Proarrhythmia related to a kinetic and dynamic interaction of mexiletine and theophylline

Abstract

Mexiletine is a group lb antiarrhythmic agent used to control ventricular dysrhythmias. Drug-mexiletine interactions have been reported,‘-4 including inhibition of caffeine metabolism5 and a report of increased theophylline levels with gastrointestinal symptoms.6 We recently observed a patient with a potentially important mexiletine-theophylline interaction. A 55year-old man with diet-controlled diabetes mellitus, mild hypertension, and a history of smoking, had two acute anterior wall myocardial infarctions in 1971 and two-vessel coronary artery bypass grafting, left ventricular aneurysmectomy, and encircling subendocardial resection in 1980 for drug-resistant, symptomatic ventricular tachycardia (VT). Eight months prior to admission, mild congestive heart failure was noted. One week prior to admission, he had witnessed ventricular fibrillation unassociated with an acute myocardial infarction. The ECG showed sinus rhythm, left atria1 abnormality, old anterolateral myocardial infarction, and nonspecific ST-T wave abnormalities. A multiple gated acquisition scan (MUGA) ejection fraction was 23%. Rhythm monitoring in the Coronary Care Unit (with summaries every 8 hours of recorded memory events) revealed multiform premature ventricular complexes (PVCs) at a frequency of <lO/hr, and couplets or triplets of fewer than 1 event per hour (Fig. 1, upper panel). On electrophysiologic testing, the patient was induced by double extrastimuli into a rapid sustained monomorphic VT (R-R interval = 250 msec) with hypotension and loss of consciousness that required external cardioversion. Procainamide did not prevent reinduction of symptomatic VT. After seven doses of mexiletine (200 mg, thrice daily; level-O.9 H/ml), recurrent episodes of spontanteous nonsustained VT (10 to 29 beats) were noted for the first time (Fig. 1, middle panel). The patient was emotionally labile, and his theophylline level was 31 rg/ml. Stable theophylline dosing of 400 mg, three times daily for 11 days, with levels of 12.5 to 15.3 Kg/ml, had been documented (Table I). The nonsustained VT responded to lidocaine; both mexiletine and theophyl-