Anti-Seizure Drugs

1. ANTIEPILEPTIC
DRUGS

2. ANTI-EPILEPTIC DRUG
(AED)
A drug which decreases the frequency
and/or severity of seizures in people with
epilepsy
Treats the symptom of seizures, not the
underlying epileptic condition
Goal: maximize quality of life by
minimizing seizures and adverse drug
effects
Currently no “anti-epileptogenic” drugs
available

3. Current
Pharmacotherapy
Just under 60% of all people with
epilepsy can become seizure free with
drug therapy
In another 20%, the seizures can be
drastically reduced
In ~ 20% of epileptic patients, seizures
are refractory to currently available
AEDs

4. Choosing
the right AED
 Seizure type
 Epilepsy syndrome
 Pharmacokinetic profile
 Interactions/other medical
conditions
 Efficacy
 Expected adverse effects
 Cost

5. Classification of AEDs
Classical
Phenytoin
Phenobarbital
Primidone
Carbamazepine
Ethosuximide
Valproate
(valproic acid)
Trimethadione
(not currently in
use)
Newer
Lamotrigine
Felbamate
Topiramate
Gabapentin/Preg
abalin
Tiagabine
Vigabatrin
Oxycarbazepine
Levetiracetam
Fosphenytoin

6. General Facts About
AEDs
Good oral absorption and bioavailability
Most metabolized in liver but some excreted
unchanged in kidneys
Classic AEDs generally have more severe
CNS sedation than newer drugs (except
ethosuximide)
Because of overlapping mechanisms of
action, best drug can be chosen based on
minimizing side effects in addition to efficacy

7. Targets for AEDs
Increase inhibitory neurotransmitter system—
GABA
Decrease excitatory neurotransmitter system
—glutamate
Block voltage-gated inward positive currents
—Na+ or Ca++
Increase outward positive current—K+
Many AEDs pleiotropic—act via multiple
mechanisms

8. AEDs:
Mechanisms of Action
Voltage-gated sodium channel
Open
Inactivated
Na+
Na+
X
I
Na+
Carbamazepine
Phenytoin
A = activation gate
I = inactivation gate
McNamara JO. Goodman & Gilman’s. 9th ed. 1996:461-486.
I
Na+
Lamotrigine
Valproate

9. AEDs:
Mechanisms of Action
Calcium channel blockade

10. AEDs:
Mechanisms of Action
GABA

11. Side effect issues
Sedation - especially with barbiturates
Cosmetic - phenytoin
Weight gain – valproic acid, gabapentin
Weight loss - topiramate
Reproductive function – valproic acid
Cognitive - topiramate
Behavioral – felbamate, leviteracetam
Allergic - many

12. END OF INTRO

13. GABA
GABA
Barbiturates
Benzodiazepines
Gabapentin
Levetiracetam
Tiagabine
Topiramate
Valproate
Vigabatrin
Na+
Na+
Carbamazepine
Lamotrigine
Oxcarbazepine
Phenytoin
Topiramate
Valproate
Ca2+
Ca2+
Ethosuximide
Levetiracetam
Pregabalin
Valproate

14. CLINICAL USES
 Generalized
Tonic-Clonic
Seizures
 Partial Seizures
 Absence Seizures
 Myoclonic & Atypical Absence
Syndromes
 Status Epilepticus
 Other Clinical Uses

15. GENERALIZE
D TONICCLONIC
SEIZURES
PARTIAL
SEIZURES
ABSENCE
SEIZURES
MYOCLONI STATUS
C&
EPILEPTICUS
ATYPICAL
SYNDROMES
Drugs of
Choice
Valproic Acid
Carbamazepine
Phenytoin
Carbamazepine
Lamotrigine
Phenytoin
Ethosuximide
Valproic
Valproic Acid
Clonazepam
Diazepam
Lorazepam
Alternativ
e Agents
Phenobarbital
Felbamate
Phenobarbital
Topiramate
Valproic Acid
Clonazepam
Levetiracetam
Topiramate
Zonisamide
Phenytoin
Phenobarbital
Adjunctive
Drugs
Lamotrigine
Topiramate
Gabapentin
Pregabalin
Lamotrigine
Levetiracetam
Zonisamide
Lamotrigine
Felbamate

16. Other Clinical Uses
 Valproic
acid –mania
 Carbamazepine, Lamotrigine –bipolar
disorder
 Carbamazepine –trigeminal neuralgia
 Gabapentin –pain of neuropathic origin
 Topiramate –migraine
 Pregabalin –neuropathic pain

17. MAIN INDICATIONS OF ANTIEPILEPTIC DRUGS

18. TOXICITY
Teratogenicity
Overdosage Toxicity
Life-Threatening Toxicity

19. Teratogenicity
 Valproic
acid –neural tube defects
 Carbamazepine –craniofacial
anomalies, spina bifida
 Phenytoin –fetal hydantoin syndrome

20. Overdosage Toxicity
Respiratory depression
 Management: supportive
 Airway management
 Mechanical ventilation

21. Life-Threatening Toxicity
 Valproic
acid –fatal hepatoxicity
 Lamotrigine –Stevens-Johnson
syndrome
 Zonisamide –severe skin reactions
 Felbamate –aplastic anemia, acute
hepatic failure

22. GENERALIZED
TONIC-CLONIC
SEIZURE
DRUGS

23. Drug Name Indication Mechanism Pharmacoki Therapeutic Drug
of Action
netics
Levels and Interaction
Dosage
Carbamazepine
Indicated It blocks
for complex sodium
partial
channels at
seizures, therapeutic
generalized concentrations
tonic-clonic and inhibits
seizures, high frequency
mixed
repetitive firing
seizure
in neurons
patterns or
other
Acts
partial or
presynaptically
generalized to decrease
seizures. synaptic
Not
transmission
indicated
for
Absence
seizures.
Absorptionvaries widely
among
patients
Maintenance
dose range:
800-1200
mg/day PO in
divided doses
Interactions are
related to the
drug’s enzymeinducing
properties
Side effects/ ContraAdverse
indications
Reactions
Common:
Diplopia and
ataxia (most
common),
gastrointestinal
Peak levels:
disturbances;
6-8 hours after Therapeutic
Propoxyphene, sedation at high
administration range: 4-12
troleandomycin, doses
mg/L (16.9valproic acid –
Distribution50.8
inhibit
Occasional:
slow
micromoles/L) carbamazepine Retention of
Volume
clearance and water and
distribution:
Maximum dose increase
hyponatremia;
1L/kg
of 1600
steady-state
rash, agitation
mg/day
carbamazepine in children
Systemic
recommended blood levels
clearance(rarely, some
Rare:
1L/kg/d
patients have Phenytoin,
Idiosyncratic
required 1.6- phenobarbital – blood
70% bound to 2.4 g/day)
decrease
dyscrasias and
plasma
steady state
severe rashes
proteins
concentration of
carbamazepine
Half-life –
36hrs
•Hypersensitivity
• Kidney disease
• Cardiovascular
disease
• Seizure
disorder,
myasthenia
gravis
• Dehydration
• hypothyroidism

24. Drug
Name
Indication Mechanis Pharmacokinet Therapeutic
m of
ics
Levels and
Action
Dosage
Phenytoin Control of
Blocks
grand mal & sodium
complex
channels
partial
seizure,
Prevents
prevention nerve
& treatment conduction
of seizure
during or
following
neurosurger
y, migraine,
trigeminal
neuralgia,
certain
psychoses,
cardiac
arrhythmias,
digitalis
intoxication,
post-event
treatment of
MI.
Absorption after
oral ingestion
may be slow,
variable and
occasionally
incomplete
Adult Initially
100 mg tid.
Maintenance:
300-400 mg
daily in equally
divided doses.
Childn ≥6 yr
T1/2 = 20-30 hrs Initially 100 mg
tid, subsequent
Rapidly
dosage should
distributed to all be adjusted
tissues
according to
therapeutic
Metabolized
response.
primarily by liver Pedia Initially 5
P450
mg/kg/day in 2-3
Highly bound to equally divided
plasma proteins doses. Max: 300
mg daily.
Maintenance: 48 mg/kg/day.
Susp Initially
125 mg/5 mL
tid, subsequent
dosage adjusted
according to
therapeutic
response.
Drug
Interaction
induces P450s
in liver
Side
effects/
Adverse
Reactions
Hirsutism &
coarsening of
facial features
Acne
increases
metabolism of Gingival
hyperplasia
many drugs
(20-40%)
Decreased
reduces action serum
of other drugs concentrations
of folic acid,
Generally, this thyroxine, and
will increase
vitamin K with
action of other long-term use.
“Fetal
drugs
hydantoin
The
combination of syndrome”:
metabolism and includes
protein binding growth
retardation,
means that
microencephal
phenytoin can y, and
both increase
craniofacial
and decrease
abnormalities
drug action,
even of the
same drug
Contraindications
History of
hypersensitivity
to phenytoin or
other
hydantoins.
Sinus
bradycardia,
SA block, 2nd& 3rd-degree
AV block.
Patients w/
Adams-Stokes
syndrome.
Lactation.

25. COST AND PRESENTATION
(Dilantin)

26. Drug
Name
Indicatio
n
Valproic Indicated
for partial
acid
Mechanism Pharmacokinetic Therapeuti Drug
of Action
s
c Levels
Interaction
and
Dosage
Valporic acid
produces
seizures,
effect on
generalize isolated
d tonicneurones.
clonic
Therapeuticall
seizures,
y relevant
myoclonic concentration
seizure ,
.
absence
Valporic
seizure .
inhibits
sustain
repetitive
firing induce
by
depolarization
cortic and
spinal cord
neurones.
Prolonged
recovery of
old age
activated
sodium Na+
channels from
inactivation.
Absorption- Raidly
and compeletly after
oral administration
Peak levels: 14hours .
Volume of
distribution: 0.2L/kg
t-1/2 =15 hours
Metabolism-Hepatic
metabolism 95%
with less than 5%
excreted
unchanged.
Initially
15mg/kg/d
Childrens :
1530mg/kg/d
Adult:start
with 200mg
TDS.
Maximum
daily dose
60mg/kg/d
Valporate
increases
plasma level of
phenobarbitone
by inhibiting its
metabolism.
Volporic acid
and
cabamazepine
induce each
other
metabolism.
Concurrent
administration
of colonazapam
and valporate is
contraindicated.
Side
effects/
Adverse
Reactions
Contraindications
Anorexia,
nausea,
vomiting,
heart burn,
drowsiness,
atxia, and
tremers –
dose side
effects.Alopa
sia , rashes ,
thrombocytop
henia
Used during
pregnancy it
has produced
spinabifida and
other neural
tube defect in
the off spring.

27. DRUG NAME
INDICATION
MOA
PHARMOKINE
TICS
THERAPEUTIC
LEVELS AND
DOSAGE
DRUG
INTERACTION
SIDE EFFECTS
SPECIAL
PRECAUTIONS
LEVETIRACETA
M
Used in
combination with
other antiseizure
medications to
treat myoclonic,
partial onset, or
tonic clonic
seizures in
children and
adults
Binds to synaptic
vesicle protein
SV2A which is
involved in
synaptic vesicle
exocytosis
Absolute oral
bioavailability is
nearly 100%. peak
plasma
concentration
achieved in about
an hour and steady
state concentration
achieved in 48
hours.
It is not
significantly
bound to plasma.
It exhibits linear,
dose
proportional,kineti
cs, with low
intrasubject and
intersubject
variability and a
half life of 6-8 hrs.
It does not
undergo hepatic
metabolism nor
induce or inhibit
cytochrome P450
enzymes.
It is excreted
through the
kindneys
unchanged as
inactive
metabolites.
Recommended daily
dose:
Adults:
3000 mg
Initiated with
1000mg daily (500
mg twice daily) and
increased by 1000
mg/day every 2
weeks up to the
maximum
recommended dose
of 3000mg/day
Children:
60 mg/kg .initiated
with 20 mg/kg
(10mg/kg twice
daily) and increased
by 20mg/kg every 2
weeks until the
recommended daily
dose is reached.
PROBENECID
reduces the
elimination of
levetiracetam by
the kidneys,
potentially
doubling the
concentration of
levetiracetam in
the body
•
•
•
•
•

PREPARATIONS
:
tablets (immediate
release) 250,
500,750 and
1000mg. Tablets
(extended release)
500 and 750 mg.
Oral solution:
100mg/ml
Injection solution:
100mg/ml
STORAGE:
It should be stored
at 25 C. Brief
storage at 15-30 C
is acceptable.
•
•
Headache
sleepiness
Weakness
Dizziness
Difficulty
walking
Mood swings
Anxiety



It should not
be
discontinued
suddenly
because of
increased
seizure
activity
It has been
associated
with increased
risk of
suicidal
thinking and
behavior
The
medication
will make you
feel dizzy or
drowsy. Do
not drive a car
or operate
machinery.
Nursing
mothers:
breastfeeding
mothers
should not
consider
breastfeeding
while taking
lebvetiracetam
.

28. DRUG NAME
INDICATION
MOA
PHARMOKINE
TICS
THERAPEUTI
C LEVELS
AND DOSAGE
DRUG
INTERACTION
SIDE
EFFECTS
SPECIAL
PRECAUTIONS
LAMOTRIGIN
E
Adjunctive
Therapy: indicate
d as adjunctive
therapy for the
following seizure
types in patients ≥
2 years of age:
partial seizures
primary
generalized tonicclonic seizures
generalized
seizures
of Lennox-Gastaut
syndrome
Monotherapy:indi
cated for
conversion to
monotherapy in
adults ( ≥ 16 years
of age) with
partial seizures
who are receiving
treatment with
carbamazepine,
phenytoin,
phenobarbital,
primidone, or
valproate as the
single antiepileptic
drug (AED).
Bipolar Disorder
LAMICTAL is
indicated for the
maintenance
treatment
of Bipolar I
Disorder
Prolongation of Na
chanel inactivation
nd suppression of
high frequency firing.
In adddition it may
directly block voltage
sensitive Na cahnnels
thus stabilizing the
presynaptic
memnbrane and
preventing the release
of excitatory
neurotransmitters
mainly glutamate and
aspartae.
WELL
ABSORBED
orally.
It is metabolized
completely in the
liver .
Half life is 24 hr.
reduced to 16 hr in
patients receiving
phenytoin,
carbazepine and
valproate inhibits
glucorinidation of
lamotrigine and
doubles the blood
level.
Recommended
daily dose:
Adults:
50 mg/daily
initially, increase
up to 300
mg/day.
Levels increaed by
valproate,
decreased by
carbamazepine,PB
, phenytoin.
Get emergency
medical help if
you have any of
these signs of an
allergic
reaction: hives;
fever; swollen
glands; painful
sores in or
around your eyes
or mouth;
difficulty
breathing;
swelling of your
face, lips,
tongue, or throat.
Report any new
or worsening
symptoms to
your doctor, such
as: mood or
behavior
changes,
depression,
anxiety, or if you
feel agitated,
hostile, restless,
hyperactive
(mentally or
physically), or
have thoughts
about suicide or
hurting yourself.
Before taking
lamotrigine, tell your
doctor or pharmacist
if you are allergic to
it; or if you have any
other allergies. This
product may contain
inactive ingredients,
which can cause
allergic reactions or
other problems. Talk
to your doctor or
pharmacist your
medical history,
especially of: kidney
disease, liver disease.
This drug may make
you dizzy or drowsy
or cause blurred
vision. Do not drive,
use machinery, or do
any activity that
requires alertness or
clear vision until you
are sure you can
perform such
activities safely.
Limit alcoholic
beverages.
PREPARATIO
NS:
Tablets:
Tablets are
supplied for
oral
administration
as 25 mg
(white), 100 mg
(peach), 150
mg (cream),
and 200 mg
(blue) tablets.
STORAGE:
Store
lamotrigine at
77 degrees F
(25 degrees C).
Brief storage at
temperatures
between 59 and
86 degrees F
(15 and 30
degrees C) is
permitted.
Store away
from heat,
moisture, and
light. Do not
store in the
bathroom.