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Nefazodone-associated torsade de pointes
International Journal of Cardiology 93 (2004) 85 – 86 www.elsevier.com/locate/ijcard
Letter to the Editor
Nefazodone-associated torsade de pointes
$
Mumtaz A. Siddiqui, Ijaz A. Khan* Division of Cardiology, Creighton University School of Medicine, 3006 Webster Street, Omaha, NE 68131, USA Received 9 October 2002; accepted 22 January 2003
Keywords: Nefazodone; Antidepressants; Long QT syndrome; Drug-induced arrhythmias; Torsade de pointes; Polymorphic ventricular tachycardia
Nefazodone is an antidepressant with a chemical structure unrelated to selective serotonin reuptake inhibitors, tricyclic antidepressants, or monoamine oxidase inhibitors. The pharmacological actions of nefazodone involve both the serotonergic system and the noradrenergic system [1]. Within the serotonergic system, nefazodone is a potent antagonist at type 2 serotonin post-synaptic receptors (5HT2). Nefazodone also inhibits pre-synaptic serotonin reuptake but this mechanism is secondary in importance. Both mechanisms increase the amount of serotonin available to interact with 5-HT receptors. Within the noradrenergic system, nefazodone inhibits norepinephrine uptake but this effect is lost with chronic dosing. In addition, nefazodone has been shown to antagonize a1-adrenergic receptors. The cardiovascular side effects associated with the use of this agent include hypotension, postural hypotension and sinus bradycardia. We report a case of syncopal event from torsade de pointes associated with nefazodone therapy. A 58-year-old woman presented with a sudden onset, witnessed syncopal event, approximately 1 h prior to the presentation. There was no preceding light-headedness, vertigo, chest pain, diaphoresis, palpitations, or seizure activity. The past medical history was of adult-onset diabetes mellitus and depression. The medications on admission
included glipizide and nefazodone (100 mg oral twice a day). Her examination was normal and the admission blood sugar was 206 mg/dl, serum potassium 4.4 mEq/l and serum magnesium 2.1 mg/dl. The patient was admitted to the cardiac unit, where after 9 h of admission she had another syncopal event. The monitor during syncope revealed torsade de pointes type polymorphic ventricular tachycardia (Fig. 1), preceded by bradycardia of 36 beats/min and a short – long – short sequencing of beats. The patient spontaneously reverted to normal sinus rhythm. Electrocardiogram demonstrated prolongation of the corrected QT interval at 506 ms. Repeat serum potassium was 4.4 mEq/l and magnesium 2.1 mg/dl. The patient received magnesium sulfate 2 g intravenously and was initiated on isoproterenol infusion. Nefazodone therapy was discontinued but glipizide was continued. Corrected QT interval became normal and remained normal after discontinuation of the isoproterenol infusion. The rest of the hospital course was unremarkable. Lengthening of the QTc interval per se causes no symptoms but can precipitate life-threatening torsade de pointes [2]. Torsade de pointes is a form of polymorphic ventricular tachycardia in which the mean electrical axis of the QRS complex within any single electrocardiographic lead appear to twist around the isoelectric line [3]. The
Fig. 1. Torsade de pointes.
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No financial support was received for this paper. * Corresponding author. Tel.: +1-402-280-4573; fax: +1-402-280-4938. E-mail address: [email protected] (I.A. Khan).
0167-5273/$ - see front matter D 2003 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/S0167-5273(03)00120-7
86
M.A. Siddiqui, I.A. Khan / International Journal of Cardiology 93 (2004) 85–86
prolongation of QTc interval may be congenital or acquired, and the acquired causes include drugs, cocaine, electrolyte disturbances and cardiac, endocrine, intracranial and nutritional disorders [4,5]. Unfortunately there is no critical QTc interval value that can be considered as a danger signal for drug-induced torsade de pointes. Women appear more prone for developing drug-induced torsade de pointes [6]. Nefazodone is an in vitro inhibitor of hepatic CYP3A4 isoenzyme [7]. The other CYP3A4 isoenzyme inhibitors, such as erythromycin, may induce QTc prolongation and torsade de pointes [8]. Glipizide, the only other medication our patient was using, has not been reported to cause torsade de pointes and no arrhythmia was noted in our patient until nefazodone therapy was instituted, which makes nefazodone the likely drug to have induced the torsade de pointes in her. Her gender goes along well with the female predisposition for drug-induced torsade de pointes.
References [1] DeVane CL, Grothe DR, Smith SL. Pharmacology of antidepressants: focus on nefazodone. J Clin Psychiatry 2002;63:10 – 7. [2] Khan IA. Clinical and therapeutic aspects of congenital and acquired long QT syndrome. Am J Med 2002;112:58 – 66. [3] Khan IA. Twelve-lead electrocardiogram of torsades de pointes. Tex Heart Inst J 2001;28:69. [4] Ponti FD, Poluzzi E, Cavalli A, Recanatini M, Montanaro N. Safety of non-antiarrhythmic drugs that prolong the qt interval or induce torsade de pointes: an overview. Drug Saf 2002;25:263 – 86. [5] Singh N, Singh HK, Singh PP, Khan IA. Cocaine-induced torsades de pointes in idiopathic long Q-T syndrome. Am J Ther 2001;8:299 – 302. [6] Makkar RR, Fromm BS, Steinman RT, Meissner MD, Lehmann MH. Female gender as a risk factor for torsade de pointes associated with cardiovascular drugs. J Am Med Assoc 1993;270:2590 – 7. [7] Greene DS, Barbhaiya RH. Clinical pharmacokinetics of nefazodone. Clin Pharmacokinet 1997;33:260 – 75. [8] Gitler B, Berger LS, Buffa SD. Torsade de pointes induced by erythromycin. Chest 1994;105:368 – 72.
Letter to the Editor
Nefazodone-associated torsade de pointes
$
Mumtaz A. Siddiqui, Ijaz A. Khan* Division of Cardiology, Creighton University School of Medicine, 3006 Webster Street, Omaha, NE 68131, USA Received 9 October 2002; accepted 22 January 2003
Keywords: Nefazodone; Antidepressants; Long QT syndrome; Drug-induced arrhythmias; Torsade de pointes; Polymorphic ventricular tachycardia
Nefazodone is an antidepressant with a chemical structure unrelated to selective serotonin reuptake inhibitors, tricyclic antidepressants, or monoamine oxidase inhibitors. The pharmacological actions of nefazodone involve both the serotonergic system and the noradrenergic system [1]. Within the serotonergic system, nefazodone is a potent antagonist at type 2 serotonin post-synaptic receptors (5HT2). Nefazodone also inhibits pre-synaptic serotonin reuptake but this mechanism is secondary in importance. Both mechanisms increase the amount of serotonin available to interact with 5-HT receptors. Within the noradrenergic system, nefazodone inhibits norepinephrine uptake but this effect is lost with chronic dosing. In addition, nefazodone has been shown to antagonize a1-adrenergic receptors. The cardiovascular side effects associated with the use of this agent include hypotension, postural hypotension and sinus bradycardia. We report a case of syncopal event from torsade de pointes associated with nefazodone therapy. A 58-year-old woman presented with a sudden onset, witnessed syncopal event, approximately 1 h prior to the presentation. There was no preceding light-headedness, vertigo, chest pain, diaphoresis, palpitations, or seizure activity. The past medical history was of adult-onset diabetes mellitus and depression. The medications on admission
included glipizide and nefazodone (100 mg oral twice a day). Her examination was normal and the admission blood sugar was 206 mg/dl, serum potassium 4.4 mEq/l and serum magnesium 2.1 mg/dl. The patient was admitted to the cardiac unit, where after 9 h of admission she had another syncopal event. The monitor during syncope revealed torsade de pointes type polymorphic ventricular tachycardia (Fig. 1), preceded by bradycardia of 36 beats/min and a short – long – short sequencing of beats. The patient spontaneously reverted to normal sinus rhythm. Electrocardiogram demonstrated prolongation of the corrected QT interval at 506 ms. Repeat serum potassium was 4.4 mEq/l and magnesium 2.1 mg/dl. The patient received magnesium sulfate 2 g intravenously and was initiated on isoproterenol infusion. Nefazodone therapy was discontinued but glipizide was continued. Corrected QT interval became normal and remained normal after discontinuation of the isoproterenol infusion. The rest of the hospital course was unremarkable. Lengthening of the QTc interval per se causes no symptoms but can precipitate life-threatening torsade de pointes [2]. Torsade de pointes is a form of polymorphic ventricular tachycardia in which the mean electrical axis of the QRS complex within any single electrocardiographic lead appear to twist around the isoelectric line [3]. The
Fig. 1. Torsade de pointes.
$
No financial support was received for this paper. * Corresponding author. Tel.: +1-402-280-4573; fax: +1-402-280-4938. E-mail address: [email protected] (I.A. Khan).
0167-5273/$ - see front matter D 2003 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/S0167-5273(03)00120-7
86
M.A. Siddiqui, I.A. Khan / International Journal of Cardiology 93 (2004) 85–86
prolongation of QTc interval may be congenital or acquired, and the acquired causes include drugs, cocaine, electrolyte disturbances and cardiac, endocrine, intracranial and nutritional disorders [4,5]. Unfortunately there is no critical QTc interval value that can be considered as a danger signal for drug-induced torsade de pointes. Women appear more prone for developing drug-induced torsade de pointes [6]. Nefazodone is an in vitro inhibitor of hepatic CYP3A4 isoenzyme [7]. The other CYP3A4 isoenzyme inhibitors, such as erythromycin, may induce QTc prolongation and torsade de pointes [8]. Glipizide, the only other medication our patient was using, has not been reported to cause torsade de pointes and no arrhythmia was noted in our patient until nefazodone therapy was instituted, which makes nefazodone the likely drug to have induced the torsade de pointes in her. Her gender goes along well with the female predisposition for drug-induced torsade de pointes.
References [1] DeVane CL, Grothe DR, Smith SL. Pharmacology of antidepressants: focus on nefazodone. J Clin Psychiatry 2002;63:10 – 7. [2] Khan IA. Clinical and therapeutic aspects of congenital and acquired long QT syndrome. Am J Med 2002;112:58 – 66. [3] Khan IA. Twelve-lead electrocardiogram of torsades de pointes. Tex Heart Inst J 2001;28:69. [4] Ponti FD, Poluzzi E, Cavalli A, Recanatini M, Montanaro N. Safety of non-antiarrhythmic drugs that prolong the qt interval or induce torsade de pointes: an overview. Drug Saf 2002;25:263 – 86. [5] Singh N, Singh HK, Singh PP, Khan IA. Cocaine-induced torsades de pointes in idiopathic long Q-T syndrome. Am J Ther 2001;8:299 – 302. [6] Makkar RR, Fromm BS, Steinman RT, Meissner MD, Lehmann MH. Female gender as a risk factor for torsade de pointes associated with cardiovascular drugs. J Am Med Assoc 1993;270:2590 – 7. [7] Greene DS, Barbhaiya RH. Clinical pharmacokinetics of nefazodone. Clin Pharmacokinet 1997;33:260 – 75. [8] Gitler B, Berger LS, Buffa SD. Torsade de pointes induced by erythromycin. Chest 1994;105:368 – 72.