Genetic and Molecular Aspects of Drug-Induced QT Interval Prolongation

Abstract

Long QT syndromes can be either acquired or congenital. Drugs are one of the many etiologies that may induce acquired long QT syndrome. In fact, many drugs frequently used in the clinical setting are a known risk factor for a prolonged QT interval, thus increasing the chances of developing torsade de pointes. The molecular mechanisms involved in the prolongation of the QT interval are common to most medications. However, there is considerable inter-individual variability in drug response, thus making the application of personalized medicine a relevant aspect in long QT syndrome, in order to evaluate the risk of every individual from a pharmacogenetic standpoint.

Prevalence of potential drug − drug interactions in the cardiothoracic intensive care unit patients in a Chinese tertiary care teaching hospital

“…Studies have shown that patients with prolonged QT intervals may have an increased length of hospital stay, which is associated with higher all − cause mortality [ 26 ]. Although there are many mechanisms leading to QT prolongation, including those with genetically related long QT syndrome, bradycardia, or hypokalemia, drug therapy, particularly DDI, is one of the major causes of these adverse events [ 27 , 28 ]. The results from a single center study showed that up to 70% of adverse events related to QT prolongation in critically ill patients were due to drug interactions [ 29 ].…”

Drug safety of frequently used drugs and substances for self-medication in COVID-19

“…However, acute conduction abnormalities have also been described, as hydroxychloroquine blocks the I kr (rapid component of the delayed rectifier potassium current) on the cardiac action potential through inhibition of the Kv 11.1 potassium channel leading to torsades de pointes . 40 This was a major problem at the beginning of the pandemic because many drugs with QT interval prolongation potential were used concomitantly. 41 – 43 On the contrary, hydroxychloroquine-induced lysosomal dysfunction also leads to the accumulation of lipofuscin, which is toxic to the photoreceptors and the retinal epithelial cells, seen in hydroxychloroquine-induced ocular toxicity.…”

“…Monitoring for acute treatment with hydroxychloroquine should involve assessing the risk factors for QT interval prolongation such as electrolyte abnormalities, renal failure, structural heart disease, and concomitant use of other drugs with known risk of QT prolongation. 40 …”

The QT interval prolongation potential of anticancer and supportive drugs: a comprehensive overview

“…7,8 The most important risk factors for developing a prolonged QT interval include a history of drug-induced torsade de pointes, a history of cardiovascular diseases, older age (>65 years), female sex, a family history of (or genetic predisposition to) congenital long QT syndrome, a high baseline QTc, hypothyroidism, the use of other drugs that can prolong the QT interval, and reduced kidney or liver function. 9,10 Patients with cancer are susceptible to QTc prolongation because they often take many drugs at the same time, including anticancer and supportive drugs alongside any drugs used for comorbidities. Furthermore, patients with cancer frequently have electrolyte imbalances due to malignancies and common gastrointestinal side effects such as nausea, vomiting, and diarrhoea, which increase the risk of QTc prolongation.…”