Mexicetine drug moa
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mexiletine mechanism of action sodium channel antiarrhythmic Class IB
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Here is a complete, textbook-sourced breakdown of mexiletine's mechanism of action:
Mexiletine - Mechanism of Action
Drug Class
Mexiletine is a Class IB antiarrhythmic agent - a local anesthetic congener of lidocaine with anticonvulsant properties, used for the oral treatment of ventricular arrhythmias.
Core Mechanism: Sodium Channel Blockade
Mexiletine's primary MOA is blocking fast voltage-gated sodium channels (I_Na):
- It inhibits the inward sodium current required for initiation and conduction of cardiac impulses
- It depresses V_max (maximum rate of rise) of phase 0 of the action potential - this is the fast depolarization phase driven by Na+ influx
- Like lidocaine, it preferentially binds inactivated sodium channels (i.e., it is more effective at faster heart rates and in depolarized/ischemic tissue) - this is termed use-dependent (frequency-dependent) block
- Its onset and offset kinetics are rapid (a key feature distinguishing Class IB from IC agents)
Electrophysiologic Effects
| Parameter | Effect |
|---|---|
| Action potential duration (APD) | Shortened - in Purkinje fibers and ventricular muscle |
| Effective refractory period (ERP) | Shortened - primarily in Purkinje fibers |
| Phase 0 V_max | Depressed (I_Na block) |
| Automaticity | Suppressed in Purkinje fibers (not in normal sinus node) |
| AV nodal conduction | Not affected |
| His-Purkinje conduction | Mildly depressed (mainly if already abnormal) |
| QT interval | Not prolonged (unlike Class IA agents); may actually shorten it |
| Atrial muscle | Not significantly affected |
Effect on Ischemic/Hypoxic Tissue
Hypoxia and ischemia potentiate mexiletine's effects - it preferentially affects depolarized tissue, making it particularly useful post-MI when ventricular ectopy arises from partially depolarized, ischemic Purkinje fibers.
Hemodynamic Profile
Mexiletine exerts no major hemodynamic effects on ventricular contractile performance or peripheral resistance - an advantage over many other antiarrhythmics.
Additional MOA: LQT3 / Sodium Channel Gain-of-Function
In Long QT syndrome type 3 (LQT3), a gain-of-function mutation in SCN5A causes persistent (late) inward Na+ current. Mexiletine blocks this late I_Na, shortening QTc by approximately 30-40 ms in LQT3 patients - making it useful as gene-specific therapy for this condition.
Pain & Myotonia MOA
Mexiletine also blocks skeletal muscle sodium channels (Nav1.4), reducing membrane hyperexcitability. This underlies its off-label use in:
- Myotonia (muscle stiffness from prolonged muscle fiber depolarization)
- Neuropathic pain (e.g., diabetic neuropathy) - by dampening ectopic sodium channel activity in injured nerves
Comparison with Class IB Siblings
| Feature | Mexiletine | Lidocaine | Phenytoin |
|---|---|---|---|
| Route | Oral | IV only | Oral/IV |
| Use | Chronic ventricular arrhythmias | Acute ventricular arrhythmias | Digitalis-induced arrhythmias |
| QT effect | Neutral/shorten | Neutral | Neutral |
| Kinetics | Fast onset/offset | Fast onset/offset | Fast onset/offset |
Key Clinical Points
- Indications: Ventricular tachyarrhythmias, LQT3, myotonia, neuropathic pain (off-label)
- Adverse effects: Predominantly neurologic (tremor, dizziness, blurred vision, nystagmus, dysarthria) and GI (nausea, vomiting) - up to 40% require dose adjustment
- Pharmacokinetics: Oral bioavailability near 100%, half-life ~10 hours (17 hours post-MI), therapeutic range 0.5-2 mcg/mL
- Drug interactions: Metabolism increased by phenytoin, phenobarbital, rifampin; reduced by cimetidine
Sources: Braunwald's Heart Disease (Electrophysiologic Actions section); Katzung's Basic and Clinical Pharmacology, 16th ed. (Mexiletine, Subgroup 1B)
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