- B. Loperamide
- C. Administer intravenous sodium bicarbonate
Discussion
The electrocardiographic findings of QT prolongation and progressive
QRS widening were attributed to loperamide toxicity. Regarding Question
1, though cocaine and nortriptyline may also potentiate QT prolongation
and ventricular dysrhythmias, the patient's urine toxicology was
negative for both drugs. Metoprolol and midazolam do not cause QT
prolongation or ventricular arrhythmias and, as such, are incorrect
answer choices. Further discussion with the patient's friends and family
revealed that he had been taking approximately 200 2-milligram tablets
of loperamide daily in the weeks preceding this presentation. Loperamide
is an opioid agonist available over-the-counter as an antidiarrheal
agent. The drug slows intestinal motility by acting on opiate receptors
within the gut; at appropriate dosing it has low bioavailability, poor
penetration of the blood-brain-barrier, and a minimal side effect
profile. At higher concentrations, loperamide can cause respiratory
depression and arrhythmias. Loperamide blocks potassium channels,
resulting in significant QT prolongation and torsades de pointes. At
even higher plasma concentrations, loperamide causes sodium channel
blockade, resulting in QRS complex widening.
Treatment of loperamide toxicity is focused on maintaining
cardiopulmonary stability. If patients present within several hours of
ingestion, gastric decontamination may minimize systemic absorption,
although in many cases the highest plasma concentrations result from
chronic ingestion. Opioid antagonists may mitigate respiratory
depression, though some patients will require intubation and mechanical
ventilation. Aggressive medical management of cardiac toxicity is
required to prevent and treat arrhythmias. Electrolyte supplementation
should be provided to ensure that the patient's potassium is greater
than 4 millimoles per liter and the magnesium is greater than 2
milligrams per deciliter. When significant widening of the QRS complex
is noted (as seen on this electrocardiogram), intravenous sodium
bicarbonate should be administered to narrow the QRS complex (Question
2). In cases of severe arrhythmias complicated by hemodynamic compromise
that are refractory to initial medical management, placement of a
transvenous pacer should be considered for overdrive pacing. Flecainide,
a class Ic antiarrhythmic, would cause increased sodium channel
blockade with QRS complex widening and, as such, is not appropriate.
Beta blockade is also inappropriate, as this would exacerbate the
patient's bradycardia.
In cases of bradycardia associated with ventricular ectopy,
isoproterenol is typically used, though intravenous infusions can be
complicated by vasodilation and worsening hemodynamics. Lidocaine may
reduce the burden of ventricular ectopy. Amiodarone may worsen QT
prolongation and paradoxically exacerbate arrhythmias. If pulseless
ventricular tachycardia or ventricular fibrillation occurs, providers
should follow ACLS protocol. Case studies support a potential benefit
from intravenous lipid emulsions and veno-arterial extracorporeal
membrane oxygenation in refractory cases.
In the context of today's devastating opioid epidemic, loperamide has
garnered increasing attention for its ability to potentiate a "high"
and to mitigate symptoms of opioid withdrawal when used in excess. The
recommended dose is 2-4 milligrams in adults, not to exceed 16
milligrams daily. As a non-prescription drug, loperamide can be
purchased in bulk, with many retailers selling up to 200 capsules at a
time for about $25.00. Cardiotoxicity has most often been seen in
chronic overuse of loperamide. In 2016, the Food and Drug Administration
issued a Drug Safety Communication to warn about "serious heart
problems that can lead to death" associated with inappropriate
loperamide use. Anecdotally, our own intensive care unit has seen a
handful of cases of ventricular arrhythmias due to loperamide over the
past year and, nationally, these numbers are on the rise. Intensivists
should familiarize themselves with the complications of loperamide
misuse and the ways in which to manage these patients.
References
-
FDA Drug Safety Communication: FDA warns about serious heart problems
with high doses of the antidiarrheal medicine loperamide (Imodium)
including from abuse and misuse. Food and Drug Administration, June
2016. (https://www.fda.gov/downloads/Drugs/DrugSafety/UCM505108.pdf).
- Litovitz T, Clancy C, Korberly B, et. al. Surveillance of loperamide
ingestions: an analysis of 216 poison center reports. J Toxicol Clin
Toxicol 1997; 35: 11-9.
-
MacDonald R, Heiner J, Villarreal J, et. al. Loperamide dependence
and abuse. BMJ Case Reports 2015. doi:10.1136/bcr-2015-209705
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Miller H, Panahi L, Tapia D, et. al. Loperamide misuse and abuse.
Journal of the American Pharmacists Association 2017; 57: S45-S50.
-
Wu PE, Juurlink DN. Clinical Review: Loperamide Toxicity. Annals of Emergency Medicine 2017; 70: 245-52.