indication

For the treatment of ventricular tachycardia and symptomatic premature ventricular beats, and prevention of ventricular fibrillation.

pharmacology

Mexiletine is a local anesthetic, antiarrhythmic agent (Class Ib), structurally similar to lidocaine, but orally active. Mexiletine has fast onset and offset kinetics, meaning that they have little or no effect at slower heart rates, and more effects at faster heart rates. It shortens the action potential duration, reduces refractoriness, and decreases Vmax in partially depolarized cells with fast response action potentials. Mexiletine either does not change the action potential duration, or decreases the action potential duration.

mechanism of action

Mexiletine, like lidocaine, inhibits the inward sodium current required for the initiation and conduction of impulses, thus reducing the rate of rise of the action potential, Phase 0. It achieves this reduced sodium current by inhibiting sodium channels. Mexiletine decreases the effective refractory period (ERP) in Purkinje fibers in the heart. The decrease in ERP is of lesser magnitude than the decrease in action potential duration (APD), which results in an increase in the ERP/APD ratio. It does not significantly affect resting membrane potential or sinus node automaticity, left ventricular function, systolic arterial blood pressure, atrioventricular (AV) conduction velocity, or QRS or QT intervals

toxicity

Symptoms of overdose include nausea, hypotension, sinus bradycardia, paresthesia, seizures, bundle branch block, AV heart block, asystole, ventricular tachyarrythmia, including ventricular fibrillation, cardiovascular collapse, and coma.

biotransformation

Primarily hepatic (85%) via CYP2D6 and CYP1A2 (primarily CYP2D6).

absorption

Well absorbed (bioavailability 90%) from the gastrointenstinal tract.

half life

10-12 hours

route of elimination

Approximately 10% is excreted unchanged by the kidney. The urinary excretion of N-methylmexiletine in man is less than 0.5%.

drug interactions

Aminophylline: Mexiletine increases the effect and toxicity of theophylline

Dyphylline: Mexiletine increases the effect and toxicity of theophylline

Ethotoin: The hydantoin decreases the effect of mexiletine

Fluvoxamine: Fluvoxamine may increase the therapeutic and adverse effects of mexiletine.

Fosphenytoin: The hydantoin decreases the effect of mexiletine

Mephenytoin: The hydantoin decreases the effect of mexiletine

Oxtriphylline: Mexiletine increases the effect and toxicity of theophylline

Phenytoin: The hydantoin decreases the effect of mexiletine

Propafenone: Propafenone may increase the effect and toxicity of mexilitine.

Ramelteon: Mexiletine increases levels/toxicity of ramelteon

Rifampin: Rifampin decreases the effect of mexiletine

Tacrine: The metabolism of Tacrine, a CYP1A2 substrate, may be reduced by strong CYP1A2 inhibitors such as Mexiletine. Consider modifying therapy to avoid Tacrine toxicity. Monitor the efficacy and toxicity of Tacrine if Mexiletine is initiated, discontinued or if the dose is changed.

Terbinafine: Terbinafine may reduce the metabolism and clearance of Mexiletine. Consider alternate therapy or monitor for therapeutic/adverse effects of Mexiletine if Terbinafine is initiated, discontinued or dose changed.

Terfenadine: Increased risk of cardiotoxicity and arrhythmias

Theophylline: Mexiletine increases the effect and toxicity of theophylline

Thiothixene: The strong CYP1A2 inhibitor, Mexiletine, may decrease the metabolism and clearance of Thiothixene, a CYP1A2 substrate. Consider alternate therapy or monitor for changes in Thiothixene therapeutic and adverse effects if Mexiletine is initiated, discontinued or dose changed.

Tizanidine: Mexilitene may decrease the metabolism and clearance of Tizanidine. Consider alternate therapy or use caution during co-administration.

Vilazodone: Monitor for increased serum concentrations/toxic effects of mexiletine if a selective serotonin reuptake inhibitor (SSRI) is initiated/dose increased, or decreased concentrations/effects if an SSRI is discontinued/dose decreased.