• V Calderone and I Cavero.
• Dipartimento di Psichiatria, Neurobiologia, Farmacologia e Biotecnologie, Sezione di Farmacologia, Università degli Studi, Pisa, Italy. calderone@farm.unipi.it
• Minerva Med. 2002 Jun 1; 93 (3): 181-97.

AbstractThe electrocardiogram shows a sequence of cardiac electrical events generated by individual electrical currents generated mainly by sodium (Na+), potassium (K+) and calcium (Ca++) ions transiting via specialized transport pathways, such as ion channels, inserted in the membranes of excitable cardiac cells. Na+ and Ca++, entering the cells, are messengers of activating, inward, depolarizing currents (INa, ICa), generating the QRS wave of the electrocardiogram, whereas K+, leaving the cells, carries outward repolarizing currents (e.g. Ito, IKr, IKs and IK1), generating the T wave of the electrocardiogram, which drives the cell to a rest condition. Therefore, a significantly prolonged repolarization process results in a prolonged QT interval which can initiate ectopic cardiac beats that may evolve into a potentially lethal ventricular tachyarrhythmia, called torsades de pointes. This implies that the measurement of QT interval, appropriately corrected (QTc) for heart rate values by applying available algorithms, is a current tool of diagnostic investigation to reveal abnormalities of the cardiac repolarisation process. Numerous non cardiovascular drugs in general clinical use (psychotropics, prokinetics, antimalarials, antibiotics, antihistamines, etc.) can prolong QT interval, often by a mechanism not necessary for their therapeutic effects, which is a reduction of the potassium current IKr conveyed by the HERG channel. The torsadogenic potential of these drugs can be facilitated by factors (female gender, bradycardia, electrolyte imbalances, cardiac diseases, simultaneous use of multiple drugs prolonging QT interval, etc.) known to have the propensity to reduce the redundant cardiac repolarization reserve, characterizing the healthy myocardium. Presently, drug candidates are routinely subjected to preclinical and clinical examination for cardiac safety, a property required by health authorities for any new medicine before allowing marketing authorization. Finally, before prescribing a medicinal product prolonging QT interval, a physician should carefully evaluate not only the disease he wants to treat but also the availability of equally effective, alternative drugs. The golden rule, to which such a prescription has always to abide, requires that the beneficial effects expected from a therapy should for each treated patient outweigh any possible adverse consequence, particularly when the latter one could be of lethal nature.

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