Our data show that the Ikr blocking effect of azimilide, dofetilide, and quinidine was attenuated at acid pH, whereas this was not the case for amiodarone. These observations may explain the efficacy of amiodarone in reducing arrhythmic death in patients after a myocardial infarction compared with other IKr blockers.

Females had greater QTc prolongation than males following sotalol administration. This enhanced response to drug action may explain the higher incidence of drug-induced TdP seen in females.

Background: Hyperkalemia is a potentially life-threatening disorder frequently occurring in hospitalized patients. The ischemic myocardium releases potassium into the extracellular space which can cause regional hyperkalemia. These changes may modify the effects of anti-arrhythmic drugs acting on the rapid component of the delayed rectifier potassium current (IKr). We evaluated the influence of increased extracellular potassium concentration [K⁺]_e on IKr inhibition by amiodarone, azimilide, dofetilide, quinidine and sotalol. Methods and Results: Experiments were performed at room temperature. IKr current was studied by using HERG gene expressed in Xenopus oocytes as a model of cardiac IKr. Two-electrode voltage clamp technique was employed. The recording bath solutions contained either 5 or 10 mmol/l KCl. Amiodarone, azimilide, dofetilide, quinidine and sotalol all produced a dose-dependent inhibition of HERG current. At 5 mmol/l [K⁺]_e, the IC₅₀ was 37.0 ± 12.5 µM for amiodarone, 5.8 ± 0.4 µM for azimilide, 1.5 ± 0. 2 µM for dofetilide, 9.1 ± 1.5 µM for quinidine, and 5.1 ± 0.8 mM for sotalol. Raising the extracellular potassium to 10 mmol/l, HERG block by azimilide, dofetilide, quinidine and sotalol was significantly decreased, while the block by amiodarone was unchanged. The differences in the percentage current block produced by 3 µM drugs at 5 and 10 mmol/l [K⁺]_e were: –0.9% for amiodarone, 13.8% for quinidine, 20.5% for azimilide, and 16.2% for dofetilide. The differences in percentage block between 5 and 10 mmol/l [K⁺]_e by sotalol 10 and 30 mM were 7.1 and 5.6%. At 10 mmol/l [K⁺]_e, the IC₅₀ was increased for azimilide, dofetilide, quinidine and sotalol but not for amiodarone; the IC₅₀ was 24.7 ± 7.4 µM for amiodarone, 29.3 ± 3.9 µM for azimilide, 2.7 ± 0.2 µM for dofetilide, 27.6 ± 4.0 µM for quinidine, and 7.2 ± 1.7 mM for sotalol. Conclusion: Inhibition of IKr by azimilide, quinidine, dofetilide and sotalol was diminished by increasing [K⁺]_e, while the inhibition by amiodarone was unchanged at normal and high [K⁺]_e. The differential effects of azimilide, dofetilide, quinidine and sotalol at normal and high [K⁺]_e could be pro-arrhythmic by favoring re-entry arrhythmias. These results further support the unique electrophysiological effect of amiodarone.

Background: Drug induced QT prolongation may precipitate life threatening cardiac arrhythmias. Evaluation of the QT prolonging effect of new pharmaceutical agents in a ‘thorough QT/QTc study’ is being mandated by FDA. The purpose of this study was to evaluate an automated 12-lead digital Holter system for a thorough QT/QTc study. Methods: Five healthy volunteers underwent 24-hour digital Holter monitoring. Each recording underwent a fully automated QT analysis (AQA) followed by an onscreen complete manual over read (MOR). Each recording was analyzed twice at least 2 weeks apart. The effect of data sampling (5-min segment/hour), the system sensitivity to detect 5-ms increase in QT, and the ability to assess circadian variation were evaluated. Results: The AQA resulted in identical QT for the first and second analyses, but with obvious errors in QT measurements. Compared to the complete onscreen MOR, the mean QT was longer with AQA (416 ± 41 vs. 387 ± 30 ms, p < 0.001), correlation; r = 0.3. The reproducibility of AQA with complete MOR was very good (QT: 387 ± 30 vs. 387 ± 30 ms, coefficient of variation: 0.2%, r = 0.986. The 5-min mean QT intervals correlated well with the hourly mean QT intervals (r = 0.994, p < 0.001, coefficient of variation = 1 ms) and both showed a similar circadian variation. The system was sensitive to detect a 5-ms change in QT intervals (5 ± 2 ms, coefficient of variation = 0.6%, r = 0.998, p < 0.001). Conclusions: The AQA is not an acceptable method, while the automatic analysis with complete MOR is a highly sensitive and reproducible method. Data sampling by analyzing 5-min segments per hour is sensitive and reproducible.

Many drugs are proarrhythmic by inhibiting the cardiac rapid delayed rectifier potassium channel (IKr). In this study, we use quinidine as an example of highly proarrhythmic agent to investigate the risk factors that may facilitate the proarrhythmic effects of drugs. We studied the influence of pacing, extracellular potassium, and pH on quinidine's IKr blocking effect, all potential factors influencing quinidine's cardiac toxicity. Since the HERG gene encodes IKr, we studied quinidine's effect on HERG expressed in Xenopus oocytes by the 2-electrode voltage clamp technique. When extracellular K+ was 5 mmol/L, quinidine blocked the HERG current dose dependently, with an IC50 of 6.3 +/- 0.2 micromol/L. The blockade was much more prominent at more positive membrane potentials. The inhibition of HERG by quinidine was not use dependent. There was no significant difference between block with or without pacing. When extracellular K+ was lowered to 2.5 mmol/L, the current inhibition by quinidine was enhanced, and IC50 decreased to 4.6 +/- 0.5 micromol/L. At 10 mmol/L extracellular K+, there was less inhibition by quinidine and the IC50 was 11.2 +/- 3.1 micromol/L. Extracellular acidification decreased both steady state and tail currents of HERG. We conclude that the inhibitory effect of quinidine on IKr was decreased with extracellular acidification, which may produce heterogeneity in the repolarization between normal and ischemic cardiac tissue. Thus, the use-independent blockade of IKr by QT-prolonging agents such as quinidine may contribute to cardiac toxicity with bradycardia, hypokalemia, and acidosis further exaggerating the proarrhythmic potential of these agents.