Differentiating Drug-Induced Multichannel Block on the Electrocardiogram: Randomized Study of Dofetilide, Quinidine, Ranolazine, and Verapamil

• Published in: Clinical pharmacology and therapeutics Vol. 96; no. 5; pp. 549 - 558
• Main Authors: Johannesen, L, Vicente, J, Mason, J W, Sanabria, C, Waite-Labott, K, Hong, M, Guo, P, Lin, J, Sørensen, J S, Galeotti, L, Florian, J, Ugander, M, Stockbridge, N, Strauss, D G
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01-11-2014
• Subjects: Acetanilides - adverse effects; Acetanilides - pharmacokinetics; Calcium Channel Blockers - pharmacology; Electrocardiography - drug effects; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels - antagonists & inhibitors; Heart Rate - drug effects; Humans; Medicin och hälsovetenskap; Phenethylamines - adverse effects; Phenethylamines - pharmacokinetics; Piperazines - adverse effects; Piperazines - pharmacokinetics; Potassium Channel Blockers - adverse effects; Prospective Studies; Quinidine - adverse effects; Quinidine - pharmacokinetics; Ranolazine; Sodium Channel Blockers - pharmacology; Sulfonamides - adverse effects; Sulfonamides - pharmacokinetics; Verapamil - adverse effects; Verapamil - pharmacokinetics
• ISSN: 0009-9236; 1532-6535; 1532-6535
• DOI: 10.1038/clpt.2014.155

Block of the hERG potassium channel and prolongation of the QT interval are predictors of drug‐induced torsade de pointes. However, drugs that block the hERG potassium channel may also block other channels that mitigate torsade risk. We hypothesized that the electrocardiogram can differentiate the effects of multichannel drug block by separate analysis of early repolarization (global J–Tpeak) and late repolarization (global Tpeak–Tend). In this prospective randomized controlled clinical trial, 22 subjects received a pure hERG potassium channel blocker (dofetilide) and three drugs that block hERG and either calcium or late sodium currents (quinidine, ranolazine, and verapamil). The results show that hERG potassium channel block equally prolongs early and late repolarization, whereas additional inward current block (calcium or late sodium) preferentially shortens early repolarization. Characterization of multichannel drug effects on human cardiac repolarization is possible and may improve the utility of the electrocardiogram in the assessment of drug‐related cardiac electrophysiology.
Clinical Pharmacology & Therapeutics (2014); 96 5, 549–558. doi:10.1038/clpt.2014.155