mexiletine (Mexitil)

Introduction

Tradename: Mexitil. Class Ib antiarrhythmic agent.

Indications

• ventricular arrhythmias
  • alone or in combination with class Ia agent
• not effective in treatment of supraventricular arrhythmias
• not proven effective in preventing recurrence of sustained life-threatening ventricular arrhythmias
• treatment of diabetic neuropathy

Contraindications

• cardiogenic shock
• 2nd or 3rd degree heart block

Caution:

• patients with pre-existing sinus node dysfunction
• coronary artery disease
• acute myocardial infarction

pregnancy category = c

safety in lactation = ?

Dosage

• loading dose 400 mg
• 200-300 mg PO every 8 hours; max 1200 mg/day
• neuropathic pain: 140 mg PO TID; max 450 mg/day

Tabs: 150, 200, 250 mg.

Pharmacokinetics

• oral bioavailability is 87%
• minimal 1st pass metabolism
• onset of action: 30 min to 2 hours
• peak occurs 2-3 hours post-dose
• 63% of the drug is bound to plasma proteins
• clearance
  • variable
  • decreases with CHF & hepatic disease
• metabolized in the liver by cyt P450 2D6
• 20% excreted unchanged in the urine

elimination via liver

elimination via kidney

1/2life = 10.1-10.7 hours

protein binding = 60-66 %

Monitor

• serum mexiletine if potential drug interactions:
  • phenytoin, rifampin, phenobarbital, cimetidine ...

Adverse effects

• common (> 10%)
  • lightheadedness, dizziness, nervousness, trembling, unsteady gait
• less common (1-10%)
  • chest pain, premature ventricular contractions (PVC), shortness of breath, blurred vision, confusion, constipation, diarrhea, headache, numbness of fingers or toes, tinnitus, rash, insomnia, weakness, increased liver function tests
• uncommon (< 1%)
  • leukopenia, agranulocytosis, thrombocytopenia, positive antinuclear antibody (ANA), diplopia
• central nervous system
  • dizziness
  • fine tremor
  • blurred vision
  • dysarthria
  • diplopia
  • nystagmus
  • gait disturbance
  • impaired consciousness
• gastrointestinal
  • nausea & vomiting
  • may be reduced by administering mexiletine with food
• cardiac
  • torsades de pointes is less common with class Ib antiarrhythmic agents than with class Ia & III agents
  • may aggravate underlying ventricular arrhythmias or conduction disturbances
• other
  • paresthesias
  • anorexia Cautions:
• the margin between therapeutic & toxic levels is small
• a minimum of 2-3 days between dose adjustments is recommended
• hepatic dysfunction & myocardial infarction may prolong 1/2life

Drug interactions

• phenytoin, rifampin & cigarette smoking increase mexiletine metabolism
• interactions with lidocaine
• mexiletine can increase theophylline levels
• drugs that effect urine pH
  • alkaline urine may decrease mexiletine clearance
  • acidic urine may increase mexiletine clearance
• metoclopramide may increase rate of mexiletine absorption
• cimetidine may slow absorption of mexiletine
• mexiletine may increase plasma digoxin concentration
• any pharmaceutical agent that inhibits cyt P450 2D6 may increase mexiletine levels
• mexiletine inhibits cyt P450 1A2
  • may increase levels of drugs metabolized by cyt P450 1A2

• drug interaction(s) of antiarrhythmic agents in combination with diuretics

Laboratory

• mexiletine in serum/plasma:
  • specimen
    • serum, plasma (EDTA, heparin)
    • stable for 10 months at -25 degrees C
  • methods: GLC, HPLC
  • therapeutic range: 0.5-2 ug/mL
• other labs with Loincs
  • mexiletine in specimen
    • mexiletine in body fluid
      • mexiletine in gastric fluid
      • mexiletine in urine

Mechanism of action

• similar to lidocaine
• class 1B antiarrhythmic
• inhibits Na+ channels decreasing rate of rise of action potential
• negative inotrope

More general terms

• antiarrhythmic agent, Group IB

Additional terms

• cytochrome p450 1A2 (cytochrome P3-450, phenacetin deethylase, cytochrome p450-4, CYP1A2)
• cytochrome P450 2D6 (cytochrome P450 2D, cytochrome P450 DB1, debrisoquine-4-hydroxylase, CYP2D6)

Database

• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=4178
• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=21467