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mexiletine (Mexitil)

Tradename: Mexitil. Class Ib antiarrhythmic agent. Indications: 1) ventricular arrhythmias - alone or in combination with class Ia agent 2) not effective in treatment of supraventricular arrhythmias 3) not proven effective in preventing recurrence of sustained life-threatening ventricular arrhythmias 4) treatment of diabetic neuropathy Contraindications: 1) cardiogenic shock 2) 2nd or 3rd degree heart block Caution: 1) patients with pre-existing sinus node dysfunction 2) coronary artery disease 3) acute myocardial infarction Dosage: 1) loading dose 400 mg 2) 200-300 mg PO every 8 hours; max 1200 mg/day 3) neuropathic pain: 140 mg PO TID; max 450 mg/day Tabs: 150, 200, 250 mg. Pharmacokinetics: 1) oral bioavailability is 87% 2) minimal 1st pass metabolism 3) onset of action: 30 min to 2 hours 4) peak occurs 2-3 hours post-dose [8] 5) 63% of the drug is bound to plasma proteins 6) clearance a) variable b) decreases with CHF & hepatic disease 7) metabolized in the liver by cyt P450 2D6 8) 20% excreted unchanged in the urine Monitor: - serum mexiletine if potential drug interactions: [8] - phenytoin, rifampin, phenobarbital, cimetidine ... Adverse effects: 1) common (> 10%) - lightheadedness, dizziness, nervousness, trembling, unsteady gait 2) 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 3) uncommon (< 1%) - leukopenia, agranulocytosis, thrombocytopenia, positive antinuclear antibody (ANA), diplopia 4) central nervous system - dizziness - fine tremor - blurred vision - dysarthria - diplopia - nystagmus - gait disturbance - impaired consciousness 5) gastrointestinal - nausea & vomiting - may be reduced by administering mexiletine with food 6) 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 7) other [4] - paresthesias - anorexia Cautions: 1) the margin between therapeutic & toxic levels is small 2) a minimum of 2-3 days between dose adjustments is recommended 3) hepatic dysfunction & myocardial infarction may prolong 1/2life Drug interactions: 1) phenytoin, rifampin & cigarette smoking increase mexiletine metabolism 2) interactions with lidocaine 3) mexiletine can increase theophylline levels 4) drugs that effect urine pH a) alkaline urine may decrease mexiletine clearance b) acidic urine may increase mexiletine clearance 5) metoclopramide may increase rate of mexiletine absorption 6) cimetidine may slow absorption of mexiletine 7) mexiletine may increase plasma digoxin concentration 8) any pharmaceutical agent that inhibits cyt P450 2D6 may increase mexiletine levels 9) mexiletine inhibits cyt P450 1A2 -> may increase levels of drugs metabolized by cyt P450 1A2 Laboratory: 1) mexiletine in serum/plasma: a) specimen - serum, plasma (EDTA, heparin) - stable for 10 months at -25 degrees C b) methods: GLC, HPLC c) therapeutic range: 0.5-2 ug/mL [8] 2) other labs with Loincs - mexiletine in specimen - mexiletine in body fluid - mexiletine in gastric fluid - mexiletine in urine Mechanism of action: 1) similar to lidocaine 2) class 1B antiarrhythmic 3) inhibits Na+ channels decreasing rate of rise of action potential 4) negative inotrope

Interactions

drug interactions

Related

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)

General

antiarrhythmic agent, Group IB

Properties

MISC-INFO: elimination route LIVER 85-95% KIDNEY 10-15% 1/2life 10.1-10.7 HOURS therapeutic-range 0.7-2.0 UG/ML toxic-range >2 UG/ML protein-binding 60-66% pregnancy-category C safety in lactation ?

Database Correlations

PUBCHEM correlations

References

  1. The Pharmacological Basis of Therapeutics, 9th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1996
  2. Harrison's Principles of Internal Medicine, 13th ed. Isselbacher et al (ed), Companion Handbook, McGraw Hill, NY, 1994
  3. Manual of Medical Therapeutics, 28th ed, Ewald & McKenzie (eds), Little, Brown & Co, Boston, 1995, pg 155
  4. Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998 - not on National VA formulary
  5. Kaiser Permanente Northern California Regional Drug Formulary, 1998
  6. Clinical Guide to Laboratory Tests, NW Tietz (ed) 3rd ed, WB Saunders, Philadelpha 1995
  7. Prescriber's Letter 13(3): 2006 Cytochrome P450 drug interactions Detail-Document#: 220233 (subscription needed) http://www.prescribersletter.com
  8. Prescriber's Letter 17(7): 2010 Recommended Lab Monitoring for Common Medications Detail-Document#: 260704 (subscription needed) http://www.prescribersletter.com