What is the mechanism of action of Keppra (levetiracetam)?

From the Guidelines

Levetiracetam (Keppra) works by binding to a specific protein called SV2A (synaptic vesicle protein 2A) in the brain, modulating neurotransmitter release and preventing abnormal electrical activity that causes seizures. This mechanism is supported by a recent study published in 2024 in the journal Neuropsychopharmacology 1. The study categorizes levetiracetam as a synaptic vesicle protein 2A (SV2A) modulator, which is presumed to have inhibitory effects on excitatory neurotransmission.

Key Points

• Levetiracetam's unique mechanism of action contributes to its broad spectrum of activity against various seizure types and its favorable drug interaction profile.
• Unlike many other antiepileptic drugs, levetiracetam does not appear to work through traditional mechanisms such as sodium channel blockade, enhancement of GABA inhibition, or antagonism of glutamate receptors.
• The medication reaches steady-state concentrations within 48 hours of starting therapy and has a half-life of about 7-8 hours in adults with normal renal function, requiring dose adjustments in patients with kidney impairment.

Clinical Implications

• Levetiracetam is typically started at 500 mg twice daily for adults and can be titrated up to 1500 mg twice daily based on clinical response.
• The use of levetiracetam in the setting of benzodiazepine-resistant status epilepticus can result in cessation of seizures in approximately half of all patients, with limited harms 1.
• Early treatment and cessation of status epilepticus with levetiracetam can reduce morbidity and mortality.

From the FDA Drug Label

The precise mechanism(s) by which levetiracetam exerts its antiepileptic effect is unknown. The antiepileptic activity of levetiracetam was assessed in a number of animal models of epileptic seizures Levetiracetam inhibits burst firing without affecting normal neuronal excitability, suggesting that levetiracetam may selectively prevent hypersynchronization of epileptiform burst firing and propagation of seizure activity Levetiracetam opposes the activity of negative modulators of GABA- and glycine-gated currents and partially inhibits N-type calcium currents in neuronal cells. A saturable and stereoselective neuronal binding site in rat brain tissue has been described for levetiracetam Experimental data indicate that this binding site is the synaptic vesicle protein SV2A, thought to be involved in the regulation of vesicle exocytosis These findings suggest that the interaction of levetiracetam with the SV2A protein may contribute to the antiepileptic mechanism of action of the drug.

The mechanism of action of Keppra (levetiracetam) is not fully understood. However, it is thought to involve the following key points:

• Inhibition of burst firing without affecting normal neuronal excitability
• Opposition to the activity of negative modulators of GABA- and glycine-gated currents
• Partial inhibition of N-type calcium currents in neuronal cells
• Binding to the synaptic vesicle protein SV2A, which may contribute to its antiepileptic effect 2

From the Research

Mechanism of Action of Keppra (Levetiracetam)

The mechanism of action of Keppra (levetiracetam) is unique and involves several key processes:

• Binding to synaptic vesicle protein 2A (SV2A), which is thought to be involved in modulating synaptic neurotransmitter release 3, 4, 5
• Inhibiting calcium release from intraneuronal stores 3
• Opposing the activity of negative modulators of GABA- and glycin-gated currents 3
• Inhibiting excessive synchronized activity between neurons 3
• Inhibiting N-type calcium channels 3

Effects on Neurotransmission

Levetiracetam has been shown to reverse synaptic deficits produced by overexpression of SV2A, and to restore normal neurotransmission 5. It also counteracts the long-term effects of pilocarpine-induced status epilepticus, including hippocampal hyperexcitability 6.

Advantages and Uses

Levetiracetam has several advantages, including:

• Rapid and complete absorption, high oral bioavailability, and minimal metabolism 3
• Lack of cytochrome P450 isoenzyme-inducing potential, reducing the risk of drug interactions 3, 7
• Efficacy in controlling seizures in patients with epilepsy, including partial onset seizures, myoclonic seizures, and primary generalized tonic-clonic seizures 3, 4
• Potential use as an antiepileptogenic and disease-modifying agent 6
• Emerging role in the treatment of seizures in brain tumor patients, with potential benefits including increased sensitivity of glioblastoma tumors to chemotherapy 7