Levetiracetam

Mechanism

Chemical and Commercial Profile

Common trade names: Keppra, Matever, Levetiracetam Normon.
Group: Second generation antiepileptic, pyrrolidone derivative.

Mechanism of Action

Levetiracetam acts through selective and stereospecific binding to the synaptic vesicle 2A (SV2A) cellular protein, abundantly located in the presynaptic terminals of the brain and spinal cord. By binding, it indirectly modulates the vesicular release of excitatory neurotransmitters such as glutamate in situations of neuronal hyperactivity, reducing epileptic synchronous firing without altering normal basal neurotransmission.

Pharmacokinetics

Pharmacokinetics

• Absorption: Rapid and almost complete orally; 100% bioavailability. It is not altered by food. The plasma peak is reached at the time of intake on an empty stomach.
• Distribution: Virtually no binding to plasma proteins (<10%). Distribution volume: 0.5-0.7 L/kg. Quickly crosses the blood-brain barrier.
• Metabolism: Not dependent on liver cytochrome enzymes. It undergoes enzymatic hydrolysis of the acetamide group in blood, erythrocytes and peripheral tissues, giving rise to the main inactive metabolite ucb L057 (24%).
• Excretion: Renal (95%) through glomerular filtration and active tubular secretion.
• Half-life (t_1/2): 7-8 hours in adults; 5-6 hours in pediatrics; It is prolonged to >11 hours in the elderly due to the physiological decrease in renal clearance. Requires dosing in two daily doses.

Indicators and dose

Indications

• Monotherapy in focal seizures with or without secondary generalization from 16 years of age.
• Adjuvant therapy in focal seizures, myoclonic seizures associated with juvenile myoclonic epilepsy, and generalized tonic-clonic seizures.
• Emergency treatment of acute seizures or status epilepticus intravenously (as a preferred alternative to phenytoin).

Dosage and Settings

• Start of Treatment (Oral): 500 mg twice a day (1000 mg/day total).
• Increments: Increase from 500 mg twice a day every two weeks progressively.
• Usual therapeutic range: 1000-3000 mg/day divided into two equivalent doses.
• IV administration: Infusion of 1000-1500 mg in saline solution over 15 minutes in acute attacks.
• Analytical adjustment in Renal Failure:
  • Cl_Cr [50-79 ml/min]: Therapeutic range of 500 to 1000 mg every 12 hours.
  • Cl_Cr [30-49 ml/min]: Therapeutic range of 250 to 750 mg every 12 hours.
  • Cl_Cr < 30 ml/min (Severe): Therapeutic range of 250 to 500 mg every 12 hours.

Security

Contraindications

• Hypersensitivity to the active substance or to other pyrrolidone derivatives.

Adverse Effects (ADR)

Psychiatric Alert · "Keppra Rage" Syndrome

Levetiracetam presents a highly characteristic and frequent adverse neuropsychiatric profile (10-15% of patients), which presents with **severe irritability, hostility, psychomotor agitation, extreme emotional lability, anxiety and outbursts of anger (Keppra Rage)**. It is more common in patients with a personal history of previous personality or psychiatric disorders. Requires monitoring and assessment of dose reduction or gradual withdrawal.

• Neurological: Daytime sleepiness (moderate), dizziness, tension headache, chronic fatigue, asthenia, unsteady gait (initial mild ataxia).
• Hematological: Mild transient thrombocytopenia (exceptional).

Clinical Interactions

• Low interaction potential: Does not interact with other drugs through hepatic cytochrome metabolic pathways. It is ideal for use in complex polypharmacy (oncology, HIV, geriatrics).

Pregnancy and Breastfeeding

FDA Category: C. Extensive human data (Euroregional pregnancy registries) demonstrate that it is one of the safest antiepileptics in pregnancy, with no evidence of an increase in major structural malformations compared to the baseline risk. Its renal clearance increases progressively during pregnancy (up to 60%), requiring close therapeutic monitoring and dose increase if clinically essential. Breastfeeding: Compatible. Reduced excretion in breast milk; Relative childhood dose estimated at 2-3%. Monitor lethargy.