Mechanisms Underlying the QT Interval–prolonging Effects of Sevoflurane and Its Interactions with Other QT-prolonging Drugs

Abstract

Prolonged ventricular repolarization observed with administration of sevoflurane results from inhibition of KvLQT1/minK and Kv4.3 cardiac K channels. Combining sevoflurane with class III antiarrhythmic drugs results in supra-additive effects on action potential duration. The results indicate that sevoflurane, when administered with this class of drug, could result in excessive delays in ventricular repolarization. The results suggest the need for further clinical studies.

Interaction of propofol with voltage-gated human Kv1.5 channel through specific amino acids within the pore region

“…These differential effects of propofol on I Kr and I Ks are qualitatively similar to those of sevoflurane (Heath and Terrar, 1996;Kang et al, 2006, Kojima et al, 2015Shibata et al, 2004). Previous studies have demonstrated that propofol concomitantly blocks other ionic currents, especially L type Ca 2+ current (I Ca,L ) in ventricular myocytes (Yang et al, 1996), which results in minimal or no effect on ventricular action potential duration and QTc interval in experimental and clinical settings (Kojima et al, 2015;Puttick and Terrar, 1992;Staikou et al, 2014).…”

Mechanisms Involved in Cardiac Sensitization by Volatile Anesthetics: General Applicability to Halogenated Hydrocarbons?

“…Another example is sevoflurane, which inhibits hERG current in Xenopus oocytes in a concentration-dependent manner (10-27% inhibition at 0.14-0.65 mmol/L) and prolongs the QTc interval in guinea pigs dose-dependently (Yamada et al, 2006). This hERG-blocking potential of sevoflurane, however, was not confirmed by other groups, who detected hardly an effect of sevoflurane (0.65 mmol/L) on isolated I Kr in guinea pig ventricular myocytes (Shibata et al, 2004) or an only marginal inhibition of hERG current at supratherapeutic concentrations (-17% at 3 mmol/L; Kang et al, 2006). Instead of an I Kr or hERG block, these two groups demonstrated an I Ks block by sevoflurane (IC 50 0.38 mmol/L) and halothane (IC 50 1.07 mmol/L) in guinea pig ventricular myocytes (Shibata et al, 2004) and in KvLQT1-minK expressing Chinese hamster ovary (CHO) cells (sevoflurane IC 50 1.3 mmol/L; Kang et al, 2006).…”

In reply: Sevoflurane in patients at risk of ventricular dysrhythmias

“…Moreover, propofol inhibits L-type calcium currents (ICa), even at clinical concentrations [4]. Blockage of ICa is known to attenuate the QT interval, prolonging the effects of many drugs [3]. However, our conclusion was probably overstated because this study did not include patients at risk of ventricular dysrhythmias.…”

“…Kang et al [3] demonstrated that sevoflurane did not block the hERG channel current (IKr), but rather inhibited the channel that carries IKs (potassium currents). IKr, rather than IKs, inhibition causes drug-induced torsades de pointes.…”