Mexiletine: Pharmacology and therapeutic use

Abstract

Summary:Mexiletine is a Class IB antianhythmic which has basic and clinical electrophysiologic properties similar to lidocaine. Like other Class I antiarrhythmic agents, mexiletine blocks the rapid inward sodium current responsible for phase 0 of the action potential. It has been noted in the clinical electrophysiology laboratory to have minimal effect on sinus node function and AV nodal and His-Purkinje system conduction. Pharmacokinetic studies have shown that oral absorption is rapid with bioavailability of 80-90%. Mexiletine is predominantly metabolized by the liver with elimination half-life of 9 to 12 hours.The antiarrhythmic effects of the primary drug's metabolites remain to be defined. Hernodynamic studies have shown mexiletine to have a lesser negative inotropic effect than procainamide or disopyramide. Although mexiletine as a single agent successfully suppresses 60 to 80% of spontaneous ventricular arrhythmias, it has lower efficacy in suppression of induced ventricular arrhythmias. Multiple studies have shown that as monotherapy mexiletine is effective in preventing the induction of ventricular tachycardia in approximately 20% of patients. When used in combination with a Class IA antiarrhythmic drug for suppression of induced ventricular arrhythmias, multiple investigators have reported greater efficacy. Neurological side effects (tremor, dizziness, memory loss) occur in approximately 10% of patients while gastrointestinal side effects (nausea, anorexia, gastric irritation) occur in up to 40% of patients. Proarrhythmia or other serious toxicity from the drug is uncommon.

Intravenous Lidocaine and Mexiletine in the Management of Trigeminal Autonomic Cephalalgias

“…Mexiletine interacts with lidocaine by displacing lidocaine from binding sites, increasing levels and toxicity [20]. Metabolites of mexiletine have minimal antiarrhythmic activity [15]. As a local anesthetic, mexiletine is a more potent analgesic than lidocaine [21], but it is not commercially available as a topical agent.…”

“…No class of antiarrhythmic drugs has been proven to reduce mortality in atrial fibrillation [13], and class 1B agents should be reserved for severe, life-threatening arrhythmias [14]. Antiarrhythmic agents can also have proarrhythmic effects leading to ventricular arrhythmias that may be fatal, although they are relatively uncommon with class 1B drugs [15].…”

Stereoselective synthesis of mexiletine and structural analogs with chiral tert-butanesulfinamide

“…1 Antiarrhythmic effects of mexiletine have been associated with its inhibition of Na + channel currents to shorten action potential durations in cardiomyocytes. 1 Clinically, mexiletine is administered as a racemate.…”

“…1 Antiarrhythmic effects of mexiletine have been associated with its inhibition of Na + channel currents to shorten action potential durations in cardiomyocytes. 1 Clinically, mexiletine is administered as a racemate. 2 However, (R)-mexiletine has been shown to be more potent than (S)-mexiletine in vitro 3 and more efficacious in preclinical models.…”

High-performance liquid chromatography for analytical and small-scale preparative separation of (R,S)-mexiletine using (S)-(—)-(N)-trifluoroacetyl-prolyl chloride and (1S)-(—)-camphanic chloride and recovery of native enantiomer by detagging

“…1) is a Class IB antiarrhythmic, antimyotonic, and analgesic agent in its racemic form [1] and used in the treatment of ventricular arrhythmia [2]. The enantiomers of (R, S)-MEX have different pharmacokinetic, pharmacodynamic, and receptor binding properties [3,4].…”