Does terfenadine-induced ventricular tachycardia/fibrillation directly relate to its QT prolongation and Torsades de Pointes?

Br J Pharmacol. 2012 Jun;166(4):1490-502. doi: 10.1111/j.1476-5381.2012.01880.x.


Background and purpose: Terfenadine has been reported to cause cardiac death. Hence, we investigated its pro-arrhythmic potential in various in vitro models.

Experimental approach: Pro-arrhythmic effects of terfenadine were investigated in rabbit isolated hearts and left ventricular wedge preparations. Also, using whole-cell patch-clamp recording, we examined its effect on the human ether-à-go-go-related gene (hERG) current in HEK293 cells transfected with hERG and on the I(Na) current in rabbit ventricular cells and human atrial myocytes.

Key results: Terfenadine concentration- and use-dependently inhibited I(Na) in rabbit myocytes and in human atrial myocytes and also inhibited the hERG. In both the rabbit left ventricular wedge and heart preparations, terfenadine at 1 µM only slightly prolonged the QT- and JT-intervals but at 10 µM, it caused a marked widening of the QRS complex, cardiac wavelength shortening, incidences of in-excitability and non-TdP-like ventricular tachycardia/fibrillation (VT/VF) without prolongation of the QT/JT-interval. At 10 µM terfenadine elicited a lower incidence of early afterdepolarizations versus non- Torsades de Pointes (TdP)-like VT/VF (100% incidence), and did not induce TdPs. Although the concentration of terfenadine in the tissue-bath was low, it accumulated within the heart tissue.

Conclusion and implications: Our data suggest that: (i) the induction of non-TdP-like VT/VF, which is caused by slowing of conduction via blockade of I(Na) (like Class Ic flecainide), may constitute a more important risk for terfenadine-induced cardiac death; (ii) although terfenadine is a potent hERG blocker, the risk for non-TdP-like VT/VF exceeds the risk for TdPs; and (iii) cardiac wavelength (λ) could serve as a biomarker to predict terfenadine-induced VT/VF.

MeSH terms

  • Action Potentials / drug effects
  • Animals
  • Anti-Arrhythmia Agents / adverse effects
  • Anti-Arrhythmia Agents / metabolism
  • Anti-Arrhythmia Agents / pharmacology
  • Atrial Appendage / cytology
  • Atrial Appendage / drug effects
  • Atrial Appendage / metabolism
  • Biological Transport
  • Cells, Cultured
  • Ether-A-Go-Go Potassium Channels / antagonists & inhibitors
  • Ether-A-Go-Go Potassium Channels / genetics
  • Ether-A-Go-Go Potassium Channels / metabolism
  • Female
  • HEK293 Cells
  • Heart Ventricles / cytology
  • Heart Ventricles / drug effects
  • Heart Ventricles / metabolism
  • Histamine H1 Antagonists, Non-Sedating / adverse effects
  • Histamine H1 Antagonists, Non-Sedating / metabolism
  • Histamine H1 Antagonists, Non-Sedating / pharmacology*
  • Humans
  • In Vitro Techniques
  • Long QT Syndrome / chemically induced*
  • Long QT Syndrome / metabolism
  • Long QT Syndrome / physiopathology
  • Myocytes, Cardiac / cytology
  • Myocytes, Cardiac / drug effects*
  • Myocytes, Cardiac / metabolism
  • Osmolar Concentration
  • Rabbits
  • Recombinant Proteins / antagonists & inhibitors
  • Recombinant Proteins / metabolism
  • Sodium Channel Blockers / adverse effects
  • Sodium Channel Blockers / metabolism
  • Sodium Channel Blockers / pharmacology
  • Tachycardia, Ventricular / etiology*
  • Terfenadine / adverse effects
  • Terfenadine / metabolism
  • Terfenadine / pharmacology*
  • Torsades de Pointes / chemically induced*
  • Torsades de Pointes / metabolism
  • Torsades de Pointes / physiopathology
  • Ventricular Fibrillation / etiology*


  • Anti-Arrhythmia Agents
  • Ether-A-Go-Go Potassium Channels
  • Histamine H1 Antagonists, Non-Sedating
  • Recombinant Proteins
  • Sodium Channel Blockers
  • Terfenadine