QT-interval prolongation by non-cardiac drugs: lessons to be learned from recent experience

Abstract

This has fostered discussion on the molecular mechanisms underlying the class-III antiarrhythmic effect shared by apparently disparate classes of drugs, on the clinical relevance of this side effect and on possible guidelines to be followed by drug companies, ethics committees and regulatory agencies in the risk-benefit assessment of new and licensed drugs. This review provides an update on the different classes of non-cardiac drugs reported to prolong the QT interval (e.g. histamine H1-receptor antagonists, antipsychotics, antidepressants and macrolides), on the possible underlying molecular mechanisms and on the clinical relevance of the QT prolonging effect. Identification and widespread knowledge of risk factors that may precipitate prolongation of the QT interval into life-threatening arrhythmias becomes an important issue. Risk factors include congenital long QT syndrome, clinically significant bradycardia or heart disease, electrolyte imbalance (especially hypokalaemia, hypomagnesaemia), impaired hepatic/renal function and concomitant treatment with other drugs with known potential for pharmacokinetic/ pharmacodynamic interactions (e.g. azole antifungals, macrolide antibacterials and class-I or -III antiarrhythmic agents). Future perspectives for drug research and development are also briefly outlined.

Acquired Long QT Syndrome: Frequency, Onset, and Risk Factors in Intensive Care Patients

“…The risk increases when 2 or more such medications are administered concurrently. [60][61][62] Among the patients in our study who had aLQTS, 10 (22%) received 2 or more QTc-prolonging medications. Among the patients who did not have aLQTS, 4 (10%) received more than 1 QTc-prolonging medication.…”

Use of azithromycin and risk of ventricular arrhythmia

“…Concerns have been raised recently regarding its arrhythmogenic potential, a risk already known to be associated with the first marketed macrolide, erythromycin. [1][2][3][4][5][6] Several case reports have described QTinterval prolongation, 7-9 torsades de pointes [10][11][12] and polymorphic ventricular tachycardia 13 following use of azithromycin. Many observational studies have reported conflicting results about the association between azithromycin use and cardiovascular death.…”

Novel Potent Human Ether-à-Go-Go-Related Gene (hERG) Potassium Channel Enhancers and Their in Vitro Antiarrhythmic Activity

“…Drug-induced (acquired) long QT syndrome, an effect manifested as prolongation of the QT interval on the surface electrocardiogram (ECG), has drawn increasing attention from regulatory agencies and the pharmaceutical industry in recent years (De Ponti et al, 2000Fermini and Fossa, 2003). The presence of delayed repolarization favors the genesis of "early after-depolarization" (EAD), which can initiate an arrhythmia referred to as "triggered activity" (Zabel et al, 1997).…”