A growing number of non-cardiac drugs have been found to delay cardiac repolarization, causing QT interval prolongation and predisposing patients to an increased risk of potentially fatal ventricular arrhythmias, known as torsade de pointes (TdP) (Letsas et al, 2007; Yap and Camm 2003; Sanguinetti and Tristani-Firouzi). These drugs include the second-generation, non-sedating antihistamines astemizole and terfenadine, withdrawn from the market in Europe and the United States (in 1997 and 1999, respectively) due to cardiac safety concerns (Davila et al, 2006; Kannankeril et al, 2010; WHO, 2011).
Drugs with the potential to cause TdP most frequently inhibit the rapid component of the delayed rectifier potassium current (IKr), which causes a …show more content…
The concept of RP postulates that in the normal cardiac ventricle and conducting system, there are mechanisms that trigger the rapid and systematic repolarization, which prevent the occurrence of the conditions (eg, re-entrant circuits or early afterdepolarizations) that are responsible for the development of TdP. Such stability of the repolarization is based on a large electrophysiological reserve. As long as identified risk factors for TdP reduce this reserve, they make it more likely that a further added stress (eg, IKr blocking drug or a subtle genetic defect) is sufficient to precipitate a TdP in individual patients (Roden, 1998). In this concept, the idea is that the complexity of repolarization includes some redundancy. As a consequence, loss of one component (such as IKr), ordinarily would not lead to failure of repolarization (eg, marked QT prolongation). Therefore, individuals with subclinical defects in other components of the reserve may display no QT change until IKr block is superimposed (De Ponti et al, 2002, Gintant et al, 2006, Roden, 2008, Varro and Baczko, …show more content…
Patients with a low RP, such as those with long QT syndrome, had a significant prolongation of the QTc interval after receiving sotalol, a well-known IKr blocker. The same was not seen in control patients without that syndrome that received the same drug (Kaab et al, 2003). This finding displays the need of multiple mechanisms acting concurrently to overcome the RP and provoke a cardiac manifestation. It shows that although IKr is an important determinant of the risk of QT prolongation and consequent TdP, it is not its sole causal
Drugs with the potential to cause TdP most frequently inhibit the rapid component of the delayed rectifier potassium current (IKr), which causes a …show more content…
The concept of RP postulates that in the normal cardiac ventricle and conducting system, there are mechanisms that trigger the rapid and systematic repolarization, which prevent the occurrence of the conditions (eg, re-entrant circuits or early afterdepolarizations) that are responsible for the development of TdP. Such stability of the repolarization is based on a large electrophysiological reserve. As long as identified risk factors for TdP reduce this reserve, they make it more likely that a further added stress (eg, IKr blocking drug or a subtle genetic defect) is sufficient to precipitate a TdP in individual patients (Roden, 1998). In this concept, the idea is that the complexity of repolarization includes some redundancy. As a consequence, loss of one component (such as IKr), ordinarily would not lead to failure of repolarization (eg, marked QT prolongation). Therefore, individuals with subclinical defects in other components of the reserve may display no QT change until IKr block is superimposed (De Ponti et al, 2002, Gintant et al, 2006, Roden, 2008, Varro and Baczko, …show more content…
Patients with a low RP, such as those with long QT syndrome, had a significant prolongation of the QTc interval after receiving sotalol, a well-known IKr blocker. The same was not seen in control patients without that syndrome that received the same drug (Kaab et al, 2003). This finding displays the need of multiple mechanisms acting concurrently to overcome the RP and provoke a cardiac manifestation. It shows that although IKr is an important determinant of the risk of QT prolongation and consequent TdP, it is not its sole causal