Mexiletine clinical pharmacology

Mexiletine
MEXILETINE HYDROCHLORIDE® FDA Package Insert
Indications and Usage
Dosage and Administration
Contraindications
Warnings and Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Overdosage
Description
Clinical Pharmacology
How Supplied/Storage and Handling
Labels and Packages
Clinical Trials on Mexiletine
ClinicalTrials.gov

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2]

Clinical Pharmacology

Mechanism of Action

Mexiletine hydrochloride is a local anesthetic, antiarrhythmic agent, structurally similar to lidocaine, but orally active. In animal studies, mexiletine has been shown to be effective in the suppres

sion of induced ventricular arrhythmias, including those induced by glycoside toxicity and coronary artery ligation. Mexiletine, like lidocaine, inhibits the inward sodium current, thus reducing the rate of rise of the action potential, Phase 0. Mexiletine decreased the effective refractory period (ERP) in Purkinje fibers. The decrease in ERP was of lesser magnitude than the decrease in action potential duration (APD), with a resulting increase in the ERP/APD ratio.

Electrophysiology in Man

Mexiletine is a Class 1B antiarrhythmic compound with electrophysiologic properties in man similar to those of lidocaine, but dissimilar from quinidine, procainamide, and disopyramide.

In patients with normal conduction systems, mexiletine has a minimal effect on cardiac impulse generation and propagation. In clinical trials, no development of second-degree or third degree AV block was observed. Mexiletine did not prolong ventricular depolarization (QRS duration) or repolarization (QT intervals) as measured by electrocardiography. Theoretically, therefore, mexiletine may be useful in the treatment of ventricular arrhythmias associated with a prolonged QT interval.

In patients with preexisting conduction defects, depression of the sinus rate, prolongation of sinus node recovery time, decreased conduction velocity and increased effective refractory period of the intraventricular conduction system have occasionally been observed.

The antiarrhythmic effect of mexiletine has been established in controlled comparative trials against placebo, quinidine, procainamide and disopyramide. Mexiletine hydrochloride, at doses of 200 to 400 mg q8h, produced a significant reduction of ventricular premature beats, paired beats, and episodes of non-sustained ventricular tachycardia compared to placebo and was similar in effectiveness to the active agents. Among all patients entered into the studies, about 30% in each treatment group had a 70% or greater reduction in PVC count and about 40% failed to complete the 3 month studies because of adverse effects. Follow-up of patients from the controlled trials has demonstrated continued effectiveness of mexiletine in long-term use.

Hemodynamics

Hemodynamic studies in a limited number of patients, with normal or abnormal myocardial function, following oral administration of mexiletine hydrochloride, have shown small, usually not statistically significant, decreases in cardiac output and increases in systemic vascular resistance, but no significant negative inotropic effect. Blood pressure and pulse rate remain essentially unchanged. Mild depression of myocardial function, similar to that produced by lidocaine, has occasionally been observed following intravenous mexiletine therapy in patients with cardiac disease.

Pharmacokinetics

Mexiletine is well absorbed (~90%) from the gastrointestinal tract. Unlike lidocaine, its first-pass metabolism is low. Peak blood levels are reached in two to three hours. In normal subjects, the plasma elimination half-life of mexiletine is approximately 10 to 12 hours. It is 50 to 60% bound to plasma protein, with a volume of distribution of 5 to 7 liters/kg. Mexiletine is mainly metabolized in the liver, the primary pathway being CYP2D6 metabolism, although it is also a substrate for CYP1A2. With involvement of CYP2D6, there can be either poor or extensive metabolizer phenotypes. Since approximately 90% of mexiletine hydrochloride is metabolized in the liver into inactive metabolites, pathological changes in the liver can restrict hepatic clearance of mexiletine hydrochloride and its metabolites. The metabolic degradation proceeds via various pathways including aromatic and aliphatic hydroxylation, dealkylation, deamination and N-oxidation. Several of the resulting metabolites are submitted to further conjugation with glucuronic acid (phase II metabolism); among these are the major metabolites p-hydroxymexiletine, hydroxy-methylmexiletine and N-hydroxy-mexiletine. Approximately 10% is excreted unchanged by the kidney. While urinary pH does not normally have much influence on elimination, marked changes in urinary pH influence the rate of excretion: acidification accelerates excretion, while alkalinization retards it.

Several metabolites of mexiletine have shown minimal antiarrhythmics activity in animal models. The most active is the minor metabolite N-methylmexiletine, which is less than 20% as potent as mexiletine. The urinary excretion of N-methylmexiletine in man is less than 0.5%. Thus the therapeutic activity of mexiletine is due to the parent compound.

Hepatic impairment prolongs the elimination half-life of mexiletine. In eight patients with moderate to severe liver disease, the mean half-life was approximately 25 hours.

Consistent with the limited renal elimination of mexiletine, little change in the half-life has been detected in patients with reduced renal function. In eight patients with creatinine clearance less than 10 mL/min, the mean plasma elimination half-life was 15.7 hours; in seven patients with creatinine clearance between 11 to 40 mL/min, the mean half-life was 13.4 hours.

The absorption rate of mexiletine is reduced in clinical situations such as acute myocardial infarction in which gastric emptying time is increased. Narcotics, atropine and magnesium-aluminum hydroxide have also been reported to slow the absorption of mexiletine. Metoclopramide has been reported to accelerate absorption.

Mexiletine plasma levels of at least 0.5 mcg/mL are generally required for therapeutic response. An increase in the frequency of central nervous system adverse effects has been observed when plasma levels exceed 2.0 mcg/mL. Thus the therapeutic range is approximately 0.5 to 2.0 mcg/mL. Plasma levels within the therapeutic range can be attained with either three times daily or twice daily dosing but peak to trough differences are greater with the latter regimen, creating the possibility of adverse effects at peak and arrhythmic escape at trough. Nevertheless, some patients may be transferred successfully to the twice daily regimen. (See DOSAGE AND ADMINISTRATION.)