What is the mechanism of action (MOA) of antiepileptic drugs (AEDs)?

Mechanisms of Action of Antiepileptic Drugs

Antiepileptic drugs work through three primary cellular mechanisms: modulation of voltage-gated ion channels (particularly sodium and calcium channels), enhancement of GABAergic inhibitory neurotransmission, and attenuation of glutamatergic excitatory neurotransmission. 1, 2, 3

Major Mechanistic Categories

Voltage-Gated Sodium Channel (VGSC) Modulation

• Carbamazepine, phenytoin, lamotrigine, lacosamide, and valproate inhibit voltage-gated sodium channels by enhancing sodium channel inactivation, which decreases high-frequency repetitive firing of action potentials 4, 5, 6
• This mechanism slows the rate of recovery of sodium channels from inactivation, preventing sustained repetitive firing that underlies seizure propagation 6
• VGSC modulators have less impact on arousal function compared to benzodiazepines but may affect sensory-perceptual functions 4

GABAergic Enhancement

• Benzodiazepines and barbiturates enhance GABA-A receptor-mediated inhibition through distinct binding sites on the GABA-A receptor channel 5, 6
• Benzodiazepines increase the frequency of GABA receptor channel openings, while barbiturates increase the open duration of these channels 6
• Valproate inhibits GABA transaminase, the enzyme that degrades GABA, thereby increasing GABA levels in the brain and enhancing inhibitory neurotransmission 4, 5
• Vigabatrin irreversibly inhibits GABA transaminase, producing greater available pools of presynaptic GABA for release 5

Calcium Channel Modulation

• Ethosuximide and valproate reduce low-threshold (T-type) calcium channel currents 5, 6
• This mechanism is particularly relevant for absence seizures, as T-type calcium currents are involved in slow rhythmic firing of thalamic neurons 6

Synaptic Vesicle Protein 2A (SV2A) Modulation

• Levetiracetam binds to synaptic vesicle protein SV2A, which is thought to be involved in the regulation of vesicle exocytosis 7
• The binding affinity for SV2A correlates with antiseizure potency in animal models, suggesting this interaction contributes to the antiepileptic mechanism 7
• Levetiracetam inhibits burst firing without affecting normal neuronal excitability, selectively preventing hypersynchronization of epileptiform activity 7
• SV2A modulators are presumed to have inhibitory effects on excitatory neurotransmission and have less impact on arousal function than benzodiazepines 4

Glutamatergic Attenuation

• Lamotrigine decreases sustained high-frequency repetitive firing, which may result in preferentially decreased release of presynaptic glutamate 5
• Some newer antiepileptic drugs may inhibit glutamatergic excitatory neurotransmission and potentially provide neuroprotective or antiepileptogenic effects 1

Clinical Implications

Drug Selection Considerations

• Mechanism of action is becoming an important criterion for selecting the most suitable antiepileptic drug or combination for individual patients 2, 3
• Different mechanisms explain varying efficacy against generalized tonic-clonic, myoclonic, and absence seizures 6

Important Caveats

• Many antiepileptic drugs have complex, multiple mechanisms of action that may not be fully understood 4
• Some drugs like phenytoin and benzodiazepines may dampen mechanisms of neural plasticity that contribute to behavioral recovery after stroke, which is a concern when using these agents in stroke patients 4
• The precise molecular mechanisms for some newer agents remain uncertain despite known binding sites or receptor interactions 7, 5