- Email: [email protected]
The Long QT Teaser: Loperamide Abuse
ECG IMAGE OF THE MONTH Julia H. Indik, MD, PhD, Section Editor
The Long QT Teaser: Loperamide Abuse Evbu O. Enakpene, MD,a Irbaz Bin Riaz, MD, MM,a Farshad M. Shirazi, MS, MD, PhD,b,c Yuval Raz, MD,d Julia H. Indik, MD, PhDa a
Sarver Heart Center, Banner-University Medical Center, University of Arizona Medical Center, Tucson; bCenter for Pharmacology, Toxicology Education & Research, University of Arizona College of Medicine-Phoenix, Phoenix; cArizona Poison & Drug Information Center, University of Arizona College of Pharmacy, Tucson; dDivision of Pulmonary and Critical Care Medicine, University of Arizona Medical Center, Tucson.
PRESENTATION The source of a 25-year-old woman’s puzzling signs and symptoms could not be determined until a search of her home yielded the answer. She had no known medical problems when she presented to the Emergency Department with a 2-week history of persistent abdominal discomfort. A routine work-up for abdominal pain was unrevealing. An electrocardiogram (ECG) showed sinus rhythm at a rate of 69 beats per minute with a QT interval of 492 ms, a corrected QT interval of 527 ms, an intraventricular conduction defect with a QRS interval of 170 ms, and nonspecific T-wave abnormalities (Figure 1). She was treated symptomatically for abdominal pain and discharged with no medications. Two weeks later, the patient was admitted after a syncopal episode while driving. Her ECG showed sinus rhythm at a rate of 64 beats per minute, with a QT interval of 480 ms, a corrected QT interval of 490 ms, an intraventricular conduction defect with a QRS interval of 140 ms, and nonspecific T wave abnormalities. An echocardiogram and cardiac magnetic resonance imaging scan showed normal cardiac structure and function. She denied the use of any over-the-counter medications or illicit substances. A diagnosis of long QT syndrome was made, and a dual-chamber implantable cardioverter defibrillator was implanted. Six weeks later, the patient was back, reporting nausea and vomiting. She had bradycardia and hypotensive shock, and her implantable cardioverter defibrillator failed to capture (Figure 2). Hemodynamically unstable, she required multiple vasopressors and was intubated for airway
Funding: None. Conflict of Interest: None. Authorship: All authors contributed equally to the manuscript. Requests for reprints should be addressed to Evbu O. Enakpene, MD, Sarver Heart Center, Banner-University Medical Center, University of Arizona Medical Center, 1501 N Campbell Avenue, Tucson, AZ 85724. E-mail address: [email protected] 0002-9343/$ -see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjmed.2015.05.019
protection and acute respiratory failure. Multiple episodes of hemodynamically unstable polymorphic ventricular tachycardia ensued. Transcutaneous pacing also failed to capture. Interrogation of her pacemaker revealed markedly elevated pacing thresholds in both the atrial and ventricular leads with normal impedance. After maximizing the pacing output to achieve capture, her ECG showed markedly widened paced ventricular complexes (Figure 3).
ASSESSMENT Initial blood work showed the following: arterial pH, 7.2; potassium level, 6 mEq/L; blood urea nitrogen, 29 mg/dL; creatinine, 2.8 mg/dL; and a magnesium level of 2 mg/dL. Despite correction of potassium and administration of atropine, the patient continued to have bradycardia and remained hemodynamically unstable. A chest x-ray study demonstrated normal atrial and ventricular lead positions. She then developed multiple episodes of nonsustained ventricular tachycardia with wide QRS duration and frequent runs of polymorphic ventricular tachycardia. We suspected our patient had sodium-channel blocker toxicity due to the markedly widened paced QRS complexes. After consultation with the toxicology service, we started empiric intravenous bicarbonate infusion, which produced a mild improvement in the QRS duration. Initial toxicology screens for drugs of abuse were negative. We then asked the patient’s friend to go to the house and look for anything the patient might have ingested. Multiple empty bottles of loperamide were found in her apartment. Subsequent toxicology testing disclosed a markedly elevated blood loperamide level of 32 ng/mL.
DIAGNOSIS The differential diagnosis of wide complex arrhythmias is broad and includes several toxic and metabolic causes that could easily be overlooked, especially if the toxic agent is unusual. A high index of suspicion should be maintained for
2
The American Journal of Medicine, Vol -, No -,
-
2015
Figure 1 An electrocardiogram was obtained during the patient’s initial evaluation for abdominal pain of 2 weeks duration. It was notable for a prolonged QT interval of 492 ms, corrected QT interval of 527 ms, and a QRS interval of 170 ms.
a toxic cause when very wide and bizarre QRS complexes are noted on the ECG. Thorough toxicology screening should be strongly considered in young and otherwise healthy patients with syncope and a markedly abnormal baseline ECG. Loperamide is a piperidine derivative and a peripheral m-opiate agonist with antisecretory and antimotility activity, and it is readily available over the counter. Side effects include constipation, nausea, dizziness, and abdominal cramps.1 Our patient initially presented with recurrent abdominal cramps. People who are addicted to opiates have increasingly turned to loperamide as an easily obtainable substitute. Loperamide has low oral bioavailability, and its penetration of the blood-brain barrier is nominal. Additionally, it is
Figure 2 capture.
almost completely extracted and metabolized by cytochrome P450 in the liver. The combination of complete extraction, lack of blood-brain barrier penetration, and low solubility make loperamide an unlikely drug to be abused at the standard antidiarrheal dosage (4 mg followed by 2 mg after each loose stool to a maximum daily dose of 16 mg). Extra-medical use of loperamide at 40-100 times the usual antidiarrheal dosage is becoming increasingly common among illicit opioid users, and it is favored as a “poor man’s” methadone to self-treat opioid withdrawal symptoms.2 At such large doses, 6-23 mg/kg, piperidines can act as sodium channel blockers, such as lidocaine.3 Cardiac toxicity stemming from loperamide abuse is not well described.
This electrocardiogram showed widened QRS complexes and the pacemaker’s failure to
Enakpene et al
Loperamide-induced Cardiac Toxicity
3
Figure 3 When the patient presented with bradycardia and shock, the pacemaker’s ventricular output was raised to achieve capture, and another electrocardiogram was performed. The paced QRS complexes are markedly widened at 360 ms.
Our patient’s case is a classic example of substitutive behavior, where loperamide was abused at high doses to replace stronger opioids. Information that describes and encourages loperamide abuse is readily available on different Internet and social media sites.2 Unfortunately, these Web sites do not highlight fatal results of its abuse. The relationship between chronic loperamide abuse and its cumulative cardiac effects is mostly unknown. Loperamide blocks several types of voltage-gated ion channels, including L-type Ca2þ channels and delayed-rectifier potassium channels.4,5 Piperidine derivatives have been shown to increase the action potential duration and slowly increase the effective refractory period in animal models.6 QTc prolongation by loperamide is becoming more widely recognized and could be connected to its blockade of calcium and potassium channels.7,8 As in our patient, these effects can translate into QT prolongation, creating a clinical impression of long QT syndrome. Further data are needed to characterize the dose-response relationship capable of inducing rhythm disturbances.9 The QRS prolongation identified in our patient cannot be definitively explained at this time, but possibly, significant sodium-channel blockade occurred. Loperamide generally is not regarded as a sodium-channel blocking agent at usual plasma concentrations.10 However, chronic abuse of loperamide at very high dosages might have spurred a major blockade of sodium channels, lengthening our patient’s QRS duration.
MANAGEMENT Our patient was given intravenous plant-based fat emulsion. At the same time, she continued to receive bicarbonate and supportive treatment in the intensive care unit. Her ECG
irregularities resolved within 1 week, and her pacing thresholds normalized. After she recovered, she finally admitted to chronic abuse of loperamide, which she had denied during previous hospitalizations. Although she had successfully completed a drug rehabilitation program in the past, she began using loperamide after learning about it from Internet sources and friends. Her care required an interdisciplinary approach, including psychosocial counseling and social services. Upon discharge, she was in good condition. Two months after discharge, the patient was readmitted in cardiopulmonary arrest after continued loperamide abuse. Despite being placed on percutaneous femoral venoarterial extracorporeal membrane oxygenation, she had no significant improvement. She died 18 hours after admission. Loperamide-induced cardiac toxicity can be fatal and should be considered in the differential diagnosis of unstable arrhythmias, long QT intervals, or widened QRS complexes. When taken in massive doses, it is a drug of abuse, serving as a substitute for opioids. Large quantities can be obtained easily over the counter without any government regulation. Increased public awareness of harmful practices and their dangerous effects is essential.
References 1. Baker DE. Loperamide: a pharmacological review. Rev Gastroenterol Disord. 2007;7(Suppl 3):S11-S18. 2. Daniulaityte R, Carlson R, Falck R, et al. “I just wanted to tell you that loperamide WILL WORK:” a web-based study of extra-medical use of loperamide. Drug Alcohol Depend. 2013;130(1-3):241-244. 3. Kaverina NV, Skoldinov AP, Dzhaparidze MM, Berdiaev Slu, Darinskiĭ NV. Hydrochlorides of N-hydroxyalkyl-alpha-piperidine carboxylic arylamides possessing antiarrhythmic activity. Farmakol Toksikol. 1984;47:25-28.
4 4. Church J, Fletcher EJ, Abdel-Hamid K, MacDonald JF. Loperamide blocks high-voltage-activated calcium channels and N-methylD-aspartate-evoked responses in rat and mouse cultured hippocampal pyramidal neurons. Mol Pharmacol. 1994;45:747-757. 5. Nozaki-Taguchi N, Yaksh TL. Characterization of the antihyperalgesic action of a novel peripheral mu-opioid receptor agonist—loperamide. Anesthesiology. 1999;90:225-234. 6. Koerner JE, Dage RC. Antiarrhythmic and electrophysiologic effects of MDL 11,939, a novel class III antiarrhythmic agent in anesthetized dogs. J Cardiovasc Pharmacol. 1990;16:383-393.
The American Journal of Medicine, Vol -, No -,
-
2015
7. Reynolds IJ, Gould RJ, Snyder SH. Loperamide: blockade of calcium channels as a mechanism for antidiarrheal effects. J Pharmacol Exp Ther. 1984;231:628-632. 8. Berger SI, Ma’ayan A, Iyengar R. Systems pharmacology of arrhythmias. Sci Signal. 2010;3:ra30. 9. Pokhrel K, Rajbhandary A, Thapa J. 1274: Loperamide: the unexpected culprit. Crit Care Med. 2013;41:A328. 10. Harmer AR, Valentin JP, Pollard CE. On the relationship between block of the cardiac Naþ channel and drug-induced prolongation of the QRS complex. Br J Pharmacol. 2011;164:260-273.
The Long QT Teaser: Loperamide Abuse Evbu O. Enakpene, MD,a Irbaz Bin Riaz, MD, MM,a Farshad M. Shirazi, MS, MD, PhD,b,c Yuval Raz, MD,d Julia H. Indik, MD, PhDa a
Sarver Heart Center, Banner-University Medical Center, University of Arizona Medical Center, Tucson; bCenter for Pharmacology, Toxicology Education & Research, University of Arizona College of Medicine-Phoenix, Phoenix; cArizona Poison & Drug Information Center, University of Arizona College of Pharmacy, Tucson; dDivision of Pulmonary and Critical Care Medicine, University of Arizona Medical Center, Tucson.
PRESENTATION The source of a 25-year-old woman’s puzzling signs and symptoms could not be determined until a search of her home yielded the answer. She had no known medical problems when she presented to the Emergency Department with a 2-week history of persistent abdominal discomfort. A routine work-up for abdominal pain was unrevealing. An electrocardiogram (ECG) showed sinus rhythm at a rate of 69 beats per minute with a QT interval of 492 ms, a corrected QT interval of 527 ms, an intraventricular conduction defect with a QRS interval of 170 ms, and nonspecific T-wave abnormalities (Figure 1). She was treated symptomatically for abdominal pain and discharged with no medications. Two weeks later, the patient was admitted after a syncopal episode while driving. Her ECG showed sinus rhythm at a rate of 64 beats per minute, with a QT interval of 480 ms, a corrected QT interval of 490 ms, an intraventricular conduction defect with a QRS interval of 140 ms, and nonspecific T wave abnormalities. An echocardiogram and cardiac magnetic resonance imaging scan showed normal cardiac structure and function. She denied the use of any over-the-counter medications or illicit substances. A diagnosis of long QT syndrome was made, and a dual-chamber implantable cardioverter defibrillator was implanted. Six weeks later, the patient was back, reporting nausea and vomiting. She had bradycardia and hypotensive shock, and her implantable cardioverter defibrillator failed to capture (Figure 2). Hemodynamically unstable, she required multiple vasopressors and was intubated for airway
Funding: None. Conflict of Interest: None. Authorship: All authors contributed equally to the manuscript. Requests for reprints should be addressed to Evbu O. Enakpene, MD, Sarver Heart Center, Banner-University Medical Center, University of Arizona Medical Center, 1501 N Campbell Avenue, Tucson, AZ 85724. E-mail address: [email protected] 0002-9343/$ -see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjmed.2015.05.019
protection and acute respiratory failure. Multiple episodes of hemodynamically unstable polymorphic ventricular tachycardia ensued. Transcutaneous pacing also failed to capture. Interrogation of her pacemaker revealed markedly elevated pacing thresholds in both the atrial and ventricular leads with normal impedance. After maximizing the pacing output to achieve capture, her ECG showed markedly widened paced ventricular complexes (Figure 3).
ASSESSMENT Initial blood work showed the following: arterial pH, 7.2; potassium level, 6 mEq/L; blood urea nitrogen, 29 mg/dL; creatinine, 2.8 mg/dL; and a magnesium level of 2 mg/dL. Despite correction of potassium and administration of atropine, the patient continued to have bradycardia and remained hemodynamically unstable. A chest x-ray study demonstrated normal atrial and ventricular lead positions. She then developed multiple episodes of nonsustained ventricular tachycardia with wide QRS duration and frequent runs of polymorphic ventricular tachycardia. We suspected our patient had sodium-channel blocker toxicity due to the markedly widened paced QRS complexes. After consultation with the toxicology service, we started empiric intravenous bicarbonate infusion, which produced a mild improvement in the QRS duration. Initial toxicology screens for drugs of abuse were negative. We then asked the patient’s friend to go to the house and look for anything the patient might have ingested. Multiple empty bottles of loperamide were found in her apartment. Subsequent toxicology testing disclosed a markedly elevated blood loperamide level of 32 ng/mL.
DIAGNOSIS The differential diagnosis of wide complex arrhythmias is broad and includes several toxic and metabolic causes that could easily be overlooked, especially if the toxic agent is unusual. A high index of suspicion should be maintained for
2
The American Journal of Medicine, Vol -, No -,
-
2015
Figure 1 An electrocardiogram was obtained during the patient’s initial evaluation for abdominal pain of 2 weeks duration. It was notable for a prolonged QT interval of 492 ms, corrected QT interval of 527 ms, and a QRS interval of 170 ms.
a toxic cause when very wide and bizarre QRS complexes are noted on the ECG. Thorough toxicology screening should be strongly considered in young and otherwise healthy patients with syncope and a markedly abnormal baseline ECG. Loperamide is a piperidine derivative and a peripheral m-opiate agonist with antisecretory and antimotility activity, and it is readily available over the counter. Side effects include constipation, nausea, dizziness, and abdominal cramps.1 Our patient initially presented with recurrent abdominal cramps. People who are addicted to opiates have increasingly turned to loperamide as an easily obtainable substitute. Loperamide has low oral bioavailability, and its penetration of the blood-brain barrier is nominal. Additionally, it is
Figure 2 capture.
almost completely extracted and metabolized by cytochrome P450 in the liver. The combination of complete extraction, lack of blood-brain barrier penetration, and low solubility make loperamide an unlikely drug to be abused at the standard antidiarrheal dosage (4 mg followed by 2 mg after each loose stool to a maximum daily dose of 16 mg). Extra-medical use of loperamide at 40-100 times the usual antidiarrheal dosage is becoming increasingly common among illicit opioid users, and it is favored as a “poor man’s” methadone to self-treat opioid withdrawal symptoms.2 At such large doses, 6-23 mg/kg, piperidines can act as sodium channel blockers, such as lidocaine.3 Cardiac toxicity stemming from loperamide abuse is not well described.
This electrocardiogram showed widened QRS complexes and the pacemaker’s failure to
Enakpene et al
Loperamide-induced Cardiac Toxicity
3
Figure 3 When the patient presented with bradycardia and shock, the pacemaker’s ventricular output was raised to achieve capture, and another electrocardiogram was performed. The paced QRS complexes are markedly widened at 360 ms.
Our patient’s case is a classic example of substitutive behavior, where loperamide was abused at high doses to replace stronger opioids. Information that describes and encourages loperamide abuse is readily available on different Internet and social media sites.2 Unfortunately, these Web sites do not highlight fatal results of its abuse. The relationship between chronic loperamide abuse and its cumulative cardiac effects is mostly unknown. Loperamide blocks several types of voltage-gated ion channels, including L-type Ca2þ channels and delayed-rectifier potassium channels.4,5 Piperidine derivatives have been shown to increase the action potential duration and slowly increase the effective refractory period in animal models.6 QTc prolongation by loperamide is becoming more widely recognized and could be connected to its blockade of calcium and potassium channels.7,8 As in our patient, these effects can translate into QT prolongation, creating a clinical impression of long QT syndrome. Further data are needed to characterize the dose-response relationship capable of inducing rhythm disturbances.9 The QRS prolongation identified in our patient cannot be definitively explained at this time, but possibly, significant sodium-channel blockade occurred. Loperamide generally is not regarded as a sodium-channel blocking agent at usual plasma concentrations.10 However, chronic abuse of loperamide at very high dosages might have spurred a major blockade of sodium channels, lengthening our patient’s QRS duration.
MANAGEMENT Our patient was given intravenous plant-based fat emulsion. At the same time, she continued to receive bicarbonate and supportive treatment in the intensive care unit. Her ECG
irregularities resolved within 1 week, and her pacing thresholds normalized. After she recovered, she finally admitted to chronic abuse of loperamide, which she had denied during previous hospitalizations. Although she had successfully completed a drug rehabilitation program in the past, she began using loperamide after learning about it from Internet sources and friends. Her care required an interdisciplinary approach, including psychosocial counseling and social services. Upon discharge, she was in good condition. Two months after discharge, the patient was readmitted in cardiopulmonary arrest after continued loperamide abuse. Despite being placed on percutaneous femoral venoarterial extracorporeal membrane oxygenation, she had no significant improvement. She died 18 hours after admission. Loperamide-induced cardiac toxicity can be fatal and should be considered in the differential diagnosis of unstable arrhythmias, long QT intervals, or widened QRS complexes. When taken in massive doses, it is a drug of abuse, serving as a substitute for opioids. Large quantities can be obtained easily over the counter without any government regulation. Increased public awareness of harmful practices and their dangerous effects is essential.
References 1. Baker DE. Loperamide: a pharmacological review. Rev Gastroenterol Disord. 2007;7(Suppl 3):S11-S18. 2. Daniulaityte R, Carlson R, Falck R, et al. “I just wanted to tell you that loperamide WILL WORK:” a web-based study of extra-medical use of loperamide. Drug Alcohol Depend. 2013;130(1-3):241-244. 3. Kaverina NV, Skoldinov AP, Dzhaparidze MM, Berdiaev Slu, Darinskiĭ NV. Hydrochlorides of N-hydroxyalkyl-alpha-piperidine carboxylic arylamides possessing antiarrhythmic activity. Farmakol Toksikol. 1984;47:25-28.
4 4. Church J, Fletcher EJ, Abdel-Hamid K, MacDonald JF. Loperamide blocks high-voltage-activated calcium channels and N-methylD-aspartate-evoked responses in rat and mouse cultured hippocampal pyramidal neurons. Mol Pharmacol. 1994;45:747-757. 5. Nozaki-Taguchi N, Yaksh TL. Characterization of the antihyperalgesic action of a novel peripheral mu-opioid receptor agonist—loperamide. Anesthesiology. 1999;90:225-234. 6. Koerner JE, Dage RC. Antiarrhythmic and electrophysiologic effects of MDL 11,939, a novel class III antiarrhythmic agent in anesthetized dogs. J Cardiovasc Pharmacol. 1990;16:383-393.
The American Journal of Medicine, Vol -, No -,
-
2015
7. Reynolds IJ, Gould RJ, Snyder SH. Loperamide: blockade of calcium channels as a mechanism for antidiarrheal effects. J Pharmacol Exp Ther. 1984;231:628-632. 8. Berger SI, Ma’ayan A, Iyengar R. Systems pharmacology of arrhythmias. Sci Signal. 2010;3:ra30. 9. Pokhrel K, Rajbhandary A, Thapa J. 1274: Loperamide: the unexpected culprit. Crit Care Med. 2013;41:A328. 10. Harmer AR, Valentin JP, Pollard CE. On the relationship between block of the cardiac Naþ channel and drug-induced prolongation of the QRS complex. Br J Pharmacol. 2011;164:260-273.