DRUG Therapy of epilepsy
Definition of Epilepsy
 Chronic disease characterized by repeated attacks (seizures or fits) of abnormal
electrical discharge of cerebral neurons resulting in EEG, motor, sensory,
autonomic or psychological changes.
Etiology
A. Primary epilepsy (unknown cause, i.e. idiopathic).
B. Secondary epilepsy caused by:
1. Trauma, meningitis, brain tumors, fevers, hypoglycemia.
2. Drugs: insulin (hypoglycemia) - TCAs – cocaine- antipsychotics – Li+.
Classification of Epilepsy
 Epilepsy is caused by a group of hyper excitable neurons with excessive electrical
discharge which might be localized (partial) or spread (generalized).
A. Partial
1. Simple Partial
 Localized: sensory, motor,
B. Generalized
1. Tonic-clonic
 Tonic
2. Absence
 Loss of
3. Myoclonic
 Sudden brief
psychic, or autonomic
followed by
consciousness
single or
disturbances. ; unaltered
clonic
, abruptly for
repetitive
consciousness
convulsions
a few seconds
jerks;
involving the
with staring
consciousness
(Psychomotor Epilepsy)
whole body
or blinking
is unaffected.
 Attacks of confused behavior
with loss of
(in children).
2. Complex Partial
& hallucinations with altered
consciousness
consciousness.
Members
I. Classic agents (major or older agents)
 Phenytoin – carbamazepine – valproic acid (valproate) - ethosuximide.
 Phenobarbital - Benzodiazepines.
II. Newer agents
 Lamotrigine – topiramate - gabapentin. : felbamate, vigabatrin,
pregabalin, tiagabine, zonisamide
Mechanism of Action of Classic agents
 reducing hyper-excitability of cerebral neurons through:
B.  Membrane Ion Permeability
A. Action on Brain Transmitters
1. Block Na+ Channels
1. Facilitate GABA Action
 Phenobarbital
 Phenytoin
 Benzodiazepines
 Carbamazepine
 Valproic acid
2.  GABA Level
2. Block T- Ca2+ Channels (in thalamus)
 Valproic acid (inhibits GABA
 Ethosuximide.
 Valproic acid
transaminase→ GABA breakdown)
Major (classic) Antiepileptics
Phenytoin
Mechanism
Carbamazepine
Block Na channels
Valproic acid
Block Na channels -Block Na channels
-Block Ca channels
-Inhibits GABA
transaminase→
GABA breakdown
A: omv
Ph.kinetics
D:all, high ppb
st
M:sd(1 o)- ld(2nd o)
E:U
1-Epilepsy
Uses:
All types except petit mal epilepsy
2-Antiarrythmic Ib
2-Mood stabiliz.
in bipolar depr.
3-Trigem. Neur.
Adverse effects:
Hypersensitivity
Skin rash  stop the drug.
Broadspectrum
2-Mood stabiliz. in
bipolar depr.
3-Migraine
GIT Disturbances
Nausea - vomiting - epigastric pain (most common with valproic acid)
 give small dose after meals.
Neurological
 Nystagmus, Diplopia,
 Diplopia,
Disturbances
Ataxia, Drowsiness.
Ataxia,
 Learning in children.
Drowsiness.
(specially in toxic

 Fine hand tremors.
 Ataxia, Less
sedative.
doses)
Hepatotoxicity
 Transient elevation of liver enzymes.
 Hepatotoxicity
(liver function
(rare but fatal).
tests required).
Effects on Hepatic
Microsomal
Enzymes
(monotherapy is
preferred)
Hematological
Effects (→regular
blood picture)
Teratogenicity →
give folic acid
Others
Enzyme inducer

 Metabolism of other
Enzyme inducer

antiepileptics, warfarin
 Osteomalacia:  vitD
 Metabolism
 Metabolism of
antiepileptics &
antiepileptics ,
other drugs.
warfarin &
Ca2+ supplements ).
other drugs.
(add folic acid supplements).

of
metabolism (→ vit D &
Megaloblastic anemia
Enzyme inhibitor
Leukopenia
Thrombocytopenia
Agranulocytosis
Lymphadenopathy
 Cleft palate & lip - heart
 Less
anomalies.
teratogenic.
1. Cosmetic disturbances
 Water
 Gingival hyperplasia
(gum hygiene required).
1. Hair loss.
2.  Appetite.
dilutional
3.  body weight.
hyponatremia
 Hirsutism - acne.
(potentiates
ADH).
level: monitor level.
Ethosuximide (safest):
Uses:of choice in petit mal
S/E: GIT upset, skin rash, dizziness, drowsiness, headache
Newer agents
 Neural tube defects.
intoxication &
 Coarse facial features.
2. Unpredictable serum
 Spina bifida.
1. Glutamate
3. Block Na+ Channels
1- felpamate: block NMDA receptors
1- Lamotrigine (sever rash)
2- topiramate: block AMPA receptors
2- Topiramate

 3-zonisamide (renal stones)
2.  GABA
1-Gabapentine, pregabaline analogue increase release of GABA
2- tiagabine : decrease uptake of GABA
3- Vigabatrin: inhibit GABA transaminase...>decrease breakdown (visual defect)
4-topiramate:
Uses: Refractory cases especially partial seizures
+
Lamotrigine: bipolar manic dis.
Topiramate: migraine
Gabapentine: trig.neur., postherpetic neur.
Choice of Antiepileptic Drugs in Different Types of Epilepsy
Partial
Generalized tonic-
Absence
Myoclonic
clonic
First line
 Valproic acid.
 Valproic acid.
 Ethosuximide.
 Valproic acid.
 Carbamazepine
 Lamotrigine.
 Valproic acid.
 Topiramate.
 Phenytoin.
 Topiramate.
 Lamotrigine.
Alternatives
 Topiramate.
 Phenytoin.
 Lamotrigine.
 Carbamazepine.
 Phenobarbital.
 Phenobarbital
 Clonazepam.
 Clonazepam.
Status Epilepticus
 Continuous or repetitive seizures > 30 min with impaired consciousness during the interictal
period.
Management (drugs are given IV)
1. Lorazepam (Preferred to diazepam as its antiepileptic effect is longer & it is non irritant
to veins.), midazolam or diazepam (IV or rectal) → for rapid control.
2. Fosphenytoin (soluble, prodrug,
safer than pheytoin (no need for the cardiotoxic
solubilizing agent propylene glycol). or phenytoin → long-acting, to maintain control.
3. Phenobarbital →2nd choice to phenytoin.
4. IV anesthesia with propofol→ in resistant cases.
General Guidelines for Antiepileptic Drug Therapy
1. Proper diagnosis of type of epilepsy & prescribing appropriate drug.
2. Monotherapy is preferred since antiepileptic drugs are either enzyme inducers
(phenytoin, carbamazepine & phenobarbitone) or enzyme inhibitors (valproate).
Combinations could result in changes in serum level of drugs.
3. Start with a small dose & a single drug and gradually  dose. If no effect, gradually
substitute or add another drug.
4. Long duration of treatment: If epileptic fits are absent for 2 years, consider terminating
therapy; but if fits recur, repeat treatment for another 2 years.
5. Gradual withdrawal of drugs: over six months to avoid status epilepticus or relapse.
6. Folic acid supplements: especially to women in child bearing period to ↓ risk of
teratogenic defects.
7. Pregnant females should receive the lowest effective dose of the least teratogenic
antiepileptic drug (e.g., carbamazepine). Pregnancy  metabolism of antiepileptics 
adjust dose.
8. Monitoring of serum level of drugs, periodically, since a drop below therapeutic level
could result in loss of seizure control while an increase in their level could result in
toxicity (CNS depression  stupor - coma - respiratory depression).
9. The newer antiepileptics lamotrigine & topiramate have fewer drug interactions → do
not require serum monitoring.