Proarrhythmia as a Class Effect of Quinolones: Increased Dispersion of Repolarization and Triangulation of Action Potential Predict Torsades de Pointes (original) (raw)
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Proarrhythmic Potential of Antimicrobial Agents
Infection, 2008
Several antiarrhythmic and non-cardiovascular drug therapies including antimicrobial agents have been implicated as the causes for QT interval prolongation, torsades de pointes (TdP) ventricular tachycardia and sudden cardiac death. Most of the drugs that have been associated with the lengthening of the QT interval or development of TdP can also block the rapidly activating component of the delayed rectifier potassium current (IKr) in the ventricular cardiomyocytes. This article presents a review of the current literature on the QT interval prolonging effect of antimicrobials based on the results of the in vitro, in vivo studies and case reports. Our observations were derived from currently available Medline database. As we found, the most frequently QT interval prolonging antimicrobials are erythromycin, clarithromycin, fluoroquinolones, halofantrine, and pentamidine. Almost every antimicrobialassociated QT interval prolongation occurs in patients with multiple risk factors of the following: drug interactions, female gender, advanced age, structural heart disease, genetic predisposition, and electrolyte abnormalities. In conclusion, physicians should avoid prescribing antimicrobials having QTprolonging potential for patients with multiple risk factors. Recognition and appropriate treatment of TdP are also indispensable.
Women are associated with longer electrocardiographic QT intervals and increased proarrhythmic risks of QT-prolonging drugs. The purpose of this study was to characterize the differences in cardiac electrophysiology between moxifloxacin and levofloxacin in men and women and to assess the balance of inward and outward currents through the analysis of QT subintervals. Data from 2 TQT studies were used to investigate the impact of moxifloxacin (400 mg) and levofloxacin (1000 and 1500 mg) on QT subintervals using algorithms for measurement of J-T peak and T peak-T end intervals. Concentration-effect analyses were performed to establish potential relationships between the ECG effects and the concentrations of the 2 fluoroquinolones. Moxifloxacin was shown to be a more potent prolonger of QT interval corrected by Fredericia (QTcF) and had a pronounced effect on J-T peak c. Levofloxacin had little effect on J-T peak c. For moxifloxacin, the concentration-effect modeling showed a greater effect for women on QTcF and J-T peak c, whereas for levofloxacin the inverse was true: women had smaller QTcF and J-T peak c effects. The different patterns in repolarization after administration of both drugs suggested a sex difference, which may be related to the combined I Ks and I Kr inhibitory properties of moxifloxacin versus I Kr suppression only of levofloxacin. The equipotent inhibition of I Ks and I Kr appears to affect women more than men. Sex hormones are known to influence cardiac ion channel expression and differences in QT duration. Differences in I Kr and I Ks balances, influenced by sex hormones, may explain the results. These results support the impact of sex differences on the cardiac safety assessment of drugs.
Circulation Journal, 2002
rug-induced long QT syndrome is currently a hot topic of concern for the pharmaceutical companies as well as for clinicians. 1,2 We have previusly assessed the effects of class II, III and IV antiarrhythmic agents and some non-cardiovascular drugs on the repolarization process using the halothane-anesthetized canine in vivo model, and found that the effects of the drugs on phase 3 repolarization in this model are quite useful for predicting drug-induced QT prolongation that might trigger torsades de pointes in clinical practice. 3-11 Class I drugs are known to affect the QT interval, 12,13 but information regarding the effects of class I antiarrhythmic drugs in this type of model is still limited. 14-17 In this study, we simultaneously assessed the in vivo electrophysiological and cardiohemodynamic effects of typical class I antiarrhythmic drugs, disopyramide and mexiletine, using the halothane-anesthetized canine model. To better analyze the electrophysiological effects on the depolarization/repolarization process, we recorded His bundle electrograms and monophasic action potentials (MAPs), respectively, in addition to the standard lead II surface ECG. Moreover, a MAP recording/pacing combination catheter was used to
In-vitro experimental models for the risk assessment of antibiotic-induced QT prolongation
European Journal of Pharmacology, 2006
The prolongation of the ventricular repolarization and proarrhythmic effects (Torsade de Pointes: TdP) of five reference antibiotics were compared in four in-vitro models. 1. Using the patch clamp technique on the human ether-a-gogo-related gene (HERG) current, the rank order for blockade of the HERG-current (IC 50 ) was: sparfloxacin (44 μM) N telithromycin = moxifloxacin = erythromycin (±100 μM). 2. Assessing their effects on action potential duration (APD 90 ) and incidence of early afterdepolarizations in isolated rabbit Purkinje fibers, the rank order was: sparfloxacin N moxifloxacin N telithromycin N erythromycin (prolongation of APD 90 at 100 μM: 83%, 48%, 33% and 17% from baseline compared to + 5% with solvent, P b 0.05, respectively). 3. Assessing the drug effects on the APD 60 , triangulation, reverse use-dependency, and instability in isolated Langendorff-perfused rabbit hearts, the rank order was: moxifloxacin N erythromycin N sparfloxacin N telithromycin. 4. Assessing their torsadogenic potentials (scores of effects on QT-interval, peak of the T wave to end of T wave: T p-e , T p-e /QT ratio, R wave on T wave (R on T) and TdP in isolated rabbit left ventricular wedge preparations, the rank order for their TdP risk score was: sparfloxacin N erythromycin N moxifloxacin N telithromycin. Additional experiments with grepafloxacin indicate that the rank order to detect grepafloxacin-induced long QT was the wedge preparation N the Purkinje fiber N HERG N the isolated heart, where the isolated heart was unable to detect grepafloxacin-induced APD prolongation. The present study demonstrates that the first three in-vitro models can be used to assess the ability of antibiotic compounds to delay ventricular repolarization. However, with respect to their known clinical effects on QT and TdP incidence, the wedge preparation appears to be more predictive and suitable for detecting torsadogenic action of antibiotics.
Pharmacology & Therapeutics, 2006
Torsades de pointes (TdP) is a potentially lethal cardiac arrhythmia that can occur as an unwanted adverse effect of various pharmacological therapies. Before a drug is approved for marketing, its effects on cardiac repolarisation are examined clinically and experimentally. This paper expresses the opinion that effects on repolarisation duration cannot directly be translated to risk of proarrhythmia. Current safety assessments of drugs only involve repolarisation assays, however the proarrhythmic profile can only be determined in the predisposed model. The availability of these proarrhythmic animal models is emphasised in the present paper. It is feasible for the pharmaceutical industry to establish one or more of these proarrhythmic animal models and large benefits are potentially available if pharmaceutical industries and patient-care authorities embraced these models. Furthermore, suggested surrogate parameters possessing predictive power of TdP arrhythmia are reviewed. As these parameters are not developed to finalisation, any meaningful study of the proarrhythmic potential of a new drug will include evaluation in an integrated model of TdP arrhythmia.
Journal of Cardiovascular Electrophysiology, 2010
Objective-This study was designed to quantitate transseptal dispersion of repolarization (DR) and delineate its role in arrhythmogenesis using the calcium agonist BayK 8644 to mimic the gain of function of calcium channel current responsible for Timothy syndrome. Background-Amplification of transmural dispersion of repolarization (TDR) has been shown to contribute to development of Torsade de Pointes (TdP) arrhythmias under long-QT conditions. Methods-An arterially-perfused septal wedge preparation was developed via cannulation of the septal artery. Action potentials (APs) were recorded using floating microelectrodes together with a transseptal electrocardiogram (ECG). These data were compared to those recorded from arteriallyperfused canine left ventricular (LV) wedge preparations. Results-Under control conditions, the shortest AP duration measured at 90% repolarization (APD 90) was observed in right ventricular (RV) endocardium (181.8±15 ms), APD 90 peaked close to mid-septum (278.0±32 ms), and abbreviated again as LV endocardium was approached (207.3±9 ms). Transseptal DR averaged 106±24 ms and T peak-T end 84±7 ms (n=6). TDR and T peak-T end recorded from LV wedge were 36±9 ms and 34±19 ms, respectively (n=30). BayK 8644 increased transseptal DR to 123.2±35 ms (n=5) and induced early and delayed afterdepolarizations (3/5), rate-dependent ST-T-wave alternans (5/5), and TdP arrhythmias (3/5). Conclusions-Our data indicate that dispersion of repolarization across the interventricular septum is twice that of the LV free wall, predisposing to development of TdP under long-QT conditions. Our findings suggest that the coronary-perfused ventricular septal preparation may be a sensitive model in which to assess the potential arrhythmogenic effects of drugs and pathophysiological conditions.
QT Dispersion and Drug-Induced Torsade de Pointes
Cureus, 2021
Background Amiodarone causes less drug-induced torsade de pointes (TdP) compared to other class III antiarrhythmics. Two theories proposed for this finding include that amiodarone has less repolarization heterogeneity, and/or decreases early after depolarization (EADs). Corrected QT (QTc) dispersion as measured on a surface electrocardiogram (ECG) represents spatial heterogeneity of ventricular repolarization. Objective The purpose of this study was to analyze the difference in QT dispersion between amiodarone and other class III antiarrhythmics and to determine the etiology of TdP. Methods This was a retrospective, observational study at Montefiore Medical Center between January 2005 and January 2015. Inclusion criteria were adults >18 years on amiodarone, dofetilide, or sotalol with prolonged QT interval on 12-lead ECG. ECGs were reviewed by three blinded observers. QTc was calculated using the Bazett and Framingham formulas. QTc dispersion was calculated by subtracting the shortest from the longest QTc. Analysis of variance (ANOVA) was applied for comparison between antiarrhythmic groups with Bonferroni correction for multiple comparisons. Results A total of 447 ECGs were reviewed and 77 ECGs met inclusion criteria. The average QT dispersion for amiodarone, dofetilide, and sotalol was 0.050, 0.037, and 0.034, respectively (p=0.006) and the average QTc dispersion by Bazett was 0.053, 0.038, and 0.037 (p=0.008) and by Framingham was 0.049, 0.036, and 0.035 (p=0.009), respectively. Conclusion Our results show that given the increase in QT dispersion seen with amiodarone, heterogeneous ventricular repolarization as measured by QTc dispersion likely does not account for the lower incidence of drug-induced TdP seen with amiodarone. The ability of amiodarone to decrease EADs via sodium-channel blockade is more likely the explanation for its lower incidence of drug-induced TdP.