Anti epileptic drugs 1

Anti epileptic drugs

The characteristic event in epilepsy is seizure.
Seizure: episodic high frequency discharge of impulses by a group of neurons.
The local abnormal discharge then spreads to other areas of brain. Site of primary
discharge and extent of its discharge determine the symptoms (ranging from loss of
consciousness to convulsions; particular features depend on functions of area of brain
affected). Involvement of motor area causes convulsions, of hypothalamus causes
autonomic discharge and of reticular formation causes loss of consciousness.

Biochemical changes: Imbalance between.

• Excitatory amino acid transmission NMDA/AMPA and Inhibitory transmission
(GABA).
• Alteration of membrane function affecting Na+/K+ channels.

Repeated seizure activity leads to neurodegeneration due to excitotoxicity

Type of seizures Drug of choice Alternative
drugs
1. Partial seizures: Carbamazepine Vigabatrin
Simple partial seizures: manifestations depend on Phenytoin Gabapentin
the area involved; motor or sensory, consciousness Phenobarbitone Felbamate
maintained. Seizure lasts 20-60 sec. Valproate Topiramate
Lamotrigine Tiagabine
Complex partial seizure: impaired consciousness, Carbamazepine Vigabatrin
lasting 30 sec to 2 minutes associated with Phenytoin Gabapentin
purposeless movements such as lip smacking, hand Phenobarbitone Felbamate
wringing. Valproate Topiramate
Lamotrigine Tiagabine
Partial with secondarily generalized tonic-clonic Carbamazepine Vigabatrin
seizures: simple or complex partial seizure evolves Phenytoin Gabapentin
into a tonic clonic seizure with loss of Phenobarbitone Felbamate
consciousness and sustained contractions (tonic ) of Valproate Topiramate
muscles throughout the body followed by periods of Lamotrigine Tiagabine
muscle contraction alternately with periods of
relaxation (clonic),typically taking 1-2 min
2. Generalized seizures: Clonazepam Clonazepam
Absence seizures (petit mal): Ethosuximide Lamotrigine
Abrupt onset of impaired consciousness associated Valproate
with staring and cessation of ongoing activities
lasting less than
30 seconds. In EEG spike and wave discharges at a
frequency of 3 per seconds.
Atonic (loss of muscle tone/strength) Valproate Phenobarbitone
Lamotrigine
Phenytoin
Clonazepam
Myoclonic seizures- a brief perhaps for a second Valproate Phenobarbitone
shock like contractions of muscles (localized or Clonazepam Lamotrigine
generalized) Topiramate
Clonazepam
Ethosuximide
Anti epileptic drugs 2

Generalised tonic clonic seizures (grand mal), Carbamazepine Vigabatrin

tonic, clonic. Loss of consciousness with sustained Phenobarbitone Clobazam
contractions (tonic) of muscles throughout the body Phenytoin Gabapentin
followed by period of muscles contraction Primidone Felbamate
alternating with periods of relaxation (clonic), Valproate Topiramate
typically lasting 1-2 minutes. Lamotrigine Tiagabine

Mechanisms of action of anticonvulsant drugs

1. Enhancement of GABA function: raises the seizure threshold. Examples:
– Phenobarbitone, benzodiazepines and topiramate –GABA-A mediated
opening of chloride channels.
– Vigabatrin –irreversible inhibition of GABA transaminase, which
inactivates GABA) –increases GABA content of the brain.
– Gabapentin- increases release of GABA.
– Tiagabine- inhibits GABA uptake
– Valproate

2. Inhibition of sodium channel function:

– Phenytoin
– Carbamazepine
– Valproate
– Lamotrigine
• Block high frequency discharge occurring in epileptic fit.
• Does not interfere with low frequency firing of neurons in normal
state.
• Depolarization, of neurons seen in PDS, increases the proportion of
the sodium channels in the inactivated state.
• These drugs bind preferentially to channels in this inactivated state,
prevent them from returning to the resting state and thus reducing
the number of functional channels available to generate APs.

3. Inhibition of calcium channels:

– Ethosuximide: type T channels- activation of which causes rhythmic
discharge seen in absence seizures.
– Gabapentin may act on L type of channels
– Valproate
– Zonisamide

4. Inhibition of excitatory transmitter NMDA or AMPA:

• Felbamate.
• Barbiturates, topiramate act by antagonizing AMPA (α amino-3 hydroxy-5
methyl 4- isoxazolepropionate) receptors.

Antiepileptic drugs:
I. Long established antiepileptic drugs: phenytoin, carbamazepine, valproate,
ethosuximide, phenobarbitone and various Bzs- diazepam, clonazepam, clobazam.
II The newer drugs: vigabatrin, gabapentin, lamotrigine, felbamate, tiagabine,
topiramate.
Anti epileptic drugs 3

I. Long established drugs

1. Phenytoin (diphenylhydantoin).
• Non sedative, effective against partial and generalized seizures,.but not against
absence seizures- may even get worst.
Mechanism of action:
• Blockade of sodium channels (use dependent) and inhibition of generation of
high frequency repetitive action potentials.
• At high conc: reduction in calcium influx- responsible for inhibition of secretory
processes: release of hormones (ADH, insulin) and neurotransmitters (NE,5HT).
promotes uptake of dopamine and inhibits MAO activity.
• Alters sodium, potassium, calcium conductance, membrane potentials and
concentrations of aminoacids and neurotransmitters.
• Drug interacts with membrane lipids and this promotes stabilization of membrane.

Pharmacokinetics
Absorption: affected by formulation of dosage form. Bioavailability problem (particle
size and additives).
Absorption from GIT is good.
On IM injection-absorption poor- gets precipitated.
Fosphenytoin (more soluble prodrug phosphate ester) is used for parenteral injection (IM,
IV)
Distribution: 90% bound to plasma proteins mainly albumin. Widely distributed. CSF
concentrations- similar to free fraction. Free fraction affects efficacy and toxicity and the
concentration of free fraction is increased in uremia, hypoalbuminemia, so measurement
of free phenytoin is important to adjust dosage.

Metabolism and excretion: Metabolised in liver by SER to parahydroxyphenyl

derivative- excreted as glucuronide in bile and urine.
– Metabolism is capacity limited; changes from first order to zero order over
the therapeutic range-small increments in dose produce disproportionately
high plasma concentrations.
– The half-life 12-36 (24) hours with mild therapy and steady state is
reached in 5-6 days but with higher levels, it may take 4-6 weeks with half
life reaching to 60 hour.
– Monitoring plasma concentration is necessary.
– Phenytoin causes enzyme induction, increases the metabolism of other
drugs like oral contraceptives, oral anticoagulants.

Adverse effects:
Dose dependent
I. Acute effects:
• Nystagmus
• Diplopia- reduce dose
• Ataxia
• Lethargy, sedation at higher concentration.
Therapeutic range: 10-12 microgram/ml

2. Chronic therapy:
Anti epileptic drugs 4

• GIT disturbances- nausea, vomiting, epigastric pain, anorexia.

• Gingival hyperplasia
• Coarsened facial features- involve altered collagen metabolism.
• Hirsutism, acne.
• Megaloblastic anemia (also produced by primidone and phenobarbitone)- due to
altered folate metabolism- responds to folic acid.
• Hemorrhagic disease of new born: hypoprothrombinemia and hemorrhage in
new borns of mothers due to altered vitamin K metabolism - use vitamin K
• Use during pregnancy- teratogenic: may produce fetal hydantoin syndrome
(hypoplastic phalanges, cleft palate, hare lip, microcephaly), which is probably
caused by its epoxide metabolite.
• Peripheral neuropathy- depressed tendon reflexes.
Endocrine effects:
• Osteomalacia with hypocalcemia due to altered vitamin D and K metabolism.
• Inhibition of release of ADH secretion
• Inhibition of insulin secretion.

II. Hypersensitivity or idiosyncratic effects

• Skin rashes, fever, and rarely Stevens-Johnson syndrome, exfoliative lesion, SLE
and fatal hepatic necrosis.
• Hematological reactions: neutropenia and leukopenia, thrombocytopenia and
rarely red cell aplasia, agranulocytosis.
• Lymphadenopathy resembling Hodgkin's disease

Uses
• Partial seizures.
• Generalized tonic-clonic seizures.
• Status epilepticus- slow IV injection.
• Trigeminal neuralgia- 2nd choice drug.
• Cardiac arrhythmias- especially digitalis induced.
.
2. Carbamazepine
• Pharmacological actions and mechanism: similar to phenytoin. Blocks Na+
channels, inhibits high frequency repetitive firing of neurons.
• Acts presynaptically to decrease synaptic transmission.
• Inhibits uptake and release of NE, potentiate postsynaptic GABA action.
The differences from phenytoin are:
• It is more effective in treating complex partial seizures (psychomotor epilepsy).
• Has active metabolite.
• Is effective in mood disorders.
• Enhances ADH action on renal tubules.

ADME
• Slowly but completely absorbed orally (poor water solubility). Available only for
oral administration.
• 75% bound to plasma proteins.
Anti epileptic drugs 5

• Metabolized by oxidation to an active metabolite (10-11 epoxide) –further

metabolism is by conjugation to inactive metabolites.
• Initial half-life is 36 hours but decreases on chronic administration to 20 hours due
to enzyme induction.

Adverse effects
1. Dose related:
CNS: diplopia is first symptom of over dose and then ataxia, unsteadiness, and
drowsiness appear at higher concentration.
GIT: mild GI upset- vomiting, diarrhea.
Other: Water retention and hyponatremia can occur in elderly as it enhances ADH
action.

2. Idiosyncratic reactions:
• Erythematous rashes.
• Blood dyscrasias: fatal aplastic anemia and agranulocytosis; mild persistent
leukopenia.
• Hepatic dysfunction.

3. Teratogenicity: fetal malformations (neural tube defects) and its combination

with valproate doubles teratogenicity

Uses
• Most effective for complex partial seizures (psychomotor epilepsy.)
• Drug of choice for generalized tonic clonic seizures and simple partial seizures
(cortical focal seizures).
• Drug of choice for trigeminal and related neuralgias (glossopharyngeal).
Phenytoin and baclofen are less efficacious alternatives.
• Also effective in lightening tabetic pain (neuropathic pain).
• Manic-depressive illness (bipolar disorder) and acute mania
• Diabetes insipidus

3. Valproic acid
• It is a simple branched chain monocarboxylic acid.
• It is a broad-spectrum anticonvulsant.

Mechanism of action
• At therapeutic concentration:
i. Blockade of voltage activated Na+ channels- like phenytoin.
ii. Blockade of NMDA receptor mediated excitation.
iii. Increase in GABA content of brain by:
• Stimulating the activity of GABA synthetase enzyme, glutamic
acid decarboxylase (GAD) enzyme responsible for GABA
synthesis.
• Inhibits GABA transporter- GAT1.
• At high concentration : inhibit 2 enzyme systems that inactivate
GABA namely GABA transaminase and succinic semialdehyde
dehydrogenase.
iv. Enhancement of postsynaptic action of GABA.
Anti epileptic drugs 6

v. Blockade of low threshold (T) Ca 2+ channels.

vi. Decrease in aspartate levels.
vii. At high conc. increase in K+ ion permeability-leading to hyperpolarization.

Adverse effects
i. Concentration dependent
– GIT- nausea, vomiting, abdominal pain, heartburn
– CNS: sedation, uncommon, may occur when given with phenobarbitone.
Fine tremor at high level.
– Others:
– Alopecia, thinning and curling of hair
– Peripheral edema.
– Weight gain, increased appetite.

ii. Idiosyncratic reactions:

– Hepatotoxicity - a rare but fulminant hepatitis in children especially below
2 years. Patients with hepatic disease or on other anticonvulsant or
hepatotoxic drug are more at risk for hepatic toxicity.
– Rashes and thrombocytopenia

iii. Teratogenic (neural tube defects), increased incidence of spina bifida, increased
CV, orofacial and digital abnormalities.

Drug interactions:
Decreased metabolism of phenobarbitone, phenytoin and increase their blood levels.

Uses
• Seizures:
• Absence seizures-many consider this as drug of choice. DOC in mixed
seizures (absence and generalized tonic clonic seizures).
• Myoclonic seizures.
• Generalized tonic and clonic seizures.
• Atonic seizures- DOC.
• Partial seizures.
• Absence seizures- status
• Bipolar illness.
• Migraine- prophylactic.

Ethosuximide
A succinimide derivative.
Clinically effective only in absence seizures, may precipitate tonic clonic seizures in
susceptible patients.

Mechanism of action
• Inhibition of calcium channels (T type) in thalamic neurons. T currents
provide a pacemaker current in thalamic neurons responsible for generating the
rhythmic cortical discharge of an absence type.
• At high concentrations:
Anti epileptic drugs 7

• Inhibition of Na+K+ATPase (needed for ATP)- depresses cerebral

metabolic rate.
• Inhibits GABA amino transferase enzyme- increases GABA levels.

Adverse effects
Dose related effects:
• GI distress, nausea, vomiting, anorexia
• CNS: lethargy, fatigue, sometimes lethargy dizziness, mood changes, agitation,
headache, drowsiness, and inability to concentrate.
Idiosyncratic reactions:
• Rare: rashes, SJ syndrome, SLE,
• Blood dyscrasias- eosinophilia, leucopenia, pancytopenia.

Uses
Absence seizures, some prefer valproate.

5. Phenobarbitone
• Its anticonvulsive actions closely resemble phenytoin.
• With continued use, sedation decreases but not anticonvulsant action.

Mechanism of action
• GABA facilitatory, GABA-mimetic -it acts on GABAA receptor and enhances
chloride conductance, causes potentiation of synaptic inhibition at therapeutic
conc.
• Antiglutamate- blocks excitatory responses of glutamate (AMPA).
• At higher conc: block Na+ and L, N type calcium channels.

ADME:
• Well absorbed. 50% bound to plasma protein has long half-life (100 hours, longer
in neonate), 75% metabolized in liver by oxidation and conjugation with
glucuronide, some (25%) excreted unchanged in urine, which is pH dependent.
• Steady state concentration are reached in 2-3 weeks, a single daily dose is
effective.
• It is a powerful enzyme inducer.

Adverse effects
• Sedation: tolerance occurs on chronic use
• Nystagmus, ataxia- at high doses.
• Long-term use -diminution of intelligence, impairment of learning and memory,
impaired school performance, behavioral abnormalities (hyperactivity in
children), depression and mental confusion in elderly.
• Megaloblastic anemia and osteomalacia on prolonged use.
• Hemorrhagic disease of new born
• Hypersensitivity reactions: rashes, exfoliative dermatitis, hypoprothrombinemia.

Contraindications
Patients with porphyrias
Anti epileptic drugs 8

Uses
• Partial seizures.
• Generalized tonic -clonic and cortical focal seizures. Not effective for absence
seizures, atonic seizures and infantile seizures- these may worsen.
• Status epilepticus.
• Febrile convulsions

6. Benzodiazepines
Mechanism of action: through GABA.
a. Clonazepam:
Uses : absence seizures, myoclonic and akinetic seizures, infantile
seizures.
b. Diazepam: drug of choice for status epilepticus. IV or per rectum in
febrile convulsions.
c. Lorazepam: status epilepticus.

Adverse effects
• Drowsiness, dizziness and lethargy- some tolerance develops on chronic
use.
• Lack of concentration, irritability, temper and other behavioral
abnormalities in children (paradoxical effect).
• Dose dependent motor disturbances: ataxia, hypotonia, dysarthria.
• Salivation and increased respiratory secretions.
• .Tolerance develops to therapeutic effect in 6 months or so.
Withdrawal syndrome- results in exacerbation of seizures if the drug is stopped
suddenly

II. Newer antiepileptic drugs

1. Vigabatrin (gamma vinyl GABA)
• An irreversible inhibitor of GABA aminotransferase (GABA transaminase,
GABA-T), which break downs GABA. Increases amount of GABA released at
synaptic sites thereby enhancing inhibitory effects
• Inhibits GABA transporter- potentiate GABA inhibitory effects.

Adverse effects
• Common: Drowsiness, dizziness, weigh gain.
• Less common but more troublesome: agitation, confusion and psychosis.
• Long term therapy: visual field defects – not reversible. Patient should be
tested regularly for visual fields.
Uses
• Useful antiepileptic in patients resistant to other drugs.
• Partial epilepsy, which is often difficult to treat.
• Infantile spasm
• West’s syndrome

Contraindications
Preexisting mental illness, like depression or psychosis.
Anti epileptic drugs 9

2. Gabapentin
• Is a highly lipid soluble, amino acid related to GABA, effective against partial
seizures.
• Alters GABA metabolism - its nonsynaptic release or its reuptake by GABA
transporter.
• Also binds to Ca++ channels.
• Effective in both types of epilepsy- generalized and partial seizures.

Adverse effects: Sedation, ataxia, dizziness, headache and tremor.

Uses
• As an adjunct in partial seizures and generalized tonic –clonic seizures or may be
used as monotherapy.
• As an analgesic for neuropathic pain- post herpetic neuralgia.
• Migraine
• Bipolar disorder

3. Lamotrigine
• Resembles phenytoin in its action.
• Acts on Na+ channels, suppresses sustained rapid firing of neurons- (voltage and
use dependent inactivation of Na+ channels), hence effective for focal epilepsy.
• Also acts on voltage activated Ca++ channels- effective in absence seizures.
• Also inhibits release of excitatory amino acids- glutamate.
• Has broad spectrum of activity

Adverse effects
1. Concentration dependent
Dizziness, headache, diplopia, vertigo, sedation, ataxia.
Nausea, vomiting.

2. Idiosyncratic or hypersensitivity reaction:

Rash, Stevens-Johnson syndrome, toxic epidermal necrolysis, some times life
threatening dermatitis in pediatric patients.
Flulike syndrome: patient should report immediately if flu like symptoms or rash
appears.

Uses:
• As add on therapy, or monotherapy in refractory partial seizures
• Absence seizures, myoclonic seizures, and generalized seizures.
• Lennox- Gastaut syndrome.

4. Felbamate
A 3rd line drug for refractory seizures.
Mechanism of action:
• Weak effect on sodium channels.
• Antagonist of NMDA receptor channels.
• Some effect on GABA.

Unwanted effects
Anti epileptic drugs 10

• Acute side effects are: nausea, vomiting, irritability, insomnia. Occasionally it

causes aplastic anemia or hepatitis. Because of these two side effects it is used
as a 3rd line drug.

Uses
• For both partial and generalized seizures.
• Lennox-Gastaut syndrome characterized by multiple seizure types, mental
retardation and refractoriness to antiseizure medication.

5. Topiramate
A substituted monosaccharide, structurally different from other antiepileptics.
It is a broad spectrum antiepileptic.

Mechanism of action:
• Blockade of voltage dependent Na+ channels- blocks repetitive firing of
neurons.
• Potentiation of inhibitory GABA responses.
• Impairment of glutamate receptor activity, blocking AMPA-Kainate subtype (s)
of glutamate receptors.
• Weak inhibitor of carbonic anhydrase.
Therapeutic spectrum is similar to phenytoin but causes less severe side effects and
simple kinetics.

Adverse effects
• Somnolence, fatigue, dizziness, ataxia, cognitive slowing, weight loss.
• Acute myopia and glaucoma- stop
• Urolithiasis.
• Teratogenic, not to be used in women of child bearing age.

Uses
• Monotherapy or as add on therapy in refractory cases of epilepsy. Effective in
multiple seizure types including partial, absence and generalized tonic –clonic
seizures.
• Lennox Gestaut syndrome
• West’s syndrome.

6. Tiagabine
• It is analog of GABA.
• Is a derivative of nipecotic acid, lipophilic.

Mechanism of action
• Blocks GABA uptake by presynaptic neurons and glial cells (GABA transport
inhibitor- inhibits transport isoform 1 (GAT-1) rather than GAT-2 and 3  inc.
extracellular GABA conc. in forebrain and hippocampus.
• Prolongs inhibitory action of synaptically released GABA.

Adverse reactions:
Anti epileptic drugs 11

• Dose dependent: nervousness, dizziness, tremor, difficulty in concentration, and

depression. Excessive confusion, somnolence and ataxia may require
discontinuation.
• Idiosyncratic reaction- rash

Uses:
• As an adjunctive treatment in partial seizures and also as monotherapy for partial
seizures.

Status epilepticus and other convulsive emergencies

i. Status epilepticus is a neurological emergency. Control convulsion- give the
drugs IV or if not possible per rectum.
• Benzodiazepine- for initial treatment- diazepam and lorazepam. Diazepam enters
brain quickly and stops seizures quickly but it quickly redistributes to fatty tissues
with a resulting fall in brain conc. Therefore a longer acting drug such as,
phenytoin is administered to eliminate recurrent convulsions.
• Or alternately lorazepam may be used because of its longer duration of action.
• IV phenytoin alone successfully treats 41-90% of patients.
• IV phenobarbitone also is effective.
• Take proper care of respiration and circulation.

ii. For Convulsive emergencies associated with drug poisoning, drug induced
seizures (local anesthetics) drug withdrawal seizures- diazepam and
phenobarbitone are effective
Anti epileptic drugs 12

Antimigraine drugs

• The initiating event is uncertain but in

some cases may be an abnormal
neuronal discharge, set off by emotional
or biochemical disturbances.
• This leads to localised spreading
depression which causes the aura and may
also lead to sensitisation of central pain
pathways.
• In migraine without aura, the primary
event is excitation (cause unknown) of
nociceptive nerve terminals in the
meningeal vessels, leading to cycle of
neurogenic inflammation shown in the
upper part of the diagram

Drugs used in acute attacks of migraine

A. Treatment of acute attack
i. Mild or moderate attack.
– Aspirin
– Paracetamol .
– Ibuprofen
– indomethacin
– Naproxen
ii. Moderate to severe attack.
a. For symptomatic treatment: Antiemetics: diphenhydramine, promethazine,
metoclopramide. Metoclopramide-preferred- a prokinetic drug- stimulates gastric
motility. Aspirin, opiates are used.

b. Specific drugs for acute attack of migraine:

i. Ergotamine 1 mg + caffeine 100 mg- 1-2 tablets at onset and then 1 tablet
every half hour (maximum 6 tablet/d, 10 per week
• Ergotamine is 5HT1 receptor partial agonist, also affects alpha
adrenoceptors- vasoconstrictor, blocks trigeminal nerve transmission.
• Poorly absorbed. Sometimes given by suppository, inhalation etc.
• Duration 12-24h
• Adverse effects: Peripheral vasoconstriction, coronary constriction.
Nausea, vomiting, oxytocic, may cause fetal damage
• Effective but use limited by side effects.

ii. Sumatriptan:
Anti epileptic drugs 13

• 5HT1D agonist. Constricts larger arteries, inhibits trigeminal

nerve transmission.
• Poorly abs. by mouth (delayed response) can be given SC. Does
not cross BBB. Plasma t ½ 1.5 h
• Adverse reactions: coronary vasoconstriction, dysrhythmias.
• Effective in 70%. Duration - short.
• C/I coronary artery disease.
iii. Naratriptan, zolmitriptan, rizatriptan:
• Act like sumatriptan with additional effects of CNS.
• Bioavailability better and longer duration of action.
• Adverse reactions are less.
• Improved pharmacokinetics and reduced cardiac side effects

B. Antimigraine drugs used for prophylaxis

i. Propranolol and other beta blockers: Beta adrenergic blocker.
Mechanism- not clear.
Adverse effects: fatigue, bronchoconstriction.
Effective and widely used

ii. Methysergide: 5HT2 antagonist /partial agonist.

Adverse effects: Nausea, vomiting, diarrhoea. Rarely but serious retroperitoneal
or mediastinal fibrosis .
Effective but rarely used, owing to side effects and insidious toxicity

iii. Pizotifen: 5HT2 antagonist + atropine like action.

Adverse effects: Weight gain, atropine like side effects

iv. Cyproheptadine: 5HT2 antagonist, H1 antagonist, and blocks calcium channels

Adverse effects: sedation, weight gain. Rarely used

V. Other drugs:
Amitriptyline, imipramine, sertraline, fluoxetine, clonidine, verapamil
(nimodipine, nifedipine and diltiazem may also be used), valproate.