Question

azole antifungals are most likely to cause torsades de pointes in which patient population?

Answer 1

Torsade de pointes

Special type of ventricular tachycardia which is preceded by the development of a long QT-interval in a patient’s electrocardiogram. Torsade de pointes can be self-terminating causing dizzy spells and syncope, or it can degenerate into ventricular fibrillation, cardiac arrest and sudden cardiac death.

Azole antifungal agents are known to cause QT-interval prolongation and in some cases subsequent torsade de pointes through inhibition of cardiac hERG (human ether receptor a go-go) potassium channels.The following drugs were searched for in conjunction with torsade de pointes: fluconazole, itraconazole, ketoconazole, posaconazole and voriconazole.The reaction term according to MedDRA (Medical Dictionary for Regulatory Activities) terminology was “Torsade de pointes”. The number of reports per drug, reporting countries, patient demographics and outcome were recorded.Cases of torsade de pointes associated with systemic azole antifungal agents reported to the WHO during the past 20 years were mainly from the Americas,.In the majority of cases co-suspected and interacting drugs were present and torsade de pointes occurred within one week of starting the drug in approximately half the cases. Clinicians should be aware of these features of azole-induced torsade de pointes and avoid interacting drugs if at all possible and monitor at-risk patients for the development of QTc-prolongation. Potential candidate genes for azole antifungal agents and the development of torsade de pointes are genes encoding drug-metabolising enzymes such as CYP2C19 and CYP2C9 which are involved in the metabolic clearance of azoles and genes encoding cardiac ion channels such as KCNH2.Concomitant treatment with other drugs known to be associated with QTc-prolongation and torsade de pointes or with drugs causing pharmacokinetic interactions leading to increased drug exposure are known risk factors for torsade de pointes

A number of important drug-safety aspects for clinicians and their patients can be drawn from these findings. Firstly, prescribing azole antifungal agents in combination with interacting drugs should be avoided if at all possible. Secondly torsade de pointes can occur soon after commencing the drug and QTc-monitoring after commencing therapy may be prudent in high-risk patients.