QT interval prolongation due to metronidazole administration/Metronidazol uygulamasina bagli QT uzamasi

The drug induced Q-T prolongation might lead to torsades de pointes (TdP), ventricular tachycardia and sudden cardiac death. Several antimicrobial agents, such as erythromycin, clarithromycin, fluoroquinolones, halofantrine and pentamidine can cause QT prolongation. Metronidazole is a widely used antimicrobial agent and the effect of this drug on QT interval is not well documented (1).

A 71-year-old female patient was admitted to emergency unit with severe dyspnea, angina, and orthopnea symptoms in the preceding 5 days. She was on treatment for chronic obstructive lung disease, diabetes mellitus, hypertension and coronary artery disease. She also had a history of drug-induced QT prolongation associated with moxifloxacin. Electrocardiogram (ECG) on admission showed atrial fibrillation with a ventricular rate of 82 /minute. The corrected Q-T interval was 396 msec (Fig. 1). She was treated with diuretics, angiotensin converting enzyme inhibitors, omeprazole and bronchodilators. On follow up diagnosis of nosocomial pneumonia was made and intravenous metronidazole was initiated. Two days after the initiation of antimicrobial therapy, the QT interval prolonged (corrected Q-T interval, 559 msec) and the T waves were inverted (Fig. 2). Laboratory tests, including serum potassium and magnesium levels, were within normal limits. Metronidazole was immediately stopped and the ECG of the patient returned to normal within 48- hours.

Commonly prescribed drugs, such as antibiotics, psychotropic agents and histamine H1-receptor antagonists, can prolong cardiac repolarization and might trigger a polymorphic ventricular tachycardia called torsades de pointes (1). Azole derivatives including ketoconazole, itraconazole and fluconazole can also prolong QT and trigger TdP directly or by interacting with other QT prolonging agents (2).

The mechanism of QT prolongation during metronidazole administration is unclear. Metronidazole is a widely used antimicrobial medication and is a potent inhibitor of CYP3A4 and CYP2C9 isoenzymes. Theoretically, it may cause QT prolongation by inhibiting the metabolism of other drugs that have potential to cause QT prolongation. The patient was also taking omeprazole. Omeprazole is also a competitive inhibitor of the enzymes CYP2C19 and CYP2C9, and may therefore interact with drugs that depend on them for metabolism (3). As a result of this mechanism metronidazole with the concomitant use of omeprazole may cause indirectly QT prolongation and TdP through its interaction with other QT prolonging agents (4). However, in our case, the patient was not taking any other medications that may interact with these enzymes or have potential to cause QT prolongation. We thought that metronidazole caused QT prolongation by another mechanism that we do not know. There is only one case in the literature showing that metronidazole alone can cause QT prolongation (5).

In our patient there were no predisposing factors for QT prolongation such as electrolyte imbalance or administration of other medications known to prolong QT interval. There were no medications discontinued within a relatively short time line before initiating metronidazole. She had similar problems in the past associated with fluoroquinolone use and might therefore be a carrier of a silent mutation in one of the congenital long QT syndrome-associated genes.

These patients are at high risk for developing QT prolongation and TdP when exposed to drugs which affect potassium channels. As a result the arrhythmogenic properties of metronidazole should be evaluated carefully, and avoid prescribing to patients at high risk for druginduced TdP, such as elderly patients with structural heart disease, renal failure or impaired liver function.

Metronidazole is widely used antimicrobial agent and the potential of this agent to prolong QT is not well documented. This case report shows that intravenous metronidazole can prolong QT interval in susceptible patients and it should be used with close monitoring of the ECG.

References

References

1. Viskin S, Justo D, Halkin A, Zeltser D. Long QT syndrome caused by noncardiac drugs. Prog Cardiovasc Dis 2003; 45: 415-27.

2. Justo D, Zeltser D. Torsade de pointes induced by systemic antifungal agents: lessons from a retrospective analysis of published case reports. Mycoses 2006; 49: 463-70.

3. Stedman CA, Barclay ML. Review article: comparison of the pharmacokinetics, acid suppression and efficacy of proton pump inhibitors. Aliment Pharmacol Ther 2000; 14: 963-78.

4. Kounas SP, Letsas KP, Sideris A, Efraimidis M, Kardaras F. QT interval prolongation and torsades de pointes due to a coadministration of metronidazole and amiodarone. Pacing Clin Electrophysiol 2005; 28: 472-3.

5. Cohen O, Saar N, Swartzon M, Kliuk-Ben-Bassat O, Justo D. First report of metronidazole-induced QT interval prolongation. Int J Antimicrob Agents 2008; 31: 180-1.