Pharmacotherapy of

Epilepsy
Nandit P B
Content
1. Introduction

2. Various types of seizures.

3. Classification of antiepileptic drugs based on their clinical uses.

4. Mechanism of action of antiepileptic drugs

Terminologies
 Seizure: refers to sudden, uncontrolled electrical disturbance in the

brain..
 Epilepsy: Chronic neurological disorder characterized by recurrent

unprovoked seizures, which is due to transient alteration in the spread

of electrical discharge of cortical neurons
 Convulsion: It is a medical condition where body muscles contract

and relax rapidly and repeatedly, resulting in an uncontrolled shaking

of the body.
Cellular Mechanism
Reduction of inhibitory synaptic activity (decreased activity of GABA
– an inhibitory neurotransmitter)

OR

Enhancement of excitatory synaptic activity (mainly mediated through

Na+ and Ca2+ currents, increased release of glutamate and aspartate –
excitatory neurotransmitters)
Etiology of epilepsy
 Genetic or heredity

 Brain lesions

 Infections like cerebral meningitis & brain abscess

 Metabolic disorders like lack of oxygen, alkalosis, hypoglycemia,

hypocalcaemia, hyperpyrexia, vitamin B12 deficiency

 Sudden withdrawal of drugs of abuse like barbiturates and alcohol

 Viewing TV, disco flashes, listening to blast pop music

Types of Seizures
1. Generalized seizures
a. Generalized tonic-clonic seizures
(GTCS, grand mal)
b. Absence seizures (petit mal)
c. Myoclonic seizures
d. Status epilepticus

2. Partial seizures
a. Simple partial seizures (SPS)
b. Complex partial seizures (CPS)
Generalized seizures
 Affects the entire brain

 Characterized by abnormal electrical activity throughout the brain

with an impairment of consciousness.

Different types include –

1. Generalized tonic – clonic seizures

2. Absence seizures

3. Myoclonic seizure
1. GTCS
 Also known as grand mal epilepsy

 Characterized by an aura → epileptic cry → loss of consciousness →

tonic spasm of all body muscles → clonic jerking → prolonged sleep &
depression of all CNS functions
 This may last for about 15 - 30 minutes

 The EEG shows bilateral diffused pattern of high-voltage polyspikes of

10-30 Hz/sec in tonic-clonic phase

 2. Absence seizures
 Also known as petit mal epilepsy

 Characterized by a brief, abrupt and self-limiting loss of consciousness

without any convulsions

 Patient stares and exhibits rapid eye blinking and cessation of ongoing

activities.
 Last for about 3 to 5 seconds

Absence seizures begin at childhood and usually cease by the age of 20

years.
EEG hallmark of typical absence seizures is a generalized symmetric 3 Hz

spikes and wave pattern of discharge per second that begins and ends suddenly.
3. Myoclonic seizure
 Characterized by sudden and brief skeletal muscle contraction that may

involve the entire body or one part of the body

 EEG shows 2 Hz spikes and wave pattern per second.
4. Status epilepticus
 When seizure activity occurs for >30 min, or two or more seizures

occur without recovery of consciousness, the condition is called status

epilepticus
 This is a medical emergency

 Attack have to be controlled as quickly as possible to prevent death and

permanent brain damage

Partial seizures
They affect only one whole hemisphere of the brain or part of the lobe.
Different types of partial seizures include:
1. Simple partial
2. Complex partial
3. Secondarily generalized partial seizure
1. Simple partial seizure
 Patient exhibits abnormal activity of a single limb or muscle group

that is controlled by the region of the brain affected

 Patient may experience sensory disturbances

 Patient does not lose consciousness

 This can occur at any age

 Episode last for about 20 to 60 seconds

2. Complex partial seizure
 Usually precedes with an aura (a perceptual disturbance)

 Patient will exhibit complex sensory hallucinations and mental

distortion
 Consciousness of the patient is altered, and usually unaware of the

surroundings or what he/she is doing

 Patient may exhibit motor dysfunctions like smacking the lips and

chewing
 This will last for about 30 seconds to 2 minutes
3. Secondarily generalized partial seizures
 Partial seizures occur first and turns to generalized seizures with the

loss of consciousness
 Patients will have the experience of an aura

 This will last for about 1 – 2 minutes

Clinical classification of
antiepileptic drugs
 Seizure type Preferred drug Alternative drug

Carbamazepine Gabapentin
Simple partial seizure Phenytoin Lamotrigine
Sodium valproate Topiramate
Carbamazepine Gabapentin
Partial seizures Complex partial seizure Phenytoin Lamotrigine
Sodium valproate Topiramate
Carbamazepine Gabapentin
Secondarily generalized
Phenytoin Lamotrigine
seizure
Sodium valproate Topiramate
Carbamazepine
Lamotrigine
GTCS Phenytoin
Topiramate
Sodium valproate
Generalized
Ethosuximide
seizures Absence seizure Lamotrigine
Sodium valproate
Lamotrigine
Myoclonic seizure Sodium valproate
Topiramate
Lorazepam
Diazepam
General anaesthetics like
Status epilepticus Fosphenytoin
– Midazolam, Propofol
Phenytoin
Phenobarbitone
General mechanism of action of
antiepileptic drugs
 ↓ axonal conduction by preventing Na+ influx through fast Na+

channels – Phenytoin, carbamazepine

 ↑ inhibitory tone by facilitation of GABA mediated hyperpolarization –

Barbiturates, benzodiazepines.
 ↓ excitatory effects of glutamate – Lamotrigine, topiramate

 ↓ presynaptic Ca2+ influx through T type of Ca2+ channels in thalamic

neurons – Ethosuximide, Sodium valproate

Phenytoin
Bind to voltage dependent Na+
Fosphenytoin channels (Prolongs the inactivated
(Prodrug) state) and prevent further entry of Na+
Carbamazepine ions into the neuron.
(Stabilize neuronal membrane )
Oxcarbazepine
(Prodrug)
Sodium valproate
Lamotrigine Inhibit the generation of
Topiramate repetitive action potentials
Zonisamide
Levitiracetam
Therefore, prevent or reduce the
spread of seizure discharges
 Facilitate GABA (+)GAD, (-) GABA-T
Benzodiazepines Sodium valproate

Phenobarbitone
Facilitates GABA GABA (-) GABA-T
Vigabatrin
GABA mimetic Promotes GABA
release
activity Gabapentin
Blocks uptake of GABA
into the neurons Tiagabine

Inhibitory neurotransmitter (GABA)

Cl- conductance into the neuron (IPSP)

Hyperpolarization

Reduced neuronal excitability

Antiepileptic effect
26
GAD= Glutamic acid decarboxylase. GABA-T = GABA-Transaminase
PHENYTOIN
 It was synthesized in 1908

 First used in 1938

 It does not cause CNS depressant

 It limits spread of seizure activity

 Mechanism of Action: Blocks high frequency repetitive firing of

action potential by prolonging inactivated state of Na+ channel.

 At high concentrations, phenytoin inhibits Ca2+ influx into neuron →

reducing glutamate levels and also increases the response towards

GABA
 Phenytoin (therapeutic doses) bind to voltage dependent Na+
channels to their inactivated state

Prolongs the inactivated state of the Na+ channels

Decreases Na+ levels at neurons and decreases neurons excitability

Prevents the spread of high frequency firing (prevents the spread

of seizure discharges)
 Na+

OPEN CHANNEL
Activation gate

Na+

Inactivation gate

Na+
 Na+

Block channels
firing at high
INACTIVATED CHANNEL
frequencies

Na+

Topiramate Phenytoin
Lamotrigine Carbamazepine
Valproate
 Pharmacokinetics
 Route of administration – Oral, i.v.

 Absorption - Slowly from intestine

 Distribution - Widely distributed in the body

 Protein binding - Highly bound to plasma proteins especially albumin

(87 – 92%)
 Metabolism - Completely metabolized in liver by hydroxylation and

glucuronide conjugation.
Microsomal enzyme induction

 Therapeutic drug monitoring of phenytoin therapy is essential

Adverse drug reactions
Overdose toxicity:
 Ataxia, nystagmus, blurred vision, lethargy, CNS depression

 I.V. injections can cause CVS collapse and coma

Chronic toxicity:
 Gum hyperplasia: Phenytoin being secreted through saliva, it inhibits

collagenase enzyme which is responsible for the breakdown of collagen

of connective tissues. Commonest in younger patients. This condition
doesn’t require withdrawal of the medication.
Contd…
 Fetal hydantoin syndrome: Caused by its toxic epoxide metabolite &

impaired DNA synthesis due to folate deficiency – hypoplastic phalanges,

broad nasal bridge, cleft palate, hare lip, microcephaly if given during
pregnancy
Megaloblastic anaemia: decreased folate absorption. Folate is
presented in foods as polyglutamate, which is then converted into
monoglutamates by intestinal conjugase. Phenytoin acts by inhibiting this
enzyme, thereby causing folate deficiency.
FOSPHENYTOIN
 To avoid the local complications of phenytoin

 Water soluble prodrug of phenytoin

 Preferred over phenytoin in status epilepticus

Advantages:
 Low incidence of cardiac toxicity

 Low incidence of local tissue injury

 CARBAMAZEPINE
 MOA - Similar to phenytoin

Carbamazepine binds to voltage dependent Na+ channels to their inactivated state

Prolongs the inactivated state of the Na+ channels

Decreases Na+ levels at neurons and decreases neurons excitability

Prevents the spread of high frequency firing (prevents the spread of seizure
discharges)
 Adverse drug reactions
Dose related adverse effects:

Due to long term therapy it causes drowsiness, followed by dizziness,

headache, slurred speech, vertigo, ataxia, and diplopia.

Idiosyncratic reactions:
 Hypersensitivity reactions like rashes, fever.

 Hepatitis, systemic lupus erythematosus, leucopenia, blood

dyscrasias, aplastic anaemia.
ETHOSUXIMIDE
Used only for the treatment of absence seizure

Mechanism of Action:

Primary action is on thalamo cortical system which is involved in the generation of

absence seizures

Ethosuximide

Selectively inhibits T – type of Ca2+ channels in the thalamic neurons

Decreases presynaptic Ca2+ influx

Reduces the repetitive spikes

Adverse drug reactions
Produces dose dependent toxicity
 Gastrointestinal complications like nausea, vomiting and anorexia.

 CNS effects like drowsiness, lethargy, euphoria, dizziness, headache

and hiccup.
 Idiosyncratic adverse effects include – skin rashes, fever, eosinophilia

and bone marrow depression

VALPROIC ACID
[1960; broad spectrum anticonvulsant]
Mechanism of action: Multiple mechanisms
1. Increases Na+ channel inactivation
2. Decreases Ca++ T current
3. Inhibits GABA transaminase  increases GABA nergic action

Kinetics:
Good oral absorption; 90% plasma protein Bound
Metabolism by liver [oxidation & glucuronidation]
T ½ 10-15 h
ADR
 Rashes, reversible alopecia, stimulation of appetite, and weight gain on

chronic therapy.
 CNS effects – sedation, ataxia and tremors.

 Curling and thinning of the hair

 Idiosyncratic adverse effects – severe and fatal hepatic injury in

patients below 3 years of age.

 Produces teratogenic effects like neural tube defects with increased

incidence of spina bifida, orofacial and digital abnormalities

Therapeutic uses
 Absence seizure

 Generalized tonic – clonic seizure

 Simple partial seizure

 Complex partial seizure

 Myoclonic seizure

 Secondarily generalized GTCS

 Mania and bipolar disorders

 Lennox – Gastaut syndrome

 Prophylaxis of migraine
Lamotrigine
 It is a broad spectrum antiepileptic drug

 Mainly used as an add-on drug during antiepileptic therapy

 Various mechanisms

 Phenytoin like action

 Inhibition of voltage gated Ca2+ channels → decreased synaptic release of

glutamate
Gabapentine
 Therapeutic uses;

 Add-on therapy for the treatment of partial seizures with or without

secondary generalization.
 Bipolar disease.

 Neuralgias.

 Migraine prophylaxis.

 ADR:

 Drowsiness, Dizziness, Ataxia, Fatigue, Weight gain

Vigabatrin
 ADR:

 Sedation, amnesia, drowsiness, dizziness and weight gain.

 Agitation, confusion, and psychosis (in elderly patients)

 Progressive and permanent bilateral vision loss.

Topiramate
 ADR:

 Sedation, drowsiness, amnesia

 Precipitation of renal calculi (Urolithiasis) due to the inhibition of carbonic

anhydrase enzyme.
 In male infants it may cause hypospadias (a congenital condition in males

in which the opening of the urethra is on the underside of the penis) as

teratogenic effect.
 General Considerations of Anticonvulsant
drug therapy
1. Try to find a cause (e.g. fever, head trauma, drug abuse)

and treat the same

2. Therapy is aimed at control of the disorder, because

drugs do not cure the disease

3. Drugs are indicated when there is two or more seizures

occurred in short interval (6months to 1 year)

4. The type of seizure determines the choice of drug

5. An initial therapeutic aim is to use only one drug (monotherapy) because
of its fewer side effects, decreased drug-drug interactions, better
compliance, lower costs

6. Start with low dose, increase dose gradually until seizures are controlled
or adverse effects become unacceptable later substitute with other drug

7. If monotherapy fails switch to combination therapy

8. Dose regulation is facilitated by monitoring of steady state plasma drug

levels.

9. A seizure diary should be maintained

10. The sudden withdrawal of drugs should be avoided which may

precipitate status epilepticus

11. Withdrawal may be considered after seizure free period of 2-3 or

more years

12. Factors favourable for withdrawal are mainly childhood epilepsy,

absence of family history, primary generalized tonic-clonic epilepsy,

absence of cerebral disorder and normal EEG

13. Individual seizure episodes do not require any treatment