Which antiepileptic drugs act as voltage‑gated sodium channel blockers and what are their typical adult dosing regimens?

Sodium Channel Blockers for Epilepsy

Primary Sodium Channel Blocking Antiepileptic Drugs

The voltage-gated sodium channel blockers used for epilepsy include carbamazepine, phenytoin, lamotrigine, oxcarbazepine, lacosamide, and sodium valproate (which also has additional mechanisms). 1, 2, 3

First-Generation Sodium Channel Blockers

• Carbamazepine and phenytoin are the original sodium channel blockers that have been used for decades in epilepsy treatment. 2, 3

• Phenobarbitone also has sodium channel blocking properties, though it primarily works through GABA enhancement. 1

Second-Generation Sodium Channel Blockers

• Lamotrigine is a second-generation agent that blocks voltage-gated sodium channels and is recommended as first-line treatment for focal onset seizures. 4, 2

• Oxcarbazepine is a keto-analogue of carbamazepine with similar sodium channel blocking properties. 2, 5

• Topiramate and zonisamide have sodium channel blocking activity among other mechanisms. 2

• Sodium valproate inhibits voltage-gated sodium channels in addition to inhibiting GABA transaminase. 1

Third-Generation Sodium Channel Blockers

• Lacosamide is a newer antiepileptic medication with activity at voltage-gated sodium channels, showing state-dependent sodium channel blockade. 1, 2

• Eslicarbazepine acetate is a third-generation sodium channel blocker, though limited data were available for network meta-analysis. 4, 2

• Rufinamide and brivaracetam are additional third-generation agents targeting sodium channels. 2, 5

Adult Dosing Regimens for Key Sodium Channel Blockers

Carbamazepine (First-Line for Focal Seizures)

• Initial dose: 200 mg twice daily (400 mg/day) for adults and children over 12 years. 6

• Titration: Increase at weekly intervals by adding up to 200 mg/day using a three or four times daily regimen. 6

• Maintenance dose: 800 to 1200 mg daily, with maximum doses of 1200 mg/day for patients over 15 years (1600 mg/day in rare adult instances). 6

• Pediatric dosing (6-12 years): Start 100 mg twice daily, increase weekly by 100 mg/day, maximum 1000 mg/day. 6

Oxcarbazepine

• Initial dose (adjunctive therapy): 600 mg/day given twice daily. 7

• Titration: May be increased by maximum of 600 mg/day at approximately weekly intervals. 7

• Maximum recommended dose: 1200 mg/day for adjunctive therapy; 2400 mg/day for monotherapy (though most patients cannot tolerate this dose due to CNS effects). 7

• Pediatric dosing (4-16 years): 8 to 10 mg/kg/day initially, with target maintenance doses of 900-1800 mg/day depending on weight. 7

Lamotrigine (First-Line for Focal Seizures)

• High-certainty evidence shows lamotrigine performs better than most other treatments including carbamazepine for treatment failure outcomes in focal seizures. 4

• Lamotrigine shows no significant difference compared to levetiracetam for treatment failure, with both performing better than other AEDs. 4

• Dosing varies significantly based on concomitant medications (especially enzyme inducers like carbamazepine or valproate), requiring careful titration to avoid serious rash. 4

Phenytoin

• Pediatric loading dose (status epilepticus): 20 mg/kg IV over 10-20 minutes (maximum 1000 mg initial dose). 1

• Infusion rate: Not to exceed 1 mg/kg per minute to avoid hypotension and arrhythmias. 1

• Phenytoin should be diluted in normal saline to avoid precipitation and is incompatible with glucose-containing solutions. 1

Lacosamide

• Lacosamide was studied extensively in painful diabetic neuropathy at 300 mg/day but was not approved for this indication despite some positive phase 3 trials. 1

• Small dose-related increases in PR interval have been associated with lacosamide treatment, requiring cardiac monitoring. 1

Evidence-Based Treatment Selection

For Focal Onset Seizures

• First-line options: Carbamazepine, lamotrigine, or levetiracetam show the best profile in terms of treatment failure and seizure control. 4

• Lamotrigine demonstrates superior tolerability compared to carbamazepine, with lower rates of treatment failure due to adverse events (HR 1.26,95% CI 1.10-1.44 favoring lamotrigine). 4

• Phenytoin and phenobarbitone performed better for time to first seizure but have worse tolerability profiles. 4

For Generalized Tonic-Clonic Seizures

• First-line treatment: Sodium valproate has the best profile compared to all other treatments. 4

• Alternative first-line options: Lamotrigine and levetiracetam are the most suitable alternatives, particularly for women of childbearing potential where valproate may not be appropriate. 4

• No significant differences were shown between sodium valproate, lamotrigine, and levetiracetam for treatment failure outcomes (moderate-certainty evidence). 4

Mechanism of Action

• Voltage-gated sodium channel blockers work by reversibly blocking spontaneous neuronal discharge without blocking normal action potential propagation. 8, 3

• These drugs exhibit voltage- and frequency-dependent inhibition of ionic currents through sodium channels, preferentially blocking rapidly firing neurons characteristic of seizure activity. 8, 3

• Third-generation agents like lacosamide show state-dependent sodium channel blockade or potential sodium channel subtype selectivity, though most agents do not differentiate between channel subtypes. 2

Common Adverse Effects

• Carbamazepine: Affects sensory-perceptual functions and cognitive functions, with potential for drowsiness, dizziness, and rash. 1

• Lamotrigine: Minimal effects on arousal and sensory-perceptual functions in pharmacodynamic studies, with better tolerability than older agents. 1

• Phenytoin: May cause hypotension and arrhythmias especially with rapid infusion; neonates have increased risk of toxicity due to decreased protein binding. 1

• Lacosamide: Generally comparable safety to other approved neuropathic pain medications, but PR interval prolongation requires monitoring. 1

Critical Drug Interactions

• Carbamazepine, phenytoin, and oxcarbazepine are strong CYP3A4 enzyme inducers, requiring dosage adjustments when used with other medications. 7

• Sodium valproate inhibits GABA transaminase and has complex interactions with other antiepileptic drugs, particularly affecting lamotrigine metabolism. 1

• When adding sodium channel blockers to existing anticonvulsant therapy, the drug should be added gradually while other anticonvulsants are maintained or gradually decreased, except phenytoin which may need to be increased. 6

Therapeutic Drug Monitoring

• Lamotrigine, oxcarbazepine, and zonisamide have the strongest justifications for therapeutic drug monitoring among newer sodium channel blockers. 5

• Salivary drug concentration measurement has potential utility for lamotrigine and topiramate monitoring. 5

• Blood level monitoring has increased the efficacy and safety of sodium channel blocking anticonvulsants, with dosage adjusted to individual patient needs. 6