Mexiletine

Mexiletine is a Class IB antiarrhythmic agent and an orally active congener of lidocaine, modified to reduce first-pass hepatic metabolism and allow chronic oral dosing.

Mechanism of Action

Mexiletine works by blocking fast (rapid) sodium channels (INa):

Depresses the maximal rate of phase 0 depolarization (V~~max~~), especially at faster heart rates (use-dependent block)
Shortens the action potential duration (APD) and effective refractory period (ERP) of Purkinje fibers, and to a lesser extent ventricular muscle
Suppresses automaticity of Purkinje fibers but does not affect the normal sinus node
Has rapid onset and offset kinetics (like lidocaine)
Does not significantly affect AV nodal conduction; may depress His-Purkinje conduction if it was already abnormal
Does not affect the QT interval in most patients (unlike Class IA agents)
Has no major hemodynamic effects on ventricular contractile performance or peripheral resistance

Katzung's Basic and Clinical Pharmacology, 16th Ed.

Pharmacokinetics

Parameter	Value
Bioavailability	Rapidly and almost completely absorbed orally
Time to peak	2-4 hours
Protein binding	~70%
Half-life	8-20 hours (healthy); ~17 hours post-MI
Metabolism	Primarily hepatic; <10% excreted unchanged in urine
Metabolites	No significant electrophysiologic activity

Absorption is delayed/incomplete with narcotics or antacids
Doses should be reduced in cirrhosis or left ventricular failure
Metabolism is induced by: phenytoin, phenobarbital, rifampin
Metabolism is reduced by: cimetidine

Braunwald's Heart Disease, A Textbook of Cardiovascular Medicine

Indications

Ventricular arrhythmias (FDA-approved) - acute and chronic ventricular tachyarrhythmias (NOT supraventricular tachycardias)
Long QT syndrome type 3 (LQT3) - corrects the aberrant late inward Na+ current caused by SCN5A gene mutations; shortens QTc and reduces arrhythmic burden in these patients
Myotonia - used in neuromuscular diseases such as myotonic dystrophy
Chronic neuropathic pain (off-label) - diabetic neuropathy and nerve injury, at 450-750 mg/d orally
Erythromelalgia in children

Combinations with quinidine, sotalol, beta-blockers, amiodarone, or procainamide may increase efficacy while reducing adverse effects when monotherapy fails.

Goodman & Gilman's Pharmacological Basis of Therapeutics; Katzung; Braunwald's Heart Disease

Dosing

Starting dose: 200 mg orally every 8 hours (when rapid control not needed)
Usual range: 600-1200 mg/day in divided doses
Maximum: 1200 mg/day total
Dose adjustments: increase or decrease by 50-100 mg every 2-3 days
Give with food to improve tolerability
Some patients can be dosed every 12 hours

Braunwald's Heart Disease

Adverse Effects

Up to 40% of patients require dose change or discontinuation due to adverse effects. Most are dose-related.

Neurologic (predominant):

Tremor
Dysarthria
Dizziness
Paresthesia
Diplopia, nystagmus
Blurred vision, lethargy
Confusion

Gastrointestinal:

Nausea, vomiting, dyspepsia (minimized by taking with food)

Cardiovascular (rare):

Hypotension
Bradycardia
Arrhythmia exacerbation

Note: Toxic effects can occur at plasma concentrations that are only slightly above therapeutic levels, requiring careful titration. Avoid concurrent lidocaine use.

Special Considerations

Can cause severe bradycardia and abnormal sinus node recovery in patients with underlying sinus node disease
Use with caution (or with backup pacing) in patients with myotonic dystrophy, as the underlying conduction disease can predispose to life-threatening bradycardia
In long-QT patients, mexiletine may be safer than Class IA agents (quinidine, etc.) that prolong QT further
Children with congenital heart disease and serious ventricular arrhythmias may benefit particularly

Therapeutic Range

Plasma concentrations of 0.5-2 mcg/mL are maintained by oral doses of 200-300 mg every 6-8 hours.

Braunwald's Heart Disease; Katzung's Basic and Clinical Pharmacology

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