Mexiletine

Usage

Mexiletine is prescribed for the treatment of documented life-threatening ventricular arrhythmias, such as sustained ventricular tachycardia, and symptomatic ventricular arrhythmias when symptoms are severe enough to warrant treatment. Due to its proarrhythmic potential, mexiletine should be reserved for patients where the benefits outweigh the risks. It is also used to treat myotonia in adults with non-dystrophic myotonic disorders.

Pharmacological Classification: Antiarrhythmic agent (Class IB).

Mechanism of Action: Mexiletine acts by blocking sodium channels in the heart, thereby reducing the rate of rise of the action potential and slowing conduction velocity, particularly in depolarized cardiac tissue. This action helps suppress abnormal heart rhythms.

Alternate Names

International Nonproprietary Name (INN): Mexiletine

Brand Names: Mexitil, Namuscla, PrMINT-MEXILETINE.

How It Works

Pharmacodynamics: Mexiletine’s primary effect is on the heart’s electrical conduction system. It reduces automaticity and slows conduction, particularly in ischemic or depolarized tissue. It has minimal effects on heart rate or blood pressure at therapeutic doses.

Pharmacokinetics:

• Absorption: Well-absorbed orally. Taking it with food enhances absorption.
• Metabolism: Primarily metabolized by the liver, specifically via CYP2D6. Genetic polymorphisms of CYP2D6 can significantly affect mexiletine levels.
• Elimination: Primarily eliminated by hepatic metabolism and renal excretion.

Mode of Action: Mexiletine blocks voltage-gated sodium channels in cardiac cells, reducing the influx of sodium ions and slowing the rate of depolarization. This primarily affects ischemic or rapidly depolarizing tissues.

Receptor binding, enzyme inhibition, or neurotransmitter modulation: Mexiletine primarily interacts with voltage-gated sodium channels. Limited information suggests potential modulation of certain neurotransmitters but this isn’t the primary mechanism.

Elimination pathways: Primarily hepatic metabolism (CYP2D6) and renal excretion. Dose adjustments are needed in hepatic impairment.

Dosage

Standard Dosage

Adults:

• Initial: 200 mg orally every 8 hours. A loading dose of 400 mg may be given for rapid control if necessary, followed by 200 mg every 8 hours. Administration with food or antacids is recommended.
• Maintenance: 200-300 mg orally every 8 hours. May increase to 400 mg every 8 hours; not to exceed 1200 mg/day.
• Therapeutic Range: 0.5-2 mg/L.

Children:

Safety and efficacy in children have not been fully established. However, doses of 1.4-5 mg/kg orally every 8 hours have been used in some settings. Start with a low dose and titrate cautiously, monitoring for adverse effects.

Special Cases:

• Elderly Patients: No dosage adjustment is required for older patients with normal renal function. However, close monitoring is recommended due to the increased risk of side effects with age.
• Patients with Renal Impairment: Dose adjustment is usually not necessary in mild to moderate impairment, but mexiletine should be avoided in severe renal impairment (creatinine clearance < 30 mL/min).
• Patients with Hepatic Dysfunction: Dose reduction may be necessary. Monitor closely. Avoid use in severe hepatic impairment.
• Patients with Comorbid Conditions: Caution is advised in patients with heart failure, conduction abnormalities, or other significant medical conditions.

Clinical Use Cases

Mexiletine is not typically indicated for routine use in the following settings:

• Intubation: Not specifically indicated.
• Surgical Procedures: Not routinely used.
• Mechanical Ventilation: Not specifically indicated.
• Intensive Care Unit (ICU) Use: Used only when ventricular arrhythmias pose an immediate threat.
• Emergency Situations: May be used in specific life-threatening arrhythmias if other options are unavailable, but not typically first-line.

Dosage Adjustments

Dosage adjustments may be necessary based on patient-specific factors:

• Renal/Hepatic dysfunction: Reduce dose based on the degree of impairment.
• Metabolic disorders or genetic polymorphisms: Particularly CYP2D6 status, may require dosage adjustment.
• Drug interactions: Concomitant use of drugs that interact with mexiletine requires careful monitoring and potential dose adjustments.

Side Effects

Common Side Effects:

Nausea, vomiting, heartburn, dizziness, lightheadedness, tremors, nervousness, coordination difficulties, blurred vision.

Rare but Serious Side Effects:

Severe allergic reactions (DRESS), new or worsening arrhythmias, liver damage (jaundice, abdominal pain), blood dyscrasias (leukopenia, agranulocytosis, thrombocytopenia).

Long-Term Effects:

Chronic complications from prolonged use are rare but may include hepatic dysfunction or blood disorders.

Adverse Drug Reactions (ADR):

DRESS syndrome, hepatic injury, agranulocytosis, thrombocytopenia.

Contraindications

• Hypersensitivity to mexiletine or other amide-type local anesthetics.
• Cardiogenic shock.
• Second or third-degree atrioventricular block (AV block) without a pacemaker.

Drug Interactions

Mexiletine interacts with numerous medications:

• CYP450 Interactions: CYP2D6 inhibitors (fluoxetine, paroxetine) can increase mexiletine levels. CYP inducers (phenytoin, rifampin) can decrease mexiletine levels.
• Commonly prescribed medications: Interactions with some antibiotics, anticoagulants, and other antiarrhythmics.
• OTC drugs and supplements: Some antacids can affect absorption.
• Food and lifestyle factors: Alcohol can worsen some side effects.

Pregnancy and Breastfeeding

Limited data available. Potential fetal risks exist although considered low. Mexiletine is excreted in breast milk. Weigh the risks and benefits carefully. The American Academy of Pediatrics considers mexiletine compatible with breastfeeding, but monitoring is essential.

Drug Profile Summary

• Mechanism of Action: Sodium channel blocker (Class IB antiarrhythmic).
• Side Effects: Nausea, vomiting, dizziness, tremors, CNS effects. Rarely: DRESS, hepatic injury, blood disorders.
• Contraindications: Hypersensitivity, cardiogenic shock, 2nd/3rd degree AV block without pacemaker.
• Drug Interactions: Numerous drug interactions, including CYP2D6 inhibitors and inducers.
• Pregnancy & Breastfeeding: Use with caution if benefits outweigh risks. Excreted in breast milk.
• Dosage: Adults: 200-400 mg every 8 hours. Children: 1.4-5 mg/kg every 8 hours. Adjust for hepatic impairment.
• Monitoring Parameters: ECG, liver function tests, blood counts.

Popular Combinations

No commonly recommended fixed combinations exist. Mexiletine is typically used as monotherapy or in combination with other antiarrhythmics based on specific clinical needs.

Precautions

• General Precautions: Screen for allergies, cardiac and hepatic dysfunction, drug interactions. Close monitoring of ECG and liver function.
• Specific Populations: See “Dosage - Special Cases.”
• Lifestyle Considerations: Alcohol may worsen side effects. Advise patients against activities requiring alertness until effects are known.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Mexiletine?

A: Adults: Initially 200mg every 8 hours, potentially increasing to 400 mg every 8 hours, not exceeding 1200 mg/day. Children: 1.4-5 mg/kg every 8 hours, titrated based on response and serum levels. Dose adjustment is necessary in hepatic impairment and for CYP2D6 poor metabolizers.

Q2: What are the common side effects of Mexiletine?

A: Common side effects include gastrointestinal issues (nausea, vomiting, heartburn), dizziness, lightheadedness, tremors, and nervousness.

Q3: What are the serious side effects of Mexiletine?

A: Serious, though less common, side effects include liver injury, blood disorders, and serious allergic reactions (like DRESS syndrome).

Q4: Can Mexiletine worsen arrhythmias?

A: Yes, mexiletine carries a proarrhythmic risk, especially in patients with pre-existing conduction abnormalities.

Q5: What are the contraindications to Mexiletine use?

A: Contraindications include cardiogenic shock, 2nd or 3rd degree heart block without a pacemaker, and hypersensitivity to mexiletine or amide-type local anesthetics.

Q6: How is Mexiletine metabolized?

A: Primarily metabolized by the liver, specifically via CYP2D6.

Q7: Does Mexiletine interact with other medications?

A: Yes, mexiletine has numerous drug interactions. It is crucial to review concomitant medications, including OTC drugs and supplements.

Q8: Can Mexiletine be used during pregnancy and breastfeeding?

A: Use cautiously during pregnancy and breastfeeding, weighing the potential benefits against the possible fetal or neonatal risks. Limited data are available, but some studies suggest its use may be compatible with breastfeeding, and the American Academy of Pediatrics supports this view if essential for maternal health. However, close monitoring and appropriate counselling remain crucial.

Q9: When should Mexiletine be avoided in patients with renal or hepatic impairment?

A: Dose adjustment is essential in hepatic impairment. It should be avoided in severe hepatic dysfunction and severe renal impairment (creatinine clearance < 30 mL/min).

Q10: What monitoring parameters should be considered for patients on Mexiletine?

A: Essential monitoring includes ECG, blood pressure, and routine laboratory tests (including liver function tests and blood counts).