Antiepileptic Drugs

Department of
Pharmacology NEIGRIHMS,
Shillong
SOME FAMOUS PEOPLE
WHO WERE AFFLICTED

•ALEXANDER THE GREAT

•JULIUS CAESAR
•NAPOLEON
What are Epilepsies?
• Group of disorders of
the CNS characterized
by paroxysmal cerebral
dysrhythmia,
manifesting as brief
episodes (seizure) of
loss of consciousness,
with or without
characteristic body
movements
(convulsions), sensory
or psychiatric
phenomena.
What are seizures?
• A seizure is a transient alteration of
behaviour due to the disordered,
synchronous, and rythmic firing of
populations of brain neurones. Seizure
can be nonepileptic and can be evoked
in normal brain
• A seizure is a paroxysmal behavioral
spell generally caused by an excessive
disorderly discharge of cortical nerve
cells.
What are Epilepsies –
Clinically?
• Epilepsy is a syndrome of two or
more unprovoked or recurrent
seizures on more than one occasion.

• Epileptic seizures range from
clinically undetectable
(electrographic seizure) to
convulsions.
How many types?

1. Generalized:
A. Generalized tonic-
Clonic Seizures
B. Absence Seizure
C. Atonic Seizures
D. Myoclonic Seizures
E. Infantile Spasms
Types of seizures –
contd.
2. Partial (focal) Seizures
A. Simple Partial Seizures
B. Complex Partial Seizures
1. Generalized seizures

A. Generalized tonic-clonic
• GTCS/major epilepsy/grand mal
• Commonest of all
• Lasts for 1-2 minutes
• Aura-cry-unconsciousness-tonic
phase-clonic phase
• Usually occurs in both the
hemispheres
• Manifestations are determined by
cortical site of seizure occurence
Generalized Seizures –
contd.
Tonic phase:
- Sustained powerful muscle
contraction (involving all body
musculature) which arrests
ventilation.

EEG: Rythmic high frequency, high

voltage discharges with cortical
neurons undergoing sustained
depolarization, with protracted
trains of action potentials.
 Generalized Seizures
– contd.
Clonic phase:
- Alternating contraction and
relaxation, causing a
reciprocating movement which
could be bilaterally symmetrical.

EEG: Characterized by groups of

spikes on the EEG and periodic
neuronal depolarizations with
clusters of action potentials.
Generalized Seizures –
contd.
Generalized Seizures –
contd.
Generalized Seizures –
contd.
B. Absence seizure:
• Also called minor epilepsy/petit mal
• Usually in Children and lasts for 1-2 minutes
• Typical generalized spike-and-wave type
discharges at 3 per second (3 Hz)
• Momentary loss of consciousness, patient stares at
one direction
• No motor (muscular component)
• No convulsions
• Minor muscular twitching restricted to eyelids
(eyelid flutter) and face.
• No loss of postural control.
Generalized Seizures –
contd.
C. Atonic Seizures:
• Unconsciousness with relaxation of all
muscles
• Patient falls down
• Loss of postural tone, with sagging of the
head or falling
D. Myoclonic Seizures:
• Isolated clonic jerks associated with brief
bursts of multiple spikes in the EEG
• Momentary contractions of muscles of
limbs or whole body
• No loss of postural control
Generalized Seizures –
contd.
E. Infantile spasm:
• An epileptic syndrome.
• Characterized by brief recurrent
myoclonic jerks muscle spasm) of
the body with sudden flexion or
extension of the body and limbs.
• Progressive mental deterioration
2. Partial (focal)
Seizures
A. Simple partial seizure
• Lasts for 20 – 60 seconds
• Confined to a group of
muscles or localized
sensory disturbances
depending on area of
cortex involved
• For example – if motor
cortex of the left thumb
then jerking movement of
left thumb, and if it is
sensory cortex then
paresthesia of left thumb.
• No alteration of
consciousness
Partial (focal) Seizures –
contd.
B. Complex partial seizure
(temporal lobe/psychomotor
epilepsy)
• Focus is located in temporal lobe
• Confused behaviour and purposeless movements
and emotional changes lasting for 30 seconds to 2
minutes
• An aura often present
• Motor activity appears as non-reflex actions.
• Automatisms (repetitive coordinated movements).
• Wide variety of clinical manifestations
• Consciousness is impaired
Complex partial seizure –
contd.
Deja vu
Partial (focal) Seizures –
contd.
C. Secondarily generalized:
(Jacksonian)

• Partial seizures initially

• Followed by generalized tonic-
clonic seizure
Secondarily
generalized seizure
Partial (focal) Seizures –
contd.
Types of Seizure:
Summery:
Status epilepticus

• Continuous seizure activity for

more than 30 minutes, or 2 or
more seizures without recovery
of consciousness.
• Emergency: Recurrent tonic-
clonic convulsions without
recovery in between.
Causes of Epilepsy

•ACUTE
•CONGENITAL
Causes of Epilepsy –
contd.
ACUTE EPILEPSY
• CORTICAL DAMAGE
• TRAUMA
• STROKE
• NEOPLASM
• AUTOIMMUNE EFFECTS
Causes of Epilepsy –
contd.
Congenital:
• Hippocampus DYSGENESIS (FAILURE
OF CORTEX TO GROW PROPERLY)
• VASCULAR MALFORMATIONS
• AT LEAST EIGHT SINGLE LOCUS
GENETIC DEFECTS ARE ASSOCIATED
WITH EPILEPSY – motor cortex,
somatosensory cortex, visual cortex,
auditory cortex, temporal lobe cortex
and olfactory.
Experimental
Models
1. Maximal electroshock seizures: tonic
phase abolished by drugs effective in
GTCS
2. PTZ clonic seizures (Pentylenetetrazole):
Can be prevented by drugs effective in
absence seizure
3. Chronic focal seizure: alumina cream in
monkey
4. Kindled seizures: bursts of weak
electrical impulses – tonic-clonic seizure
Classification –
antiepileptic drugs
1) Hydantoins: phenytoin, phosphenytoin
2) Barbiturates: phenobarbitone
3) Iminostilbenes: carbamazepine, oxcarbazepine
4) Succinimides: ethosuximide
5) Aliphatic carboxylic acid: Valproic acid,
divalproex
6) Benzodiazepines: clonazepam, diazepam,
lorazepam
7) New compounds: gabapentin, lamotrigine,
tiagabine, topiramate, vigabatrin, zonisamide,
felbamate
 Mechanisms of seizure
& antiseizure drugs:
Most common ones:
• Modification of ion conductance
 Prolongation of Na+ channel inactivation
 Inhibition of `T` type Ca++ current
• Increase inhibitory (GABAergic)
transmission.
• Glutamate receptor antagonism
(NMDA, AMPA, or kainic acid)
• Genetic mechanism
Anticonvulsant mechanism
– contd.
The Sodium Channel: Na+
A. Resting State

B. Arrival of Action
Potential causes
depolarization and
channel opens allowing Na+
sodium to flow in.

C. Refractory State,
Inactivation – reduce the
rate of recovery. Na+
Sustain
channel in
this
conformation
The Sodium Channel –
contd.
Drugs acting via this channel:
Phenytoin, Sodium Valproate,
Carbamezepine, Lamotrigine,
Topiramide and Zonisamide
Anticonvulsant
mechanism – contd.
T type Ca++ current inhibition:
• T type current is responsible for 3 Hz spike-
and-wave
• Throughout the thalamus `T` current has
large amplitudes
• Bursts of action potential is by action of T
current
• In absence seizure
• Drugs – ethosuximide, valproate and
trimethadione
Anticonvulsant
mechanism – contd.
• The GABA
mediated CL-
channel opening
• Drugs:
barbiturates,
benzodiazepines,
vigabatrin,
gabapentin and
valproate
Individual Drugs
Phenobarbitone
• First effective organic antiseizure agent
• Mechanism:
• Mechanism of CNS depression like other barbiturates,
but less effect on Ca++ channel and glutamate release
– less hypnotic effect
• GABAA receptor mediated like other Barbiturates
• Continued use – sedation effect lost but not
anticonvulsant action
• Raises seizure threshold and limits spread
• Suppresses kindled seizures
• Pharmcokinetics:
• Slowly absorbed and long t1/2 (80 – 120 hrs)
• Metabolized in liver and excreted unchanged in kidney
• Single dose after 3 wks. – steady state
Phenobarbitone – contd.
(Gardenal/Luminal)
• Adverse effects: • Uses:
• Sedation • Many consider them
• Behavioural the drugs of choice for
abnormalities seizures only in infants
• Hyperactivity in • GTC
children • SP and CPS
• Rashes, megaloblastic • Dose:
anaemia and • 60 mg 1-3 times a day
osteomalacia
Primidone: Child: 3-6 mg/kg/day
deoxybarbiturate • Available as tabs –
Phenobarbitone and 30/60mg, syr. and inj.
PEMA Short half life 6-
14 hrs
Phenytoin
(Dilantin/Epsolin/Eptoin)
• Pharmacological actions:
• Not CNS depressant
• But muscular rigidity and excitement at
toxic doses
• Abolish tonic phase of GTC seizure
• No effect on clonic phase
• Prevents spread of seizure activity
• Tonic-clonic phase is suppressed but no
change in EEG and aura
• In CVS – depresses ventricular
automaticity, accelerates AV conduction
Phenytoin sodium –
contd.
• Mechanism of action:
• Prevents repetitive detonation of
normal brain cells during
`depolarization shift`
• Prolonging the inactivation of voltage
sensitive Na+ channel
• No high frequency discharges
• Na+ channel recovers
• No interference with kindling – only on
high frequency firing
Phenytoin sodium –
contd.
• Pharmacokinetics:
• Slow oral absorption
• 80-90% bound to plasma protein
• Metabolized in liver by hydroxylation and
glucoronide conjugation
• Elimination varies with dose – first order
to zero order
• T1/2 life is 12 to 24 hrs
• Cannot metabolize by liver if plasma
conc. Is above 10 mcg/ml
• Monitoring of plasma concentration
Phenytoin sodium –
contd.
Adverse effects:
• Hirsutism, coarsening of facial features and acne
• Gum hypertrophy and Gingival hyperplasia.
• Hypersensitivity – rashes, lymphadenopathy
• Megaloblastic anaemia
• Osteomalacia
• Hyperglycaemia
• Cognitive impairment
• Exacerbates absence seizures
• Fetal Hydantoin Syndrome
Phenytoin sodium –
contd.
• Uses: It is the first line
antiepileptic for
• GTCS, no effect in absence seizure
• Status epilepticus
• Trigeminal neuralgia – 2nd to
Carbamazepine
• Available as caps/tabs/inj
25 to 100 mg caps and tabs.
Phenytoin sodium –
contd.
• Drug Interactions:
• Phenytoin and carbamazepine
increases each others metabolism
• Induces microsomal enzyme –
steroids, digitoxin etc
• Phenytoin metabolism inhibition –
by warfarin, isoniazide etc.
• Sucralfate – decreases phenytoin
ebsorption
Phenytoin sodium –
contd.
Phenytoin sodium –
contd.

Fetal Hydantoin Syndrome

Phenytoin Toxicities
Images of Phenytoin
preparations
Carbamazepine
(Tegretol/Tegrital)
• Chemically related to imipramine
• Trigeminal neuralgia
• Resembles phenytoin in
pharmacological actions
• Unlike phenytoin – inhibits kindling,
modifies electroshock seizures and
raises threshold to PTZ and
electroshock
Carbamazepine – contd.

• Pharmacokinetics:
• Poorly water soluble and oral
absorption is low
• 75% bound to plasma protein
• Metabolized in liver: active 10-11
epoxy carbamazepine
• Substrate and inducer of CYP3A4
• Half life – 20 to 40hrs. Decreases
afterwards due to induction
Carbamazepine – contd.

• Adverse effects:
• Autoinduction of metabolism
• Nausea, vomiting, diarrhoea and visual
disturbances
• Hypersensitivity – rash, photosensitivity,
hepatitis, granulocyte supression and aplastic
anemia
• ADH action enhancement – hyponatremia and
water retention
• Teratogenicity
• Exacerbates absence seizures
Carbamazepine – contd.
• Uses:
• Complex partial
seizure
• GTCS and SPS
• Trigeminal and
related neuralgias
• Manic depressive
illness and acute
mania
• Available as tabs
(100mg 200, 400 etc.)
and syr.
• Oxcarbamazepine
Carbamazepine – contd.

• Interactions:
• Enzyme inducer – reduce efficacy
of OCPs and others
• Metabolism is induced by –
phenobarbitone, phenytoin,
valproate
• Inhibits its metabolism – isoniazide
and erythromycin
Ethosuximide
• Drug of choice for absence seizures
• Does not modify maximal electroshock seizure or
inhibit kindling
• High efficacy and safety
• Not plasma protein or fat binding
• Mechanism of action involves reducing
lowthreshold Ca2+ channel current (T-type channel)
in thalamus
At high concentrations:
• Inhibits Na+/K+ ATPase
• Depresses cerebral metabolic rate
• Potentiates GABA
• Phensuximide = less effective
• Methsuximide = more toxic
Ethosuximide – contd.
• Toxicity:
• Gastric distress, including, pain, nausea and
vomiting
• Lethargy and fatigue
• Headache
• Hiccups
• Euphoria
• Skin rashes
• Doses:
• 20-30mg/kg/day
• Available as syr./caps.
Valproic acid
(Encorate/Valparin)
• Broad spectrum anticonvulsant
• Effects on chronic experimental seizure and kindling
• Potent blocker of PTZ seizure
• Effective in partial, GTCS and absence seizures
• Mechanism:
• Na+ channel inactivation
• Ca++ mediated `T` current attenuation
• Inhibition of GABA transaminase
• Pharmacokinrtics: well absorbed orally, 90%
bound to plasma protein and completely metabolized
in liver and excreted in urine t1/2 is 10-15 hrs.
Valproic acid – contd.
• Adverse effects:
• Elevated liver enzymes including own – rise in
serum transaminase
• Nausea and vomiting
• Abdominal pain and heartburn
• Tremor, hair loss, weight gain
• Idiosyncratic hepatotoxicity
• In Girls – polycystic ovarian disease and
menstrual irregularities
• Negative interactions with other antiepileptics
• Teratogenicity: spina bifida
• Available as tabs. (200/300/500, syr. and
inj.)
Valproic acid – contd.

• Drug Interactions:
• Valproate and carbamazepine induce each
others metabolism
• Inhibits phenobarbitone metabolism and
increases its plasma level
• Displaces phenytoin from protein binding sites
and thereby decreases its metabolism –
phenytoin toxicity
Benzodiazepines
• Mainly used agents – Clonazepam,
Diazepam, Lorazepam and Clobazam
• Antiseizure properties:
• Prevents PTZ induced seizures prominently and
modifies electroshock seizure pattern
• Clonazepam has potent effect on PTZ induced
seizures but almost nil action on ME seiures
• Suppress the spread of kindled seizures and
generalized convulsions
• Do not abolish abnormal discharges at site of
stimulation
Benzodiazepines –
contd.
• Pharmacokinetic properties:
• Well absorbed orally (peak 1-4 hrs)
• IV administration – redistribution
• Diazpam rapid redistribution (1 hr)
• Diazepam – 99%, Clonazepam – 85% bound to plasma
protein
• N-desmethyldiazepam (metabolite) is less active than
diazepam – partial agonist
• Diazepam and NDD – hydroxylated to active
metabolite – oxazepam – t1/2 is 1 to 2 days
• Clonazepam – reduction of nitro group to inactive 7-
amino derivatives
• Lorazepam – conjugation with glucoronic acid – t 1/2 is
14hrs
Benzodiazepines –
contd.
• Adverse effects:
• Long term use of Clonazepam –
drowsiness and lethargy – tolerance to
antiseizure effects
• Muscular incoordination and ataxia
• Hypotonia, dysarthria and dizzziness
• Behavoiural abnormalities in children –
aggression, hyperactivity, irritability and
difficulty in concentration
• Increased bronchial and salivary
secretions
• Exacerbation of seizures
Benzodiazepines –
contd.
• Therapeutic uses:
• Cloonazepam in absence seizure
and myoclonic seizure in children
(1 to 6 months)
• Dose initial – 1.5mg/day, children –
0.01 to 0.03mg/kg/day
• Status epilepticus – Diazepam
Lorazepam may be used as
alternative
Benzodiazepines –
contd.
Gabapentin
• GABA molecule covalently bound to a
cyclohexane ring
• Originally designed to be centrally active
GABA agonist – rapid transfer across BBB
• Pharmaqcological Effects:
• Inhibits hindlimb extension in ME seizure
• Inhibits clonic seizures induced by PTZ
• Efficacy is equal to valproic acid but different
from carbamazepine and phenytoin
Gabapentin – contd.
• Mechanism of action:
• Unknown
• Does not mimic GABA
• Probably, promotes nonvesicular release
of GABA
• Binds a protein in cortical membrane –
similar to L type of voltage sensitive Ca+
+ channel
• But, do not alter Ca++ currents
• Does not reduce repetitive firing of
action potentials
Gabapentin – contd.
• Pharmacokinetics:
• Absorbeed orally
• Not metabolized in humans
• Not bound to plasma proteins and excreted
unchanged in urine
• Half life is 4 to 6 hrs.
• No known drug interaction
• Uses:
• Partial seizures with or without secondary
generalization in addition to other drugs
• 900-1800mg/day is equivalent to 300 mg/day of
carbamazepine if used alone
• Usual starting dose is 300mg/day
• Adverse effects: somnolence, dizziness, ataxia etc.
Lamotrigine
• Phenyltriazine derivative
• Originally, as antifolate agent
• Pharmacological Effects and Mechanisms:
• Suppresses tonic hindlimb extension in ME seizure
• Partial and secondarily generalized in kindling
• No action on PTZ seizures
• Delays recovery from inactivation of Na+ channels –
carbamazepine and phenytoin
• Effective against partial and secondarily generalized
seizures
• Broad spectrum activity – action in areas other than
Na+ channels
• Inhibition of glutamate release
Lamotrigine
– contd.
• Pharmacokinetics:
• Completely absorbed from GIT and metabolized
by glucoronidation
• Plasma half-life – 15 to 30 hrs
• Phenobarbitone, carbamazepine and phenytoin –
reduces half life
• Valproate – increases plasma concentration but
its concentration reduces
• Together with Carbamazepine – increase in
10,11-epoxide and toxicity
• Uses: Monotherapy and add on therapy in simple
partial and secondarily generalized seizures
Topiramate
• Sulfamate substituted monosaccharide
• Pharmacological effects and MOA:
• Broad spectrum antiseizure drug
• Carbonic anhydrase inhibitor
• Antiseizure activity against PTZ, ME seizure and
partial and secondarily generalized tonic-clonic
kindling
• Multiple actions – Na+ channel, K+ channel, GABAA,
AMPA-kainate subtypes of glutamate
• Pharmacokinetics:
• Rapidly absorbed orally, 10-20% bound to plasma
protein, excreted unchanged in urine
• Metabolized by hydroxylation, glucoronidation and
hydrolysis
• Reduction in estradiol level
Major Drug
Interactions
• Phenytoin:
• With P.barbitone – unpredictable overall reaction
• With Carbamazepine – increases each other`s
metabolism
• With Valproate – displaces phenytoin from protein
binding
• Mainly significant interactions are due to
displacement of protein binding - sulfonamides
• Carbamazepine:
• Increase in metabolism of other drugs like primidone,
phenytoin, ethosuximide, valproic acid, and
clonazepam
• Phenobarbitone and Phenytoin increases its
metabolism
• Significant interactions are due to enzyme induction
Major Drug Interactions
– contd.
• Valproate:
• Due to Protein binding and inhibition of
metabolism
• Phenytoin is displaced from binding
• Inhibits metabolism of phenobarbitone,
phenytoin and carbamazepine
• Ethosuximide:
• Valproate inhibits metabolism and
clearance
Other uses of AEDs:

• Gabapentin, carbamazepine — neuropathic pain

• Lamotrogine, carbamazepine — bipolar disorder

• Valproate, topirimate, gabapentin — migraine

• Diazepam – Tetanus, eeclampsia and convulsant drug poisoning

Treatment of Epilepsies
1. Aim of the treatment:
• Control and prevent all seizure activity (seizure
- freedom and improvement in quality of life!)
• To search the cause of epilepsy
• Attempts to remove the causes
• Symptomatic treatment with antiepileptic
drugs
• To consider status epilepticus as medical
emergency and treat efficiently and promptly
2. Choice of Drugs: According to the seizure
types.
Treatment of Epilepsies
– Drug choices
Seizure types 1st choice 2nd choice
Generalized tonic-clonic or Carbamazepine, Phenobarbitone
simple partial seizure Phenytoin and and Valproate
Valproic acid
Absence seizure Valproate Ethosuximide
Complex partial seizure Phenytoin, Gabapentin
with or without Carbamazepine Lamotrigine
generalization and Valproate
Myoclonic Valproate Lamotrigine
Topiramate
Status epilepticus Diazepam Phenytoin IV
Lorazepam Phosphenytoin IV

Febrile convulsions Diazepam rectal -

0.5mg/kg
Treatment of Epilepsies
– contd.
3. Initiation of treatment:
• Initiate therapy even if it is isolated tonic-clonic
seizure with family history of seizure, abnormal
neurological examination, abnormal EEG and an
abnormal MRI
• Treat with monotherapy
• Substitute another drug if fails
• Combination therapy – only when all
monotherapy fail
• Therapeutic monitoring of drugs – dose
adjustments
Treatment of Epilepsies
– contd.
4. Seizure diary
5. Withdrawal of drugs:
• Gradual withdrawal
• Prolong therapy – life long/3yrs
after last seizure
• Withdrawal – childhood epilepsy,
absence of family history,
primarily generalized tonic-clonic
seizure and normal EEG
Treatment of Epilepsies
– contd.
6. Antiepileptics and pregnancy
• Drugs should not be stopped if
conceive – status epilepticus
• Fits during pregnancy – birth defects,
mental retardation etc.
• Folic acid and vit.K supplementation
• Care during attacks: tonic-clonic
seizures
• Surgical removal
Generalized Onset
Seizures
• Tonic-clonic, myoclonic, and absence
seizures: 1st line drug is usually valproate
• Generalized seizures: Phenytoin and
carbamazepine are effective on tonic-
clonic seizures but not other types of
seizures
• Absence seizures: Valproate and
ethosuximide are equally effective in
children, but only valproate protects
against the tonic-clonic seizures that
sometimes develop.
• Risk of hepatoxicity with valproate—should
not be used in children under 2
Partial Onset Seizures
• Without generalization
• Phenytoin and carbamazepine may be slightly
more effective

• With secondary generalization

• First-line drugs are carbamazepine and
phenytoin (equally effective)
• Valproate, phenobarbital, and primidone are also
usually effective

• Phenytoin and carbamazepine can be used together

(but both are enzyme inducers)
Partial Onset Seizures—
New Drugs
• Adjunctive (add-on) therapy: newer drugs
felbamate, gabapentin, lamotrigine,
levetiracetam, oxcarbazepine, tiagabine,
topiramate, and zonisamide
• Phenytoin and carbamazepine failure:
Lamotrigine, oxcarbazepine, felbamate
approved for monotherapy –
• Refractory partial seizures: Topirimate can
be effective.
Status Epilepticus
• Defn.: Continuous seizure activity for more
than 30 minutes, or 2 or more seizures
without recovery of consciousness.
Recurrent tonic-clonic convulsions without
recovery in between
• Goal of therapy: rapid termination of
seizure activity – more difficult to control –
permanent brain damage
• Prompt treatment with effective Drugs
• Attention to hypoventilation and
hypotension
• Treatment is IV only
Status Epilepticus –
contd.
• Diazepam 10mg IV bolus injection
(2mg/min)
• Fractional dose at every 10 min. or
titrated dose by slow infusion
• Lorazepam: 0.1mg/kg
• Followed by Phenobarbitone IM/IV (100-
200mg) or Phenytoin slow IV in saline (25-
50mg/min)
• Resistant cases (refractory): IV
anaesthetics
• General supportive measures
Attentions

• Selection of an appropriate
antiseizure agent
• Use of single drug
• Withdrawal
• Toxicity
• Fetal malformations
Thank You