Anti epileptic drugs(AED) L1

Professor Dr Sinaa A. Kadhim

M.B.Ch.B, GP.Rad., M.Sc., Ph.D.Pharm
 This lecture consists of 2 parts:
1st part is a key points about the disease (for your
information)
2nd part is the objectives (about drug
informations)

Objectives:
1. know types of antiepileptic drugs
2. Know MOA, kinetics, pharmacological action,
clinical indication, interaction and adverse effects
of drugs.
1st part
Seizure: is a transient alteration in brain function(motor,
consciousness, sensation, vision….) due to a disordered
rhythmic depolarization of a population of brain neurons.

Epilepsy: a disorder of brain function that is

characterized by periodic and unpredictable occurrence of
seizure, the most common 4th neurologic disorder after
migraine, stroke and Alzheimer’s disease.
Convulsion: is an involuntary, violent and spasmodic
contraction of skeletal muscles.
Normally when we move any muscle of our body there are
signals arising from the brain resulting from firing
(depolarization) of certain neurons,
while in epilepsy there is uncontrollable spontaneous firing
of some neurons in the brain.
 Pathophysiology
-Normally GABA (an inhibitory neurotransmitter) are likely
presented in balance with glutamate & aspartate(excitatory
neurotransmitters ).
if GABA is decreased or excitatory neurotransmitters
increased , this lead to disturbance of balance . more
dominant action of excitatory neuro.
when this disturbance in balance occur , glutamate and
aspartate neuro. Will activate Na channel Na channel
will open depolarization (firing) occurs and
epilepsy will developed .
- Opening of t-type calcium channel suddenly, Ca channel
relay between center and cortex of brain its opening leads to disturb
connection(open connection) and epilepsy occur (absent seizure)
* GABA in balance action with glutamate
and aspartate

If GABA Gluta. & Aspart.

(inhibitory) (Excitatory aa.)

open Na channel(NMDA)

depolarization(firing)
*If t-type Ca channel opened loss of relay
absent attack (epilepsy)
*note: N-methyl-D-aspartate (NMDA) receptors, a family of glutamate
Symptoms: depend on site and size of seizure occurrence

Site size
if the affected area: -Focal
• Temporal lobe
auditory hallucination -Generalize

• Occipital lobe -Focal with

visual abn. 2ndary
generalization
• Motor cortex
convulsion or jerky
movement
Classification of epileptic seizures:
1-Generalized seizures. It begins over the entire
surface of brain (both hemisphere) there is loss of
consciousness from the beginning
2- Focal (in past named as Partial) :involve only a portion
of the brain, typically part of one lobe of one hemisphere.

3-Focal secondarily generalization: it starts as focal then

spread to both hemisphere and becomes tonic-clonic.
1. Generalized seizure:
a- Absence seizure(“petit mal”) : occurs in young
children characterized by brief loss of consciousness(4 –20
seconds, usually <10 seconds). By other words (abrupt
onset of impaired consciousness associated with
starring and cessation of ongoing activity), with
no warning and immediate resumption of
consciousness (no postictal abnormality).

Pre-ictal (pre ictal (= during Postictal(= after

attack= aura) attack) attack)

b. Myoclonic seizure: brief shock-like involuntary,

c. Tonic clonic seizures(“grand mal”): characterized by
tonic followed by clonic contraction . The person loses
consciousness, apnea, falls, stiffness,…… (tonic phase),
and jerks (clonic phase). usually last for less than 3
minutes but are followed by confusion and tiredness of
variable duration (postictal period).

d- Febrile seizure: attack associated with fever in children

(occurs from 6 month -5 years). It is not epilepsy.

e- Atonic type: there is sudden loss of muscle tone.

f- Tonic type: increase body tone.
**Status epilepticus: a prolong seizure for >20 min. : a
process in which the seizures tend to occur one after the
other without preservation of conscious in between. **
2. Focal onset seizure (previously = partial):

A. Focal aware onset (previously Simple partial): it

is associated with preservation of consciousness.
Note : The electrical discharge does not spread, and the
patient does not lose consciousness

B. Focal impaired onset (Complex partial): it is

associated with impaired consciousness, associated
with movement.

**others infantile spasms (West’s syndrome), Lennox-Gastaut syndrome, juvenile

myoclonic epilepsy………*
2nd part
Drugs:
The antiepileptic drugs can act by :

1.Block Na or t- type Ca++ channels

2.Increase the activity of inhibitory neurotransmitter

(GABA).
3.Decrease the activity of excitatory neurotransmitter
like glutamate and aspartate.
.
Classical = 1st generation(including benzodiazepine)
Newer = 2nd generation ( excitatory neuro.)
1st differ from 2nd by Older, no action on excitatory n., more side effects
1st generation antiepileptic
1- Phenytoin : (diphenyl hydantoin)
• Phenytoin (1st generation)
• Fosphenytoin( 2nd generation) after enter the body Converted to
phenytoin.

Phenytoin Mechanism of action:

1- block Na + channel in brain and heart(Decreasing
movement of Na and K in neurons) leading to
decrease firing.

2- At high conc. It enhances the activity of GABA

But it produces some drowsiness and lethargy without progression to

hypnosis (bs phenytoin is not generalized CNS depressant).
Pharmacokinetics:
1- Pharmaceutical form : greatly affects the bioavailability
of phenytoin.

2.It has a plasma protein binding activity.

3.Phenytoin is subjected to zero order kinetics and at

therapeutic level it transfers to 1st order kinetics(dose
dependent).

4.It is hepatic enzyme inducer. it induces insignificantly its

own metabolism but the metabolism of other drugs
significantly induced including other antiepileptic drugs
so
phynetoin accelerates metabolism of many drugs like
vitamin D, folate leading to reduce their therapeutic
efficacy.

5. Affected by liver enzymes inhibitors like Sodium

valproate, cimetidine, and erythromycin.

6. Taken orally (the best)or intravenously i.v .. bs Phenytoin

is insoluble and crystallizes out in intramuscular i.m
injection site, so i.m is contraindicated because of the risk
of necrosis and damage the tissue.

7. Intravenous phenytoin is irritant to veins and tissues

because of high pH, thus giving slowly in large vein.
**Fosphynetoin is water soluble, can be taken i.v.
Therapeutic uses:
A- The epileptic uses:
1. Tonic-clonic seizures.
2. Status epilepticus (by slow I.V.):1st we start with rapid acting drug
like diazepam then with long acting phenytoin.

B- Non epileptic uses:

1- Trigeminal neuralgia (2nd choice drug after carbamazepine).
2-Anti-arrhythmic(class I B) in cardiac arrhythmia
(stabilizing effect to the tissues).
Side effects:
1. Decrease the ability to learn. Also impairment of cognitive function

2. CNS side effects including: NAD nystagmus, ataxia and diplopia,

sedation up to delirium .

3. Allergic effects like rashes, urticaria,

4. Inhibition of collagenase enz.(after long treatment) This leads to

inhibition of collagen catabolism which causes gum hypertrophy
(hyperplasia) and coarsening of facial features.

5.It may cause duputriens contracture

(mediated through the peripheral stimulation of tissue growth
.factors )
6. Megaloblastic anemia ( due to decrease folic acid level bs
phenytoin accelerates metabolism of folate).
7. Osteomalacia ( bs it accelerates metabolism of Vit. D).
8. Hirsutism ( Increase in fibroblast growth factor but mostly
it is androgen dependent.).
9- Hyperglycemia or glucosuria (bs of decrease insulin
release) .
.
in pregnancy:
Teratogenic, in first trimester of pregnancy, can cause fetal
hydantoin syndrome (Children may develop wide mouth (cleft lip
and palate), short nose, mild webbing of the neck, hypoplastic
nails, microcephaly, congenital heart defects and mental
subnormality).
2.Carbamazepine (tegretol), Oxcarbazepine (2nd generatio)
, Eslicarbazepine acetate (TRICYCLIC GROUP):
Carbamazepine It is structurally related to anti-
depressants (Imipramine).
Mechanism of action:
1- Blocking Na channels so it stabilize membrane to
depolarization.
2- Modulation of calcium channels by Oxcarbazepine.
**Carbemazepine May aggravate absence and myoclonic
attack
Kinetics:
1- Carbamazepine
• It is absorbed completely slowly
• It cross BBB rapidly (high lipid solubility)
• It acts as enzymes inducer ( induce folate metabolism leads to
megaloplastic anemia)+ auto induction (increase its on metabolism).
• Its metabolism in liver is inhibited by cimetidine & valproate
• 75-85 % bioavailability, t1/2= 10-20 hr , in multiple dosing

2- Oxcarbazepine: less potent than carbamazepine, 100%

bioavailibility, is effective for partial seizures, with t1/2 of 1-2 hr and
fewer interactions.

3- Eslicarbazepine acetate: Similar to oxcarbazepine but it is given once

daily and rapidly converted to the active metabolite.
Uses of
carbamazepine:

1. Focal seizures (1st choice)

2. Tonic clonic seizure( 2nd choice).
3. Trigeminal neuralgia(1st choice).
4. Bipolar depression (in Manic depressive) patients
Side effects:
1.CNS: NDA (nystagmus , diplopia, ataxia). but coma and
respiratory depression may occur with chronic
administration.
2.GIT: Irritation of stomach, nausea and vomiting.
3. Blood : a- Megaloplastic anemia (bs of
folate deficiency).
b- Agranulocytosis and thrombocytopenia.
4. Liver toxicity.
5. Teratogenic : produce: a- craniofacial anomaly (cleft
palate)
b-neural tube defect (spina
bifida)
6. Side effects profile of Eslicarbazepine are
serious such as rash, psychiatric side effects,
3. Barbiturates:
A. Phenobarbital: long acting barbiturates act by
1- Enhancing the activity of GABA by allosteric
modulation of GABA A receptor
2- Blocking of Na channel
3- GABA like action(GABA
Agonist).

Uses:
1- Febrile convulsions in children (1st choice ).
2- Tonic clonic seizure
3- Status epilepticus.
 Adverse effects
• CNS: NDA(nystagmus, diplopia, ataxia), dizziness, …
………. Respiratory depression in toxic dose
• Liver: enz. Inducer
• Blood :Megaloblastic anemia ( due to acceleration of
folate metabolism).
• Teratogenic : including:
a- craniofacial anomaly (cleft palate)
b- neural tube defect (spina bifida)
• Tolerance and physical dependence
• Its used limited bs of many adverse
• effects.
B. Primidone

• It metabolized in the body slowly to phenobarbitone and

rapidly metabolized to PEMA (phenyl ethyl
malonamide).
• Much of its anti-convulsive activity is related to
phenobarbitone
• can be used with carbemazepine and
phenytoin allowing smaller doses of
these drugs to be used.

**Side effects: similar to that of phenobarbitone. (NDA, ….)

 Case
70 yrs old male, aknown case of epilepsy,
present to Medical Consultant Unit with gum
hypertrophy (hyperplasia) and coarsening of facial
features.

Q1 : Which drug can cause this effects?

Q2 : Explain why this effect were happened ?
THANK YOU
For your informations