Drugs that prolong QT interval as an unwanted effect: assessing their likelihood of inducing hazardous cardiac dysrhythmias

Abstract

Medicinal products that, as an unwanted effect, prolong the QT interval of the electrocardiogram (ECG) can trigger episodes of polymorphic ventricular dysrhythmias, called torsades de pointes, which occasionally culminate in sudden death. The accurate measurement of QT interval requires the adoption of appropriate criteria of recording, measurement and data processing. Traditionally, QT interval is standardised to a reference heart rate of 60 beats/min by using the Bazett algorithm. However, this correction method can bias observed QT intervals in either direction. The ECG reflects cardiac electrical currents generated by ions (Na+, K+ and Ca2+) entering and leaving the cytosol mainly via transmembrane channels. Na+ and Ca2+ carry inward depolarising currents (INa, ICa) whereas K+ carries outward repolarising currents (Ito, IKr, IKS and IK1). Sometimes, a prolonged QT interval is a desired drug effect but, more commonly it is not, and reflects abnormalities in cardiac repolarisation heralding torsades de pointes. Furthermore, the potential torsadogenic activity of drugs is favoured by concurrent cardiac risk factors (old age, female gender, bradycardia, electrolyte imbalances, cardiac diseases etc.) which reduce cardiac repolarisation reserve. The evaluation of the cardiac safety of drug candidates can be started by determining their potency as IKr blockers in cloned Human Ether-a-go-go Related Gene (HERG) channels expressed in mammalian cells. Compounds passing successfully this test (desirable cardiac safety index > 30, calculated as ratio of IC50 against IKr over ED50 determined in an efficacy test) should be further investigated in other relevant human cardiac ion currents, in in vitro animal heart preparations and finally in in vivo pharmacodynamic models. The decision as to whether the potential benefit of a new drug outweighs the cardiac risk inherent in its therapeutic use should be made in the light of the condition that it is expected to treat and with reference to alternative drug therapies. If a drug represents a unique therapeutic advance, non-clinical and clinical signals of unsatisfactory cardiac safety may not constitute sufficient grounds to abandon its development. However, if the drug offers only marginal benefits over existing therapies, decisions concerning its possible development should be taken by corporate policy makers.

Functional consequences of methionine oxidation of hERG potassium channels

“…1) and short perfusion procedure in which the bath chamber was perfused for 1 min with ChT-solution followed by a wash-out period of 3 to 4 min (Figs. [3][4][5][6][7][8]. In some experiments, the wash-out period lasted for more than 10 min.…”

“…Defects in the hERG1 gene or pharmacological interventions that alter the hERG1 channel properties can give rise to inherited (long QT-syndrome 2) or acquired cardiac arrhythmias, respectively [3,[5][6][7]. In addition to their importance in the heart, hERG channels are also important for neuronal function; the variants hERG2 and hERG3 in particular are expressed in neuronal tissue where they may take part in regulation of cellular excitability [8].…”

Validation of a [3H]Astemizole Binding Assay in HEK293 Cells Expressing HERG K+ Channels

“…A plethora of drugs including methanesulfonanilides (e.g., dofetilide, MK-499, and E-4031) are known to cause QT prolongation by blocking I Kr K + channels (acquired long QT syndrome), which is the underlying cause of life-threatening torsade de pointes, a form of polymorphic ventricular arrhythmia, in susceptible individuals (3,6). Syncope and sudden death due to torsade de pointes caused by noncardiovascular drugs such as terfenadine (antihistamine), astemizole (antihistamine), and cisapride (gastrokinetic) led to their withdrawal from the market (7,8). Consequently, cardiac safety relating to I Kr K + channels has become a major concern of regulatory agencies, as HERG channel inhibition has been identified as the firmest link to QT prolongation.…”

QT PRODACT: In Vivo QT Assay in Anesthetized Dog for Detecting the Potential for QT Interval Prolongation by Human Pharmaceuticals

“…On the other hand, a number of non-cardiovascular drugs, such as the antihistamines, antipsychotics, and antimicrobial agents, also cause undesirable delay of ventricular repolarization in clinical use. This delayed ventricular repolarization is almost always associated with blockage of the human ether-a-go-go-related gene (hERG) channel that is responsible for the rapidly activating component of the delayed rectifier K + current (I Kr ), and is reflected by delayed phase 3 of the cardiac action potential, which can be exposed by prolongation of QT interval in the electrocardiogram (ECG) (1,2). Over the past few years, there as been increasing interest in the potential of non-cardiovascular drugs to cause QT interval prolongation as this undesirable effect has been shown to increase the risk of malignant polymorphic ventricular tachyarrhythmia, known as torsade de pointes (TdP), which may cause syncope and degenerate into ventricular fibrillation and sudden death (3,4).…”