Mixilatine
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Mexiletine is a Class IB antiarrhythmic drug used to treat ventricular arrhythmias. It works by blocking fast sodium channels, shortening the action potential duration. It is structurally similar to lidocaine but is orally active.
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mexiletine antiarrhythmic drug mechanism uses dosing
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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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