QT Interval Prolongation and Torsades de Pointes Due toa Coadministration of Metronidazole and AmiodaroneSTAVROS P. KOUNAS, KONSTANTINOS P. LETSAS, ANTONIOS SIDERIS,MICHALIS EFRAIMIDIS, and FOTIOS KARDARASFrom the Second Department of Cardiology, Evagelismos Hospital, Athens, Greece

KOUNAS, S.P., ET AL.: QT Interval Prolongation and Torsades de Pointes Due to a Coadministrationof Metronidazole and Amiodarone. This report documents the occurrence of torsades de pointes (TdP)caused by marked QT interval prolongation in the case of a 71-year-old woman receiving both metronida-zole and amiodarone for the treatment of pseudomembranous colitis and paroxysmal atrial fibrillation.The case highlights a previously unknown drug interaction. The role of inhibition of cytochrome P-450CYP3A4 is discussed. (PACE 2005; 28:472–473)

torsades de pointes, metronidazole, amiodarone

Case ReportA 71-year-old Caucasian woman with a his-

tory of coronary artery bypass grafting and parox-ysmal atrial fibrillation was hospitalized due toantibiotic-associated pseudomembranous colitis.She was started on oral metronidazole, 1,500mg/day in three divided doses. An electrocardio-gram (ECG) on admission demonstrated a QTc in-terval of 440 ms with negative T waves in all pre-cordial leads (Fig. 1A). During the next 3 days, theECG was unchanged. On the third day, the pa-tient developed an episode of atrial fibrillation.Intravenous amiodarone was given as a 450 mgbolus followed by 900 mg/day. Conversion to si-nus rhythm was achieved 2 days later and theECG showed a prolonged QTc interval of 625 ms(Fig. 1B). Later on the patient developed an R onT phenomenon (Fig. 1C) that induced sustainedpolymorphic torsades de pointes (TdP) ventricu-lar tachycardia (Fig. 1D), requiring defibrillationto restore sinus rhythm. Metronidazole and amio-darone were immediately withdrawn. Clinical ex-amination and chest x-rays did not reveal anysignificant findings. Blood tests including serumpotassium and magnesium were within normallimits. Transthoracic echocardiography showed aleft ventricle of normal dimensions with an ejec-tion fraction of 55% and mild mitral and tricuspidvalve regurgitations. During the next 6 days, theQTc interval gradually decreased to its initial val-ues without clinically significant arrhythmias. Thepatient was finally discharged on β-blocking andanticoagulation therapy.

Address for reprints: Stavros P. Kounas, M.D., 14 TrapezoudosStr, Drossia 145 72, Athens, Greece. Fax: 0030-210-8137026;e-mail: skounas@hol.gr

Received April 15, 2004; revised August 17, 2004; acceptedJanuary 14, 2005.

DiscussionA variety of commonly prescribed non-

cardiovascular drugs including antiinfectives, gas-trointestinal prokinetic agents (e.g., cisapride),psychotropic drugs, and certain histamine H1-receptor antagonists, possess the adverse prop-erty of prolonging repolarization and triggeringpolymorphic torsades de pointes (TdP) ventriculartachycardia.1 Azole derivatives, mainly antifungalagents such as ketoconazole, itraconazole, and flu-conazole, have been implicated in drug-inducedTdP due to QT prolongation.2 When taken alone,azoles are associated with a low risk of TdP. Ke-toconazole administration had a minimal effecton QT interval compared with placebo.3 However,cardiac toxicity could arise from the interactionof these drugs with other agents known to prolongthe QT interval. Inhibition of the cytochrome P450CYP 3A4 enzyme system by ketoconazole resultedin the accumulation of unmetabolized terfenadine,a QT prolonging antihistaminic agent, with accom-panying ECG changes.4

Metronidazole, a widely used azole derivativewith antibacterial and antiprotozoal properties, isa potent inhibitor of CYP3A4 and CYP2C9 isoen-zymes, and may therefore be implicated in suchdrug interactions. In a previous study, metron-idazole and ciprofloxacin have been consideredas cytochrome P-450 CYP3A4 inhibitors leadingto decreased clearance of quinidine, a class Iantiarrhythmic agent known to prolong the QTinterval.5

Amiodarone is known to be a class III antiar-rhythmic drug with low torsadogenic activity (lessthan 1%).6 Amiodarone is mainly metabolized bycytochrome P-450 CYP3A4 isoenzyme.7 Drugs orsubstances that inhibit CYP3A4 may lead to in-creased mean and maximum serum concentrationof amiodarone.8 Although amiodarone pharma-cokinetics are difficult to define, higher serum con-centrations are associated with increased risk forside effects such as QT interval prolongation.9

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DRUG-INDUCED TORSADES DE POINTES

Figure 1. (A) ECG on admission. (B) ECG showing QT prolongation. (C) ECG showing an R on Tphenomenon. (D) Twisting of the QRS axis around the isoelectric line of the ECG.

In our patient, a strong temporal relationexisted between metronidazole and amiodaronecoadministration and the development of TdP.Therefore, a possible drug interaction betweenmetronidazole and amiodarone might have oc-curred leading to marked QT interval prolongationand TdP.

Drug-induced QT interval prolongation mostcommonly occurs in a susceptible group of pa-tients that carries silent mutations in one of thegenes responsible for the congenital long QT syn-drome. These patients are unexpectedly at highrisk of developing TdP if exposed to either cardiacor noncardiovascular drugs that block potassiumchannels.10

References1. Stratmann HG, Kennedy HL. Torsades de pointes associated with

drugs and toxins: Recognition and management. Am Heart J 1987;113:1470–1482.

2. Wassmann S, Nickenig G, Bohm M. Long QT syndrome and torsadede pointes in a patient receiving fluconazole. Ann Intern Med 1999;131:797.

3. Paserchia LA, Hewett J, Woosley RL. Effects of ketoconazole onQTc. (abstract) Clin Pharmacol Ther 1994; 55:146.

4. Honig PK, Wortham DC, Zamani K, et al. Terfenadine-ketoconazoleinteraction: Pharmacokinetic and electrocardiographic conse-quences. JAMA 1993; 269:1513–1518.

5. Cooke CE, Sklar GE, Nappi JM. Possible pharmacokinetic interac-tion with quinidine: Ciprofloxacin or metronidazole? Ann Pharma-cother 1996; 30:364–366.

6. Hohnloser SH, Klingenheben T, Singh BN. Amiodarone-associatedproarrhythmic effects. A review with special reference to tor-

sade de pointes tachycardia. Ann Intern Med 1994; 121:529–535.

7. Fabre G, Julian B, Saint-Aubert B, et al. Evidence for CYP3A-mediated N-deethylation of amiodarone in human liver microso-mal fractions. Drug Metab Dispos 1993; 21(6):978–985.

8. Libersa CC, Brique SA, Motte KB, et al. Dramatic inhibition of amio-darone metabolism induced by grapefruit juice. Br J Clin Pharmacol2000; 49(4):373–378.

9. Pollak PT, Sharma AD, Carruthers SG. Correlation of amiodaronedosage, heart rate, QT interval and corneal microdeposits withserum amiodarone and desethylamiodarone concentrations. AmJ Cardiol 1989; 64(18):1138–1143.

10. Napolitano C, Schwartz PJ, Brown AM, et al. Evidence for a cardiacion channel mutation underlying drug-induced QT prolongationand life threatening arrhythmias. J Cardiovasc Electrophysiol 2000;11:691–696.

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