Lacosamide

Mechanism

Chemical and Commercial Profile

Common trade names: Vimpat, Lacosamide Normon.
Group: Third generation antiepileptic, functionalized amino acid (derived from serine).

Mechanism of Action

Lacosamide acts through a unique biophysical mechanism: **selectively stimulates the slow inactivation of voltage-gated sodium channels**, without affecting their rapid inactivation. By prolonging this state of slow inactivation, the channel conductance specifically decreases in those neurons subjected to sustained and repetitive depolarization (characteristic of epileptic seizure), restoring the physiological firing threshold without depressing normal basal synaptic conduction. In addition, it binds to the collapsin response mediator protein 2 (CRMP-2), modulating secondary axonal growth.

Pharmacokinetics

Pharmacokinetics

• Absorption: Rapid and complete after oral intake; 100% bioavailability. It is not altered by food. The plasma peak is reached 1-2 hours after taking it on an empty stomach.
• Distribution: Very low binding to plasma proteins (<15%). Volume of distribution of 0.6 L/kg. It easily crosses the blood-brain barrier.
• Metabolism: Hepatic through oxidative demethylation catalyzed by the isoenzymes CYP2C19 (30%) and secondary hydroxylation by CYP3A4 and CYP2D6. Produces the major inactive metabolite O-desmethyl-lacosamide (clinically non-functional).
• Excretion: Renal (95%) in the form of inactive metabolite and 40% as unchanged drug.
• Half-life (t_1/2): 13 hours; It allows a stable administration schedule divided into two daily doses.

Indicators and dose

Indications

• Monotherapy and adjuvant therapy in focal seizures with or without secondary generalization from 4 years of age.
• Emergency treatment of acute focal crises by slow intravenous route (in hospital infusion).

Dosage and Settings

• Start (Oral): 50 mg twice daily (100 mg/day total).
• Titration: Increase 50 mg twice a day each week progressively.
• Usual therapeutic range: 200-400 mg/day divided into two equivalent doses.
• Loading Dose (Status / Urgency IV): 200 mg administered by slow intravenous infusion over 15 minutes in saline.
• Kidney Failure:
  • Cl_Cr < 30 ml/min: Reduce the maximum therapeutic maintenance dose to 300 mg/day total.
• Liver Failure: Does not require adjustments in Child-Pugh A or B; caution in Child-Pugh C due to decreased metabolic clearance.

Security

Contraindications

• Known second or third degree atrioventricular block (absolute contraindication due to the risk of inducing prolongation of the PR interval and ventricular bradyarrhythmias).

Adverse Effects (ADR)

Cardiovascular and Driving Safety Alert

Lacosamide can produce a **dose-dependent prolongation of the PR interval** in the electrocardiogram, with the risk of triggering sinus bradyarrhythmias, nodal conduction blocks and syncope of cardiac origin. It requires a baseline ECG prior to treatment and periodic controls in elderly patients, patients with ischemic heart disease or users of concomitant bradycardia drugs (such as beta-blockers or digoxin).

• Neurological: Early onset postural dizziness, headache, transient reversible diplopia, mild intention tremor, horizontal nystagmus, drowsiness.
• Gastrointestinal: Transient nausea, vomiting of peripheral cholinergic origin, motor constipation.

Clinical Interactions

• Low interactive potential: As it is metabolized in a minority way by cytochromes and has low protein binding, interactions with other drugs are extremely rare.

Pregnancy and Breastfeeding

FDA Category: C. Very limited data; Its use is not recommended unless the benefits prove to outweigh the direct fetal risk. Breastfeeding: Avoid; Its milk excretion has been objectiveized with measurable childhood levels in animal experimental models.