Mechanism of Action of Mexiletine
Mexiletine is a Class IB antiarrhythmic agent that functions primarily by blocking fast sodium channels, reducing the phase 0 maximal upstroke velocity of the action potential, similar to lidocaine but orally active. 1, 2
Primary Mechanism
- Mexiletine inhibits the inward sodium current, thus reducing the rate of rise of the action potential (Phase 0) 1
- It decreases the effective refractory period (ERP) in Purkinje fibers, with the decrease in ERP being of lesser magnitude than the decrease in action potential duration (APD), resulting in an increase in the ERP/APD ratio 1
- The drug demonstrates marked rate-dependent sodium channel blockade, which explains its efficacy against ventricular tachyarrhythmias while having minimal effect on normal conduction 3
Electrophysiological Effects
- Unlike Class IA antiarrhythmics (quinidine, procainamide, disopyramide), mexiletine does not prolong ventricular depolarization (QRS duration) or repolarization (QT intervals) 1, 4
- In patients with normal conduction systems, mexiletine has minimal effect on cardiac impulse generation and propagation 1
- The drug shortens action potential duration while increasing the ratio of effective refractory period to action potential duration 5, 4
- Mexiletine has little effect on sinus node function and AV nodal and His-Purkinje system conduction in patients with normal conduction 2
Hemodynamic Effects
- Mexiletine produces small, usually not statistically significant decreases in cardiac output and increases in systemic vascular resistance 1
- It has minimal negative inotropic effect compared to other antiarrhythmics like procainamide or disopyramide 2
- Blood pressure and pulse rate remain essentially unchanged with mexiletine administration 1
- The drug can be administered without causing adverse hemodynamic effects to patients with complicating factors such as acute myocardial infarction or congestive heart failure 4
Pharmacokinetics
- Mexiletine is well absorbed (~90%) from the gastrointestinal tract with low first-pass metabolism 1
- Peak blood levels are reached in two to three hours after oral administration 1
- The plasma elimination half-life is approximately 10-12 hours in normal subjects 1, 3
- It is 50-60% bound to plasma protein, with a volume of distribution of 5-7 liters/kg 1
- Mexiletine is mainly metabolized in the liver, primarily through CYP2D6 metabolism, although it is also a substrate for CYP1A2 1
Clinical Applications
- Mexiletine is effective in suppressing ventricular arrhythmias, including those induced by glycoside toxicity and coronary artery ligation 1
- As monotherapy, mexiletine successfully suppresses 60-80% of spontaneous ventricular arrhythmias but has lower efficacy (approximately 20%) in suppression of induced ventricular tachycardia 2
- When used in combination with a Class IA antiarrhythmic drug, mexiletine shows greater efficacy for suppression of induced ventricular arrhythmias 2
- The drug may be useful in the treatment of ventricular arrhythmias associated with a prolonged QT interval due to its lack of QT prolongation effects 1
Adverse Effects
- Common side effects include neurological symptoms (tremor, dizziness, memory loss) in approximately 10% of patients and gastrointestinal effects (nausea, anorexia, gastric irritation) in up to 40% of patients 2
- Mexiletine can cause heat intolerance due to its effects on sodium channels involved in thermoregulation 6
- Proarrhythmia or other serious toxicity from mexiletine is uncommon compared to other antiarrhythmic agents 2, 4
- In patients with preexisting conduction defects, mexiletine may cause depression of the sinus rate, prolongation of sinus node recovery time, decreased conduction velocity, and increased effective refractory period 1
Mexiletine's unique profile as a Class IB antiarrhythmic with minimal hemodynamic effects and QT prolongation makes it particularly valuable in specific clinical scenarios, though its side effect profile must be carefully considered when selecting it for treatment.