Drug-induced prolonged QT interval

Drugs associated with QT prolongation include (1):

• tricyclic antidepressants
• antiarrhythmics:
  • quinidine
  • disopyramide
  • procainamide
  • amiodarone
  • sotalol
• non-sedative antihistamine toxicity
  • terfenadine
  • astemizole
• antimalarials
  • especially halofantrine
• antipsychotics
  • notably droperidol and thioridazine
• cisapride
  
  
• methadone
  
  
• cocaine has been shown to increase QT intervals acutely (2)
  
  
• citalopram (3)

• ondansetron (3)

Normal QT interval (3):

• QT interval varies with heart rate
• females have a longer QT interval than males
• definitions vary in the literature but as a guide, normal QTc intervals are <450 milliseconds (ms) for men and <460 ms for women
• a QTc between these values and 500 ms is considered prolonged
  • a QTc >500 ms is considered clinically significant and is likely to confer an increased risk of arrhythmia

Magnitude of drug induced changes in QT interval (3):

• the degree by which a drug changes the QTc interval from baseline is also important
  • an increase in baseline QTc of around 5 ms or less is not considered significant and this is the threshold for regulatory concern
  • for drugs that increase the QTc interval by less than 20 ms the data are inconclusive with regard to arrhythmic risk
    • a change in baseline QTc of >20 ms should raise concern and a change of >60 ms should raise greater concern regarding the potential for arrhythmias
    • evidence from congenital long QT syndrome indicates that for every 10 ms increase in QTc there is a 5-7% increase in risk of torsades de pointes
  • drug-induced QT prolongation is often dose related and risk of torsades de pointes is increased with intravenous administration (particularly if given rapidly)
  • mechanism for most potential QT-prolonging medications is inhibition of the KCNH2-encoded HERG (human ether-a-go-go related gene) potassium channel (4)

Notes:

• it is beyond the scope of GPnotebook to provide a list of all medicines that prolong the QT interval. The American website http://www.crediblemeds.org/ has regularly updated lists of medicines which cause prolongation of the QT interval. Information can also be found in the British National Formulary (BNF, available via http://www.evidence.nhs.uk/ ), Summaries of Product Characteristics (SPCs, www.medicines.org.uk) and Stockley’s Drug Interactions (subscription required). Medicines information departments and pharmacists can help with determining the risks of individual medicines

Reference:

• CSM/MCA (1996), drug-induced prolongation of the QT interval, Current Problems in Pharmacovigilance, 33, 1-2.
• RCGP (2007). Drug misuse and dependence: UK guidelines on clinical management
• NHS Specialist Pharmacy Service (January 2020). What issues should be considered regarding drug-induced QT prolongation?
• Ayad RF, Assar MD, Simpson L, Garner JB, Schussler JM. Causes and management of drug-induced long QT syndrome. Proc (Bayl Univ Med Cent). 2010 Jul;23(3):250-5.