ANTISEIZURE DRUGS

Dr Sultan Zeb Khan

In 400 B.C., the early
physician Hippocrates
suggested that epilepsy was a
disorder of the brain
Famous Persons Afflicted:
◦ ALEXANDER THE GREAT
◦ JULIUS CAESAR
◦ NAPOLEON
◦ LEWIS CARROLL
History of Epilepsy
What is a seizure?

Finite episodes of brain

dysfunction resulting from
abnormal discharge of cerebral
neurons.
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
Classification of Epileptic
Seizures
I. Generalised seizures
1. Generalised tonic-clonic seizures
2. Absence seizures
3. Atonic seizures
4. Myoclonic seizures
5. Infantile spasms

II. Partial seizures

1. Simple partial seizures
2. Complex partial seizures
3. Simple partial or complex partial seizures
secondarily generalized
Generalised tonic-clonic seizures
(Grand mal)

Commonest,
lasts 1–2 min.
The usual sequence is aura—cry
—unconsciousness—tonic spasm
of all body muscles—clonic
jerking followed by prolonged
sleep and depression of all CNS
functions.
Tonic clonic seizures
Absence seizures(Petit
Mal)
prevalent in children,
lasts about 1/2 min.
Momentary loss of
consciousness, patient
apparently freezes and stares in
one direction, no muscular
component.
Atonic seizures (Akinetic
epilepsy): Unconsciousness with
relaxation of all muscles due to
excessive inhibitory discharges.
Patient may fall.

Myoclonic seizures Shock-like

momentary contraction of
muscles of a limb or the whole
body
Partial seizures
Simple partial seizures
lasts1/2–1 min.
Often secondary.
Convulsions are confined to a
group of muscles or localized
sensory disturbance depending
on the area of cortex involved in
the seizure, without loss of
consciousness.
Complex partial seizures
attacks of bizarre and confused
behaviour and purposeless
movements, emotional changes
lasting 1–2 min along with
impairment of consciousness. An
aura often precedes.
The seizure focus is located in
the temporal lobe.
Simple partial or complex
partial seizures secondarily
generalized
The partial seizure occurs first
and evolves into generalized
tonic-clonic seizures with loss of
consciousness.
Why Seizures occurs?
Idopathic
Children: Birth traumas,
infections – meningitis and
congenital abnormalities
Middle age: Alcohol, infections,
head injury and Drugs like
cocaine, low blood sugar, low
oxygen, low blood Na+ and low
Ca+ etc.
Elderly: Stroke, tumors etc
Why Seizures occurs?
(cont)
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
 Classification of Antiepileptic
drugs
 Hydantoins: phenytoin, phosphenytoin
 Barbiturates: phenobarbitone
 Iminostilbenes: carbamazepine,
oxcarbazepine
 Succinimides: ethosuximide
 Aliphatic carboxylic acid: Valproic
acid, divalproex
 Benzodiazepines: clonazepam,
diazepam, lorazepam
 New compounds: gabapentin,
lamotrigine, tiagabine, topiramate,
vigabatrin, zonisamide, felbamate
Cellular Mechanisms Of Epileptic
Seizures
Excitation (Too Much)
Ionic inwards Na, Ca Currents
Neurotransmitters ; glutamate,
asparate

Inhibition (Too Little)

Ionic inwards Cl; outwards K
currents
Neurotransmitter; GABA
Mechanisms of Antiseizure
Drugs:
Most common ones:
 Modification of ion conductance
 Prolongation of Na+ channel
inactivation
 Inhibition of `T` type Ca++ current
 Increase inhibitory (GABAergic)
transmission – Cl- Channel.
 Glutamate receptor antagonism
(NMDA, AMPA, or kainic acid)
 Genetic mechanism
Anticonvulsant mechanism – contd.

The Sodium Channel:

A. Resting State

B. Arrival of Action Potential causes

depolarization and channel opens
allowing sodium to flow in.

C. Refractory State, Inactivation –

reduce the rate of recovery.
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:
 Thalamic neurons exhibit prominent T
current which is a low threshold Ca++
current
 T type current is responsible for 3 Hz
spike-and-wave
 Throughout the thalamus `T` current has
large amplitudes – thalamocortical
oscillations
 Bursts of action potential is by action of T
current
in absence seizure
Anticonvulsant mechanism –
contd.

The GABA mediated CL- channel

opening

Drugs:barbiturates,
benzodiazepines, vigabatrin,
gabapentin and valproate
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

◦ GABA A receptor mediated like other

Barbiturates

◦ Continued use – sedation effect lost

but not anticonvulsant action
Phenobarbitone – contd.
(Gardenal/Luminal)
Pharmacokinetics:

◦ Slowly absorbed and long t1/2 (80 –

120 hrs)

◦ Metabolized in liver and excreted

unchanged in kidney
Phenobarbitone – contd.
(Gardenal/Luminal)
Uses:
◦ Many consider them the drugs of
choice for seizures only in infants
◦ GTCS
◦ SP and CPS
Adverse effects:
◦ Sedation
◦ Behavioural abnormalities
◦ Hyperactivity in children
◦ Rashes, megaloblastic anaemia and
osteomalacia
Phenytoin
(Dilantin/Epsolin/Eptoin)

Pharmacological actions:

◦ Abolish tonic phase of GTC seizure

◦ No effect on clonic phase
◦ Prevents spread of seizure activity
◦ Tonic-clonic epilepsy is suppressed
but no change in EEG and aura..
◦ In CVS – depresses ventricular
automaticity, accelerates AV
conduction
Phenytoin – 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
Phenytoin – 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
◦ Monitoring of plasma concentration
Phenytoin sodium – contd.
Uses:
It is the first line antiepileptic for

◦ GTCS, no effect in absence seizure

◦ Status epilepticus

◦ Trigeminal neuralgia – 2nd to

Carbamazepine
Phenytoin – 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
Gingival Hyperplasia
Fetal Hydantoin Syndrome
Phenytoin – contd
Drug Interactions:
◦ Phenytoin and carbamazepine
increases each others metabolism
◦ Induces microsomal enzyme
◦ Phenytoin metabolism inhibition – by
warfarin, isoniazid etc.
◦ Sucralfate – decreases phenytoin
ebsorption
Carbamazepine
(Tegral/Tegrital)
Chemically related to imipramine
Lithium like action – mood stabilizer
Resembles phenytoin in
pharmacological actions

MOA:
◦ Stabilizes Na+ channel (Voltage
gated) in inactivated state – less
excitability
◦ Potentiation of GABA receptor
Carbamazepine – contd.
Uses:
◦ Complex partial seizure
◦ GTCS and SPS
◦ Trigeminal and related neuralgias
◦ Manic depressive illness and acute mania
Interactions:
◦ Enzyme inducer – reduce efficacy of OCPs
and others
◦ Metabolism is induced by –
phenobarbitone, phenytoin, valproate
◦ Inhibits its metabolism – isoniazide and
erythromycin
Carbamazepine – contd.
Adverse effects:
◦ Autoinduction of metabolism
◦ Nausea, vomiting, diarrhea and visual
disturbances
◦ Hypersensitivity – rash, photosensitivity,
hepatitis, granulocyte suppression and
aplastic anemia
◦ ADH action enhancement –
hyponatremia and water retention
◦ Teratogenicity
◦ Exacerbates absence seizures