ANTIEPILEPTIC DRUGS

DINA TRI AMALIA, MD

ISWANDI DARWIS, MD

MEDICAL FACULTY
UNIVERSITY OF LAMPUNG
 E.P.I.L.E.P.S.I

Gangguan fungsional kronik pada saraf yang ditandai

terjadinya serangan yg timbul mendadak, episodik,
berlebihan & cepat.

akibat lepasnya muatan listrik yang tidak terkontrol

Konsep John H. Jakson (Bapak epilepsi modern)

Prevalensi di Indonesia 1% dari jumlah penduduk.

PATOLOGI

• Lazimnya pelepasan muatan listrik ini terjadi scr

teratur dan terbatas pd kelompok-kelompok kecil yg
memberikan ritme normal pd EEG

• Terjadinya epilepsi  e.c aksi serentak & mendadak

dari sekelompok besar sel-sel saraf di otak. Aksi ini
disertai pelepasan muatan listrik yang berlebihan dari
neuron-neuron tsb.
Pada tingkat membran sel dpt dijelaskan
fenomena biokimia tertentu a.l:

1. Ketidakstabilan membran sel saraf sehingga lebih

mudah diaktifkan.
2. Neuron hipersensitif dg ambang rangsang yg
menurun, sehingga mudah terangsang scr berlebihan

Pengeluaran energi listrik oleh sel-sel saraf motorik

dpt meningkat sampai 1000 mV/detik
 Etiology
Congenital defects, head injuries, trauma, hypoxia

Infection e.g. meningitis, brain abscess, viral encephalitis

Concussion, depressed skull, fractures.

Brain tumors (including tuberculoma), vascular occlusion.

Drug withdrawal, e.g. CNS depressants .

Fever in children (febrile convulsion).

Hypoglycemia

PKU

Photo epilepsy
 Triggers factor

poor
Fatigue stress
nutrition

sleep
alcohol
deprivation.
 Focal or partial

• The electrical discharge is

Simple partial cofined to the motor area.
(Jacksonian)

• The electrical discharge is

Complex confined in certain parts of
partial the temporal lobe concerned
(psychomotor) with mood as well as muscle.
 Primary generalized
• Patient fall in convulsion & may bite his tongue & may lose
Tonic- clonic control of his bladder or bowel.

• Some patients, after dropping unconscious experience only

Tonic the tonic or clonic phase of seizure.

• Starts between the ages 2-5 yrs. The patients legs simply give
Atonic (akinetic) under him & drops down

• Sudden, brief shock like contraction which may involve the

Myoclonic entire body or be confined to the face, trunk or extremities

• Loss of consciousness without involving motor area. Most

Absence common in children (4-12 yrs )

Status epilepticus (re- • Continuous seizure without intervening return of

consciousness
occuring seizure)
Jenis epilepsi yg paling sering dijumpai:
1. Petit mal/ absence
antara beberapa detik – 30 detik
2. Grand mal/tonik- klonik
Lama serangan 1 – 2 menit
3. Status epileptikus
Serangan lebih dari 30 menit,cepat
tanpa diselingi keadaan sadar.
NEUROTRANSMITTER IN BRAIN

Aspartate and
glutamate

GABA
Na and Ca Channels
GABA
Mechanism of Action Antiepileptic Drugs
Acting on the neuronal membrane action potential :

• Membrane Stabilization: Phenytoin; Carbamazepine: Phenobarbital;

Lamotrigine; Topiramate, Zonisamide.
• Prolong refractory period: e.g: Ethosuximide; Valproate

Inhancement of GABA neurotransmissions :

• Inhibit GABA catabolism (inhibit GABA transaminase) e.g: Valproate;

Vigabatrin
• Inhibit re-uptake of GABA: benzodiazepines
• Analog of GABA: e.g: Gabapentin
• Increase the activity of GABA: phenobarbitone; Topiramate; Gabapentin

Antagonizing the action of Aspartate and Glutamate e.g:

Lamotrigine
 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

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

Alternatives: Clonazepam
Lamotrigine
Myoclonic, Atonic Valproate
Drug of choice
Alternatives: Clonazepam

Status Epilepticus Diazepam, i.v.

Drug of choice or Phenytoin, i.v. or Vaproate
Alternatives: Phenobarbital, i.v
Febrile Seizures Diazepam, rectal*
Diazepam ,i.v
Valproate
* Preferred
 Principles of epileptic therapy
Up to 80% of patiens can expect partial or
complete control of seizures with
appropriate treatment

Antiepileptic drugs suppress but do not cure

seizures

Antiepileptics are indicated when there is

two or more seizures occurred in short
interval (6month -1 years)

An initial therapeutic aim is to use only one

drug (monotherapy)
 Phenytoin
• Well absorbed when given orally
• 80-90% protein bound
Pharmacokinetics • Metabolized by the liver to inactive metabolite
• Excreted in urine as glucuronide conjugate

• Membrane stabilization by blocking Na & Ca influx

Mechanism of into the neuronal axon.
Action • Inhibits the release of excitatory amino acids via
inhibition of Ca influx

• Used for partial Seizures & generalized tonic-clonic

Clinical Uses seizures. But not effective for absence Seizures
• Also can be used for Rx of ventricular fibrillation.
 SIDE EFFECT
Dose Related:
• G.I.T upset
• Neurological like headache, vertigo, ataxia, diplopia, nystagmus
• Sedation

Non-dose related
• Gingival hyperplasia
• Hirsutism
• Megaloblastic anaemia
• Hypersensitivity reactions (mainly skin rashes and lesions, mouth ulcer)
• Hepatitis –rare
• Fetal malformations- esp. cleft plate
• Bleeding disorders (infants)
• Osteomalacia due to abnormalities in vit D metabolism

Pharmacokinetic Interactions
• Inhibitors of liver enzymes elevate its plasma levels e.g. Chloramphenicol, INH,etc.
• Inducers of liver enzymes reduce its plasma levels e.g. Carbamazipine; Rifampicin
 Carbamazepine

Mechanism of • similar to that of phenytoin. Also for treatment

Actions Neuralgia trigeminal

• Well absorbed
• 80 % protein bound
• Metabolized by the liver
Pharmacokinetics • Strong inducing agent including its own (can lead to
failure of other drugs) e.g. oral contraceptives,
warfarin, etc.
• Excreted in urine as glucuronide conjugate
Side Effects
• G.I upset
• Drowziness, ataxia and headache; diplopia
• Hepatotoxicity
• Late hypersensitivity reaction (erythematous skin rashes,
mouth ulceration and lymphadenopathy.
• Blood dyscrasias as fetal aplastic anemia (stop
medication); mild leukopenia (decrease the dose)

Pharmacokinetic interactions
• Inducers of liver enzymes reduce its plasma level e.g.
Phenytoin; Phenobarbital; Rifampicin
• inhibitors of liver enzymes elevate its plasma levels e.g.
erythromycin, INH ,verapamil, cimetidine
 Phenobarbital
• Increases the inhibitory neurotransmitters (e.g:
Mechanism of GABA) and decreasing the excitatory transmission.
• Also, it also prolongs the opening of Cl- channels.
Action

• Well Absorbed
• Distributed by protein plasma
Pharmacokinetics • Metabolized in hepatic into glucoronide
• Excreted in urine (inactive form)

• Treatment convultions state expecially for infant

Indications
Sodium Valproate or Valproic Acid

• Metabolized by the liver (inactive)

• High oral bioavailability
• Inhibits metabolism of several drugs such as
Pharmacokinetics Carbamazepine; phenytoin, Topiramate and phenobarbital.
• Excreted in urine (glucuronide )
• Plasma t1/2 approx. 15 hrs

Mechanism of • May be due to increase in GABA content of the brain

(inhibits GABA –transaminase and succinic semialdehyde
action 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

Side Effects
• Nausea, vomiting and GIT disturbances
• Increased appetite & weight gain
• Transient hair loss
• Hepatotoxicity
• Thrombocytopenia
• Neural Tube defect

Contraindicated
• pregnancy
 Lamotrigine
Pharmacokinetics

• Well absorbed from GIT

• Metabolized 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
 Gabapentin
• Not bound to proteins
• Not metabolized and excreted unchanged in
Pharmacokinetics: urine
• Does not induce or inhibit hepatic enzymes
• Plasma t ½ 5-7 hours ; 3x1

Mechanism of • Structural analogue of GABA ,

May increase the activity of
Action GABA or inhibits its re-uptake

• As an adjunct with other

Indication antiepileptics

• Somnolence, dizziness, ataxia,

Side effects fatigue and nystagmus
 Topiramate
• Well absorbed orally ( 80 % )
• Food has no effect on absorption
• Has no effect on microsomal enzymes
• 9-17 % protein bound (minimal )
Pharmacokinetics
• Mostly excreted unchanged in urine

• Blocks sodium channels (membrane stabilization) and also

potentiates the inhibitory effect of GABA.
Mechanism of
Action
Clinical Uses

• Recently, this drug become one of the safest

antiepileptics which can be used alone for partial and
generalized tonic-clonic, and absence seizures

Side effects

• Psychological or cognitive dysfunction

• Weight loss
• Sedation
• Dizziness
• Fatigue
• Urolithiasis
• Paresthesias (abnormal sensation )
• Teratogenecity (in animal but not in human)
 Vigabatrin (restricted)
Pharmacological effects
• Drug of choice for infantile spasms
• Not bound to proteins
• Not metabolized and excreted unchanged in urine
• Plasma t1/2 4-7 hrs

Mechanism of action
• Inhibits GABA metabolising enzyme & increase GABA
content in the brain( similar to valproate)
Side effects:
• Visual field defects, psychosis and depression (limits its
use)
 Zonisamide
Pharmacokinetics:
• Well absorbed from GIT (100 %)
• Protein binding 40%
• Extensively metabolized in the liver
• No effect on liver enzymes
• Plasma t ½ 50 -68 hrs
Clinical Uses
• Add-on therapy for partial seizures

Side Effects:
• Drowsiness, ataxia , headache, loss of appetite,nausea&
vomiting, Somnolence
 Tiagabine
Mechanism of action

• inhibits GABA uptake and increases its level

Pharmacological effects

• Bioavailability > 90 %
• Highly protein bound ( 96% )
• Metabolized in the liver
• Plasma t ½ 4 -7 hrs

Indications

• Adjunctive therapy in partial and generalized tonic-clonic seizures

Side effects

• Asthenia
• Sedation
• Dizziness
• Mild memory impairment
• Abdominal pain
 Drug Selection
Newly Diagnosed Epilepsy
•Considering starting th/ after 2nd seizure

First-choice drug
• Choose drug appropriate for the patient's type of seizure.
Consider toxicity of the agent & characteristics of the patient
• Gradually titrate the dosage to that which is maximally tolerated and/or produces
optimal seizure control.

Seizures persist Seizures free

Second-choice drug
• 2nd drug is titrated to a therapeutic level that controls seizures before tapering
and discontinuing the original antiseizure agent.
• If 1st drug is associated with signicant AE, it should be tapered while 2nd drug is added.
 ....(cont)...Drug Selection

Seizures persist Seizures free

Rational combination of 2 drugs Alternative drug therapy

Seizures persist Seizures free

Consider vagal nerve stimulation

 Common Causes of Failure of
Antiepileptics
Improper diagnosis of the type of
seizures

Incorrrect choice of drug

Inadequate or excessive dosage

Poor compliance
 Antiepeliptics and Pregnancy
Seizure very harmful for pregnant women

Monotherapy usually better than drugs combination;

Use the lowest effective dose

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
 MAN JADDA WA JADA

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