Drugs Used In Epilepsy

Objectives:
.Describe types of epilepsy
List the antiepileptic drugs.
Describe briefly the mechanism of action of antiepileptic
drugs.
Enumerate the clinical uses of each drug.
Describe the adverse effects of each antiepileptic drug &
treatment of status epilepticus.
Classify antiepileptic drugs according to the type of
epilepsy treated and generation introduced
Expand on pharmacokinetic and dynamic patterns of first
and second generation antiepileptic drugs.

Editing 0File
 Epilepsy
Epilepsy is a chronic medical condition characterized by 2 or
more unprovoked seizures (within 6-12 months). It is a syndrome.

the difference between seizure & epileptic syndrome

Seizures: are abnormal movements
Epilepsy: is a group of related
or behavior due to unusual electrical
disorders characterized by a
activity in the brain, are a symptom
tendency for recurrent seizures
of epilepsy

:The difference between a syndrome and a disease is

A syndrome is a set of medical signs and symptoms that occur together and
suggest the presence of a certain disease or an increased chance of developing the
disease(Usually not curable, idiopathic & combination of symptoms).
A disease is the actual diagnosed impairment of health or a condition of abnormal
functioning (Usually curable , non- idiopathic & it's a combination of symptoms) .

Etiology(causes):
•Congenital defects, head injuries, trauma, hypoxia
1 :Triggers
•Infection ( bacteria or virus ) e.g. meningitis, brain abscess,

2
viral encephalitis. Fatigue
•Concussion, depressed skull, fractures.
3
Stress
•Brain tumors (including tuberculoma), vascular occlusion,
stroke Sleep
4
deprivation
•Drug withdrawal, e.g. CNS depressants, alcohol or drug
abuse or drug overdose ,e.g. penicillin.
5 Poor
•A poison, like lead nutrition
6

7
•Fever in children (febrile convulsion). (Februs in Latin means fever)
Alcohol
•Hypoglycemia
8 Triggers can cause
an episode even
•PKU Phenylketonuria is a rare inherited disorder that causes an amino under medication
acid called phenylalanine to build up in body caused by absent or
9 virtually absent phenylalanine hydroxylase (PAH) enzyme activity
Phenylalanine hydroxylase
•Photo epilepsy is a type of epilepsy, in which all, or almost
all, seizures are triggered by flashing or flickering light Phenylalanine tyrosine
10
 Classification of Epilepsy

Partial (focal) Primary Generalized

Arise in one cerebral Both hemispheres + loss of consciousness.
hemisphere
They are interconnected sometimes
[1] Simple: • Tonic-clonic (Grand mal): Stiffness (15-30
consciousness is retained sec) followed by violent contractions &
[2] Complex (psychomotor): relaxation (1-2 minute)
Altered consciousness • Tonic: Muscle stiffness
• Clonic: Spasms of contraction & relaxation
• Atonic (loss of tone): Patients legs give
under him & drop down
• Myoclonic: Jerking movement of the body
Secondarily
• Absence(Petit mal):Brief loss of
generalized consciousness with minor muscle twitches
eye blinking In children
Begins as partial (simple or • Status epilepticus: Re-occuring tonic-clonic
complex) and progress into seizure (30 min or more)(Emergency situation
tonic- clonic (grand mal) may lead to death by Resp. failure)
seizure.

8:49 min | very helpful!

General rules for treatment of epilepsy:

- Epilepsy is usually controlled but not cured with medication.
- Up to 80% of pts can expect partial or complete control of seizures with
appropriate treatment. 20% has resistance
- Antiepileptic drugs are indicated when there is two or more seizures occurred in
short interval (6 m -1y) with no cause
- An initial therapeutic aim is to use only one drug (monotherapy).
• Drugs are usually administered orally except in status epilepsy (IV).
• Monitoring plasma drug level is useful
• Triggering factors can affect seizure control by drugs.
• Sudden withdrawal of drugs should be avoided.

Withdrawal considered
▪ Seizure–free period of 2-5 years or longer
▪ Normal IQ
▪ Normal EEG prior to withdrawal
▪ No juvenile myoclonic epilepsy (in children)
▪ Relapse rate when antiepileptics are withdrawn is 20-40%.
 Treatment of Epilepsy

Vagal nerve
Drugs mainly stimulation Surgery Ketogenic diet

Ketogenic diet may

help because it will
lead to
accumulation of
Mechanism of anti-epileptic Ketones which are
acidic compounds
:inhibit depolarization of neuron by and acidosis cause
neuronal suppression

Blockage of Increase
Inhibition of enhancement of
voltage-gated outward positive
excitatory NTs inhibitory NTs
positive current current
(glutamate) (GABA)
(Na,Ca) (K)

Vagal nerve stimulation

It is an alternative for patients who

have been refractory to multiple
drugs

Who are sensitive to many adverse

effects of antiepileptic drugs

It is an expensive procedure
Not very effective
 Important notes

Prof. Yieldez said :

● important to know Mechanism of action, characteristic ADRs &
uses for each drug .
● Case: A boy was playing and suddenly he stopped,also he was
staring , blinking and then he got back to normal , wath is this
condition?
Absence(batite) seizure.
● If we have to treat pregnant woman , We use the least harmful
drug which is Topiramate
● Valproate, phenytoin & Carbamazepine are contraindicated
during pregnancy.
 Classification of antiepileptic drugs

First generation Seconds generation

Phenytoin Lamotrigine

Carbamazepine Topiramate

Valproate Levetiracetam

Ethosuximide Gabapentin

Phenobarbital &
Vigabatrin
Primidone

Benzodiazepines
Felbamate
(e.g. Clonazepam,
lorazepam and
diazepam)

Zonisamide
Mnemonics:
-Phenytoin:
(ADRs:gingival) ‫فيني؟ ب جينجيفال‬
-Carbamazepine:
‫ تعطشين‬carb ‫لما تأكلين‬
(ADRs: hyponatremia & water intoxication)
-Lamotrigine
(ADRs: skin rash) ‫تستخدم كريم جونسون لبشرتها )لمى(لمو‬ Differ from the 1st generation in the
-Topiramate effect on microsomal enzymes,
‫رميته ألنه صار وسيع )ثوبي(توبي‬ most of the 2nd gen drugs don’t
(ADRs: weight loss) have this effect
 1st Generation
Drug Fosphenytoin Phenytoin
M.O.A is very important
- Blockade of Na+ & Ca2+ influx into neuronal axon.
Mech. of
action

- Inhibit the release of excitatory transmitters .

- Potentiate the action of GABA.

o Parenteral form of phenytoin (IV & IM) o Given orally, well

absorbed from
o A Prodrug. GIT.(most drugs here
are taken orally)
o rapidly converted to phenytoin in the
o Also available as
body.
capsule & IV
o Advantage over phenytoin:
P.K

o more rapid IV administration than o Enzyme inducer.

phenytoin (increase its
o may be administered by IM injection metabolism → the
o Lower local tissue and cardiac toxicity action decreases)
than phenytoin o Metabolized by the
o Less pain and phlebitis at injection site liver to inactive
than phenytoin metabolites.
o Half life approx. 20 hr.
o Excreted in urine.
Therapeutic

● Partial and generalized tonic-clonic seizures.

Uses

● Not in absence seizure.

● In status epilepticus, given IV.

• Nausea or vomiting.
• Neurological like headache, vertigo, ataxia, diplopia , nystagmus.
• Sedation due to increased GABA
• Gum(gingival) hyperplasia. (very important)
ADRs

• Hirsutism.(abnormal hair growth, not a good option in females )

• Acne. (‫)حب الشباب‬
• Folic acid deficiency. (megaloblastic anemia)
• Vit D deficiency → (osteomalacia)
• Teratogenic effects. (very common side effect in all antiepileptics)
 1st Generation (cont.)
Drug
Carbamazepine
o Blockade of Na+ & Ca2+ influx into neuronal axon.
MOA

o Inhibit the release of excitatory transmitters.

o Potentiate the action of GABA.
o (similar to Phenytoin in many things)

o Available as capsule & syrup only orally.

o Well absorbed.
o Strong enzyme inducer. (including its own metabolism)
P.K

o Metabolized by the liver to active & inactive metabolites.

o T1\2=18-35 hr.
o Excreted in urine.

o Drug of choice in partial seizures. (Both simple & complex)

uses

o Tonic-clonic seizures. (1ry & 2ry generalized)

o Not in absence seizures. → because it may cause an increase in
seizures
o Other uses: Bipolar depression , Trigeminal neuralgia
*carbamazepine will cause thirst >> excessive water intake >>
o GIT upset. disturbances in water-electrolytes balance >> water intoxication
ADRs

o Hypersensitivity reactions.
o Drowsiness , ataxia, headache & diplopia.
o Hyponatremia & *Water intoxication. (anti-diuretic effect, and thus
it should not be given to children or old patients)
o Teratogenicity.

Drug Ethosuximide
MOA o Inhibits T- type Ca2+ channels in thalamocortical neurons.

o Absorption is complete.
o Syrup & capsule forms. (to be easily taken for children)
o Not bound to plasma proteins or tissues.
P.K
o Metabolized in liver.
o T1\2 = 52-56 hr.
o 10-20% of a dose is excreted unchanged the urine.

uses o Absence seizures. Mainly given to children

o Gastric distress :
o Nausea
ADRs o vomiting
o Drowsiness, fatigue, hiccups, headaches.
 1st Generation (cont.)
Drug Sodium Valproate
o Blocks activated Na+ channels.
o Enhances GABA synthesis & reduces degradation.
MOA

o Suppress glutamate action.

o Blocks T-type Ca2+ channels. (that’s why it can be used for
absence seizures)
o Broad spectrum antiepileptic
o Available as capsules, Syrup, I.V.
o Metabolized by the liver. (to inactive form)
P.K

o Enzyme inhibitor. Inducers ‫اللي قبل كانوا‬

o T1\2=12-16 hr.
o Excreted in urine.

o It is effective for all forms of epilepsy → very broad spectrum

o Generalized tonic-clonic seizures. (1ry & 2ry )
Therapeutic

o Absence seizures But Ethosuximide

it's drug of choice in this coundiction, cause it’s selective .
Uses

o Complex partial seizures.

o Myoclonic.
o Atonic.
o photosensitive epilepsy.

o GI (nausea, vomiting, heart burn).

o Weight gain (↑ appetite).
o Transient hair loss, with re-growth of curly hair.
ADRs

o Thrombocytopenia decreased platelet.( not used with aspirin or

coumadin “ antiplatelet drugs”)
o Hepatotoxicity(Transient increase in liver enzymes). (we do periodic
assessment)
o Teratogenicity (neural tube defect) C.I in pregnancy

o Bipolar disorder and mania. (as a mood stabilizer)

(Sodium Valproate is more favorable to treat bipolar disorder than carbamazepine)
Other uses

o Prophylaxis of migraine.
o Lennox-Gastaut syndrome.
→ The Lennox-Gastaut syndrome (LGS) is a type of epilepsy with
multiple different types of seizures, particularly tonic (stiffening) and
atonic (drop) seizures. Intellectual development is usually, but not
always, impaired
 2nd generation
Dru
g Topiramate Lamotrigine
o Blockade of Na+
o Blocks Na+ channels (membrane channels
MOA

stabilization) o Inhibits excitatory amino

o Potentiates the inhibitory effect of acid release
GABA. (glutamate &
aspartate)

o Available as oral tablets

o Well absorbed from GIT
o Well absorbed orally ( 80 % )
o Metabolized primarily
o Food has no effect on absorption
by glucuronidation.
o Has no effect on microsomal enzymes
o Does not induce or
(most important difference from the first
inhibit
gen)
P.K

C. P-450 isozymes
o 9-17 % protein bound (minimal)
(most important
o Mostly excreted unchanged in urine.
difference from the first
o Plasma t½ 18-24 hrs
gen)
o T1\2= approx. 24 hr

o As add-on therapy or as
Therapeutic Uses

monotherapy in partial
o Can be used alone for partial,
seizures & generalized
generalized tonic-clonic, and absence
tonic-clonic seizures →
seizures.
to be more effective.
o Lennox- Gastaut syndrome
o Lennox-Gastaut
( or lamotrigine, or valproate ).
syndrome
o Bipolar depression

o Psychological or cognitive dysfunction

o Influenza-like symptoms.
o Weight loss (can be desirable side
o Skin rashes (may
effect)
progress to Steven –
o Sedation
Johnson syndrome )
ADRs

o Dizziness
o Somnolence (sedation)
o Fatigue
o Blurred vision
o Urolithiasis (kidney stone)
o Diplopia
o Paresthesias (abnormal sensation )
o Ataxia (can be
o Teratogenicity (in animal but not in
teratogenic)
human)
 Treated by
1) carbamazepine
2) Phenytoin
Partial
3) valproate
seizures
Type of seizure

4) lamotrigine

Valproate or
Tonic-clonic carbamazepine or
(grand mal) phenytoin or
lamotrigine

Valproate,
Myoclonic clonazepam
Generalized
seizures
Valproate,
Absence ethosuximide

Atonic Valproate

Drugs used for treatment of Status Epilepticus

Most seizures last from few seconds to few minutes. When seizures
follow one another without recovery of consciousness, it is called
“status epilepticus”. It has a high mortality rate.
Death is from cardiorespiratory failure.

Antiepileptics used in status epilepticus

Through IV injection of:

| | |

Lorazepam
Diazepam Sodium
Phenytoin Phenobarbital Fosphenytoin
Valproate
(drug of choice)

Lorazepam has a shorter pharmacokinetic half-life but stays in the brain longer than diazepam.
 Pregnancy & anti-epileptics

• Seizure is very harmful for pregnant woman.

• No antiepileptic drug is safe in pregnancy.

•Monotherapy usually better than drug combination.

•Valproate , phenytoin & Carbamazepine are

contraindicated during pregnancy.

• Patient has to continue therapy.

(Summary (important

1. Epilepsy is classified into partial or generalized according to

the site of lesion.
2. The exact mechanism of action of AED is not known.
3. Phenytoin is mainly used for treatment of generalized tonic-
clonic seizures.
4. Carbamazepine is mainly used for treatment of partial
seizures.
5. Sodium valproate is a broad spectrum antiepileptic drug.
6. Lamotrigine & levetiracetam are used as monotherapy or
adjunctive therapy in refractory cases.
7. Lorazepam, diazepam, phenytoin are used intravenously for
treatment of status epilepticus.
 Summary of 1st Generation Drugs
Drug Sodium valproate Ethosuximide Carbamazepine Phenytoin

- Block influx of
Ca2+ and Na+
into neuronal
Mechanism of action

axon →
- Block Na+ and T - Block influx of potentiate the
type Ca2+ channels Ca2+ and Na+ into action of
neuronal axon → GABA.
- Enhances GABA Block T type potentiate the - Inhibit the
synthesis Ca2+ channels action of GABA release of
- Inhibit the release excitatory
- Suppress glutamate of excitatory transmitters.
action transmitters.
Fosphenytoin

Parenteral form
of phenytoin.

1- status
Indications

epilepticus
Partial and
Absence 2- partial and
All types of epilepsy generalized tonic-
seizure generalized
clonic seizures
tonic-clonic
seizures

Hair loss
Hyponatremia and 1- Folic acid &
water intoxication vit.D deficiency
Thrombocytopenia Hiccups
(osteomalacia)
ADRs

Teratogenicity 3- teratogenic
Hepatotoxicity Gastric distress
effect
Hypersensitivity 4- hirsutism
Weight gain drowsiness
5- gum
Git upset hyperplasia
teratogenicity

Strong enzyme Enzyme inducer

Enzyme inhibitor
inducer Fosphenytoin is
Comments

Could be used in
given I.V to
1-bipolar disorder and Has very long
Drug of choice in treat status
mania half life = 52-56
partial seizures epilepticus
2-in migraine as h
its transformed
prophylactic drug
Strong drug rapidly into
3- lennox-gastaut
inducer phenytoin
 Summery of 2nd generation drugs
Drug Tobiramate Lamotrigine
Mechanism of action

- Block Na+ channels - Block Na+ channels

- Potentiate the inhibitory effect of - Inhibit glutamate and

GABA aspartate release.

o Does not induce or inhibit

PK Has no effect on microsomal enzymes
C. P-450 isozymes

Lennux-gastaut syndrome

- Urolithiasis -Influenza like syndrome

- Skin rashes → may
- Paresthesia progress to Steven –
ADRs
Johnson syndrome
- Weight loss - Somnolence (desire to
sleep)
- Teratogenicity - Ataxia

- Metabolized by
Extra glucuronidation
info. - Does not induce or inhibit
CP450 isoenzyme
 Questions
MCQs

1 ) Which of the following drugs is an enzyme inhibitor?

A-Sodium Valproate
B-Carbamazepine
C-Phenytoin
D-Ethosuximide

2 ) Which of the following drugs is a broad spectrum antiepileptic?

A-Lamotrigine
B-Phenytoin
C-Sodium Valproate
D-Topiramate

3 ) Which drug has a minimum adverse effects?

A-Carbamazepine
B-Topiramate
C-Lamotrigine
D-Ethosuximide

4 ) Steven-Johnson syndrome is a possible adverse effect of?

A-Phenytoin
B-Lamotrigine
C-Sodium Valproate
D-Topiramate

5 ) What is the drug of choice in case of partial seizures?

A-Carbamazepine
B-Ethosuximide
C-Lamotrigine
D-Phenytoin
 Questions
MCQs

6 ) Which of the following drugs may cause psychological effect ?

A-Topiramate
B-Sodium Valproate
C-Ethosuximide
D-Fosphenytoin

7 ) Which drug is contraindicated in females ?

A-Lamotrigine
B-Carbamazepine
C-Fosphenytoin
D-Topiramate

8 ) Which drug is the drug of choice in case of Status Epilepticus ?

A-Phenobarbital
B-Benzodiazepines MCQs
C-Fosphenytoin answers:
1-A
D-Valproate 2-C
3-D
4-B
5-A
6-A
7-C
8-B

SAQ

Q1 ) a 5 years old epileptic boy came to the dentist suffering from

enlargement of his gum due to antiepileptic drug.

Which drug did he use ?

Fosphenytoin

What is the mechanism of action of this drug ?

Block of Na and Ca influx

potentiate the action of GABA
 Team leaders:
Ghaida Saad Alsanad
Omar Alsuhaibani

Team Members:
Dimah Alaraifi
Ghada Alqrni
Razan Alhamidi
Mohammed Nouri

Special thank to Afnan Almustafa

References:

- Doctors’ slides and notes.

- pharmacology Team 435.

Special thank for team 435

@Pharma4370 Pharm437@[Link]