Repolarization failure

Many factors can interact with dmgs to make this problem worse. These include genetic factors, such as mutations in sodium, potassium and calcium channel genes that predispose people to repolarization failure [11-13]. This is the main explanation for the fact that dmgs with this side-effect have it in only a small fraction of the population. In principle, it should become possible to screen for such genetic predispositions to exclude such patients in clinical trials and to avoid treating them with drugs that interact in this way (Fig. 9.2). 

Phase 1 is followed by a postdepolarization phase (phase 2) during which only the actions of nicotinic receptor agonists are blocked. This phase takes place after nicotine has acted for several minutes. At this time, the cell partially repolarizes, and its electrical excitabihty returns. The main factor responsible for phase 2 block appears to be desensitization of the receptor to ACh, which causes transmission failure. 

Undrovinas, A. I., Belardinelli, L, Nidas, A., Undrovinas, R. N. and Sabbah, H. N. Ranolazine improves abnormal repolarization and contraction in left ventricular myocytes of dogs with heart failure by inhibiting late sodium current. Journal of Cardiovascular Electrophysiology 2006, 17 S169—S177. 

A, Naso C, et al. 2002. Effects of sildenafil citrate (viagra) on cardiac repolarization and on autonomic control in subjects with chronic heart failure. Am. Heart J. 143 703-10... 

Quinidine blocks open sodium channels, which decreases the rate of repolarization in a dose-dependent manner. Thus, the cardiac tissue may still depolarize normally, and the propensity for cardiac failure is lessened. Amiodarone, conversely, blocks resting channels, preventing depolarization in a dose-dependent manner. This could prevent excitation, particularly if the drug is in excess, leading to cardiac failure. Thus, this drug has a more pronounced cardiodepressant effect, as compared to quinidine, and a smaller margin of safety. 

The most frequent sources of cardiovascular stress and of consequently reduced repolarization reserve (e.g., heart failure, liver failure, and kidney disease) all prolong the QT interval. 

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