Brands, Medical Use, Clinical Data
Drug Category
Dosage Forms
- Capsule (150 mg, 200 mg and 250 mg)
Brands / Synonyms
Mexiletina [INN-Spanish]; Mexiletine HCL; Mexiletinum [INN-Latin]; Mexilitine; Mexitil; Mexitil
Indications
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. 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
Absorption
Well absorbed (bioavailability 90%) from the gastrointenstinal tract.
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.
Biotrnasformation / Drug Metabolism
Primarily hepatic (85%) via CYP2D6 and CYP1A2 (primarily CYP2D6).
Contraindications
Mexitil® (mexiletine hydrochloride, USP) is contraindicated in the presence of cardiogenic shock or
pre-existing second- or third-degree AV block (if no pacemaker is present).
Drug Interactions
Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or
induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal,
single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the
coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor
metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6
metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by
about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study,
the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine.
Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc,
RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with
mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect.
In a large compassionate use program Mexitil® has been used concurrently with commonly employed
antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics
such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When
phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with
Mexitil®, lowered Mexitil® plasma levels have been reported. Monitoring of
Mexitil® plasma levels is recommended during such concurrent use to avoid ineffective therapy.
In a formal study, benzodiazepines were shown not to affect Mexitil® plasma concentrations. ECG
intervals (PR, QRS, and QT) were not affected by concurrent Mexitil® and digoxin, diuretics, or
propranolol.
Concurrent administration of cimetidine and Mexitil® has been reported to increase, decrease, or
leave unchanged Mexitil® plasma levels; therefore patients should be followed carefully during
concurrent therapy.
Mexitil® does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat
gastrointestinal symptoms due to Mexitil®, has been reported to lower serum digoxin levels.
Concurrent use of Mexitil® and theophylline may lead to increased plasma theophylline levels. One
controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels.
This increase was observed at the first test point which was the second day after starting Mexitil®.
Theophylline plasma levels returned to pre-Mexitil® values within 48 hours after discontinuing
Mexitil®. If Mexitil and theophylline are to be used concurrently, theophylline blood levels should be
monitored, particularly when the Mexitil® dose is changed. An appropriate adjustment in theophylline
dose should be considered.
Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was
decreased 50% following the administration of Mexitil®.
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