Mexiletine

Mexiletine an antiarrhythmic Class 1 B agent belonging to Sodium channel blocker.

Mexiletine is a sodium channel blocker used in the treatment of ventricular tachycardia and symptomatic premature ventricular beats and prevention of ventricular fibrillation.

Mexiletine ventricular tachycardia and symptomatic premature ventricular beats, and prevention of ventricular fibrillation.

The common side effects are Dyspepsia, nausea, diarrhea, vomiting, gastroenteritis, gastritis, GERD, dysphagia, abdominal pain, constipation, abdominal distention, etc.

Mexiletine is available in the form of a dosage form such as Capsules.

Mexiletine is available in Switzerland, Europe, India, Japan, U.S.

Mexiletine, like lidocaine, inhibits the inward sodium current required for the initiation and conduction of impulses, thus reducing the rate of rising 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.

The Duration of Action of Mexiletine was within 8-10 hrs.

The Tmax was about 6-7 hr, and Cmax was about 9 h, respectively.

Mexiletine is available in the form of Capsules.

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

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

• Suppression of Ventricular Tachycardia

Dosing regimens for the use of Mexiletinesulfate in suppressing life-threatening ventricular arrhythmias have not been adequately studied. Described regimens have generally been similar to the regimen described just above for the prophylaxis of symptomatic atrial fibrillation/flutter. Where possible, therapy should be guided by the results of programmed electrical stimulation and/or Holter monitoring with exercise.

Dosing information:

Initial: 200 mg PO q8hr; may load with 400 mg followed by 200 mg PO q8hr if necessary for rapid control of ventricular arrhythmia

Dose range: 200-300 mg PO q8hr

May increase to 400 mg q8hr; not to exceed 1200 mg/day

Take with food or antacid

Therapeutic range: 0.5-2 mg/L

Although not approved there have been certain off label use documented for Mexiletine which includes:-

• Local anaesthetic

The dosage and the duration of treatment should be as per the clinical judgment of the treating physician.

Mexiletine is available in various dosage strengths of 150,200 and 250 mg.

Mexiletine is available in the form of Capsules in strength of a 150,200 and 250 mg.

Dose Adjustment in Kidney patient:

• CrCl less than 15 mL/min: Safety and efficacy have not been established.

Dose Adjustment in Hepatic Impairment Patient:

• Severe liver dysfunction (Child-Pugh C): Safety and efficacy have not been established.

Dose Adjustment in the pediatric patient:

• Safety and effectiveness in pediatric patients have not been established.

Mexiletine should be used for the treatment of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension.

Hypertension: It has been observed that the low-salt Dietary Approaches to Stop Hypertension (DASH) diet lowers blood pressure. Sometimes after a few weeks, its effects on blood pressure become noticeable.

The dietary restriction should be individualized as per the patient requirements.

Mexiletine may be contraindicated in the following

• Bradycardia,
• Palpitations,
• Angina
• Ventricular premature contractions, heart block,
• Hypotension

The treating physician must closely monitor the patient and keep pharmacovigilance as follows.

• Proarrhythmic Effects

Like many other drugs (including all other Class la antiarrhythmics), Mexiletine prolongs the QT c interval, and this can lead to torsades de pointes , a life-threatening ventricular arrhythmia . The risk of torsades is increased by bradycardia, hypokalemia, hypomagnesemia, or high serum levels of quinidine, but it may appear in the absence of any of these risk factors. The best predictor of this arrhythmia appears to be the length of the QT c interval, and Mexiletine should be used with extreme care in patients who have preexisting long-QT syndromes, who have histories of torsades de pointes of any cause, or who have previously responded to Mexiletine(or other drugs that prolong ventricular repolarization) with marked lengthening of the QT c interval. Estimation of the incidence of torsades in patients with therapeutic levels of Mexiletine is not possible from the available data, resulting ventricular rate may be very high (greater than 200 beats per minute) and poorly tolerated. This hazard may be decreased if partial atrioventricular block is achieved prior to initiation of Mexiletine therapy, using conduction-reducing drugs such as digitalis, verapamil, diltiazem, or a (beta)-receptor blocking agent.

• Exacerbated Bradycardia in Sick Sinus Syndrome

In patients with the sick sinus syndrome, Mexiletine has been associated with marked sinus node depression and bradycardia.

Vagolysis

Because Mexiletine opposes the atrial and A-V nodal effects of vagal stimulation, physical or pharmacological vagal maneuvers undertaken to terminate paroxysmal supraventricular tachycardia may be ineffective in patients receiving quinidine.

Precautions

• General

All the precautions applying to regular Mexiletine therapy apply to this product. Hypersensitivity or anaphylactoid reactions to quinidine, although rare, should be considered, especially during the first weeks of therapy. Hospitalization for close clinical observation, electrocardiographic monitoring, and determination of serum Mexiletine levels are indicated when large doses of Mexiletine are used or with patients who present an increased risk.

• Laboratory Tests

Periodic blood counts and liver and kidney function tests should be performed during long-term therapy; the drug should be discontinued if blood dyscrasias or evidence of hepatic or renal dysfunction occurs.

• Heart Block

In patients without implanted pacemakers who are at high risk of complete atrioventricular block (e.g., those with digitalis intoxication, second-degree atrioventricular block, or severe intraventricular conduction defects), Mexiletine should be used only with caution.

Alcohol consumption with Mexiletine may increase the risk of low blood pressure and cause adverse effects, such as Dizziness, fainting, light-headedness, or headache.

Mexiletine use in breastfeeding patients is not recommended.

Pregnancy Category X

Risk Summary

Mexiletine may cause fetal harm when administered to a pregnant woman and is contraindicated during pregnancy.

Mexiletine was teratogenic and embryotoxic in rats at doses with exposures to an unbound drug that were approximately 8 Times and 2 times, respectively, the human exposure. In rabbits, Mexiletine led to abortions at 4 times the human exposure and fetal toxicity with exposures approximately 13 times the human exposure. If Mexiletine is used in pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus.

Avoid smoking tobacco while taking Quinidine. Mexiletine doses higher than 2.5 mg three times a day may be considered to match exposure seen in nonsmoking patients. In patients who smoke tobacco, plasma concentrations of Mexiletine are reduced by 50% to 60% compared to nonsmokers.

Decreased serum concentration with St. John’s wort.

The adverse reactions related to molecule Mexiletine can be categorized as

• Common Adverse effects:

Hemodynamic compromise, Dizziness, peripheral ischemia, dry mouth, asthenia, and somnolence.

• Less Common adverse effects:

Asymptomatic and symptomatic hypotension, burning, crawling, itching, numbness.

• Rare adverse effects:

Bradycardia, decompensated heart failure, cardiac arrest, and heart block.

The clinically relevant drug interactions of Mexiletine is briefly summarized here.

• Decreased serum concentration with antacids, PPI, CYP3A4 inducers (e.g., phenytoin, rifampicin).
• The metabolism of Acetaminophen can be decreased when combined with Mexiletine
• Increased plasma concentration with CYP1A1 (e.g. erlotinib), CYP3A4 inhibitors (e.g., clarithromycin), potent P-GP/BCRP inhibitors (e.g. ciclosporin, azole antifungals, protease inhibitors).
• The metabolism of Acyclovir can be decreased when combined with Mexiletine
• Potentially Fatal: Enhanced hypotensive effect with amyl nitrate, nitroglycerin, PDE-5 inhibitors (e.g. sildenafil, tadalafil, vardenafil).
• The metabolism of Mexiletine can be increased when combined with Albendazole.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

No overall differences in safety or effectiveness have been observed between elderly and younger patients.

Symptoms:

Resp depression or distress, ataxia, apnoea, severe hypotension, syncope, diarrhea, vomiting, anuria, absence of P waves, PR and QT interval, and QRS complex broadening, extrasystoles, ventricular arrhythmias, heart block, heart failure, coma, irritability, lethargy, thrashing, hallucinations, twitching, paraesthesia, generalized seizures, signs of cinchonism.

Management:

Symptomatic treatment. Monitor ECG and BP. Perform gastric lavage, induce emesis, or administer activated charcoal for recent ingestion. May require artificial resp or other supportive measures.

Pharmacodynamics:

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.

Pharmacokinetics:

Absorption:

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

Distribution:

Mexiletine has a volume of distribution of 5-7 L/kg with congestive heart failure, and 3-5 L/kg in patients with liver cirrhosis

Metabolism:

Mexiletine is mainly metabolized in the liver by cytochrome P450 enzymes, specifically CYP2D6 and CYP1A2. Mexiletine has an elimination half-life of about 12 hours.

Excretion:

The elimination of Mexiletine is achieved by the renal excretion of the unchanged drug (15 to 40% of total clearance) and its hepatic biotransformation to a variety of metabolites (60 to 85% of total clearance).

1. https://go.drugbank.com/drugs/DB00379
2. https://www.ncbi.nlm.nih.gov/books/NBK519045/
3. https://reference.medscape.com/drug/mexiletine-342303
4. https://www.mayoclinic.org/diseases-conditions/ventricular-tachycardia/symptoms-causes/syc-20355138