Antiarrhythmic drugs: Mexiletine (Class 1B)

Mexiletine is an oral Class IB antiarrhythmic and sodium channel blocker structurally related to lidocaine, used primarily for ventricular arrhythmias and selected channelopathies such as LQT3 where late sodium current inhibition is desired.
Its key antiarrhythmic actions are fast-on/fast-off block of fast Na+ channels with preference for inactivated channels in ischemic tissue, leading to rate‑dependent suppression of ventricular ectopy with minimal effect at normal heart rates.

Classification

• Class IB antiarrhythmic (Vaughan–Williams), sodium-channel blocker with rapid kinetics and high preference for inactivated channels.
• Distinct from Class IA/IC: produces minimal QRS widening at therapeutic doses and tends to shorten action potential duration (APD) in ventricular myocardium.

Mechanism

• Blocks voltage‑gated fast Na+ channels during phase 0 in fast-response tissues, more avidly in depolarized/ischemic myocardium where channels dwell in the inactivated state.
• Decreases slope of phase 0 in diseased tissue, shortens APD and effective refractory period (ERP) in Purkinje/ventricular fibers, often increasing the ERP/APD ratio, which can reduce reentry.
• Inhibits late sodium current (INa,late), which is clinically useful for repolarization abnormalities (e.g., congenital LQT3) by abbreviating repolarization and reducing triggered activity.

Electrophysiology

• Ventricular tissue: decreases APD and ERP modestly; suppresses automaticity and triggered activity in ischemic regions.
• Atria/AV node: minimal clinically meaningful effects at therapeutic levels; not a rate‑control or AV nodal drug.
• ECG: little to no change in QRS or QT at usual doses; mild PR or QRS changes can occur at higher concentrations; QT shortening may be observed in LQT3.

Pharmacokinetics

• Oral bioavailability high (approximately 85–90%); onset within hours, enabling chronic outpatient use.
• Peak concentration typically 2–4 hours for immediate‑release; controlled‑release products exist in some regions.
• Volume of distribution moderate; protein binding ~50–60%.
• Hepatic metabolism predominates (CYP2D6 major; CYP1A2 contributory); active metabolites are minimal contributors in most patients.
• Elimination half‑life roughly 10–12 hours; renal excretion of parent drug is limited (~10%), so renal impairment has modest effect compared with hepatic impairment.

Indications and role

• Documented, clinically significant ventricular arrhythmias: sustained VT, symptomatic non‑sustained VT, frequent PVCs with symptoms or cardiomyopathy concern when first‑line strategies fail or are not tolerated.
• Adjunct in structural heart disease, particularly ischemic substrates, to reduce VT burden and ICD shocks when beta‑blockers and/or amiodarone are insufficient or poorly tolerated.
• Channelopathies: useful in congenital LQT3 and in acquired scenarios with increased late INa to shorten QT and reduce torsadogenic triggers.
• Not a first‑line agent for supraventricular arrhythmias and not indicated for rate control.

Dosing and administration

• Typical adult start: 150–200 mg orally every 8 hours with food to minimize GI upset.
• Usual maintenance range: 200–300 mg every 8 hours (total daily 450–900 mg), adjusted by response and tolerability; some patients use 250–300 mg every 12 hours in extended‑release formulations where available.
• Titration: increase every 2–3 days based on symptom/arrhythmia surveillance, side effects, and ECG.
• Hepatic impairment or poor CYP2D6 metabolizers: consider lower starting dose (e.g., 50–100 mg every 8–12 hours) and slower titration.
• Take with meals or antacid to reduce dyspepsia, nausea, and epigastric discomfort.

Contraindications and cautions

• Absolute: cardiogenic shock; second‑/third‑degree AV block or severe sinus node dysfunction without a pacemaker; hypersensitivity to mexiletine or local anesthetic–type agents.
• Relative/caution: significant hepatic impairment; seizure disorders; persistent severe bradycardia; concomitant drugs that markedly slow conduction or lower seizure threshold; recent MI with ongoing ischemia (specialist management required).
• Not for asymptomatic PVC suppression in the absence of other indications given historical mortality concerns with Class I agents post‑MI; reserve for carefully selected cases.

Adverse effects

• Gastrointestinal: nausea, dyspepsia, epigastric pain, vomiting; often dose‑limiting but improved with food or dose splitting.
• Neurologic: tremor, dizziness, ataxia, paresthesias, blurred vision, insomnia; dose‑related and improve with reduction.
• Cardiac: bradyarrhythmias or conduction slowing at high levels; proarrhythmia is uncommon compared with IA/IC but can occur, especially with electrolyte imbalance or interacting QT‑active drugs.
• Hepatic: transaminase elevations (usually mild); rare clinically significant injury.
• Dermatologic and hypersensitivity reactions are uncommon but possible.

Drug interactions

• CYP2D6 substrate: strong inhibitors (e.g., fluoxetine, paroxetine, quinidine) can raise levels; poor metabolizers may have higher exposure.
• CYP1A2: inducers (e.g., smoking) may lower levels; inhibitors (e.g., fluvoxamine, ciprofloxacin) may raise levels.
• Additive conduction slowing with other membrane‑active antiarrhythmics or high‑dose beta‑blockers; caution with amiodarone (pharmacodynamic and metabolic interactions), lidocaine (overlapping toxicity), and other QT‑active agents even though mexiletine usually shortens QT.
• Theophylline and other narrow therapeutic index drugs metabolized by CYP1A2 may have bidirectional interactions; monitor levels and effects when co‑administered.

Special populations

• Hepatic impairment: reduce dose and titrate slowly with close monitoring for neuro/GI toxicity.
• Renal impairment: usually no major adjustment until severe impairment; monitor for accumulation in combined hepatic/renal dysfunction.
• Older adults: increased sensitivity to CNS and GI effects; start low and go slow.
• Pregnancy/lactation: limited human data; use only if benefits justify potential risks and consider alternatives first in non‑life‑threatening scenarios.

Monitoring

• Baseline and follow‑up ECG for QRS/PR and rhythm burden; ambulatory monitoring (e.g., Holter) to gauge PVC/VT reduction and symptom correlation.
• Electrolytes (K+, Mg2+), particularly in patients on diuretics or with GI losses; maintain K+ in high‑normal range to mitigate proarrhythmia.
• Hepatic function at baseline and periodically; consider levels or pharmacogenetic context when toxicity appears out of proportion to dose.
• Clinical surveillance for neurologic and GI intolerance; adjust dose or dosing frequency accordingly.

Clinical pearls

• Best suited for ischemia‑related ventricular ectopy/VT because of preferential binding to inactivated Na+ channels prevalent in depolarized tissue.
• Oral “analogue of lidocaine”: lidocaine for acute IV suppression in the hospital, mexiletine for longer‑term outpatient suppression when appropriate.
• In LQT3, late INa inhibition can shorten QTc and reduce arrhythmic events; ensure careful ECG follow‑up and avoid concomitant QT‑prolonging triggers.
• If tremor or GI upset emerges during titration, try food co‑administration, smaller but more frequent dosing, or a modest dose reduction before abandoning therapy.
• Consider as adjunct to reduce ICD shocks when amiodarone or sotalol are limited by intolerance, bradycardia, or QT effects—often alongside beta‑blockade.

Comparison to other Class I agents

• Versus Class IA/IC (e.g., quinidine, flecainide, propafenone): lower proarrhythmic risk in structural heart disease and minimal QRS widening at therapeutic doses, but typically less potent for maintaining sinus rhythm in atrial arrhythmias.
• Versus lidocaine: similar mechanism and ischemia selectivity, but mexiletine is orally bioavailable and suitable for chronic use.

Practical initiation checklist

• Confirm indication (symptomatic VT/PVCs with impact on quality of life or ICD therapies; selected LQT3) and rule out safer alternatives.
• Baseline ECG, electrolytes, hepatic function, medication review for CYP2D6/1A2 and QT/conduction interactions.
• Start low (e.g., 150 mg every 8–12 hours with food), reassess symptoms/ECG in 3–7 days, titrate in 50–100 mg increments per dose.
• Educate on expected GI/CNS effects, adherence with meals, and when to seek care (syncope, marked dizziness, visual disturbances, persistent vomiting).
• Reassess efficacy with ambulatory monitoring in 2–6 weeks; continue only if clinically meaningful benefit with acceptable tolerability.