Mechanism of Action of Levetiracetam (Keppra)
Levetiracetam primarily acts as a synaptic vesicle protein 2A (SV2A) modulator, binding to SV2A protein to inhibit excessive neuronal synchronization and regulate vesicle exocytosis, thereby preventing seizure propagation. 1
Primary Mechanism: SV2A Binding
Levetiracetam has a unique mechanism of action compared to other antiepileptic drugs:
- SV2A Binding: Levetiracetam selectively binds to the synaptic vesicle protein SV2A, which is involved in the regulation of vesicle exocytosis 1, 2
- Vesicular Entry: The drug appears to enter recycling vesicles during synaptic activity to reach its SV2A binding site, explaining why its effects often require prolonged incubation periods 3
- Inhibition of Burst Firing: Levetiracetam inhibits hypersynchronization of epileptiform burst firing and propagation of seizure activity without affecting normal neuronal excitability 1
Secondary Mechanisms
Levetiracetam also exhibits several additional mechanisms that contribute to its antiepileptic effects:
- Calcium Regulation: Partially inhibits N-type calcium currents in neuronal cells 1, 4
- Neurotransmitter Modulation: Opposes the activity of negative modulators of GABA- and glycine-gated currents 1, 4
- Vesicular Pool Modulation: Reduces the readily releasable pool of vesicles in a frequency-dependent manner, with greater effects on rapidly discharging neurons 3
- Synaptotagmin Regulation: Normalizes synaptic levels of the calcium-sensor protein synaptotagmin, whose stability and trafficking are regulated by SV2A 5
What Levetiracetam Does NOT Do
Unlike many other antiepileptic drugs, levetiracetam:
- Does NOT bind to GABA, benzodiazepine, glycine, or NMDA receptors 1
- Does NOT directly affect neuronal voltage-gated sodium channels 1
- Does NOT directly facilitate GABAergic neurotransmission 1
- Does NOT inhibit T-type calcium currents 1
- Does NOT have cytochrome P450 isoenzyme-inducing potential 4
Clinical Implications of Mechanism
The unique mechanism of action of levetiracetam has important clinical implications:
- Minimal Drug Interactions: Levetiracetam has minimal pharmacokinetic interactions with other drugs, including other antiepileptic medications 4
- Cognitive Profile: Unlike some other antiepileptic drugs, levetiracetam is not associated with cognitive impairment 4
- Driving Performance: Studies show levetiracetam has no statistically significant effect on arousal function and may actually improve cognitive functions 6
- Adverse Effects: The most common side effects (somnolence, dizziness, infection, asthenia) are generally mild to moderate 4, 7
- Behavioral Effects: Some patients may experience behavioral adverse effects 4
Pharmacological Characteristics
- Absorption: Rapid and almost complete absorption (100% bioavailability) 1
- Distribution: Minimal protein binding (<10%) 1
- Metabolism: Limited metabolism (24% of dose) via enzymatic hydrolysis of the acetamide group 1
- Elimination: Primarily renal excretion (66% of dose excreted unchanged) 1
- Half-life: Approximately 6-8 hours in adults with normal renal function 1
The unique SV2A-targeting mechanism of levetiracetam represents a distinct approach to seizure control compared to traditional antiepileptic medications, explaining its efficacy in various seizure types and favorable side effect profile.