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

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 e...

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Bibliographic Details
Published in:Clinical pharmacology and therapeutics 2014-11, Vol.96 (5), p.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: Article
Language:English
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
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Summary: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
ISSN:0009-9236
1532-6535
1532-6535
DOI:10.1038/clpt.2014.155