Department of Pharmacology, SMS Medical College, JPR

Anti epileptic Drugs Dr Shivankan Kakkar,

MBBS, MD
 Learning Outcomes
❖ To understand nature & neurochemical mechanisms
underlying epilepsy
❖ To enumerate main animal models used for study of
epilepsy
❖ To classify various drugs used to treat epilepsy
❖ To understand their mechanism of action and
pharmacological characteristics
Epilepsy - Common Disorder (0.5 to 1%
affected)
❖ Characterised by Seizures (episodic neuronal discharges)
❖ Various forms (depends upon the part of brain affected)
❖ May occur due to unknown cause or genetic (often referred as
idiopathic). It can occur after brain damage as trauma, stroke,
infection or tumor growth, or other neurological diseases.
❖ Mainly treated with drugs (surgery for severe cases). Current
drugs effective in 70% - 80% cases. Use often limited due to
side effects
Types of Epilepsy
Generalised seizures (whole brain is affected)
❖ Generalised tonic-clonic seizures (Grand mal epilepsy)-
characterised by following sequence of events - aura, cry, loss of consciousness, fall to ground, tonic
phase, clonic phase, period of relaxation, post epileptic automatism with confusional state

❖ Absence seizures (Petit mal epilepsy)-

characterised by sudden onset of staring, unresponsiveness and momentary loss of consciousness

❖ Myoclonic seizures

Partial seizures (part brain is affected)

❖ Simple partial seizures
❖ Complex partial seizures (with loss of consciousness)
The neurochemical basis of the abnormal
discharge is not well understood
It may be associated with

❖ Abnormal electrical properties of the affected cells

❖ Enhanced excitatory amino acid transmission,
❖ Impaired inhibitory transmission or
❖ Several susceptibility genes, mainly encoding ion
channels, have been identified
Many animal models have been devised
❖ Electrically induced generalised seizures
❖ Chemically induced generalised seizures
❖ Production of local chemical damage
❖ Kindling
These provide good prediction of anti epileptic drug effects in humans
Classification of Anti epileptic drugs
Chemically anti epileptics can be classified as:

❖ 1. Hydantoins : Phenytoin, fosphenytoin

❖ 2. Barbiturate : Phenobarbitone
❖ 3. Iminostilbenes : Carbamazepine, oxcarbazepine
❖ 4. Aliphatic Carboxylic acid derivatives : Sodium valproate, divalproex
❖ 5. Succinimide : Ethosuximide
❖ 6. Benzodiazepines : Lorazepam, diazepam, clonazepam, clobazam
❖ 7. Adjuvant/Newer/Other Drugs : Lamotrigine, topiramate, felbamate,
gabapentin, pregabalin, tiagabine, vigabatrin, zonisamide, levetiracetam,
lacosamide
Mnemonic for Classification of Anti epileptic drugs

Chemically anti epileptics can be classified as:

B H A I S A B (elder Brother)
❖ B=Barbiturate : Phenobarbitone
❖ H=Hydantoins : Phenytoin, fosphenytoin
❖ A=Aliphatic Carboxylic acid derivatives : Sodium valproate, divalproex
❖ I=Iminostilbenes : Carbamazepine, oxcarbazepine
❖ S=Succinimide : Ethosuximide
❖ A=Adjuvant/Newer/Other Drugs : Lamotrigine, topiramate, felbamate, gabapentin,
pregabalin, tiagabine, vigabatrin, zonisamide, levetiracetam, lacosamide
❖ B=Benzodiazepines : Lorazepam, diazepam, clonazepam, clobazam
 Mechanisms of action
❖ Decreasing axonal conductance by preventing Na+ influx
through fast Na+ channels :
Carbamazepine, phenytoin, valproate, lamotrigine

❖ Increasing inhibitory tone by facilitating GABA-mediated hyper

polarisation :
Baribiturates, benzodiazepines

❖ Decreasing excitatory effects of glutamic acid :

Lamotrigine, topiramate (blocks AMPA receptors), felbamate (blocks NMDA receptors)

❖ Decreasing pre synaptic Ca+2 influx through type T channels in

thalamic neurons :
Ethosuximide, valproate
 Seizure types and Effective drugs
❖ Partial (Simple or Complex): Valproate, phenytoin,
carbamazepine, lamotrigine
Note: Phenobarbital is 1st line in neonates

❖ General tonic-clonic: Valproate, phenytoin, carbamazepine,

lamotrigine
Note: Phenobarbital is 1st line in neonates

❖ General Absence: Ethosuximide, Valproate

❖ Status Epilepticus: Lorazepam, diazepam, phenytoin,
fosphenytoin
IV fosphenytoin is more water soluble
 Individual drugs
Valproate
❖ Mechanism: Increases Na+ channel inactivation, increases
GABA concentration by inhibiting GABA transaminase
❖ Adverse effects: GI, distress, rare but fatal hepatotoxicity,
neural tube defects (spina bifida), C/I in pregnancy,
tremors, weight gain
❖ Special points: Also used for myoclonic seizure and
bipolar disorder
Mnemonic for adverse effects of valproate:
VALPROATE
❖ V=Vomiting
❖ A=Alopecia
❖ L=Liver toxicity
❖ P=Pancreatitis
❖ R=Rashes & thrombocytopenia (Rare)
❖ O=Oedema
❖ A=Ataxia
❖ T=Tremors & teratogenicity (causes neural tube defects)
❖ E=Enzyme inhibition so interacts with many drugs including other anti epileptics
Phenytoin
❖ Mechanism: Increases Na+ channel inactivation, follows
zero-order kinetics
❖ Adverse effects: Nystagmus, diplopia, ataxia, sedation,
gingival hyperplasia, hirsutism, peripheral neuropathy,
megaloblastic anemia, teratogenesis, SLE-like
syndrome, induction of cytochrome P-450, Stevens-
Johnson syndrome, osteopenia
❖ Special points: fosphenytoin for par enteral use
Mnemonic for adverse effects of phenytoin:
PHENYTOIN
❖ P=Plasma level monitoring needed because of its zero-order kinetics
❖ H=Hypertrophy of gums
❖ E=Enzyme induction so interacts with many drugs including other anti epileptics
❖ N=Neutropenia and other hypersensitivity reactions
❖ Y=Young girls beware! Causes hirsutism, coarsening of facial features and acne
❖ T=Teratogenic (causes fatal hydantoin syndrome)
❖ O=Osteomalacia due to interference with calcium absorption
❖ I=Interference with folate absorption leads to megaloblastic anemia
❖ N=Neurological manifestations at higher doses: Ataxia, vertigo and nystagmus
Carbamazepine
❖ Mechanism: Increases Na+ channel inactivation
❖ Adverse effects: Diplopia, ataxia, blood dyscrasias
(agranulocytosis, aplastic anemia), liver toxicity,
teratogenesis, induction of cytochrome P-450, SIADH,
Stevens-Johnson syndrome
❖ Special points: First line treatment for trigeminal
neuralgia
Lamotrigine
❖ Mechanism: Blocks voltage-gated Na+ channels and
glutamate receptors
❖ Adverse effects: Stevens-Johnson syndrome (must be
titrated slowly
Ethosuximide
❖ Mechanism: Blocks thalamic T-type Ca+2 channels
❖ Adverse Effects: GI, fatigue, headache, urticaria, Stevens-
Johnson syndrome
❖ Special points: First line for Generalized Absence seizures

Mnemonic for adverse effects: E F G H I J

❖ E=Ethosuximide cause F=fatigue, G=GI distress,
H=headache, I=itching, Steven-J=Johnson syndrome
Benzodiazepines (Lorazepam, diazepam)
❖ Mechanism: Increases GABA A action by increasing the
frequency of Cl- channel opening
❖ Adverse effects: Sedation, tolerance, dependence,
respiratory depression
❖ Special points: First line in status epilepticus. It can be
given for eclampsia seizures (but first line in eclampsia
seizures would be MgSO4)
Barbiturates (Phenobarbital)
❖ Mechanism: Increases GABA A action by increasing the
duration of opening of Cl- channels
❖ Adverse effects: Sedation, tolerance, dependence,
induction of cytochrome P-450, cardio respiratory
depression
❖ Special points: Contraindicated in porphyria. First line
in neonates.
 Most important table* Lets revise*
Seizure types and Effective drugs

❖ Partial (Simple or Complex):

Valproate, phenytoin, carbamazepine, lamotrigine
Note: Phenobarbital is 1st line in neonates

❖ General tonic-clonic:
Valproate, phenytoin, carbamazepine, lamotrigine
Note: Phenobarbital is 1st line in neonates

❖ General Absence:
Ethosuximide, Valproate

❖ Status Epilepticus:
Lorazepam, diazepam, phenytoin, fosphenytoin
IV fosphenytoin is more water soluble
 Watch out* Word of Caution*

❖ For drugs that can cause potentially fatal Stevens-

Johnson syndrome:
Lamotrigine, Phenytoin, Carbamazepine, Ethosuximide

❖ Stevens-Johnson syndrome: Prodrome of malaise and

fever followed by rapid onset of erythematous/
purpuric macules (oral, ocular, genital). Skin lesions
progress to epidermal necrosis and sloughing
Clinical Integration

In the wards
How To Treat Acute Seizure?

How To Treat Status Epilepticus?

Clinical Integration

In the Outpatient
Who Does Not Need AEDs?

Who Should Be Treated?

Choice of AED
 References
❖ Bertram G Katzung, Basic & Clinical Pharmacology, 14th
Edition
❖ K D Tripathi, Essentials of Medical Pharmacology, 8th
Edition
❖ Rang & Dale's Pharmacology, 9th Edition
❖ T V Shanbhag, Pharmacology for Medical Graduates, 4th
Edition
❖ V Seth, Mnemonics in Pharmacology