Antiepileptic Drug pdf - D. Hussain

Antiepileptic Drugs

Dr. Hussain adday aljabery

FICMS ( RAD. )

Pharmacology

Basic information

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Epilepsy, a chronic disease, occurs approximately  1% of the population. The cause of most
cases of epilepsy is unknown, although   some   people develop epilepsy as the result of
brain injury  , stroke, brain tumor and drug toxicity. Genetic mutations are linked to a small
proportion of thee disease.

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Epileptic seizures result from excessive and abnormal cortical nerve c cell activity in the
brain.

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Thee diagnosis typically involves ruling out other conditions that cause similar neurological

symptoms. This may be confirmed by brain imaging and electroencephalogram ( (EEG) but
normal test does not exclude the condition.

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Antiepileptic drugs (AEDs ) are effective for about 80% of these patients. Lifelong

treatment may be necessary s.

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It may take weeks to establish adequate drug plasma levels and to determine the

adequacy of therapeutic improvement. Lack of compliance is responsible for many
treatment failures.

AED s are most effective and have the least e adverse effects
when they are used as monotherapy .

Addition or withdrawal of any drug should be gradual , because

seizures may occur on withdrawal.

Some AEDs are teratogenic this may call for the reduction or

termination of therapy during pregnancy .

Definitions

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Convulsion:

Sudden attack of involuntary muscular

contractions and relaxations.

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Seizure:

Abnormal central nervous system electrical activity.

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Epilepsy:

A group of recurrent disorders of cerebral function

characterized by both seizures and convulsions.

Background

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Epilepsy: Neurological disorder affecting the CNS.

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Approximately 2.5 million people in the U.S. (~1% general pop)

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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.

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Causes:

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Genetic (autosomal dominant genes)

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Congenital defects

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Severe head trauma

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Ischemic injury, tumor

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Drug abuse

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Unknown

http://www.med.uc.edu/neurology/images/

Basic Neuroscience Relevant to Seizure

Disorders and Epilepsy

The Brain

An extremely complex organ
made up of billions of
connections between neurons.

These connections are each
highly controlled and regulated.

Nerve Cell Communication

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Neurons communicate between themselves using small molecules called
neurotransmitters.

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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+).

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Usually these processes work synergistically to produce normal behavior and activity.

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When dysfunctional, abnormal electrical activity occurs and can produce seizures.

Cellular Mechanisms of
Seizure Generation

⬧ Excitation (too much)

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Ionic: inward Na

and Ca

currents

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Neurotransmitter: glutamate, aspartate

⬧ Inhibition (too little)

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Ionic: inward CI

, outward K

currents

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Neurotransmitter: GABA

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Neurotransmitters

Sodium Ions/Channels

Potassium Ions/Channels

Action Potential

(Glutamate, GABA)

GABA Receptors

GABA is the major inhibitory neurotransmitter in the CNS. There

are 2 types of receptors:

▪

GABA

receptor

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Postsynaptic fast inhibition

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Specific recognition sites (see next slide)

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Inhibition mediated by CI

current

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GABA

receptor

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Postsynaptic slow inhibition

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Pre-synaptic reduction in calcium influx

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Inhibition mediated by K

current

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P-Slide

GABA Receptors

Diagram of the GABA

receptor

P-Slide 15

GABA site

Barbiturate site

Benzodiazepine

site

Steroid site

Picrotoxin site

Glutamate Receptors

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Group I mGluRs (mGluRs 1 and 5)

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Primarily postsynaptic/perisynaptic

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Net excitatory effect (ictogenic)

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Couple to inositol triphosphate

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Long-lasting effects (epileptogenic)

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Group II (mGluRs 2 & 3) and group III (4,6,7,8)

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Primarily presynaptic

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Net inhibitory effect; reduce transmitter release

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Negatively coupled to adenylate cyclase, reduce cAMP

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Glutamate Receptors

P-Slide 17

Diagram of the various glutamate receptor

subtypes and locations

TYPES OF SEIZURES

Partial (focal) Seizures

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Excessive electrical activity in one cerebral hemisphere. -
Affects only part of the body.

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

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Motor

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Sensory

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Autonomic

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Key feature: preservation of consciousness.

Partial (focal) Seizures

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Complex Partial:

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Loss of awareness at seizure onset. Person seems dazed or

confused and exhibits meaningless behaviors.

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Typically originate in frontal or temporal lobes (e.g. Temporal lobe

epilepsy)

Generalized Seizures

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Excessive electrical activity in both cerebral hemispheres.

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Usually originates in the thalamus or brainstem.

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Affects the whole body.

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Loss of consciousness is common.

Generalized Seizures

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Myoclonic: Brief shock-like muscle jerks generalized or restricted to part of one
extremity.

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Atonic: Sudden loss of muscle tone.

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Tonic Seizures: sudden stiffening of the body, arms, or legs

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

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Tonic-clonic (grand mal):

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Tonic phase followed by clonic phase

Tonic-Clonic Seizure

Can last from one to several minutes

Therapeutic intervention = lorazepam injection

Status epilepticus  :
Prolonged seizure   (>20 0 min) of any of the
types previously   described; the most common
is life threatening   generalized  tonic–clonic
status epilepticus.

Generalized Seizures

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Absence (petit mal):

Person appears to “blank out” - “Daydreaming”

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Simple Absence (primarily effects consciousness only)

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Complex Absence

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Atypical Absence (Includes physical symptoms like eye blinking or lip movements)

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Lenox-Glastaut Syndrome.

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Atypical absence, atonic and myclonic

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Status Epilepticus: A seizure lasting longer than 30 min, or 3 seizures without a normal period in
between

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May be fatal

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Emergency intervention required

Absence Seizure

Can last from a second to several minutes

Incidence of Seizure Types

Mayo Clinic Proceedings 1996; 71:576-568

Seizure Facts

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Seizures are not usually life threatening.

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The brain almost always stops the seizure on its own.

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Breathing may cease for a few seconds, and the patient may turn

blue.

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People don’t feel pain during a seizure; muscles may be sore
afterward.

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Person may be “different” for a while after the seizure.

Antiepileptic Drug

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An antiepileptic drug (AED) is a drug which decreases the
frequency and/or severity of seizures in people with epilepsy

⬧

Treats the symptom of seizures, not the underlying epileptic
condition

⬧

Does not prevent the development of epilepsy in individuals
who have acquired a risk for seizures (e.g., after head
trauma, stroke, tumor)

▪

Goal of therapy is to maximize quality of life by eliminating
seizures (or diminish seizure frequency) while minimizing
adverse drug effects

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Treatment

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

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Recurrent seizures that cannot be attributed to any cause are seen in

patients with epilepsy.

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Therapy is aimed at control

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drugs do not cure.

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The type of seizure determines the choice of drug!

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

seizures controlled with medications.

Treatment

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Monotherapy with anticonvulsant

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Increase dose gradually until seizures are controlled or adverse effects

become unacceptable.

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Multiple-drug therapy may be required.

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Achieve steady-state kinetics

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Monitor plasma drug levels

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Avoid sudden withdrawal

Diphenylhydantoin ( Phenytoin)

Mechanism:
it blocks Na +  , K +  and   Ca2+
channels   in the brain (and   heart) leading to decrease propagation   of
abnormal impulses. It produces  some  degree of drowsiness.

Therapeutic uses

Partial and generalized seizures
Status epilepticus : it should be given i.v. in the form of fosphenytoin (prodrug

Ventricular arrhythmia .

Adverse effects
– CNS  : Nystagmus, diplopia, ataxia.
– Hepatotoxicity  .
– Microsomal enzyme induction  .
– Bone marrow depression   & Megaloblastic  anemia (due to ↓ folic acid).
– Teratogenicity a y: craniofacial abnormalities.
– Gingival hyperplasia  :   2ry to increased expression   of platelet   derived growth
factor (PDGF )).
- Lymphadenopathy

Phenytoin Induced Gingival Hyperplasia

17 year old boy treated with

300mg/day phenytoin for 2

years (unsupervised)

Partial recovery at 3 months

after discontinuation

Images in Clinical Medicine (Feb 2000) 342:325

2. Carbmazepine (Tegretol)

Mechanism: it blocks Na+ channels & ↓ excitability of cortical neurons.
Therapeutic uses

Partial and generalized seizures (grand mal epilepsy).

Trigeminal neuralgia.

Adverse effects
– CNS: diplopia & ataxia.
– Hepatotoxicity.
– Microsomal enzyme induction.
– Bone marrow depression.
– Congestive heart failure (CHF).
3.

Valproic acid (Depakene)

Mechanism: it activates glutamic acid decarboxylase enzyme→ ↑ GABA synthesis.
Therapeutic uses: all types of epilepsy.
Adverse effects
– Sedation
– Microsomal enzyme inhibition
– Teratogenicity.
– Alopecia

Ethosuximide (Zarontin

)

Mechanism: blocks neuronal voltage-dependent Ca2+ and Na+ channels.
Therapeutic uses: absence seizures (petit mal epilepsy) (1st choice).
Adverse effects
– Sedation
– Vomiting
– Leucopenia
5.

Benzodiazepines: Clonazepam and diazepam

Mechanism: allosteric modulation of GABA action to facilitate its effects.

Therapeutic uses

Clonazepam: petit mal epilepsy.
Diazepam: status epilepticus.

Adverse effects: see before.
6.

Barbiturates: Phenobarbitone

Mechanism: enhancement of GABA-mediated inhibition of glutamate excitation.
Therapeutic uses: grand mal epilepsy (contraindicated in petit mal epilepsy).
Adverse effects: see before.
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NEWER ANTIEPILEPTIC DRUGS

Felbamate

Mechanism

Block glycine site on the N-methyl-D-aspartate (NMDA) receptors.

2+ +

Block voltage-dependent Ca & Na channels.

Therapeutic uses: wide variety of partial and generalized seizures.
Adverse effects
– Hepatotoxicity
– Microsomal enzyme induction.
– Bone marrow depression.

Lamotrigine

Mechanism

Decreases glutamate and aspartate, which are excitatory neurotransmitters
Blocks sodium channels and high voltage-dependent calcium channels leading

to ↓ excitability.
Therapeutic uses: wide variety of partial and generalized seizures and typical
absence seizures in children and adults.
3.

Gabapentin

Mechanism: unknown but may interfere with voltage-dependent Ca2+ channels
Therapeutic uses: as adjuvant therapy in wide variety of partial and generalized
seizures.
Adverse effects: headache, nystagmus, dizziness & ataxia.
4.

Tiagabine

Potent and specific inhibitor of GABA uptake into glial and other neurons. Thus, it
enhances the action of GABA by decreasing its removal from the synaptic

Status epilepticus management

During pregnancy

Safer antiepileptics

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Carbamazepine

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Oxcarbamazepine

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Lamotrigine

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Ethosuximide

Folic acid supplement

Summary

Na+ Channel Drugs

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Phenytoin (Dilantin, Phenytek)

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Cabamazepine (Tegretol, Carbatrol)

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Valproic Acid (Depakene, Depakote)

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Lamotrigine (Lamictal)

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Topiramate (Topamax)

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Zonisamide (Zonegran)

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Lidocaine

GABA Drugs

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Barbiturates:

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Phenobarbital (Luminal)

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Pimidone (Mysoline)

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Benzodiazepines:

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Diazepam (Valium)

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Lorazepam (Ativan)

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Clonazepam (Klonopin)

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Clorazepate (Tranxene-SD)

•Tiagabine (Gabitril)

•Valproic Acid (Depakene, Depakote)

•Topiramate (Topamax)

•Zonisamide (Zonegran)

Channel Drugs

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Ethosuximide (Zarontin)

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Valproic Acid (Depakene, Depakote)

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Zonisamide (Zonegran)

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Gabapentin (Neurontin)

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Pregabalin (Lyrica)

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Levetiracetam (Keppra)

Other/Unknown MOA

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Magnesium chloride

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Paraldehyde

Primary Generalized Tonic-Clonic
(Grand Mal) Seizures

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Drugs of Choice:

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Phenytoin

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Carbamazepine

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Oxcarbazepine

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Valproate

•Alternatives

•Lamotrigine
•Topiramate
•Zonisamide
•Levetiracetam
•Primidone
•Phenobarbital
•Diazepam

Partial, Including Secondarily
Generalized Seizures

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Drugs of Choice:

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Phenytoin

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Carbamazepine

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Oxcarbazepine

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Valproate

•Alternatives

•Lamotrigine
•Topiramate
•Zonisamide
•Levetiracetam
•Primidone
•Phenobarbital
•Gabapentin
•Pregabalin
•Tiagabine

Absence (Petit Mal)

▪

Drugs of Choice:

▪

Ethosuximide

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Valproate

•Alternatives

•Clonazepam
•Zonisamide

Atypical Absence, Myoclonic, Atonic
Seizures

▪

Drug of Choice:

▪

Valproate

•Alternatives

•Clonazepam
•Topiramate
•Zonisamide
•Levetiracetam