Drug-Induced QT Interval Prolongation: Mechanisms, Risk Factors, Genetics and Clinical Management

Abstract

Long QT syndrome (LQTS) characterized by prolongation of the QT interval, may occur as congenital or drug-induced forms. Drug-induced QT interval prolongation (DI-QTP) is closely associated with severe ventricular arrhythmias [especially torsade de pointes (TdP)] and sudden cardiac death. In particular, development of DI-QTP is generally associated with multiple risk factors. Cardiac and non-cardiac drugs may cause QT interval prolongation (QTP) and TdP. Most of the QT-prolonging drugs act by blocking the rapid component of the delayed rectifier potassium channel whereas a smaller number of drugs act by modifying Ca2+ and Na+ currents. In addition, pharmacokinetic drug interactions are among the reasons of DI-QTP. The corrected QT interval (QTc) according to heart rate by Bazett’s formula is the most commonly used. Genetic susceptibility is another important issue in predicting DI-QTP and TdP risk. Silent mutations and/or polymorphisms associated with cardiac ion channels may cause a risk for DI-QTP. Firstly, for treatment, drugs that cause QTP should be stopped rapidly, electrolyte abnormalities and other pathologies should be rapidly corrected. Intravenous magnesium sulphate, overdrive pacing, isoproterenol and plasma alkalinisation via sodium bicarbonate are the main useful treatments for DI-QTP and related TdP therapy. Class 1B antiarrhythmic drugs and intravenous potassium are thought to may be effective in TdP. The purpose of this article is to review the underlying mechanisms of QTP, risk factors and genetics of DI-QTP, how to measurement of QT interval and treatment of acquired LQTS. Key-words: Drugs, QT interval, QT prolongation and torsade de pointes. Sudden cardiac death which is caused by mostly (% 80–85) acute ventricular arrhythmias, is a common cause of mortality. Prolongation of ventricular repolarization is an important cause of ventricular arrhythmias (1). Long QT syndrome (LQTS) characterized by QT interval prolongation (QTP) which represents ventricular depolarization and repolarization, may occur as congenital form or acquired form which induced by drugs. Many drugs have QT-prolonging effects and they may cause severe ventricular arrhythmias. Drug-induced QT interval prolongation (DI-QTP) is more common than congenital QT prolongation and particularly important in people with multiple risk factors (1–4). The purpose of this article is to review the underlying mechanisms of QTP, risk factors and genetics of DI-QTP, how to measurement of QT interval and treatment of acquired LQTS. Drugs that have QT-prolonging effects Cardiovascular and non-cardiovascular many agents may cause QTP and severe ventricular arrhythmias [especially torsade de pointes (TdP) which is defined as ventricular polymorphic tachycardia] (4). Drugs that have been associated with QTP and TdP, are shown in Table 1 (1, 5–11). TdP is important in routine clinical practice because it may degenerate into ventricular fibrillation and drug-induced TdP incidence is not sufficiently known (10, 12). In a observational study, 3.1% of patients treated with non-cardiac drugs have been reported to develop TdP (13). Most antiarrhythmic drugs, such as quinidine and sotalol, usually have a higher risk of TdP than non-cardiovascular drugs (7). Amiodarone, an antiarrhythmic drug, is one of the exceptions. Although amiodarone can significantly prolong QT interval, it rarely causes TdP (14). Antimicrobials and psychotropic drugs, which are non-cardiovascular drugs, are also one of the most common cause of DI-QTP (10). Macrolides and fluoroquinolones are antimicrobial drug groups that frequently prescribed and known to associated with QTP (4). INTRODUCTION Aktürk & Kalkan. Drug-Induced QT Interval Prolongation J Basic Clin Health Sci 2019; 3:193-198 194 In the last decade, there are many marketed drugs [antibiotics (sparfloxacin, grepafloxacin), atypical antipsychotic (sertindol), antihistaminics (terfenadine, astemizol) and prokinetic agent (cisapride)] which are withdrawal because of the risk of the TdP (13, 15). Therefore, clinicians should be careful about possible risks before prescribing QT prolonging medications (9). Measurement of the QT interval The QT interval on a surface electrocardiogram (ECG) is the period from the beginning of the QRS complex to the end of the T wave (15). There is insufficient data about which lead should be used to measure the QT interval (16). Lead II is one of the most widely used leads because of the possibility of having the longest QT interval. Determining the T wave end point is an important issue in the measurement of the QT interval (17). In this regard the tangent method is one of the methods of determining the end of the T wave. This method determine the T wave end point by using the intersection of a tangent to the steepest slope of T wave and the baseline (13). Heart rate changes influence the duration of QT interval, therefore usually the corrected QT interval (QTc) according to heart rate is used. For the rate correction, the RR interval prior to the QT interval should be measured (3). There are several methods for calculating the QTc value and it is not defined which is the most effective method. In clinical practice, Bazett’s formula is the most Table 2. Corrected QT interval formulas Formula QTc calculation Bazett QT/(RR) 1/2 Fredericia QTc=QT/(RR) 1/3 Framingham QTc=QT+0.154× (1-RR) Hodges QTc=QT+1.75× (HR-60) Table 1. Drugs associated with QT interval prolongation and torsade de pointes