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2005 VOLUME 7 ISSUE 3 tox pdate UTAH POISON CONTROL CENTER Drug-Induced QT Prolongation Introduction Drug-induced prolongation of the QT interval has been known to occur after administration of antiarrhythmics for more than 20 years.1 Recently, drug-induced long QT syndrome (LQTS) has been observed after administration of non-antiarrhythmic medications.1 The additional attention paid to the mechanisms of hereditary QT prolongation has led to numerous advances in our understanding of how drugs produce QT prolongation.1 Torsades de Pointes (TdP) is a concern in any patient receiving a drug with QT prolonging potential. TdP is a polymorphic ventricular arrhythmia which may result from LQTS and can lead to cardiac arrest. At least nine drugs have been withdrawn from the market world-wide because of their propensity to cause TdP. In fact, more drugs have been removed from the market within the past 10 years in the United States for increased risk for TdP than any other reason.2 Fortunately, the risk of developing TdP is small (<0.01% in the absence of risk factors)3 despite prolongation of the QT interval. This is because the etiology of TdP is more complex than simple QT prolongation.2 This review will discuss the pathophysiology, causes and management of drug-induced QT prolongation. Pathophysiology The length of the QT interval is inversely related to the heart rate. The faster the heart rate the shorter the QT interval. The most common method to eliminate the effect of the heart rate is the Bazett formula for the QTc, which divides the QT interval by the square root of the RR interval. The QT interval is equal to the QTc interval when the heart rate is 60 bpm.1 Normal QTc intervals are less than 430 ms for males and less than 450 ms for females. It is not considered prolonged until it exceeds 450 ms in males and 470 ms in females. Lengthening of the QT interval occurs when cardiac repolarization is delayed. Depolarization occurs when positive ions (mostly sodium) flow into the ventricular myocyte and repolarization when positive ions (potassium) flow out. The action potential is lengthened when there is an augmentation of inward depolarizing currents or inhibition of outward repolarizing potassium currents in ventricular myocytes.2 Most types of congenital LQTS are a result of genetic mutations in the ion channels active during the ‘plateau’ phase (phase 2) of the action potential responsible for the delicate balance between depolarization and repolarization. Drugs that prolong the QT interval (drug-induced LQTS) almost universally interfere with potassium outflow through the rapidly activating delayed rectifier potassium channels (IKr).1 The IKr channels are coded for by the human Ether-à-go-go Related Gene (hERG) and are also called hERG channels. Other potassium channels may also be implicated in drug-induced QT prolongation.2 Recent studies have shown variability in the sensitivity of cardiac myocytes to pharmacologic interference with repolarization based on location within the myocardium.2 Myocytes within the endocardium and epicardium are less susceptible to QT prolongation by certain pharmacologic agents than are mid-myocardium cells (M cells) found in the deep structures of the ventricular myocardium. This difference in susceptibility is due to ion flow through membrane channels (smaller IKs and a larger late INa and sodium-calcium exchange current (INa-Ca)). Agents known to cause TdP (quinidine, sotalol, etc.) do so through a transmural dispersion of repolarization. Repolarization is delayed in one region of the myocardium (M cells) more than in another region (endocardium and epicardium). The end result is a lengthened T-wave on the surface ECG. TdP develops in experimental models when the time difference in repolarization between the M cells and other regions of the ventricular myocardium approaches 90 ms. When endocardial and epicardial depolarization occur before M cell repolarization is complete, TdP results.4 This premature depolarization is also called early afterdepolarization (EAD).5 A Program of the University of Utah College of Pharmacy Drugs causes of QTc prolongation Table 3. Drugs in Overdose Associated with TdP7 methadone lithium thioridazine risperidone quetiapine ziprasidone venlafaxine nortriptyline amitriptyline imipramine desipramine paroxetine fluoxetine arsenic sertraline fluoride propoxyphene haloperidol The occurrence of TdP in patients not taking class IA, 1C, and III antiarrhythmics is due to an idiosyncratic reaction. Several reviews have identified female gender as the most common risk factor in patients who developed TdP.1 A variety of other risk factors have also been identified and are listed in Table 1. Table 1. Risk Factors for TdP with QTc Prolongation6 Female gender Heart disease (heart failure, cardiomyopathies,hypertrophy) Hypokalemia Concomitant administration of multiple QT-prolonging drugs Bradycardia Familial history of LQTS Recent conversion of atrial fibrillation with a QTprolonging drug Hypocalcemia Hypomagnesemia High levels of a QT-prolonging drug More than 70 commercially available and investigational drugs have been implicated in QTc prolongation.2 The University of Arizona maintains a list of currently available medications that cause QTc prolongation 7 (www.torsades.org). Table 2 lists examples of general drug Table 2. Drug Classes and Specific Drugs Associated with TdP7 Drug Class Specific Examples Macrolide antibiotics erythromycin, clarithromycin Antifungals voriconazole Fluoroquinolone antibiotics gemifloxacin, sparfloxacin, gatifloxacin, levofloxacin Antipsychotics haloperidol, chlorpromazine, thioridazine Antiemetics cisapride, promethazine, dolasetron, droperidol Antiarrhythmics ibutilide, amiodarone, dofetilide, quinidine, sotalol, disopyramide, procainamide Miscellaneous methadone classes associated with QTc prolongation and specific drugs of concern. A more complete list can be found elsewhere.7 QT prolongation and risk for TdP is most likely to occur during therapeutic administration of medications. However, QT prolongation may also occur after an acute overdose. Table 3 lists drugs commonly associated with QT prolongation in overdose. Magnesium Treatment for Prolonged QTc and TdP Prolongation of the QTc is harmless by itself, but patients have increased risk of developing TdP and resultant cardiac arrest when their QTc exceeds 500 ms.6 Magnesium chloride has been shown to prevent depolarization at action potentials larger than -70 mV (the usual trigger point) and suppress early afterdepolarizations in canine cardiac myocytes.5 However, magnesium sulfate failed to correct QTc intervals lengthened by haloperidol overdose in a canine model.8 In a case series of 12 patients with QTc in intervals ranging from 540 to 720 ms who developed TdP, intravenous magnesium sulfate (2-4 grams IV bolus) successfully reversed TdP and prevented its recurrence.9 No significant changes in the QTc interval were observed after treatment. The mechanism by which magnesium functions to reverse and prevent TdP without shortening a prolonged QTc interval remains uncertain. Current theories include acting as a cofactor to enhance sodium-potassium ATPase function, stabilizing the membrane potential and correcting dispersed repolarization.8 There are no published guidelines for magnesium administration in the setting of QTc prolongation that are based on prospective studies. However, it is reasonable to administer magnesium intravenously to every patient with a QTc exceeding 500 ms. Patients who possess any of the The Utah Poison Control Center expresses its sincere thanks to MCNEIL CONSUMER & SPECIALTY PHARMACEUTICALS for their generous contribution that allows us to produce and distribute this newsletter. Administrative (801) 587-0600 • http://uuhsc.utah.edu/poison Page 2 common risk factors (see Table 1) may also benefit from magnesium administration when their QTc is > 450 ms in males or > 470 ms in females. Management The first step in managing patients with QT prolongation is discontinuation of the offending agent. Maintain serum potassium concentrations between 4 and 4.5 mmol/L as hypokalemia has been associated with LQTS. For asymptomatic patients, magnesium sulfate 1-2 gm over 2 minutes is appropriate. For symptomatic patients, or those with TdP, administer a 2 gm IV bolus of magnesium sulfate infused over 30-60 seconds and repeat every 5-15 minutes as needed. Continuous magnesium sulfate infusions of 2-4 mg/min may be required. Monitor the serum magnesium concentrations and for clinical signs of magnesium toxicity (depressed deep tendon reflexes, muscle weakness, bradycardia). Large doses of magnesium sulfate may result in hypotension and cardiac arrest. Patients refractory to magnesium administration or those with long pauses after premature ventricular contractions may require cardiac pacing to prevent development of TdP.1 QT prolongation after tricyclic antidepressant (TCA) overdose will usually present with QRS widening as well. Sodium bicarbonate infusion is the therapy of choice for these patients.10 Meet the UPCC Staff Marty Malheiro has been the Outreach Education Provider for the UPCC since November 2003. She holds a master’s degree in health education from the University of Utah, and is a Certified Health Education Specialist (CHES). She is a member of the AAPCC’s Public Education Committee on E-Resource. In her short time at the center, she has traveled from one end of the state to the other giving public education presentations on poison prevention and awareness. Marty’s favorite poison education topic is senior medication management. She is married and has two awesome daughters, a dog, and a cat. She loves to knit and play in the outdoors. 6. Roden DM. Drug-Induced Prolongation of the QT Interval. N Engl J Med 2004;350:1013-22. 7. www.torsades.org; accessed April 14, 2005. 8. Satoh Y, Sugiyama A, Tamura K, Hashimoto K. Effect of magnesium sulfate on the haloperidol-induced QT prolongation assessed in the canine in vivo model under the monitoring of monophasic action potential. Jpn Circ J. 2000;64:445-451. 9. Tzivoni D, et al. Treatment of torsade de pointes with magnesium sulfate. Circulation 1988;77:392–7. 10. Kerr GW, McGuffie AC, Wilkie S. Tricyclic antidepressant overdose: a review. Emerg Med J 2001;18:236–41. Summary New Employees QT prolongation may occur following therapeutic and toxic doses of a number of drugs. Magnesium sulfate is a viable therapeutic option in the treatment of patients with QTc prolongation or TdP. The UPCC is available for consultation regarding the management of overdose patients with drugs that prolong the QTc interval. The Utah Poison Control Center is pleased to welcome Remington Johnson as our new customer satisfaction survey intern. Remington is a senior in the Political Science Department and the History Department at The University of Utah. We are also pleased to have Mike Andrus, Chad Condie and Mike Whipple join us as Poison Information Providers. Mike, Chad and Mike are all students in the University of Utah Doctorate of Pharmacy program. Welcome! Joshua Walsh, PharmD References 1. Abriel H, Schlapfer J, Keller DI, Gavillet B, Buclin T, Biollaz J, Stoller R, Kappenberger L. Molecular and clinical determinants of drug-induced long QT syndrome: an iatrogenic channelopathy. Swiss Med Wkly. 2004;134:685-94. 2. Antzelevitch C. Arrhythmogenic mechanisms of QT prolonging drugs: is QT prolongation really the problem? J Electrocardiol. 2004;37 Suppl:1524. 3. Frothingham, R. Rates of torsades de pointes associated with ciprofloxacin, ofloxacin, levoflocacin, gatifloxacin, and moxifloxacin. Pharmacology 2001;21:1468-72. 4. Shimizu W, Antzelevitch C. Cellular basis for the ECG features of the LQT1 form of the long QT syndrome: Effects of b-adrenergic agonists and antagonists and sodium channel blockers on transmural dispersion of repolarization and Torsade de Pointes. Circulation 1998;98:2314-22. 5. Kaseda S, Gilmour RF Jr, Zipes DP. Depressant effect of magnesium on early afterdepolarizations and triggered activity induced by cesium, quinidine, and 4-aminopyridine in canine cardiac Purkinje fibers. Am Heart J. 1989;118:458-66. A Publication for Health Professionals Public Education Checkout the UPCC website at http://uuhsc.utah.edu/poison for public education updates. The POISON Poison ANITDOTE, antidote our seasonal newsletter, highlights current prevention topics. Look for our new plant identification page coming in September. It will have a searchable database, as well as color photographs of common poisonous plants in Utah. Page 3 Utah Poison Control Center Staff Employment Opportunities The UPCC has an open position available. You can find out more about this position on our website at http://uuhsc.utah.edu/poison/employment. Director Barbara Insley Crouch, PharmD, MSPH Medical Director E. Martin Caravati, MD, MPH Associate Medical Director Douglas E. Rollins, MD, PhD Assistant Director Heather Bennett, MPA Office Support Julie Gerstner Specialists in Poison Information Kathleen T. Anderson, PharmD, CSPI* Bradley D. Dahl, PharmD, CSPI* Su Bryner-Brown, RN, BSN David Evans, PharmD, RPh, CSPI* Scott Marshall, PharmD, CSPI* Deborah Melle, RN, BS Ed Moltz, RN, BSN, CSPI* Sandee Oliver, RN, BSN John Stromness, BS Pharm, RPh, CSPI* Mary Towns, BSN, MS, APRN, CSPI* Erlynn R. Wallace, RN, CSPI* Poison Information Providers Michael Andrus Chad Condie Michael Whipple UPCC 2004 Annual Report The UPCC is pleased to announce the publication of its 2004 Annual Report. This report provides a summary of the calls received by the UPCC in 2004. In addition, the report highlights the many and varied outreach educational activities of the UPCC. The report can be found on the UPCC website at http://uuhsc.utah.edu/poison. Follow the link for “About us” and select annual reports. Shortly the 2004 Annual Report of the American Association of Poison Control Centers Toxic Exposure Surveillance System will be published. This report characterizes over 2 million poison exposures reported to over 60 poison centers nationwide. The report can be found at the AAPCC website at www.aapcc.org. Follow the link for “Poisoning DataTESS” and choose annual reports. Alternatively, look for the report published in the September issue of the American Journal of Emergency Medicine. Utah Poison Control Center 585 Komas Dr., Suite 200 Salt Lake City, UT 84108 NON-PROFIT ORG. U.S. POSTAGE PAID Salt Lake City, Utah Permit No. 1529 ADDRESS SERVICE REQUESTED Outreach Education Provider Marty C. Malheiro, MS, CHES Intern, Community Outreach Joel Arvizo Survey Intern Remington Johnson UTOX Editors E. Martin Caravati, MD, MPH Barbara Insley Crouch, PharmD, MSPH Publisher Heather Bennett, MPA Please send comments and suggestions for future articles to the editor of UTOX Update at: 585 Komas Dr., Suite 200 Salt Lake City, Utah 84108 Or send e-mail to [email protected] *CSPI denotes Certified Specialist in Poison Information. http://uuhsc.utah.edu/poison Page 4