What is the mechanism of action of Mexiletine in treating Premature Ventricular Contractions (PVCs)?

Mechanism of Action of Mexiletine in Treating PVCs

Mexiletine suppresses PVCs by blocking fast sodium channels in cardiac myocytes, which reduces the rate of rise of the action potential (Phase 0) and increases the ratio of effective refractory period to action potential duration, thereby stabilizing the myocardial membrane and preventing ectopic ventricular activity. 1

Electrophysiologic Properties

Mexiletine is a Class IB antiarrhythmic agent structurally similar to lidocaine but orally active, with distinct electrophysiologic effects that make it particularly suited for ventricular arrhythmias 1, 2:

• Blocks inward sodium current during Phase 0 of the action potential, reducing the maximal upstroke velocity 1
• Decreases the effective refractory period (ERP) in Purkinje fibers, but the decrease in action potential duration (APD) is even greater, resulting in an increased ERP/APD ratio 1
• Does not prolong QRS or QT intervals, unlike Class IA agents (quinidine, procainamide), making it theoretically useful for arrhythmias associated with prolonged QT 1, 2
• Minimal effect on cardiac impulse generation and propagation in patients with normal conduction systems 1

Specific Anti-PVC Effects

The mechanism translates to clinical PVC suppression through several pathways 2:

• Stabilizes myocardial membranes by reducing Phase 0 upstroke velocity, which prevents the rapid depolarization needed for ectopic PVC generation 1
• Increases the threshold for ectopic firing by altering the relationship between refractory period and action potential duration 1
• Suppresses automaticity in Purkinje fibers and ventricular myocardium where PVCs commonly originate 2

Clinical Efficacy Data

Mexiletine at doses of 200-400 mg every 8 hours produces significant PVC reduction 1:

• Achieves 50% or greater PVC reduction in 25-79% of patients with or without underlying cardiac disease 2
• In controlled trials, approximately 30% of patients achieved 70% or greater reduction in PVC count, comparable to quinidine, procainamide, and disopyramide 1
• Effective dose is typically 600 mg daily (200 mg every 8 hours) in responders 3

Important Hemodynamic Considerations

A critical advantage of mexiletine's mechanism is its minimal negative inotropic effect 1, 2:

• Produces only small, usually non-significant decreases in cardiac output and increases in systemic vascular resistance 1
• Blood pressure and pulse rate remain essentially unchanged 1
• Can be safely administered to patients with acute myocardial infarction or congestive heart failure without adverse hemodynamic effects 2

Comparison to Other Antiarrhythmics

Unlike Class IA agents, mexiletine's mechanism offers distinct advantages 2:

• No QT prolongation, reducing risk of torsades de pointes
• Low proarrhythmic potential compared to other sodium channel blockers 2
• Similar efficacy to quinidine (69% vs 70% PVC reduction) but with different side effect profile 4

Clinical Caveats

Despite its mechanism of action, important limitations exist 5:

• Class I antiarrhythmic medications are generally avoided for PVC suppression due to concerns for adverse effects, with beta blockers or calcium channel blockers preferred as first-line therapy 5
• The 2017 ACC/AHA/HRS guidelines note that while Class I agents "can be effective," they are typically reserved for cases where first-line agents fail 5
• Primary metabolism via CYP2D6 (with CYP1A2 as secondary pathway) creates potential for drug interactions 1

Practical Application

When mexiletine is used for PVC suppression 3, 6:

• Start at 600 mg daily (200 mg every 8 hours) as this dose is effective in the majority of responders 3
• Peak blood levels occur in 2-3 hours with plasma elimination half-life of 10-12 hours 1
• Therapeutic response typically seen within 3 weeks of consistent dosing 3
• Most common side effects are gastrointestinal and CNS effects, which can be managed through dosage adjustment 2, 6