Levetiracetam for Managing Neurologic and Psychiatric Disorders

Muhammad U. Farooq; Archit Bhatt; Arshad Majid; Rishi Gupta; Atul Khasnis; Mounzer Y. Kassab


Am J Health Syst Pharm. 2009;66(6):541-561. 

In This Article


Levetiracetam is chemically unrelated to existing antiepileptic drugs (AEDs). The chemical name of levetiracetam, a single enantiomer, is (–)-(S)-α-ethyl-2-oxo-1-pyrrolidineacetamide with molecular formula C8H14N2O2 and molecular weight 170.21.[1] It is an S-enantiomer of piracetam.


There are several potential mechanisms of action by which levetiracetam exerts its antiepileptic effects. It possesses unique antiepileptogenic properties because of its neuromodulatory and neuroinhibitory effects.[2,3] At concentrations up to 10 µM, levetiracetam did not demonstrate binding affinity for receptors for benzodiazepines, γ-aminobutyric acid (GABA), glycine, N-methyl-D-aspartate (NMDA), reuptake sites, and second messenger systems. Levetiracetam does not have any effect on neuronal voltage-gated sodium or T-type calcium currents. Moreover, it does not appear to directly facilitate GABAergic neurotransmission. In vitro studies have demonstrated that levetiracetam opposes the activity of negative modulators of GABA- and glycinegated currents and partially inhibits N-type calcium currents in neuronal cells. A saturable and stereoselective neuronal binding site in the brain tissue of rats has been described for levetiracetam.[4] Experimental data indicate that this binding site is the synaptic vesicle protein SV2A, which is thought to be involved in the regulation of vesicle exocytosis. This suggests that the SV2A may be the target of levetiracetam, resulting in the antiepileptic action of the drug.[5]

Multiple studies have shown that levetiracetam protects against secondarily generalized activity from focal seizures induced by pilocarpine and kainic acid. These two epileptogenic compounds can induce seizures that mimic some features of human-complex-partial seizures with secondary generalization. Marini et al.[6] have shown that levetiracetam has a protective effect against kainite-induced toxicity. Epileptogenesis has been described in remote brain regions without any detectable lesions, giving rise to dual epileptogenic foci. The mesial-temporal structures may learn to potentiate and generate seizure activity, which is often independent of the primary epileptogenic focus; this process is known as kindling.[7,8] Levetiracetam markedly suppresses kindling at doses devoid of adverse effects, with persistent suppression of kindled seizures even after termination of treatment.[2,9] Brain-derived neurotrophic factor (BDNF) and neuropeptide Y (NPY), key modulators of seizure activity, are involved in kindling epileptogenesis. There is up regulation of BDNF- and NPY-messenger ribonucleic acid levels and down regulation of Y1 and Y5 receptors in the hippocampus during kindling. Levetiracetam markedly delays the progression of kindling and shows an anticonvulsant effect by its effect on BDNF, NYP, Y1, and Y5. Levetiracetam results in increased levels of hippocampal Y1- and Y5-like receptors; this might be responsible for its antiepileptic properties.[10] Carunchio et al.[11] have proposed a new mechanism of action of levetiracetam involving modulation of α-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid subtype glutamate receptor (AMPAR). They showed that levetiracetam significantly decreases kainite- and AMPAR-induced currents and decreases the amplitude and frequency of miniature excitatory postsynaptic currents in cortical neurons in vitro.


Absorption. Levetiracetam is rapidly and almost completely absorbed following oral ingestion. Its peak plasma concentration occurs approximately one hour after oral administration.[12] Intravenous and oral levetiracetam are bioequivalent. Levetiracetam 1500 mg given as an i.v. infusion is equivalent to three 500-mg oral tablets.[13,14]

Distribution. Levetiracetam has predictable, linear, and dose- proportional steady-state pharmacokinetics.[15] Levetiracetam is not significantly protein bound (<10% bound), and its volume of distribution is close to the volume of intra-cellular and extracellular water.[15,16] Its steady-state concentration is achieved within two days of initiation of administration.

Metabolism. There is no difference in the metabolism of i.v. and oral levetiracetam. It is not extensively metabolized in humans. The major metabolic pathway (24% of dose) is enzymatic hydrolysis of the acetamide group. The major metabolic pathway is not dependent on any liver cytochrome P-450 (CYP) isoenzymes.[12] It also does not inhibit or induce hepatic enzymes to produce clinically relevant interactions. The major metabolites have no known pharmacologic activity, and the measurement of serum levels of levetiracetam and its metabolites is not recommended in most of cases in clinical practice.

Elimination. The plasma half-life of levetiracetam is approximately 6-8 hours.[12] Its half-life is not affected by dose, route of administration, or repeated administration.[12] About 66% of levetiracetam is eliminated unchanged from the systemic circulation by renal excretion, and 24% is metabolized to an inactive metabolite that can be detectable in blood and urine. The total body clearance is 0.96 mL/min/kg, and the renal clearance is 0.6 mL/min/kg. The mechanism of excretion is glomerular filtration with subsequent partial tubular reabsorption. Levetiracetam's elimination is correlated to creatinine clearance.[15] Levetiracetam's clearance is reduced in patients with impaired renal function.[17] Its half-life rises to 10-11 hours in patients with mild or moderate renal impairment (creatinine clearance, 30-70 mL/min) and rises to around 24 hours if creatinine clearance is less than 30 mL/min.


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