Multiple Mechanisms Leading to QT Prolongation

Cocaine is another example of a dmg with a complex pharmacological profile responsible for different properties probably concurring due to QT prolongation. It has a local anesthetic action (and therefore shares the pharmacological properties mentioned above), but recent reports also indicate the blockade of hERG K+ currents [47-49]. Thus, it is not unexpected that cocaine has been associated with QT prolongation and occurrence of TdP [50-53]. 

A detailed discussion of the possible mechanisms leading to prolongation of the APD and QT interval is beyond the scope of this chapter, and the reader is referred to the reviews by Sheridan [62] and Malik and Camm [63]. 

All agents so far identified as torsadogenic have been shown to block the hERG K+ channels, which are undoubtedly the primary antitarget when exploring the QT liability of a compound. 

However, it is important to recognize that (a) there are some h E RG blockers that are unlikely to cause TdP and (b) not only blockade, but also interference with the processing of mature hERG channels can lead to QT liability. 

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