Skip to main content
SpringerLink
Log in

Is Gender a Risk Factor for Adverse Drug Reactions?

The Example of Drug-Induced Long QT Syndrome

  • Leading Article
  • Published:
Drug Safety Aims and scope Submit manuscript

Abstract

Drug-induced torsade de pointes is a rare life-threatening adverse drug reaction (ADR) which is strongly influenced by gender. Drugs that prolong cardiac repolarisation include antiarrhythmics, gastrokinetics, antipsychotics, antihistamines and antibacterials. Such drugs share the potential to block cardiac voltagegated potassium channels, particularly the rapid component (IKr) of the delayed rectifier potassium current (IK). By doing so, such drugs usually, but not always, prolong the QT interval. Even if the electrocardiographic signs are subdued, the underlying blockade of IKr current may precipitate the occurrence of arrhythmia.

Women are perceived to be more prone to ADRs than men. Such a propensity may result from gender-associated differences in drug exposure, in the number of drugs prescribed (polypharmacy), in drug pharmacology, as well as from possible differences in the way the adverse event is perceived. A prolonged QT interval on the electrocardiogram (time that elapses from the onset of the cardiac ventricular depolarisation to the completion of its repolarisation) is associated with the occurrence of torsade de pointes and related ventricular arrhythmias. The QT interval is influenced by heart rate, autonomic nervous system, electrolyte disturbances and above all, drugs that block potassium channels.

Two-thirds of the cases of drug-induced torsade de pointes occur in women. Therefore, this adverse effect represents a perfect example of gender differences impairing women’s health. Clinical and experimental studies show that female gender is associated with a longer corrected QT interval at baseline and a greater response to drugs that block IKr, both of which facilitate the emergence of arrhythmia. This results most likely from a specific regulation of ionic channel expression (potassium, calcium, etc) by sex steroids, even though nongenomic effects may play a role as well. Estrogens facilitate bradycardia-induced prolongation of the QT interval and the emergence of arrhythmia whereas androgens shorten the QT interval and blunt the QT response to drugs. Hence, underlying genetic defects of potassium channels that may be asymptomatic in normal conditions, may precipitate drug-induced arrhythmia in women more frequently than in men. Even in the presence of a drug that mildly blocks IKr and seldom prolongs the QT interval, women are still more prone to drug-induced torsade de pointes, due to their reduced cardiac “repolarisation reserve’. This is an important aspect of IKr blockade to be aware of during the development of new drugs.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Table I

Similar content being viewed by others

References

  1. Stampfer MJ, Colditz GA, Willett WC. Menopause and heart disease: a review. Ann N Y Acad Sci 1990; 592 193–203; 57-62

    Article  PubMed  CAS  Google Scholar 

  2. Rosengren A, Dotevall A, Eriksson H, et al. Optimal risk factors in the population: prognosis, prevalence, and secular trends. Data from Goteborg population studies. Eur Heart J 2001; 22(2): 136–44

    Article  PubMed  CAS  Google Scholar 

  3. Guentert TW, Banken L, Hilton S, et al. Moclobemide: relationships between dose, drug concentration in plasma, and occurrence of adverse events. J Clin Psychopharmacol 1995; 154 Suppl. 2: 84S–94S

    Article  PubMed  CAS  Google Scholar 

  4. Moore RD, Fortgang I, Keruly J, et al. Adverse events from drug therapy for human immunodeficiency virus disease. Am J Med 1996; 101(1): 34–40

    Article  PubMed  CAS  Google Scholar 

  5. Tran C, Knowles SR, Liu BA, et al. Gender differences in adverse drug reactions. J Clin Pharmacol 1998; 38(11): 1003–9

    Article  PubMed  CAS  Google Scholar 

  6. Fattinger K, Roos M, Vergeres P, et al. Epidemiology of drug exposure and adverse drug reactions in two Swiss departments of internal medicine. Br J Clin Pharmacol 2000; 49(2): 158–67

    Article  PubMed  CAS  Google Scholar 

  7. Harris RZ, Benet LZ, Schwartz JB. Gender effects in pharmacokinetics and pharmacodynamics. Drugs 1995; 50(2): 222–39

    Article  PubMed  CAS  Google Scholar 

  8. Strohle A. Increased response to a putative panicogenic nocebo administration in female patients with panic disorder. J Psychiatr Res 2000; 34(6): 439–42

    Article  PubMed  CAS  Google Scholar 

  9. Saxon L, Hiltunen AJ, Hjemdahl P, et al. Gender-related differences in response to placebo in benzodiazepine withdrawal: a single-blind pilot study. Psychopharmacology (Berl) 2001; 153(2): 231–7

    Article  CAS  Google Scholar 

  10. Hulst LK, Fleishaker JC, Peters GR, et al. Effect of age and gender on tirilazad pharmacokinetics in humans. Clin Pharmacol Ther 1994; 55(4): 378–84

    Article  PubMed  CAS  Google Scholar 

  11. Luzier AB, Killian A, Wilton JH, et al. Gender-related effects on metoprolol pharmacokinetics and pharmacodynamics in healthy volunteers. Clin Pharmacol Ther 1999; 66(6): 594–601

    PubMed  CAS  Google Scholar 

  12. Drici MD, Raybaud F, De Lunardo C, et al. Influence of the behaviour pattern on the nocebo response of healthy volunteers. Br J Clin Pharmacol 1995; 39(2): 204–6

    Article  PubMed  CAS  Google Scholar 

  13. Edmeads JG, Millson DS. Tolerability profile of zolmitriptan (Zomig; 311C90), a novel dual central and peripherally acting 5HT1B/1D agonist: international clinical experience based on > 3000 subjects treated with zolmitriptan. Cephalalgia 1997; 17Suppl. 18: 41–52

    PubMed  Google Scholar 

  14. Casper RC, Tollefson GD, Nilsson ME. No gender differences in placebo responses of patients with major depressive disorder. Biol Psychiatry 2001; 49(2): 158–60

    Article  PubMed  CAS  Google Scholar 

  15. Dessertenne F. La tachycardie ventriculaire à deux foyers opposés variables. Arch Mal Coeur Vaiss 1966; 59 263–72

    PubMed  CAS  Google Scholar 

  16. Napolitano C, Priori SG, Schwartz PJ. Torsade de pointes. Mechanisms and management. Drugs 1994; 47(1): 51–65

    Article  PubMed  CAS  Google Scholar 

  17. Roden DM. Mechanism and management of proarrhythmia. Am J Cardiol 1998; 82(4A) 49I–57I

    Article  PubMed  CAS  Google Scholar 

  18. Roden DM. Taking the ‘idio’ out of ‘idiosyncratic’: predicting torsades de pointes. Pacing Clin Electrophysiol 1998; 21(5): 1029–34

    Article  PubMed  CAS  Google Scholar 

  19. Bazett H. An analysis of the time relationship of electrocardiograms. Heart 1920; 7: 353–70

    Google Scholar 

  20. Glancy JM, Garratt CJ, Woods KL, et al. QT dispersion and mortality after myocardial infarction. Lancet 1995; 345(8955): 945–8

    Article  PubMed  CAS  Google Scholar 

  21. Day CP, McComb JM, Campbell RW. QT dispersion: an indication of arrhythmia risk in patients with long QT intervals. Br Heart J 1990; 63(6): 342–4

    Article  PubMed  CAS  Google Scholar 

  22. Hii JT, Wyse DG, Gillis AM, et al. Precordial QT interval dispersion as a marker of torsade de pointes: disparate effects of class Ia antiarrhythmic drugs and amiodarone. Circulation 1992; 86(5): 1376–82

    Article  PubMed  CAS  Google Scholar 

  23. Yang T, Roden DM. Extracellular potassium modulation of drug block of IKr: implications for torsade de pointes and reverse use-dependence. Circulation 1996; 93(3): 407–11

    Article  PubMed  CAS  Google Scholar 

  24. Coumel P, Maison-Blanche P. Physiology of QT interval dynamicity. Cardiac Electrophysiol Rev 1997; 1: 364–7

    Article  Google Scholar 

  25. Priori SG, Barhanin J, Hauer RN, et al. Genetic and molecular basis of cardiac arrhythmias; impact on clinical management. Study group on molecular basis of arrhythmias of the working group on arrhythmias of the european society of cardiology. Eur Heart J 1999; 20(3): 174–95

    Article  PubMed  CAS  Google Scholar 

  26. Napolitano C, Schwartz PJ, Brown AM, et al. Evidence for a cardiac ion channel mutation underlying drug-induced QT prolongation and life-threatening arrhythmias. J Cardiovasc Electrophysiol 2000; 11(6): 691–6

    Article  PubMed  CAS  Google Scholar 

  27. Abernethy DR, Greenblatt DJ, Shader RI. Imipramine disposition in users of oral contraceptive steroids. Clin Pharmacol Ther 1984; 35(6): 792–7

    Article  PubMed  CAS  Google Scholar 

  28. Drici MD, Burklow TR, Haridasse V, et al. Sex hormones prolong the QT interval and downregulate potassium channel expression in the rabbit heart. Circulation 1996; 94(6): 1471–4

    Article  PubMed  CAS  Google Scholar 

  29. Liu XK, Katchman A, Drici MD, et al. Gender difference in the cycle length-dependent QT and potassium currents in rabbits. J Pharmacol Exp Ther 1998; 285(2): 672–9

    PubMed  CAS  Google Scholar 

  30. Hara M, Danilo PJ, Rosen MR. Effects of gonadal steroids on ventricular repolarization and on the response to E4031. J Pharmacol Exp Ther 1998; 285(3): 1068–72

    PubMed  CAS  Google Scholar 

  31. Chen YJ, Lee SH, Hsieh MH, et al. Effects of 17beta-estradiol on tachycardia-induced changes of atrial refractoriness and cisapride-induced ventricular arrhythmia. J Cardiovasc Electrophysiol 1999; 10(4): 587–98

    Article  PubMed  CAS  Google Scholar 

  32. Drici MD, Knollmann BC, Wang WX, et al. Cardiac actions of erythromycin: influence of female sex. JAMA 1998; 280(20): 1774–6

    Article  PubMed  CAS  Google Scholar 

  33. Benton RE, Sale M, Flockhart DA, et al. Greater quinidine-induced QTc interval prolongation in women. Clin Pharmacol Ther 2000; 67(4): 413–8

    Article  PubMed  CAS  Google Scholar 

  34. Abbott GW, Sesti F, Splawski I, et al. MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia. Cell 1999; 97(2): 175–87

    Article  PubMed  CAS  Google Scholar 

  35. Sesti F, Abbott GW, Wei J, et al. A common polymorphism associated with antibiotic-induced cardiac arrhythmia. Proc Natl Acad Sci U S A 2000; 97(19): 10613–8

    Article  PubMed  CAS  Google Scholar 

  36. Priori SG, Napolitano C, Schwartz PJ. Low penetrance in the long-QT syndrome: clinical impact. Circulation 1999; 99(4): 529–33

    Article  PubMed  CAS  Google Scholar 

  37. Merri M, Benhorin J, Alberti M, et al. Electrocardiographic quantitation of ventricular repolarization. Circulation 1989; 80(5): 1301–8

    Article  PubMed  CAS  Google Scholar 

  38. Morcet JF, Safar M, Thomas F, et al. Associations between heart rate and other risk factors in a large French population. J Hypertens 1999; 17(12 Pt 1): 1671–6

    Article  PubMed  CAS  Google Scholar 

  39. Stramba-Badiale M, Spagnolo D, Bosi G, et al. Are gender differences in QTc present at birth? MISNES Investigators. Multicenter Italian Study on Neonatal Electrocardiography and Sudden Infant Death Syndrome. Am J Cardiol 1995; 75(17): 1277–8

    Article  PubMed  CAS  Google Scholar 

  40. Nagy E, Orvos H, Bardos G, et al. Gender-related heart rate differences in human neonates. Pediatr Res 2000; 47(6): 778–80

    Article  PubMed  CAS  Google Scholar 

  41. Rautaharju PM, Zhou SH, Wong S, et al. Sex differences in the evolution of the electrocardiographic QT interval with age. Can J Cardiol 1992; 8(7): 690–5

    PubMed  CAS  Google Scholar 

  42. Kassotis J, Costeas C, Bedi AK, et al. Effects of aging and gender on QT dispersion in an overtly healthy population. Pacing Clin Electrophysiol 2000; 23(7): 1121–6

    Article  PubMed  CAS  Google Scholar 

  43. Lehmann MH, Hardy S, Archibald D, et al. Sex difference in risk of torsade de pointes with d,l-sotalol. Circulation 1996; 94(10): 2535–41

    Article  PubMed  CAS  Google Scholar 

  44. Pratt CM, Camm AJ, Cooper W, et al. Mortality in the Survival With ORal D-sotalol (SWORD) trial: why did patients die? Am J Cardiol 1998; 81(7): 869–76

    Article  PubMed  CAS  Google Scholar 

  45. Lehmann MH, Hardy S, Archibald D, et al. JTc prolongation with d,l-sotalol in women versus men. Am J Cardiol 1999; 83(3): 354–9

    Article  PubMed  CAS  Google Scholar 

  46. Ebert SN, Liu XK, Woosley RL. Female gender as a risk factor for drug-induced cardiac arrhythmias: evaluation of clinical and experimental evidence. J Womens Health 1998; 7(5): 547–57

    Article  PubMed  CAS  Google Scholar 

  47. Cramer G. Early and late results of conversion of atrial fibrillation with quinidine. A clinical and hemodynamic study. Acta Med Scand Suppl. 1968; 490: 5–102

    PubMed  CAS  Google Scholar 

  48. Makkar RR, Fromm BS, Steinman RT, et al. Female gender as a risk factor for torsades de pointes associated with cardiovascular drugs. JAMA 1993; 270(21): 2590–7

    Article  PubMed  CAS  Google Scholar 

  49. Prystowsky EN, Benson DW, Fuster V, et al. Management of patientswith atrial fibrillation. Astatement for healthcare professionals. From the subcommittee on electrocardiography and electrophysiology, American Heart Association. Circulation 1996; 93(6): 1262–77

    Article  PubMed  CAS  Google Scholar 

  50. Viskin S. Long QT syndromes and torsade de pointes. Lancet 1999; 354(9190): 1625–33

    Article  PubMed  CAS  Google Scholar 

  51. Wesche DL, Schuster BG, Wang WX, et al. Mechanism of cardiotoxicity of halofantrine. Clin Pharmacol Ther 2000; 67(5): 521–9

    Article  PubMed  CAS  Google Scholar 

  52. Woosley RL. Georgetown University Medical Center. A representative list of drugs that prolong the QT interval and/or induce torsade de pointes with substantial evidence for a gender difference (when mentioned). 2001. Available from URL: http://www.torsades.org. [Accessed Oct 2000]

    Google Scholar 

  53. Cheymol G. Clinical pharmacokinetics of drugs in obesity: an update. Clin Pharmacokinet 1993; 25(2): 103–14

    Article  PubMed  CAS  Google Scholar 

  54. Schwartz JB, Capili H, Daugherty J. Aging of women alters S-verapamil pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther 1994; 55(5): 509–17

    Article  PubMed  CAS  Google Scholar 

  55. Simon T, Mary-Krause M, Funck-Brentano C, et al. Sex differences in the prognosis of congestive heart failure: results from the Cardiac Insufficiency Bisoprolol Study (CIBIS II). Circulation 2001; 103(3): 375–80

    Article  PubMed  CAS  Google Scholar 

  56. Perry PJ, Lund BC, Sanger T, et al. Olanzapine plasma concentrations and clinical response: acute phase results of the North American Olanzapine Trial. J Clin Psychopharmacol 2001; 21(1): 14–20

    Article  PubMed  CAS  Google Scholar 

  57. Lehmann MH, Timothy KW, Frankovich D, et al. Age-gender influence on the rate-corrected QT interval and the QT-heart rate relation in families with genotypically characterized long QT syndrome. J Am Coll Cardiol 1997; 29(1): 93–9

    Article  PubMed  CAS  Google Scholar 

  58. Hashiba K. Sex differences in phenotypic manifestation and gene transmission in the Romano-Ward syndrome. Ann NY Acad Sci 1992; 644 142–56

    Article  PubMed  CAS  Google Scholar 

  59. Locati EH, Zareba W, Moss AJ, et al. Age- and sex-related differences in clinical manifestations in patients with congenital long-QT syndrome: findings from the International LQTS Registry. Circulation 1998; 97(22): 2237–44

    Article  PubMed  CAS  Google Scholar 

  60. Larsen JA, Tung RH, Sadananda R, et al. Effects of hormone replacement therapy on QT interval. Am J Cardiol 1998; 82(8): 993–5

    Article  PubMed  CAS  Google Scholar 

  61. Rosano GM, Leonardo F, Sarrel PM, et al. Cyclical variation in paroxysmal supraventricular tachycardia in women. Lancet 1996; 347(9004): 786–8

    Article  PubMed  CAS  Google Scholar 

  62. Drici MD, Ducic I, Morad M, et al. Gender differences in cardiac repolarization depends on IK1 and ItoK+ channel currents in the rabbit. Circulation 1996; 94(8): I–473

    Google Scholar 

  63. Knollmann BC, Ender SI, Franz MR, et al. Acute effects of 17beta-estradiol and dihydrotestosterone on action potential duration and QT-interval in isolated rabbit hearts. J Invest Med 1996; 44(3): 209A

    Google Scholar 

  64. Pragnell M, Snay KJ, Trimmer JS, et al. Estrogen induction of a small, putative K+ channel mRNA in rat uterus. Neuron 1990; 4 807–12

    Article  PubMed  CAS  Google Scholar 

  65. Stumpf WE, Sar M. Autoradiographic localization of estrogen, androgen, progestin and glucocorticosteroid in ‘target tissues’ and b‘non target tissues’. In: Pasqualini J, editor. Receptors and mechanism of action of steroid hormones. New York (NY): Marcel Dekker, 1976: 41–84

    Google Scholar 

  66. Waldegger S, Lang U, Herzer T, et al. Inhibition of minK protein induced K+ channels in Xenopus oocytes by estrogens. Naunyn Schmiedebergs Arch Pharmakol 1996; 354(6): 698–702

    Article  CAS  Google Scholar 

  67. Moller RA, Datta S, Strichartz GR. Beta-estradiol acutely potentiates the depression of cardiac excitability by lidocaine and bupivacaine. J Cardiovasc Pharmacol 1999; 34(5): 718–27

    Article  PubMed  CAS  Google Scholar 

  68. Liu XK, Katchman A, Ebert SN, et al. The antiestrogen tamoxifen blocks the delayed rectifier potassium current, IKr, in rabbit ventricular myocytes. J Pharmacol Exp Ther 1998; 287(3): 877–83

    PubMed  CAS  Google Scholar 

  69. Moller RA, Datta S, Fox J, et al. Effects of progesterone on the cardiac electrophysiologic action of bupivacaine and lidocaine. Anesthesiology 1992; 76(4): 604–8

    Article  PubMed  CAS  Google Scholar 

  70. Song J, Standley PR, Zhang F, et al. Tamoxifen (estrogen antagonist) inhibits voltage-gated calcium current and contractility in vascular smooth muscle from rats. J Pharmacol Exp Ther 1996; 277(3): 1444–53

    PubMed  CAS  Google Scholar 

  71. Ruehlmann DO, Steinert JR, Valverde MA, et al. Environmental estrogenic pollutants induce acute vascular relaxation by inhibiting L-type Ca2+ channels in smooth muscle cells. FASEB J 1998; 12(7): 613–9

    PubMed  CAS  Google Scholar 

  72. Funck-Brentano C, Jaillon P. Rate-corrected QT interval: techniques and limitations. Am J Cardiol 1993; 72(6): 17B–22B

    Article  PubMed  CAS  Google Scholar 

  73. Schwartz PJ, Priori SG, Locati EH, et al. Long QT syndrome patients with mutations of the SCN5A and HERG genes have differential responses to Na+ channel blockade and to increases in heart rate. Implications for gene-specific therapy. Circulation 1995; 92(12): 3381–6

    Article  PubMed  CAS  Google Scholar 

  74. Hirao H, Shimizu W, Kurita T, et al. Frequency-dependent electrophysiologic properties of ventricular repolarization in patients with congenital long QT syndrome. J Am Coll Cardiol 1996; 28(5): 1269–77

    Article  PubMed  CAS  Google Scholar 

  75. Krahn AD, Klein GJ, Yee R. Hysteresis of the RT interval with exercise: a new marker for the long-QT syndrome? Circulation 1997; 96(5): 1551–6

    Article  PubMed  CAS  Google Scholar 

  76. Vincent GM, Jaiswal D, Timothy KW. Effects of exercise on heart rate, QT, QTc and QT/QS2 in the Romano-Ward inherited long QT syndrome. Am J Cardiol 1991; 68(5): 498–503

    Article  PubMed  CAS  Google Scholar 

  77. Demolis JL, Funck-Brentano C, Ropers J, et al. Influence of dofetilide on QT-interval duration and dispersion at various heart rates during exercise in humans. Circulation 1996; 94(7): 1592–9

    Article  PubMed  CAS  Google Scholar 

  78. Stark G, Schwarzl I, Heiden U, et al. Magnesium abolishes inadequate kinetics of frequency adaptation of the Q-aT interval in the presence of sotalol. Cardiovasc Res 1997; 35(1): 43–5

    Article  PubMed  CAS  Google Scholar 

  79. Kliegfield P, Lax KG, Okin PM. QT interval-heart rate relation during exercise in normal men and women: definition by linear regression analysis. J Am Coll Cardiol 1996; 28(6): 1547–55

    Article  Google Scholar 

  80. Stramba-Badiale M, Locati EH, Martinelli A, et al. Gender and the relationship between ventricular repolarization and cardiac cycle length during 24-h Holter recordings. Eur Heart J 1997; 18(6): 1000–6

    Article  PubMed  CAS  Google Scholar 

  81. Drici MD, Arrighi I, Chouabe C, et al. Involvment of IsK associated K+ channel in heart rate control of repolarization in a murine engineered model of Jervell and Lange-Nielsen syndrome. Circ Res 1998; 83: 95–102

    Article  PubMed  CAS  Google Scholar 

  82. Liu XK, Wang W, Ebert SN, et al. Female gender is a risk factor for torsades de pointes in an in vitro animal model. J Cardiovasc Pharmacol 1999; 34(2): 287–94

    Article  PubMed  CAS  Google Scholar 

  83. Larsen JA, Kadish AH. Effects of gender on cardiac arrhythmias. J Cardiovasc Electrophysiol 1998; 9(6): 655–64

    Article  PubMed  CAS  Google Scholar 

  84. Shipley RA, Hallaran WR. The four lead electrocardiogram in two hundred normal men and women. Am Heart J 1936; 11 325–45

    Article  Google Scholar 

Download references

Acknowledgements

Part of this work was supported by the Delegation à la Recherche Clinique du Centre Hospitalier et Universitaire de Nice, the CNRS UMR 6097 in Sophia Antipolis, France and the Department of Pharmacology of Georgetown University Medical Center in Washington DC, USA.

Author information

Authors and Affiliations

  1. Department of Pharmacology, Pasteur University Hospital and University of Nice-Sophia Antipolis, Avenue de Valombrose, 06107, Nice Cedex 02, France

    Milou-Daniel Drici

  2. Centre Hospitalier Princesse Grace, Monte Carlo, Principauté de Monaco

    Nathalie Clément

Authors
  1. Milou-Daniel Drici
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nathalie Clément
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Milou-Daniel Drici.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Drici, MD., Clément, N. Is Gender a Risk Factor for Adverse Drug Reactions?. Drug-Safety 24, 575–585 (2001). https://doi.org/10.2165/00002018-200124080-00002

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00002018-200124080-00002

Keywords

Search

Navigation