“

EPILEPSY
”
Mita Restinia, M.Farm, Apt
 OUTLINE
 Definition
 Pathophysiology
 Clinical Presentation (symptoms, sign)
 Diagnosis Test
 Desired Outcome
 Treatment
 General approach
 Mechanism of action
 Special case in female
 Pharmacokinetics
 Adverse Effect
 Drug Interaction
Definition
 Pathophysiology

 excessive excitation
 Alterations of ion channels in neuronal
membranes
 Increased excitatory (Glutamat)
 Decreased inhibitory (GABA)
 Biochemical modifications of receptors
 Modulation of second messaging systems and
gene expression
 Changes in extracellular ion concentrations
 Local neurotransmitter imbalances (e.g.,
glutamate,γ-aminobutyric acid [GABA]),
acetylcholine, norepinephrine, and serotonin)
Clinical Presentation

 Symptoms of a specific seizure

depend on seizure type.
 CP seizures may include
somatosensory or focal motor
features. They are associated with
altered consciousness.
 GTC seizures are major convulsive
episodes and are always associated
with a loss of consciousness.
Diagnosis

 Symptomps
 Electroencephalographic (EEG) is used
to record the electrical activity of the
brain. EEG
 very useful in the diagnosis of various
seizure disorders. The EEG may be
normal in some patients who still have
the clinical diagnosis of epilepsy.
 MRI is very useful (especially imaging of
the temporal lobes), CT scan typically is
not helpful except in the initial
evaluation for a brain tumor or cerebral MRI
bleeding.
Desired Outcome

 control or reduce the frequency of seizures,

 minimize side effects, and
 ensure compliance,
 allowing the patient to live as normal a life as possible
International Classification of Epileptic Seizures

Commission on Classification and Terminology of the International League Against Epilepsy.

Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 1989;30:389–399.
Treatment
“Drugs of Choice for Specific-Seizure Disorders”

Treatments are
determined by
seizure type
Pharmacokinetic

 Attention : protein bound. Some of AED are low therapeutic index drug
Conditions altering AED protein binding include chronic renal failure, liver
disease, hypoalbuminemia, burns, pregnancy, malnutrition, displacing
drugs, and age (neonates and the elderly). Unbound concentration
 Monitoring is especially useful for phenytoin.
 Neonates and infants may metabolize drugs more slowly, and children
may metabolize drugs more rapidly than adults. Lower doses of AEDs are
often required in the elderly. Some elderly patients have increased
receptor sensitivity to CNS drugs, making the accepted therapeutic range
invalid.
Antiepileptic Drug Pharmacokinetic Data
Side Effect
Drug Interaction
 Phenobarbital, phenytoin, primidone, and carbamazepine are potent
inducers of cytochrome P450 (CYP450), epoxide hydrolase, and uridine
diphosphate glucuronosyltransferase enzyme systems.
 Valproic acid inhibits many hepatic enzyme systems and displaces some
drugs from plasma albumin.
Spesific Anti Epileptic Drug
Carbamazepin

 Carbamazepine may act primarily by inhibition of voltage-gated sodium channels.

 Food may enhance bioavailability.
 The liver metabolizes 98% to 99% of a dose of carbamazepine (mostly by CYP3A4), and
the major metabolite is carbamazepine-10,11-epoxide, which is active.
 it is considered an AED of first choice for newly diagnosed partial seizures and for primary
GTC seizures that are not considered an emergency.
 Neurosensory side effects (e.g., diplopia, blurred vision, nystagmus, ataxia, dizziness, and
headache) are the most common, occurring in 35% to 50% of patients initially.
 Rashes may occur in 10% of patients. Other side effects include hepatitis, osteomalacia,
cardiac conduction defects, and lupus-like reactions.
 Carbamazepine may interact with other drugs by inducing their
metabolism. Valproic acid increases concentrations of the 10,11-epoxide
metabolite without affecting the concentration of carbamazepine. The
interaction of erythromycin and clarithromycin (CYP3A4 inhibition) with
carbamazepine is particularly significant.
Ethosuximide

 Ethosuximide is believed to act primarily by inhibition of T-type calcium

(Ca) channel.
 It is a first-line treatment for absence seizures.
Felbamate

 Felbamate appears to act by blocking N-methyl-D-aspartate responses

and by modulating GABAA receptors.
 It is approved for treating atonic seizures in patients with Lennox-Gastaut
syndrome and is effective for partial seizures as well.
 Because of the reports of aplastic anemia (1 in 3,000 patients) and
hepatitis (1 in 10,000 patients), it is now recommended only for patients
refractory to other AEDs.
Phenobarbital

 Phenobarbital may act by interacting with GABA receptors, blocking high

voltage-activated Ca channels, and blocking α-amino-3-hydroxy-5-
methylisoxazole-4-propionic acid and kainate receptors.
 Phenobarbital is the drug of choice for neonatal seizures, but in other situations
it is reserved for patients who have failed other AEDs.
 Phenobarbital is a potent enzyme inducer and interacts with many drugs.
 The amount of phenobarbital excreted renally can be increased by giving
diuretics and urinary alkalinizers.
 The most common side effects are fatigue, drowsiness, and depression.
 Phenobarbital can usually be dosed once daily, and bedtime dosing may
minimize daytime sedation.
Phenytoin

 Phenytoin inhibits voltage-dependent sodium channels.

 Phenytoin is a first-line AED for primary generalized convulsive seizures and
for partial seizures.
 Food may slow absorption.
 Phenytoin is metabolized in the liver mainly by CYP2C9, but CYP2C19 is
also involved. Zero-order kinetics occurs within the usual therapeutic
range, so any change in dose may produce disproportional changes in
serum concentrations.
 Common but usually transient side effects are lethargy, incoordination,
blurred vision, higher cortical dysfunction, and drowsiness
Valproic Acid

 Valproic acid may potentiate postsynaptic GABA responses, may have a

direct membrane-stabilizing effect, and may affect potassium channels.
 At least 10 metabolites have been identified, and some may be active. One
may account for hepatotoxicity (4-ene-valproic acid), and it is increased by
concurrent dosing with enzyme-inducing drugs. At least 67 cases of
hepatotoxicity have been reported, and most deaths were in mentally
retarded children less than 2 years old who were receiving multiple drug
therapy.
 Valproic acid is an enzyme inhibitor that increases serum concentrations of
concurrently administered phenobarbital and may increase concentrations of
carbamazepine 10,11-epoxide without affecting concentrations of the parent
drug. It also inhibits the metabolism of lamotrigine.
 Lamotrigine blocks voltage-dependent sodium channels and inhibits
 high-voltage activated Ca channels.
 • It is useful as both adjunctive therapy for partial seizures and as monotherapy.
 It may also be a useful alternative for primary generalized seizures,
 such as absence and as adjunctive therapy for primary GTC seizures.
 • The most frequent side effects are diplopia, drowsiness, ataxia, and headache.
 Rashes are usually mild to moderate, but Stevens-Johnson reaction has also
 occurred. The incidence of the more serious rashes appears to be increased in
 patients who are also receiving valproic acid and who have rapid dosage
 titration. Valproic acid substantially inhibits the metabolism of lamotrigine.
Oxcarbazepine

 Oxcarbazepine (a prodrug) is structurally related to carbamazepine, but it

is converted to a monohydrate derivative, which is the active component.
 It blocks voltage-sensitive sodium channels, modulates the voltage-
activated Ca currents, and increases potassium conductance.
 The most frequently reported side effects are dizziness, nausea, headache,
diarrhea, vomiting, upper respiratory tract infections, constipation,
dyspepsia, ataxia, and nervousness.
 About 25% to 30% of patients who have had a rash with carbamazepine
will have a cross-reaction with oxcarbazepine.