Therefore, TdP frequently occurs at low or subtherapeutic serum levels . Administration of more than one drug that prolong repolarization increases the risk of drug-induced LQTS, selleck chem CXCR inhibitor but in most cases the mechanism of increased risk is due to drug-drug interactions altering metabolism, rather than simple additive effects on IKr. Cytochrome P450 superfamily of proteins is responsible for the metabolism of most of the drugs by liver and CYP3A4 is the predominant cytochrome P450. Coadministration of drugs which are substrates for CYP3A4 and/or IKr blockers results in further QT prolongation. Drugs that prolong Blebbistatin 856925-71-8 QT interval and inhibitors of CYP3A4 are shown in Tables ?Tables22 and ?and3.3. Amiodarone rarely causes torsades de pointes despite significant QT prolongation.
Amiodarone blocks IKr without reverse use dependence and prolongs action potential duration in a homogenous manner, thus reducing heterogeneity of refractoriness and making myocardium less susceptible to reentry. Additional electrophysiologic effects that explain its safety include noncompetitive �� antagonism and inward L-calcium channel blockade which may reduce EADs Acetyltransferase . The incidence of torsades de pointes at currently used doses is <1% [54, 55] while with sotalol the incidence ranges from 0.8 to 3.8%  and with ibutilide from 3.6 to 8.3% [57, 58]. Verapamil, even though a potent IKr blocker, rarely causes torsades de pointes . Verapamil reduces EADs by blocking inward calcium current , reduces transmural dispersion of refractoriness, and shortens QT interval and the incidence of TdP in a model of acquired LQTS from combined IKs and IKr block .