Mechanisms of Drug Induced QT Interval Prolongation

Abstract

The long QT syndrome (LQTS) is characterized by a prolonged QT interval, as well as a propensity to develop syncope and sudden cardiac death caused by the malignant polymorphic ventricular arrhythmia called torsades de pointes (TdP). The QT interval is measured from the onset of the QRS complex to the end of the T wave and can be affected by both ventricular conduction velocities as well as by the velocity of repolarization. In most cases, QT prolongation is caused by factors that prolong the duration of the action potential, mainly by delaying the repolarization phase 3. The molecular mechanism is partially known. There are two well described mechanisms: blocking of the ion channel cavity of HERG; or causing an abnormal protein trafficking required for the location of HERG subunits in cell membrane. Both of them impair the I(Kr) current. However the blockade of ion channels is not the only condition to generate TdP. Other factors may play an important role, e.g. myocardium heterogeneity, drug-drug interaction, genetic polymorphism, and Electrolyte disturbances. Several drugs had been subject of withdrawal because QT-prolongation and arrhythmia. Understanding of processes involved in drug-induced QT prolongation is needed for the study and prevention of life-threatening arrhythmias.

Targeted Cancer Therapy: Giving Histone Deacetylase Inhibitors All They Need To Succeed

“…Although not completely understood, the mechanism of QT interval prolongation has been explained by aberrant cellular trafficking and/or functioning of the human ether-ago-go (hERG) K + channel [66]. The latter being the most accepted mechanism for the HDACi induced QT interval prolongation [59].…”

Assessment of the cardiac safety and pharmacokinetics of a short course, twice daily dose of orally-administered mifepristone in healthy male subjects

“…QT prolongation via this mechanism is not typically seen acutely but after some days of treatment. Examples of drugs that cause QT prolongation thorough inhibition of hERG traffi cking are arsenic trioxide, pentamidine, and fl uoxetine [13][14][15][16][17][18].The second and perhaps more likely mechanism is that mifepristone causes QT prolongation through an indirect mechanism. Mifepristone blocks the cortisol receptor and this leads to high circulating cortisol concentrations through feedback on the hypothalamic-pituitary axis.…”

Clinical ECG Assessment

“…Often, this can be achieved with 6 to 8 timepoints, and the balance between the number of timepoints and the likelihood of false-positive results needs to be taken into account; this likelihood increases with the number of timepoints. Even so, it is important to also include some late timepoints, e.g., 24 h after dosing, to capture delayed effects including hERG trafficking (Dennis et al 2012;Ficker et al 2004;Kuryshev et al 2005;Ponte et al 2010). To avoid alterations of autonomic tone, which also has an impact the QTc interval, it is important to avoid timepoints at which subjects may be sleeping, i.e., nighttime.…”