What is the mechanism of action of lamotrigine?

Mechanism of Action of Lamotrigine

Lamotrigine works primarily by blocking voltage-gated sodium channels (VGSC), which stabilizes neuronal membranes and prevents excessive release of excitatory neurotransmitters, particularly glutamate and aspartate. 1

Primary Mechanism

• Lamotrigine functions as a voltage-gated sodium channel modulator that inhibits these channels at the presynaptic neuronal membrane level 1
• The drug selectively prolongs slow inactivation of sodium channels, specifically inhibiting repetitive high-frequency firing in depolarized neurons 2
• This sodium channel blockade prevents the pathological release of excitatory amino acids, particularly glutamate and aspartate, which are key mediators of seizure activity 3, 4
• The inhibitory effect on excitatory neurotransmission forms the basis for both its antiepileptic and mood-stabilizing properties 1

Secondary Mechanisms

• Research evidence suggests lamotrigine may also have calcium antagonistic properties, though this is a secondary mechanism 5
• In experimental models, lamotrigine demonstrates additive effects with calcium channel blockers like verapamil, suggesting possible action on calcium channels in addition to its primary sodium channel effects 5
• This calcium channel interaction may contribute to its efficacy in both epilepsy and mood disorders, though the sodium channel blockade remains the predominant mechanism 5

Functional Impact on Neural Systems

• As a VGSC modulator, lamotrigine demonstrates minimal impact on arousal function compared to other antiepileptic drugs 1
• Pharmacodynamic studies at therapeutic doses (50-300 mg/day) show no statistically significant impairment in arousal function, sensory-perceptual functions, or cognitive functions 1
• This favorable functional profile distinguishes lamotrigine from other sodium channel modulators like carbamazepine, which shows significant impairment across these domains 1
• The drug may affect sensory-perceptual functions to some degree, though this effect is inconsistent and generally not clinically meaningful with chronic administration 6

Clinical Relevance of the Mechanism

• The sodium channel blockade mechanism provides broad-spectrum efficacy against both partial seizures with or without secondary generalization and primary generalized seizures 3, 4
• The stabilization of neuronal membranes through this mechanism results in sustained seizure reduction with long-term therapy without significant tolerance development 4
• The mechanism produces less sedation and cognitive impairment compared to drugs that primarily enhance GABAergic inhibition, making it particularly suitable for patients requiring preserved cognitive function 1