Overview of drug induced hemodynamic, autonomic and electrophysiological effects
Table 1 allows differentiating two main profiles among torsadogenic drugs at the first dose level causing either QTc prolongation and/or increase in HFQT oscillations. The first profile corresponds to drugs causing non blunted QTc prolongation. All these drugs showed a rapid onset in QTc prolongation within 1-2 hours after dosing. All the other torsadogenic drugs exhibited a profile characterised by blunted QTc prolongation or no QTc prolongation at the first dose showing an increase in HFQT oscillations. Blunted QTc prolongation was characterised by a delayed onset in QTc prolongation and delayed peak of QTc prolongation. 13 out of 15 torsadogenic hERG blocking drugs induced increases in HFQT oscillations. In addition, 13 experiments were conducted in combination with atenolol, a β-adrenoceptor blocking drug. Two non-torsadogenic drugs were also found inducing increases in HFQT oscillations and reported in the list for comparison: prasozin, an α1 adrenoceptors competitive antagonist and milrinone, a phosphodiesterase 3 inhibitor. Four non torsadogenic hERG blockers (ciprofloxacin, ranolazine, ebastin, verapamil) presented no QTc prolongation and no increase in HFQT oscillations at the first dose levels showing cardiovascular effects and/or changes in autonomic control.