How are Antiepileptic Drugs (AEDs) classified based on their mechanisms of action?

Classification of Antiepileptic Drugs by Mechanism of Action

Antiepileptic drugs are classified into three primary mechanistic categories: those that enhance GABAergic inhibition, those that block neuronal ion channels, and those with mixed or uncertain mechanisms.

1. GABAergic Enhancement

AEDs that facilitate GABA-mediated neurotransmission work through distinct pathways 1, 2:

Modulation of GABAA Receptor-Chloride Channels

• Benzodiazepines (diazepam, clonazepam, lorazepam) increase the frequency of GABAA receptor channel openings, enhancing inhibitory neurotransmission 1, 3
• Barbiturates (phenobarbital, primidone) increase the open duration of GABAA receptor channels rather than opening frequency 1, 3
• Both drug classes bind to different sites on the GABAA receptor complex 1

GABA Metabolism Inhibition

• Vigabatrin irreversibly inhibits GABA transaminase, the enzyme that degrades GABA, thereby increasing presynaptic GABA pools available for synaptic release 3, 4

GABA Reuptake Inhibition

• Tiagabine blocks GABA reuptake into presynaptic terminals, prolonging GABA's inhibitory effects 2, 4

GABA Concentration Enhancement

• Valproate enhances brain GABA concentration and may increase GABA release from nerve terminals, though its full mechanism remains incompletely understood 1, 3

2. Neuronal Ion Channel Blockade

Voltage-Gated Sodium Channel Blockers

• Phenytoin, carbamazepine, and valproate reduce sustained high-frequency repetitive firing of action potentials by slowing the rate of recovery of sodium channels from inactivation 1, 3
• Lamotrigine decreases sustained high-frequency repetitive firing through voltage-dependent sodium channel blockade, preferentially decreasing presynaptic glutamate release 3, 4
• Newer agents including felbamate, zonisamide, topiramate, and oxcarbazepine share this voltage- and use-dependent sodium channel blocking mechanism 4

Voltage-Gated Calcium Channel Blockers

• Ethosuximide specifically reduces low-threshold (T-type) calcium currents in thalamic neurons involved in slow rhythmic firing patterns characteristic of absence seizures 1, 3
• Valproate also reduces T-type calcium channel currents 3
• Multiple newer AEDs (gabapentin, zonisamide, felbamate, lamotrigine, oxcarbazepine) attenuate voltage-sensitive calcium channels through different mechanisms and targeting different calcium channel classes 4

3. Mixed or Uncertain Mechanisms

Multiple Mechanism Agents

• Topiramate combines sodium channel blockade, GABAA receptor allosteric modulation, and unique AMPA/kainate receptor antagonism 4
• Felbamate blocks sodium channels, modulates GABAA receptors, attenuates calcium channels, and uniquely modulates NMDA-mediated excitatory neurotransmission 4
• Zonisamide affects sodium channels, calcium channels, and GABAA receptors 4

Uncertain Mechanisms

• Gabapentin binds to a high-affinity neuronal membrane site with restricted CNS distribution, possibly related to active neuronal transport, but its precise mechanism remains uncertain despite effects on GABA levels and calcium channels 3, 4

Clinical Classification Context

Non-Enzyme-Inducing AEDs

The National Comprehensive Cancer Network classifies levetiracetam and valproic acid as non-enzyme-inducing AEDs, making them preferable when avoiding cytochrome P450-mediated drug interactions is critical 5, 6

Enzyme-Inducing AEDs to Avoid

Phenytoin, phenobarbital, and carbamazepine should be avoided when possible due to significant effects on the cytochrome P450 system, which can alter metabolism of chemotherapeutic agents including irinotecan, gefitinib, erlotinib, and temsirolimus 5

Common Pitfalls

• Do not assume all AEDs within a mechanistic class have identical clinical profiles—subtle differences in receptor binding sites, channel kinetics, or secondary mechanisms create distinct efficacy and tolerability patterns 1, 3
• Recognize that many newer AEDs have multiple mechanisms of action, which may account for broader anticonvulsant efficacy but also complicate prediction of drug interactions 4
• In patients with brain tumors receiving chemotherapy, levetiracetam is generally better tolerated than valproic acid due to lower risk of hematologic toxicities, despite both being non-enzyme-inducing 6