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Drug-Induced QT Interval Prolongation and Torsade De Pointes: Identification of Risk Factors

Year 2010, Volume: 2010 Issue: 1, 49 - 53, 01.01.2010

Abstract

A progressively increasing number of non-cardiac agents prolong cardiac repolarization predisposing to polymorphic ventricular tachycardia, termed torsade de pointes (TdP), and sudden cardiac death. Drug-induced QT interval prolongation is considered the most frequent cause of withdrawal or relabeling of marketed drugs. Although the exact mechanisms are incompletely understood, the majority of these agents exhibit direct electrophysiological effects on the rapidly activating delayed rectifier potassium current. Additionally, pharmacokinetic interactions with drugs known to inhibit cytochrome P450 isoenzymes may enhance the torsadogenic potential of these agents. Genetic analyses have identified the subclinical congenital form in 5-10% of patients with drug-induced long QT syndrome. The likelihood of drug-induced long QT syndrome is difficult to be predicted in routine clinical practice. However, clinical history may reveal well-established risk factors that act as “effect amplifiers” making an otherwise relatively safe drug dangerous with regard to risk for TdP. The current review describes the underlying mechanisms of drug-induced QT interval prolongation and TdP as well as the risk factors that predispose to this potentially life-threatening conditions. Kardiyoloji alanı dışında kullanılmakta olan önemli sayıda ilaç, Torsade de pointes (TdP), olarak isimlendirilen, polimorfik ventrikül taşikardisine ve ani kardiyak ölüme zemin hazırlayan kardiyak repolarizasyonu uzatmaktadır Piyasadaki ilaçların toplatılmasının ya da yeniden sürülmesinin en sık nedeninin ilaca bağlı QT interval uzaması olduğu görülmektedir. Tam işleyişleri bütünüyle anlaşılamamasına rağmen, bu ilaçların çoğunluğu gecikmiş düzenleyici potasyum akımını hızlıca etkinleştirerek doğrudan elektrofizyolojik etkiler gösterir. Ek olarak, sitokrom P450 isoenzimlerini baskıladığı bilinen ilaçlar ile farmakokinetik etkileşimleri bu ilaçların proaritmik etkilerini artırabilir. Genetik analizler, ilaca bağlı uzun QT sendromlu hastaların %5-10'unda doğuştan subklinik form ortaya koymuştur. İlaca bağlı uzun QT sendromu ihtimalinin rutin klinik uygulamada tahmin edilmesi zordur. Ancak, klinik öykü, normalde TdP riskiaçısından oldukça güvenli bir ilacı tehlikeli hale sokan “etki yükseltici“ olarak rol oynayan iyi belirlenmiş risk faktörlerini açığa çıkarabilir. Bu derlemede ilaca bağlı QT uzaması ve TdP mekanizmaları ve yaşamı tehdit eden durumlara zemin hazırlayan risk faktörleri ele alınmaktadır.

References

  • Letsas KP, Efremidis M, Filippatos GS, Sideris AM. Drug- induced long QT syndrome. Hellenic J Cardiol 2007;48:296- 9.
  • Letsas KP, Filippatos GS, Kounas SP, Efremidis M, Sideris A, Kardaras F. QT interval prolongation and Torsades de Pointes in a patient receiving zolpidem and amiodarone. Cardiology 2006;105:146-7.
  • 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.
  • Letsas K, Korantzopoulos P, Pappas L, Evangelou D, Efremidis M, Kardaras F. QT interval prolongation asso- ciated with venlafaxine administration. Int J Cardiol 2006;109:116-7.
  • Roden DM. Drug-induced prolongation of the QT interval. N Engl J Med 2004;350:1013-22.
  • De Ponti F, Poluzzi E, Montanaro N, Ferguson J. QTc and psychotropic drugs. Lancet 2000;356:75-6.
  • Heist EK, Ruskin JN. Drug-induced proarrhythmia and use of QTc-prolonging agents: clues for clinicians. Heart Rhythm 2005;2(2 Suppl):S1-8.
  • Straus SM, Sturkenboom MC, Bleumink GS, Dieleman JP, van der Lei J, de Graeff PA, et al. Non-cardiac QTc- prolonging drugs and the risk of sudden cardiac death. Eur Heart J 2005;26:2007-12.
  • Viskin S, Rosovski U, Sands AJ, Chen E, Kistler PM, Kalman JM, et al. Inaccurate electrocardiographic interpretation of long QT: the majority of physicians cannot recognize a long QT when they see one. Heart Rhythm 2005;2:569-74.
  • Garson A Jr. How to measure the QT interval--what is nor- mal? Am J Cardiol 1993;72:14B-16B.
  • Viskin S, Justo D, Halkin A, Zeltser D. Long QT syn- drome caused by noncardiac drugs. Prog Cardiovasc Dis 2003;45:415-27.
  • Yap YG, Camm AJ. Drug induced QT prolongation and torsades de pointes. Heart 2003;89:1363-72.
  • Algra A, Tijssen JG, Roelandt JR, Pool J, Lubsen J. QTc prolongation measured by standard 12-lead electrocardiog- raphy is an independent risk factor for sudden death due to cardiac arrest. Circulation 1991;83:1888-94.
  • Bednar MM, Harrigan EP, Ruskin JN. Torsades de pointes associated with nonantiarrhythmic drugs and observations on gender and QTc. Am J Cardiol 2002;89:1316-9.
  • Priori SG, Schwartz PJ, Napolitano C, Bloise R, Ronchetti E, Grillo M, et al. Risk stratification in the long-QT syndrome. N Engl J Med 2003;348:1866-74.
  • Bednar MM, Harrigan EP, Anziano RJ, Camm AJ, Ruskin JN. The QT interval. Prog Cardiovasc Dis 2001;43(5 Suppl 1):1-45.
  • Antzelevitch C, Sicouri S, Di Diego JM, Burashnikov A, Viskin S, Shimizu W, et al. Does Tpeak-Tend provide an index of transmural dispersion of repolarization? Heart Rhythm 2007;4:1114-6.
  • Kanters JK, Haarmark C, Vedel-Larsen E, Andersen MP, Graff C, Struijk JJ, et al. T(peak)T(end) interval in long QT syndrome. J Electrocardiol 2008;41:603-8.
  • Yamaguchi M, Shimizu M, Ino H, Terai H, Uchiyama K, Oe K, et al. T wave peak-to-end interval and QT dispersion in acquired long QT syndrome: a new index for arrhythmoge- nicity. Clin Sci 2003;105:671-6.
  • Gupta A, Lawrence AT, Krishnan K, Kavinsky CJ, Trohman RG. Current concepts in the mechanisms and management of drug-induced QT prolongation and torsade de pointes. Am Heart J 2007;153:891-9.
  • Kannankeril PJ, Roden DM. Drug-induced long QT and torsade de pointes: recent advances. Curr Opin Cardiol 2007;22:39-43.
  • Antzelevitch C. Role of transmural dispersion of repolar- ization in the genesis of drug-induced torsades de pointes. Heart Rhythm 2005;2(2 Suppl):S9-15.
  • Kay GN, Plumb VJ, Arciniegas JG, Henthorn RW, Waldo AL. Torsade de pointes: the long-short initiating sequence and other clinical features: observations in 32 patients. J Am Coll Cardiol 1983;2:806-17.
  • Schulze-Bahr E. Susceptibility genes and modifiers for car- diac arrhythmias. Prog Biophys Mol Biol 2008;98:289-300.
  • Priori SG, Napolitano C, Schwartz PJ. Low penetrance in the long-QT syndrome: clinical impact. Circulation 1999;99:529-33.
  • Yang P, Kanki H, Drolet B, Yang T, Wei J, Viswanathan PC, et al. Allelic variants in long-QT disease genes in patients with drug-associated torsades de pointes. Circulation 2002;105:1943-8.
  • Letsas KP, Efremidis M, Kounas SP, Pappas LK, Gavrielatos G, Alexanian IP, et al. Clinical characteristics of patients with drug-induced QT interval prolongation and torsade de pointes: identification of risk factors. Clin Res Cardiol 2009;98:208-12.
  • Zeltser D, Justo D, Halkin A, Prokhorov V, Heller K, Viskin S. Torsade de pointes due to noncardiac drugs: most patients have easily identifiable risk factors. Medicine 2003;82:282-90.
  • Arya A. Gender-related differences in ventricular repolariza- tion: beyond gonadal steroids. J Cardiovasc Electrophysiol 2005;16:525-7.
  • Curtis LH, Østbye T, Sendersky V, Hutchison S, Allen LaPointe NM, Al-Khatib SM, et al. Prescription of QT-prolonging drugs in a cohort of about 5 million outpa- tients. Am J Med 2003;114:135-41.
  • Banai S, Tzivoni D. Drug therapy for torsade de pointes. J Cardiovasc Electrophysiol 1993;4:206-10.
  • Khan IA. Clinical and therapeutic aspects of congenital and acquired long QT syndrome. Am J Med 2002;112:58-66.
  • Viskin S. Torsades de Pointes. Curr Treat Options Cardiovasc Med 1999;1:187-95.

İlaca Bağlı QT İnterval Uzaması ve Torsade De Pointes: Risk Faktörlerinin Saptanması

Year 2010, Volume: 2010 Issue: 1, 49 - 53, 01.01.2010

Abstract

Kardiyoloji alanı dışında kullanılmakta olan önemli sayıda ilaç, Torsade de pointes (TdP), olarak isimlendirilen, polimorfik ventrikül taşikardisine ve ani kardiyak ölüme zemin hazırlayan kardiyak repolarizasyonu uzatmaktadır Piyasadaki ilaçların toplatılmasının ya da yeniden sürülmesinin en sık nedeninin ilaca bağlı QT interval uzaması olduğu görülmektedir. Tam işleyişleri bütünüyle anlaşılamamasına rağmen, bu ilaçların çoğunluğu gecikmiş düzenleyici potasyum akımını hızlıca etkinleştirerek doğrudan elektrofizyolojik etkiler gösterir. Ek olarak, sitokrom P450 isoenzimlerini baskıladığı bilinen ilaçlar ile farmakokinetik etkileşimleri bu ilaçların proaritmik etkilerini artırabilir. Genetik analizler, ilaca bağlı uzun QT sendromlu hastaların %5-10'unda doğuştan subklinik form ortaya koymuştur. İlaca bağlı uzun QT sendromu ihtimalinin rutin klinik uygulamada tahmin edilmesi zordur. Ancak, klinik öykü, normalde TdP riskiaçısından oldukça güvenli bir ilacı tehlikeli hale sokan “etki yükseltici“ olarak rol oynayan iyi belirlenmiş risk faktörlerini açığa çıkarabilir. Bu derlemede ilaca bağlı QT uzaması ve TdP mekanizmaları ve yaşamı tehdit eden durumlara zemin hazırlayan risk faktörleri ele alınmaktadır.

References

  • Letsas KP, Efremidis M, Filippatos GS, Sideris AM. Drug- induced long QT syndrome. Hellenic J Cardiol 2007;48:296- 9.
  • Letsas KP, Filippatos GS, Kounas SP, Efremidis M, Sideris A, Kardaras F. QT interval prolongation and Torsades de Pointes in a patient receiving zolpidem and amiodarone. Cardiology 2006;105:146-7.
  • 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.
  • Letsas K, Korantzopoulos P, Pappas L, Evangelou D, Efremidis M, Kardaras F. QT interval prolongation asso- ciated with venlafaxine administration. Int J Cardiol 2006;109:116-7.
  • Roden DM. Drug-induced prolongation of the QT interval. N Engl J Med 2004;350:1013-22.
  • De Ponti F, Poluzzi E, Montanaro N, Ferguson J. QTc and psychotropic drugs. Lancet 2000;356:75-6.
  • Heist EK, Ruskin JN. Drug-induced proarrhythmia and use of QTc-prolonging agents: clues for clinicians. Heart Rhythm 2005;2(2 Suppl):S1-8.
  • Straus SM, Sturkenboom MC, Bleumink GS, Dieleman JP, van der Lei J, de Graeff PA, et al. Non-cardiac QTc- prolonging drugs and the risk of sudden cardiac death. Eur Heart J 2005;26:2007-12.
  • Viskin S, Rosovski U, Sands AJ, Chen E, Kistler PM, Kalman JM, et al. Inaccurate electrocardiographic interpretation of long QT: the majority of physicians cannot recognize a long QT when they see one. Heart Rhythm 2005;2:569-74.
  • Garson A Jr. How to measure the QT interval--what is nor- mal? Am J Cardiol 1993;72:14B-16B.
  • Viskin S, Justo D, Halkin A, Zeltser D. Long QT syn- drome caused by noncardiac drugs. Prog Cardiovasc Dis 2003;45:415-27.
  • Yap YG, Camm AJ. Drug induced QT prolongation and torsades de pointes. Heart 2003;89:1363-72.
  • Algra A, Tijssen JG, Roelandt JR, Pool J, Lubsen J. QTc prolongation measured by standard 12-lead electrocardiog- raphy is an independent risk factor for sudden death due to cardiac arrest. Circulation 1991;83:1888-94.
  • Bednar MM, Harrigan EP, Ruskin JN. Torsades de pointes associated with nonantiarrhythmic drugs and observations on gender and QTc. Am J Cardiol 2002;89:1316-9.
  • Priori SG, Schwartz PJ, Napolitano C, Bloise R, Ronchetti E, Grillo M, et al. Risk stratification in the long-QT syndrome. N Engl J Med 2003;348:1866-74.
  • Bednar MM, Harrigan EP, Anziano RJ, Camm AJ, Ruskin JN. The QT interval. Prog Cardiovasc Dis 2001;43(5 Suppl 1):1-45.
  • Antzelevitch C, Sicouri S, Di Diego JM, Burashnikov A, Viskin S, Shimizu W, et al. Does Tpeak-Tend provide an index of transmural dispersion of repolarization? Heart Rhythm 2007;4:1114-6.
  • Kanters JK, Haarmark C, Vedel-Larsen E, Andersen MP, Graff C, Struijk JJ, et al. T(peak)T(end) interval in long QT syndrome. J Electrocardiol 2008;41:603-8.
  • Yamaguchi M, Shimizu M, Ino H, Terai H, Uchiyama K, Oe K, et al. T wave peak-to-end interval and QT dispersion in acquired long QT syndrome: a new index for arrhythmoge- nicity. Clin Sci 2003;105:671-6.
  • Gupta A, Lawrence AT, Krishnan K, Kavinsky CJ, Trohman RG. Current concepts in the mechanisms and management of drug-induced QT prolongation and torsade de pointes. Am Heart J 2007;153:891-9.
  • Kannankeril PJ, Roden DM. Drug-induced long QT and torsade de pointes: recent advances. Curr Opin Cardiol 2007;22:39-43.
  • Antzelevitch C. Role of transmural dispersion of repolar- ization in the genesis of drug-induced torsades de pointes. Heart Rhythm 2005;2(2 Suppl):S9-15.
  • Kay GN, Plumb VJ, Arciniegas JG, Henthorn RW, Waldo AL. Torsade de pointes: the long-short initiating sequence and other clinical features: observations in 32 patients. J Am Coll Cardiol 1983;2:806-17.
  • Schulze-Bahr E. Susceptibility genes and modifiers for car- diac arrhythmias. Prog Biophys Mol Biol 2008;98:289-300.
  • Priori SG, Napolitano C, Schwartz PJ. Low penetrance in the long-QT syndrome: clinical impact. Circulation 1999;99:529-33.
  • Yang P, Kanki H, Drolet B, Yang T, Wei J, Viswanathan PC, et al. Allelic variants in long-QT disease genes in patients with drug-associated torsades de pointes. Circulation 2002;105:1943-8.
  • Letsas KP, Efremidis M, Kounas SP, Pappas LK, Gavrielatos G, Alexanian IP, et al. Clinical characteristics of patients with drug-induced QT interval prolongation and torsade de pointes: identification of risk factors. Clin Res Cardiol 2009;98:208-12.
  • Zeltser D, Justo D, Halkin A, Prokhorov V, Heller K, Viskin S. Torsade de pointes due to noncardiac drugs: most patients have easily identifiable risk factors. Medicine 2003;82:282-90.
  • Arya A. Gender-related differences in ventricular repolariza- tion: beyond gonadal steroids. J Cardiovasc Electrophysiol 2005;16:525-7.
  • Curtis LH, Østbye T, Sendersky V, Hutchison S, Allen LaPointe NM, Al-Khatib SM, et al. Prescription of QT-prolonging drugs in a cohort of about 5 million outpa- tients. Am J Med 2003;114:135-41.
  • Banai S, Tzivoni D. Drug therapy for torsade de pointes. J Cardiovasc Electrophysiol 1993;4:206-10.
  • Khan IA. Clinical and therapeutic aspects of congenital and acquired long QT syndrome. Am J Med 2002;112:58-66.
  • Viskin S. Torsades de Pointes. Curr Treat Options Cardiovasc Med 1999;1:187-95.
There are 33 citations in total.

Details

Primary Language Turkish
Journal Section Articles
Authors

Konstantinos P. Letsas This is me

Publication Date January 1, 2010
Published in Issue Year 2010 Volume: 2010 Issue: 1

Cite

APA Letsas, K. P. (2010). İlaca Bağlı QT İnterval Uzaması ve Torsade De Pointes: Risk Faktörlerinin Saptanması. Balkan Medical Journal, 2010(1), 49-53.
AMA Letsas KP. İlaca Bağlı QT İnterval Uzaması ve Torsade De Pointes: Risk Faktörlerinin Saptanması. Balkan Medical Journal. January 2010;2010(1):49-53.
Chicago Letsas, Konstantinos P. “İlaca Bağlı QT İnterval Uzaması Ve Torsade De Pointes: Risk Faktörlerinin Saptanması”. Balkan Medical Journal 2010, no. 1 (January 2010): 49-53.
EndNote Letsas KP (January 1, 2010) İlaca Bağlı QT İnterval Uzaması ve Torsade De Pointes: Risk Faktörlerinin Saptanması. Balkan Medical Journal 2010 1 49–53.
IEEE K. P. Letsas, “İlaca Bağlı QT İnterval Uzaması ve Torsade De Pointes: Risk Faktörlerinin Saptanması”, Balkan Medical Journal, vol. 2010, no. 1, pp. 49–53, 2010.
ISNAD Letsas, Konstantinos P. “İlaca Bağlı QT İnterval Uzaması Ve Torsade De Pointes: Risk Faktörlerinin Saptanması”. Balkan Medical Journal 2010/1 (January 2010), 49-53.
JAMA Letsas KP. İlaca Bağlı QT İnterval Uzaması ve Torsade De Pointes: Risk Faktörlerinin Saptanması. Balkan Medical Journal. 2010;2010:49–53.
MLA Letsas, Konstantinos P. “İlaca Bağlı QT İnterval Uzaması Ve Torsade De Pointes: Risk Faktörlerinin Saptanması”. Balkan Medical Journal, vol. 2010, no. 1, 2010, pp. 49-53.
Vancouver Letsas KP. İlaca Bağlı QT İnterval Uzaması ve Torsade De Pointes: Risk Faktörlerinin Saptanması. Balkan Medical Journal. 2010;2010(1):49-53.