Antiepileptics

2
Objectives
• Classify antiepileptic drugs
• Describe pharmacology of antiepileptic drugs
– Mechanism of action
– Relevant pharmacokinetics
– Indications
– Adverse drug reactions
– Important drug interactions
• Explain pharmacological management of
epilepsy

MECHANISM OF ACTION OF ANTIEPILEPTIC DRUGS
Three main mechanisms –
• Enhancement of GABA action
• Inhibition of sodium channel function
• Inhibition of calcium channel function.
Other mechanisms include -
- Inhibition of glutamate release and
- Block of glutamate receptors.

5
Classification of Anticonvulsants
Action on Ion
Channels
Enhance
GABA
Transmission
Inhibit EAA
Transmissi
on
Na+:
Phenytoin,
Carbamazepine,
Lamotrigine
Topiramate
Valproic acid
Ca++:
Ethosuximide
Valproic acid
Benzodiazepines
(diazepam,
clonazepam)
Barbiturates
(phenobarbital)
Valproic acid
Gabapentin
Vigabatrin
Topiramate
Felbamate
Felbamate
Topiramate

Mechanism of action of antiepileptic
drugs
Phenytoin, Carbamazepine,
felbamate, lamotrigine, valproic acid
• Block voltage-dependent sodium
channels at high firing frequencies

Mechanism of action of antiepileptic drugs
 Barbiturates
• Prolong GABA-mediated chloride
channel openings
 Benzodiazepines
• Increase frequency of GABA-
mediated chloride channel
openings
7

Valproate
 May enhance GABA transmission in
specific circuits
 Blocks voltage-dependent sodium channels
 Blocks T-type calcium currents
Ethosuximide
• Blocks slow, threshold, “transient” (T-type) calcium
channels in thalamic neurons
8
Mechanism of action of antiepileptic drugs(AEDs)

Newer AEDs: mechanism of action
Vigabatrin: Irreversibly inhibits GABA transaminase
Tiagabine: Interferes with GABA re-uptake
Topiramate:
– Blocks voltage-dependent sodium channels at high
firing frequencies
– Increases frequency at which GABA opens Cl-
channels (different site from benzodiazepines)
– Antagonizes glutamate actions at receptor subtype
Gabapentin: May modulate amino acid transport into brain &
May interfere with GABA re-uptake
9

Phenobarbitone
• GABA-facilitatory
• GABA-mimetic
• Adverse effects
– sedative action.
– Long term administration - behavioral
abnormalities, impairment of learning and
memory, hyperactivity in children, mental
confusion in older people.
– Rashes, megaloblastic anaemia and osteo-
malacia on prolonged use.

Uses/indications
• Generalized tonic-clonic (GTC), simple partial
(SP) and complex partial (CP) seizures:
60 mg 1-3 times a day in adults; in children (3-6
mg/kg/ day).
• Status epilepticus: may be injected i.m. or i.v.
but response is slow to develop.
• not effective in absence seizures.

Phenytoin (Diphenylhydantoin)
• Most commonly used.
• Phenytoin prolongs the inactivated state of
voltage sensitive neuronal Na+ channel and
reduces the neuronal excitability.

Pharmacokinetics
• Absorption is formulation dependent
• highly bound to plasma proteins
• fosphenytoin is for IV, IM routes
• The kinetics changes from first order to zero
order over the therapeutic range(small
increments in dose produce
disproportionately high plasma
concentrations.)
• The t1/2 - 12-24 hours progressively ↑es upto
60 hr when plasma concentration rises above
10 ug/ml as metabolizing enzymes get
saturated.

Adverse effect
At therapeutic levels -
• Gum hypertrophy:
• Hirsutism:
• Hypersensitivity reactions:
• Megaloblastic anaemia:
• Osteomalacia:
• Hyper-glycaemia.
• foetal hydantoin syndrome (hypoplastic phalanges, cleft
palate, hare lip, microcephaly),due to its areneoxide
metabolite.

Adverse effect
At high plasma levels (dose related toxicity)
• CNS- Cerebellar and vestibular manifestations:
ataxia, vertigo, diplopia, nystagmus are the most
characteristic features.
Drowsiness, behavioral alterations, mental
confusion and hallucinations.
• GIT - Epigastric pain, nausea and vomiting:
minimised by taking the drug with meals.
• CVS – hypotension & arrhythmias.

Uses
• Generalized tonic-clonic, simple and comp
lex partial seizures.
• It is ineffective in absence seizures.
Dose: 100 mg BD, maximum 400 mg/day; Children 5-8
mg/kg/day,
• Status epilepticus: occasionally used by slow
i.v. injection.
• Trigeminal neuralgia - second choice drug to
carbamazepine.

Carbamazepine
• Adverse effects
– Dose related neurotoxicity—sedation, dizziness,
vertigo, diplopia and ataxia.
– Vomiting, diarrhea
– Acute intoxication - coma, convulsions and
cardiovascular collapse.
– Hypersensitivity reactions:rashes,photosensitivity
hepatitis, lupus like syndrome
– Water retention and hyponatremia in the elderly as it
enhances ADH action.
– Teratogenic

Uses
• It is the most effective drug for CPS
• First choice drug with phenytoin for GTC and
SPS .
• Trigeminal and related neuralgias - is the drug
of choice.
• Manic depressive illness and acute mania - as
an alternative to lithium

ETHOSUXIMIDE
• Inhibit T type Ca+2 current in thalamic
neurons.
• Adverse effects
– GI intolerance, tiredness, mood changes,
agitation, headache, drowsiness and inability
to concentrate
• Uses
– Only in ABSENCE SEIZURES but Use has now
declined as many consider valproic acid to be
superior to it.

VALPROIC ACID (Sodium Valproate)
Multiple mechanisms of action :
• Phenytoin like frequency dependent
prolongation of Na* channel inactivation.
• Attenuation of Ca2+ mediated 'T' current
(ethosuximide like)
• Augmentation of release of inhibitory
transmitter GABA by inhibiting its degradation
(by GABA-transaminase) & by increasing its
synthesis.

Uses
• Highly effective in absence seizure.
• Alternative /adjuvant drug for GTCS, SPS and
CPS.
• Myoclonic and atonic seizures—control is
often incomplete, but it is the drug of choice.
• Mania and bipolar illness: as alternative to
lithium.

Adverse effects
• anorexia, vomiting, loose motions, heart burn
• Drowsiness, ataxia, tremors
• Alopecia, curling of hair, increased bleeding
tendency
• Fulminant hepatitis (very rare0
• Pancreatitis
• High incidence of PCOD in young girls
• Teraotogenic
22

LAMOTRIGINE
Blocks sodium as well as high voltage
dependent calcium channels
Uses
• Broad spectrum antiepileptic.
• Refractory cases of partial seizures and GTCS
• Absence and myoclonic or akinetic epilepsy .
• Lennox-gastaut syndrome
Adverse effects
• sleepiness, dizziness, diplopia,ataxia and vomiting.
• better tolerated than carbamazepine or phenytoin.
• Rash may be a severe

GABAPENTIN
• Enhances GABA release in brain.
• does not act as agonist at GABAA receptor.
• Reduces seizure frequency in refractory partial
seizures with or without generalization.
• Effective in SPS and CPS
• Manic depressive illness and migraine
• first line drug for pain - diabetic neuropathy and
postherpetic neuralgia,
• Adverse effects - mild sedation, tiredness, dizziness
and unsteadiness.

VIGABATRIN
• Inhibitor of GABA-transaminase which degrades
GABA
• Effective in refractory epilepsy, specially partial
seizures with or without generalization.
• Adverse effects- behavioral changes, depression
and psychosis . drowsiness, amnesia, visual field
contraction, motor disturbances, agitation in
children.

TIAGABINE
• Recently developed anticonvulsant -
potentiates GABA mediated neuronal
inhibition by depressing GABA transporter
GAT-1 which removes synaptically released
GABA into neurons & glial cells.
• Uses – add on therapy of partial seizures with
or without secondary generalization.
• Adverse effects- mild sedation, nervousness,
asthenia, amnesia & abdominal pain.

Reference
• Lippincots illustrated pharmacology 6th edition
page 157-168
• Essentials of Medical Pharmacology 7th edition
by KD tripathi
30

Antiepileptics

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