Drug-induced QT prolongation.

What do the following drugs all have in common?--grepafloxacin (Raxar), terfenadine (Seldane), cisapride (Propulsid), and astemizole (Hismanal). Each of these were once commercially available products, approved by the US Food and Drug Administration (FDA) to treat a variety of ailments. Unfortunately, postmarketing surveillance revealed that each of these agents could cause prolongation of the QT interval which potentially could lead to the development of a life threatening arrhythmia (ie, torsade de pointes). (1,2,3)

This topic is discussed in this issue of the Southern Medical Journal in the article by Goldner et al entitled, "The Effect of Ciprofloxacin and Levofloxacin on the QT Interval: Is This a Significant 'Clinical Event?'" (4) This particular study compares the QT prolongation of two quinolone antibiotics, a class of drugs that has been associated with inducing arrhythmias. Because of the potential severity and the unpredictability of this adverse reaction, medical researchers and the pharmaceutical industry have spent considerable time investigating this drug-induced occurrence. (1,2,3)

Over the past decade much information has been learned about this side effect. Because it is theorized that even a small increase in the QT interval may lead to the development of a life-threatening arrhythmia, the pharmaceutical industry has spent a great deal of time and money investigating why certain drugs induce QT prolongation and which subjects are more prone to this adverse reaction. Because life-threatening manifestations of QT prolongation are generally quite rare in premarketing trials with new drugs, this serious side effect has historically not been recognized until the medication is approved and introduced into the general population and used by many more individuals. Being able to predict how this side effect occurs and which patients are at greatest risk can greatly help reduce the incidence of drug-induced QT prolongation. (1,2,3)

QT prolongation appears to be a result of delayed ventricular repolarization which may be mediated by an efflux of intracellular potassium. Researchers believe that certain drugs can potentially impede the flow of potassium through these channels thus setting up an environment conducive to developing prolongation of the QT interval. Certain individuals appear to be more susceptible than others: females; the elderly; individuals with electrolyte disturbances, congestive heart failure and other cardiac abnormalities. Also, using two or more drugs concurrently that affect this potassium channel can also lead to a greater incidence of QT prolongation. (1,2,3)

QT prolongation appears to be a dose-dependent side effect, thus, individuals who are prone to drug accumulation may be at greater risk. With a greater understanding of hepatic drug metabolism and the cytochrome P-450 enzyme system, the FDA and the pharmaceutical industry have developed techniques to assess how specific agents are metabolized. (5) Some individuals may metabolize particular drugs more slowly than others, making side effects more prevalent. Drugs metabolized via particular CYP-450 enzymes (ie, CYP3A4) may also be greatly affected by interactions from other drugs leading to potential drug accumulation. As an example, when the nonsedating antihistamine terfenadine was commercially available, certain "azole" antifungal agents had the potential to increase concentrations of terfenadine by inhibiting its metabolism thus increasing the prevalence of terfenadine side effects (eg, QT prolongation). (1,2,3)

Practitioners must have a thorough understanding of this potential adverse effect to avoid its occurrence in their patients. A recent study by Al-Khatib et al demonstrated that many health care practitioners do not understand how to correctly measure QT intervals. (6) Knowing which drugs can prolong the QT interval and being able to properly assess this side effect is necessary to its prevention. The following website is devoted to collecting information (from practitioners) on "long QT syndrome" and it may offer physicians some up-to-date information on the subject: http://www.qtsyndrome.ch/index.html. (7)

Before new agents are prescribed, physicians must be aware of potential adverse effects like QT prolongation and possible drug interactions which might potentiate these adverse effects. Medications known to prolong the QT interval should be avoided in those patients at risk. Hopefully, in the future, this potential side effect can be avoided.

References

1. Liu BA, Juurlink DN. Drugs and the QT interval--Caveat Doctor. N Engl J Med 2004;351:1053-1056.

2. Gussak I, et al. Drug induced cardiac toxicity: Emphasizing the role of electrocardiography in clinical research and drug development. J Electrocard 2004;37:19-24.

3. Roden DM. N Engl J Med 2004;350:1013-1022.

4. Makaryus AN, Byrns K, Makaryus MN, et al. The effect of ciprofloxacin and levofloxacin on the QT interval: Is this a significant 'clinical event?' South Med J 2006;99:52-56.

5. Wilkinson GR. Drug metabolism and variability among patients in drug response. N Engl J Med 2005;352:2211-2221.

6. Al-Khatib SM, et al. Al. A survey of health care practitioners' knowledge of the QT interval. J Gen Intern Med 2005; 20:392-396.

7. Mettler JN, Moroz PD, Sersa A, et al. QTSyndrome.ch website, Zurich, Switzerland. Reviewed December 15, 2005.

James M. Wooten, PHARMD

From the University of Missouri, Kansas City School of Medicine, Kansas City, MO.

Reprint requests to James M. Wooten, PharmD, University of Missouri, Kansas City School of Medicine, Gold Unit 4, 2411 Holmes Street, Kansas City, MO 64108. Email: [e-mail]

Accepted August 29, 2005.