loss.
• Hepatotoxicity
• Thrombocytopenia
• Neural Tube defect (e.g. Spina bifida) in the offspring of women.
(contraindicated in pregnancy)

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Valproic Acid (Valproate; Depakene, Depakote):

Drug Interactions:
–Affects metabolism of many drugs through liver enzyme inhibition
–Phenobarbital “Drunkenness”
–Clorazepam Prolonged absence seizures
Adverse Effects:
• Weight gain (30-50%)
• Dose-related tremor
• Transient hair loss
• Polycystic ovary syndrome and menstrual disturbances
• Bone loss
• Ankle swelling
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 TREATMENT OF SEIZURES
Seizure disorder Drugs
Tonic-clonic(Grand mal) Valproate
Drug of Choice Topiramte
Lamotrigine

:Alternatives Carbamazepine
Phenobarbital
Phenytoin

Partial (simple or complex) Carbamazepine

Drug of choice Phenytoin
Valproate
:Alternatives Phenobarbital
Lamotringine (as adjunct or alone)
Gabapentin (as adjunct )

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 TREATAMENT
Absence ( petit mal) Valproate
Drug of choice Ethosuximide

Alternatives: Clonazepam, Lamotrigine

Myoclonic, Atonic Valproate

Drug of choice
Alternatives: Clonazepam

Status Epilepticus Lorazepam, Diazepam, i.v.

Drug of choice or Phenytoin, i.v. or Vaproate
Alternatives: Phenobarbital, i.v
Febrile Seizures Diazepam, rectal*
Diazepam ,i.v
Valproate

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 TREATMENT

• Advantage of monotherapy:
• fewer side effects, decreased drug-drug interactions, better
compliance, lower costs
• Addition of a second drug is likely to result in significant
improvement in only approx. 10 % of patients.

DURING PREGNANCY
Safer antiepileptics
• Carbamazepine
• Oxcarbamazepine
• Lamotrigine
• Ethosuximide
Folic acid supplement 51
 WHEN TO WITHDRAW ANTIEPILEPTIC DRUGS?

o Normal neurological examination

o Normal IQ
o Normal EEG prior to withdrawal
o Seizure- free for at least 3 yrs
o NO juvenile myoclonic epilepsy

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 PART#2
ENHANCEMENT OF GABA INHIBITION

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 GABA DRUGS
• Barbiturates:
•Tiagabine (Gabitril)
– Phenobarbital (Luminal)
•Valproic Acid (Depakene, Depakote)
– Pimidone (Mysoline)
• Benzodiazepines: •Topiramate (Topamax)

– Diazepam (Valium) •Zonisamide (Zonegran)

– Lorazepam (Ativan)
– Clonazepam (Klonopin)
– Clorazepate (Tranxene-SD)

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 Enhancement Of GABA Inhibition

• Barbiturate drugs: Phenobarbital (Luminal) & Primidone (Mysoline):

– Mechanism of Action:
• Increases the duration of GABAA-activated Cl- channel opening.

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 ENHANCEMENT OF GABA INHIBITION

• Phenobarbital (Luminal):

– Indications:
• Second choice for partial and generalized tonic-clonic
seizures.
• Rapid absorption has made it a common choice for seizures in
infants, but adverse cognitive effects cause it to be used less in
older children and adults.
• Status epilepticus
– Contraindications:
• Absence Seizures
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• Phenobarbital (Luminal) & Primidone (Mysoline):

– Drug Interactions:
• Other CNS depressants
• Increased metabolism of vitamin D and K
• Phenytoin increases the conversion of primidone to
phenobarbital.
– Adverse Effects:
• Agitation and confusion in the elderly.
• Worsening of pre-existing hyperactivity and aggressiveness
in children
• Sexual side effects
• Physical dependence
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• Benzodiazepine drugs:

– Diazepam (Valium), lorazepam (Ativan), clonazepam (Klonopin), clorazepate

(Transxene-SD)
– Mechanism of Action:
• Increases the frequency of GABA A-activated Cl- channel opening.

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• Benzodiazepine drugs:

– Indications:
• Only clonazepam & clorazepate approved for long-term treatment.
• Clorazepate
– In combination for partial seizures
• Clonazepam
– Lennox-Gastaut Syndrome, myoclonic, atonic, and absence seizures
– Tolerance develops after about 6 months
• Diazepam and lorazepam are used in treatment of status epileticus.
– Diazepam is painful to inject; lorazepam is more commonly used in acute
treatment.
• Diazepam
– Intermittent use for control of seizure clusters
– Diazepam frequently combined with phenytoin. 60
• Benzodiazepine drugs:

– Contraindications:
• Diazepam in children under 9
• Narrow angle glaucoma
– Adverse Effects:
• Hypotonia, Dysarthria
• Muscle in-coordination (clonazepam)
• Behavioral disturbances (especially in children)
– Aggression, Hyperactivity, Irritability and Difficulty concentrating

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• Tiagabine (Gabitril):
– Mechanism of Action:
• Inhibition of GABA transporter (GAT-1) – reduces reuptake of GABA by neurons and glial
cells.
– Indications:
• Approved in 1998 as an adjunct therapy for partial seizures in patients at least 12 years old.
– Contraindications:
• Absence seizures

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• Tiagabine (Gabitril):

– Interactions:
• Blood levels decreased by CBZ, phenytoin, phenobarbital, & primidone

– Adverse Effects:
• Asthenia
• Abdominal pain

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 PART#3
CALCIUM CHANNEL BLOCKERS

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 CA2+ CHANNEL DRUGS
• Ethosuximide (Zarontin)

• Valproic Acid (Depakene, Depakote)

• Zonisamide (Zonegran)
• Gabapentin (Neurontin)
• Pregabalin (Lyrica)
• Levetiracetam (Keppra)

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• Ethosuximide (Zarontin):
– Mechanism of Action:
• Reduces low threshold Ca2+currents (T currents) in the thalamic neurons.
• Half-life is ~60 hr in adults; ~30hr in children.
– Indications:
• First line for absence seizures
– Contraindications:
• May exacerbate partial & tonic-clonic seizures
– Adverse Effects:
• Psychotic behavior
• Blood dyscrasias
• Persistent headaches
• Anorexia(loss of appetite)
• Hiccups (are involuntary contractions of the diaphragm)
– Toxicity:
• parkinson-like symptoms
• Photophobia (is a condition in which bright lights hurt your eyes) 66
 BLOCKADE OF CALCIUM CHANNELS ()

• Gabapentin (Neurontin):

– Mechanism of Action:
• Originally designed to be a centrally acting GABA agonist.
• Selective inhibition of v-g Ca2+ channels containing the α2δ1 subunit.

– Indications:
• Adjunct therapy in adults and children with partial & secondarily
generalized seizures.
• Also effective as monotherapy.

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• Gabapentin (Neurontin):

– Contraindications:
• Can exacerbate myoclonic & absence seizures.
– Adverse Effects:
• Weight Gain (5%) with ankle edema
• Irritability
• Behavioral problems in children (6%)
• Has been associated with movement disorders.

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 Part# 4
Other/Unknown MOA

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• Levetiracetam (Keppra):

– Mechanism of Action:
• Not exactly known
• Binding affinity to Synaptic Vesicle Protein 2A correlates with its
anticonvulsant activity.
• Also blocks calcium channel N-currents, increases intracellular Ca2+ levels,
modulates GABA channel currents
– Indications:
• Approved in 1999 as an adjunct therapy for adults with partial seizures.
• Some patients have success with monotherapy

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 LAMOTRIGINE
Pharmacological effects
• Resembles phenytoin in its pharmacological effects
• Well absorbed from GIT
• Metabolised primarily by glucuronidation
• Does not induce or inhibit C. P-450 isozymes ( its metabolism is
inhibitted by valproate )
• Plasma t 1/2 approx. 24 hrs.
• Mechanism of Action:
Inhibits excitatory amino acid release (glutamate & aspartate ) by
blockade of Na channels.
• Uses: As add-on therapy or as monotherapy

• Side effects:
• Skin rash, somnolence, blurred vision, diplopia, ataxia, headache,
aggression, influenza – like syndrome
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 TOPIRAMATE
• Pharmacological Effects:
• Well absorbed orally ( 80 % )
• Food has no effect on absorption
• Has no effect on microsomal enzymes
• 9-17 % protein bound ( minimal )
• Mostly excreted unchanged in urine
• Plasma t1/2 18-24 hrs
• Mechanism of Action:
• Blocks sodium channels (membrane stabilization) and also
potentiates the inhibitory effect of GABA.

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 TOPIRAMATE
Side effects:
• Psychological or cognitive dysfunction
• Weight loss
• Sedation
• Dizziness
• Fatigue
• Urolithiasis (presence of calculi in the urinary system)
• Paresthesias (abnormal sensation )
• Teratogenecity (in animal but not in human)(a birth defect)

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Common Causes Of Failure Of Antiepileptics

1. Improper diagnosis of the type of seizures

2. Incorrrect choice of drug
3. Inadequate or excessive dosage
4. Poor compliance

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 Antiepeliptics and Pregnany

– Seizure very harmful for pregnant women.

– Monotherapy usually better than drugs combination.
– 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.
– Experience with new anticonvulsants still not reliable to
say that are better than old ones.

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