Classification of Drugs for Epilepsy (Antiepileptic Drugs / AEDs)

Antiepileptic drugs (AEDs) can be classified in several complementary ways: by generation, by mechanism of action, and by seizure type/indication. All three frameworks are used clinically.

1. Classification by Generation

First-Generation (Older / Classic) AEDs

Drug	Key Feature
Phenobarbital	Oldest AED; GABA-A potentiation
Phenytoin	Narrow therapeutic index; nonlinear kinetics
Carbamazepine	Drug of choice for focal seizures
Ethosuximide	Drug of choice for pure absence seizures
Valproic acid (Valproate)	Broadest spectrum; drug of choice for juvenile myoclonic epilepsy
Primidone	Metabolized to phenobarbital
Clonazepam	Benzodiazepine; mainly adjunctive

Second-Generation (Newer) AEDs

Drug	Key Feature
Lamotrigine	Broad-spectrum; well tolerated; risk of SJS rash
Levetiracetam	Unique SV2A mechanism; minimal drug interactions
Topiramate	Broad-spectrum; weight loss; cognitive dulling
Gabapentin	Adjunctive for focal seizures; also used for neuropathic pain
Pregabalin	Similar to gabapentin; weight gain
Oxcarbazepine	Safer alternative to carbamazepine
Vigabatrin	Irreversible GABA-T inhibitor; used for infantile spasms
Tiagabine	GABA reuptake inhibitor
Zonisamide	Broad-spectrum; sulfonamide derivative
Felbamate	Broad-spectrum but hepatotoxic/aplastic anemia risk

Third-Generation (Newest) AEDs

Drug	Key Feature
Lacosamide	Slow inactivation of sodium channels; adjunctive focal seizures
Perampanel	AMPA glutamate receptor antagonist
Brivaracetam	SV2A modulator (like levetiracetam, less mood side effects)
Eslicarbazepine	Active metabolite of oxcarbazepine
Cenobamate	Dual mechanism; high seizure-free rates in focal seizures

2. Classification by Mechanism of Action

Sodium Channel Blockers (reduce membrane excitability)

Phenytoin, Carbamazepine, Oxcarbazepine, Eslicarbazepine, Lamotrigine, Zonisamide, Lacosamide

GABA Potentiators (enhance inhibitory neurotransmission)

Subtype	Drugs
GABA-A receptor (allosteric)	Benzodiazepines (diazepam, lorazepam, clonazepam), Barbiturates (phenobarbital)
GABA synthesis increase	Valproate (indirect)
GABA-transaminase inhibitor (irreversible)	Vigabatrin
GABA reuptake inhibitor	Tiagabine

T-type Calcium Channel Blockers (suppress thalamo-cortical rhythms - key for absence seizures)

Ethosuximide, Valproate, Zonisamide

SV2A (Synaptic Vesicle Protein) Modulators (reduce neurotransmitter release)

Levetiracetam, Brivaracetam

Glutamate (Excitatory) Antagonists

Target	Drug
AMPA receptor	Perampanel, Topiramate (partial)
NMDA receptor	Valproate (partial)

Potassium Channel Openers

Retigabine/Ezogabine (KCNQ2-5 opener; largely discontinued due to pigmentation side effects)

Multiple / Mixed Mechanisms

Drug	Mechanisms
Valproate	Na⁺ channel block + T-Ca²⁺ block + GABA potentiation + NMDA inhibition
Topiramate	Na⁺ channel + AMPA block + GABA potentiation + Ca²⁺ channel block + carbonic anhydrase inhibition

3. Classification by Seizure Type / Indication

Focal (Partial) Seizures - Drugs of Choice

Carbamazepine, Oxcarbazepine (first-line)
Lamotrigine, Levetiracetam, Lacosamide (alternatives/adjuncts)
Phenytoin, Phenobarbital, Valproate (effective but older)

Generalized Tonic-Clonic Seizures (GTCS)

Valproate (first-line, especially if absence co-exists)
Lamotrigine, Levetiracetam, Topiramate
Phenytoin, Carbamazepine (effective but not for other generalized types)

Absence Seizures

Ethosuximide - drug of choice for pure absence
Valproate - drug of choice if absence + GTCS co-exist
Lamotrigine (less effective, but used in females of childbearing age)
Avoid: Carbamazepine, Phenytoin, Gabapentin, Vigabatrin (may worsen absence)

Juvenile Myoclonic Epilepsy (JME)

Valproate - first-line
Levetiracetam, Lamotrigine, Topiramate (alternatives)
Lifelong treatment usually required

Infantile Spasms (West Syndrome)

Vigabatrin (especially tuberous sclerosis)
ACTH (corticotropin) - first-line hormonal therapy
Pyridoxine in pyridoxine-dependent cases

Lennox-Gastaut Syndrome

Valproate, Lamotrigine (drug of choice for drop attacks), Topiramate
Clobazam, Rufinamide, Felbamate (adjunctive)
Cannabidiol (Epidiolex)

Status Epilepticus (Acute)

Lorazepam IV (first-line)
Diazepam IV / rectal
Phenytoin / Fosphenytoin IV (second-line)
Valproate IV, Levetiracetam IV, Phenobarbital IV
Midazolam IM (when IV access unavailable)

4. Summary Table of Key Drugs

Drug	Generation	Mechanism	Best For	Key Adverse Effect
Valproate	1st	Multiple	Broad-spectrum (JME, GTCS, absence)	Teratogenicity, hepatotoxicity, weight gain
Phenytoin	1st	Na⁺ channel	Focal, GTCS	Nonlinear kinetics, gingival hyperplasia, hirsutism
Carbamazepine	1st	Na⁺ channel	Focal seizures	Hyponatremia, skin rash (SJS in HLA-B*1502)
Ethosuximide	1st	T-Ca²⁺ channel	Absence seizures	GI upset, headache
Phenobarbital	1st	GABA-A	Focal, GTCS	Sedation, cognitive impairment
Lamotrigine	2nd	Na⁺ channel	Broad-spectrum	SJS rash (slow titration required)
Levetiracetam	2nd	SV2A	Broad-spectrum	Mood disturbance, irritability
Topiramate	2nd	Multiple	Broad-spectrum	Cognitive dulling ("dopamax"), nephrolithiasis
Oxcarbazepine	2nd	Na⁺ channel	Focal seizures	Hyponatremia
Vigabatrin	2nd	GABA-T inhibitor	Infantile spasms	Irreversible visual field defects
Gabapentin	2nd	Ca²⁺ channel (alpha-2-delta)	Focal (adjunct)	Sedation, weight gain
Lacosamide	3rd	Na⁺ channel (slow inactivation)	Focal seizures	PR interval prolongation
Perampanel	3rd	AMPA antagonist	Focal + GTCS (adjunct)	Dizziness, aggression
Brivaracetam	3rd	SV2A	Focal seizures	Better tolerated than levetiracetam

Sources:

Adams and Victor's Principles of Neurology, 12th Ed., Table 15-5 (Antiepileptic Drugs - Mechanisms, Indications, Limitations)
Katzung's Basic and Clinical Pharmacology, 16th Ed., Ch. 24 (Antiseizure Medications)

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