A very special welcome to our newest hound, Jeanna Marraffa, PharmD, DABAT! You can learn more about her here . . .

by Jeanna Marraffa

Circa Feb 2012

Poison Center: “Um, Jeanna, there is a doc on the line that has a quick question for you. I’m going to send it through to your line.”

Me: “Uh-OK. <What is this about?> Oh hello, Dr., this is Jeanna Marraffa, I’m one of the clinical toxicologists here at the poison center.”

Said doctor: “Yeah, I have a 43 year old female that keeps going in and out of torsades. So far, we’ve shocked her 9 times. She says she has been abusing 144 tablets of loperamide daily. Does that do this?”

Me: <DAMMIT. If I hang up the phone, will he realize it? Why did I pick up the phone?> “OK, can you tell me anything else? Is she on any other meds?”

Meanwhile, I am frantically asking Dr. Google if loperamide can do this. Dr. Google was useless. Cue the sweaty palms.

“When you shock her and you get a perfusing rhythm back, what is the QRS and QTc?” . . . AKA . . . me, buying time . . .

﻿

The easy part initially was “treat what you see and let me do more research.” She received sodium bicarbonate, magnesium, more electricity and fatty acid emulsion until a transvenous pacer was placed and overdrive pacing initiated.

Could this be real? Do people really abuse loperamide? Does loperamide cause torsades des pointes (TdP)? Is there antiperspirant for hands? We’re toxicologists . . .so, let the search for zebras commence.

6 years later, and it is safe to say that loperamide abuse and loperamide-induced cardiac toxicity is well documented. It still does elicit the side eye though from the majority of our colleagues. Not to mention the looks we get from people not in the medical field.

Loperamide: An effective anti-diarrheal agent . . . when used at therapeutic doses

Before we get into loperamide abuse and its cardiac toxicity, let’s first talk about loperamide used therapeutically.

Loperamide is a readily available, inexpensive antidiarrheal agent. First made available as an over the counter (OTC) product in the early 1980s, it was considered to be ‘free of abuse potential’1 despite being a mu-opioid receptor agonist. At therapeutic doses it has limited oral bioavailability (< 1%) and does not cross the blood brain barrier due to p-glycoprotein (p-gp) efflux. Its peak concentration is achieved within 3-4 hrs, and it has an elimination half life of 4-11 hours. Its major metabolite is n-desmethyl-loperamide (DLOP) which was long believed to be inactive. Because of its poor absorption, the serum concentrations achieved after therapeutic doses are <2 ng/ml.

Is there validity to it being an effective opioid substitute?

Loperamide is structurally similar to haloperidol and methadone. It is an opioid agonist but doses of even up to 16 mg do not cause central opioid effects. (Disclaimer: Kids aren't little adults and their p-gp is underdeveloped. So this does not apply to them.) The opioid effects, however, can be achieved when the p-gp pump isn’t doing what its supposed to be doing. And for those of us that forgot what it does….P-gp is a member of the ABC superfamily of efflux transporters and are located in the blood brain barrier, the GI tract and the kidneys. There are numerous xenobiotics that are inhibitors of p-gp including quinine, quinidine, cimetidine, and proton pump inhibitors.

The idea that blocking p-gp could result in loperamide having CNS depressant effects was first reported by Sadeque et al., back in 2000.2 Even when a p-gp inhibitor is not employed, excessive crazy high doses of loperamide can overcome the p-gp efflux pump resulting in CNS penetration and opioid effects.

Both approaches have been employed in patients with loperamide abuse.

What do we know about the cardiac toxicity?

Prior to 2011, the risk of cardiac toxicity secondary to loperamide use was not recognized, largely because it isn't seen with therapeutic dosing. And also interesting, single acute overdoses of loperamide have not resulted in cardiac toxicity. The cardiac toxicity cases reported in the medical literature all involve excessive chronic dosing.3

At high plasma concentrations, loperamide and DLOP interfere with cardiac conduction, by blocking both sodium and potassium channels, resulting in widening of the QRS complex and QT interval prolongation. Not surprising this can result in ventricular arrhythmias. Although there have been reports of both QRS widening and QTc prolongation, QTc prolongation is more commonly reported. For those of you that would like an in-depth review on the cardiac cycle, refer to one of our previous posts. There have even been reports of bradycardia suggesting a direct myocardial depressant effect.4

Let’s dive a bit into the mechanism that have been implicated….

After the first reports of cardiac toxicity, the quest to identify the mechanism of toxicity began. The data is scarce but what there is has given some insight and has led to additional questions. So what is this data thus far? Well, it involves less than 5 published papers and generally is in vitro data; although there are some animal models being done with the data yet to be published. What do we know so far? We know that loperamide, and to a lesser degree DLOP, blocks cardiac sodium channels. The primary culprit in deaths though is its ability block the human ether-a-go-go-related potassium channel. For those who remember our last post this means it blocks potassium channels.5–7 The big question remains….how much loperamide and metabolite is needed to block these channels. What we do know from in vitro models is that at therapeutic doses, it doesn’t happen. But, loperamide concentrations of 40 nmol/L (much higher than concentrations achieved at therapeutic doses), inhibit the hERG channel to half of its activity. As the concentration of loperamide increases, the blockade of the hERG channel increases.7,8

A dose-response curve for cardiac toxicity has not been defined, however the cases described in the literature report elevated serum concentrations of several fold higher than the expected therapeutic serum concentrations.3,9

The North Carolina medical examiner’s office published a series of 19 deaths with elevated loperamide concentrations. 17 out of 19 cases had loperamide induced-toxicity listed as the primary cause of death.10 Whether these deaths were due to respiratory depression or cardiac arrhythmias is impossible to determine.

Two fatal cases of loperamide abuse had elevated post-mortem loperamide concentrations of 77 ng/ml and 140 ng/ml, respectively.11

A recent review of the FDA Medwatch system from 1976 through December 2015 described 48 cases of loperamide abuse with serious cardiac events and 10 deaths. The median daily dose of loperamide in these cases were 250 mg (range: 70-1600 mg). Keep in mind the therapeutic dose is 2 mg. Yes, this means people were, on average, taking over a hundred over the counter tablets in a day. Even more interesting is that only 4 cases reported concurrent use of a p-gp or CYP 3A inhibitor further strengthening that the p-gp efflux pump can be overwhelmed with excessive doses.12

Let me summarize all of this in a way that my brain can understand…the patients that appear to be at the highest risk for developing cardiac toxicity from loperamide are those that chronically take high doses of loperamide. The exact definition of what ‘high doses’ means is not well defined but we know that it is likely more than 70 mg per day.

How should you approach treating these patients?

The good news is that you should treat what you see. The bad news is that you can only treat what you see.

Put a bunch of toxicologists in a room and the inevitable conversation about GI decontamination will occur. For ‘x’ toxin, would you employ lavage? What about activated charcoal? What about more than one dose of activated charcoal? What about whole bowel irrigation? There will likely be a debate without a definitive agreement. I know…our parties are riveting and ever so exciting! Hey, don’t be jealous. But, I digress. The data surrounding GI decontamination is what it is, but a dose of activated charcoal is reasonable after single acute overdoses of loperamide. There is no evidence that loperamide undergoes enterohepatic recirculation or entero-enteric clearance so there is likely no role for charcoal in patients with chronic loperamide use.

In patients with symptoms consistent with opioid toxicity, naloxone should be given, titrated to effect to reverse respiratory depression. It should be started at low doses and titrated upwards.

For patients with life-threatening arrhythmias, standard management should be employed. Synchronized cardioversion for patients with ventricular tachycardia and hemodynamic instability, or defibrillation if ventricular fibrillation or ventricular tachycardia without pulses. For polymorphic ventricular tachycardia/TdP, electricity first, then your therapy of choice.

Since both loperamide and DLOP are sodium channel blockers, sodium bicarbonate may be helpful. However, the few case reports describe inefficacy of sodium bicarbonate in narrowing the QRS complex duration.5 In a patient with QRS widening, sodium bicarbonate 1-2 meq/kg as an intravenous bolus should be attempted. It is imperative to follow serum potassium closely and replace to within normal range in a patient receiving sodium bicarbonate as hypokalemia contributes to and worsens the degree of QTc prolongation and can make cardiovascular toxicity worse.

How long should we expect these patients to be symptomatic?

I’d like to say that after review of the pharmacokinetic properties of loperamide and its metabolite combined with clinical experience that the answer is……. If you look at the known kinetics after therapeutic doses, with a worst case scenario half life of up to 11 hours and employing the ‘rule’ of 3-5 half-lives for a drug to be fully eliminated from the body, then you would think that the effects should be gone within 36 hours. Worst case scenario. But unfortunately, the kinetics of these super high doses of loperamide are unknown. One single case report, in a patient with Crohn's disease (which makes any extrapolation to any patient with a normal GI tract nearly impossible), the half life was 34.8 hours.13 Just ponder that. Five half-lives of 35 hours is, 8 days. And what is the half-life of n-desmethyl-loperamide? We don’t know. The case reports provide evidence that the toxicity can be prolonged, in the range of days.3

So here goes my well-thought out, highly unscientific answer to this question….watch them until their ECG is back to normal/their baseline. I know….mind-blown!

My final thoughts on loperamide abuse

Compared to the public health crisis of abuse of other opioids, the incidence of loperamide misuse and abuse is comparatively low. But, the despite the low incidence, the risk of severe cardiac toxicity is high and when compared to other opioids, it has a high probability of causing severe cardiac effects.

More research is needed to answer so many unknowns. Being aware of this new trend is important and in patient, particularly those with opioid use disorder, with unexplained syncope or abnormal ECG, think about and ask about loperamide abuse.

Flaming Man by Aziz Acharki

1. Rev Gastroenterol Disord. 2007;7 Suppl 3:S11-8. PubMed] Baker D. Loperamide: a pharmacological review.. 2007;7 Suppl 3:S11-8. 2. Clin Pharmacol Ther. 2000;68(3):231-237. PubMed] Sadeque A, Wandel C, He H, Shah S, Wood A. Increased drug delivery to the brain by P-glycoprotein inhibition.. 2000;68(3):231-237. 3. Ann Emerg Med. 2017;70(2):245-252. PubMed] Wu P, Juurlink D. Clinical Review: Loperamide Toxicity.. 2017;70(2):245-252. 4. J Emerg Med. 2017;53(1):73-84. PubMed] Borron S, Watts S, Tull J, Baeza S, Diebold S, Barrow A. Intentional Misuse and Abuse of Loperamide: A New Look at a Drug with “Low Abuse Potential”.. 2017;53(1):73-84. 5. Bioorg Med Chem Lett. December 2017. PubMed] Vaz R, Kang J, Luo Y, Rampe D. Molecular determinants of loperamide and N-desmethyl loperamide binding in the hERG cardiac K+ channel.. December 2017. 6. Naunyn Schmiedebergs Arch Pharmacol. 2016;389(10):1133-1137. PubMed] Kang J, Compton D, Vaz R, Rampe D. Proarrhythmic mechanisms of the common anti-diarrheal medication loperamide: revelations from the opioid abuse epidemic.. 2016;389(10):1133-1137. 7. JACC Clin Electrophysiol. 2016;2(7):784-789. PubMed] Klein M, Haigney M, Mehler P, Fatima N, Flagg T, Krantz M. Potent Inhibition of hERG Channels by the Over-the-Counter Antidiarrheal Agent Loperamide.. 2016;2(7):784-789. 8. Pharmacotherapy. 2018;38(3):341-348. PubMed] Lehmann D, Eggleston W, Wang D. Validation and Clinical Utility of the hERG IC50:C max Ratio to Determine the Risk of Drug-Induced Torsades de Pointes: A Meta-Analysis.. 2018;38(3):341-348. 9. Clin Toxicol (Phila). 2014;52(9):952-957. PubMed] Marraffa J, Holland M, Sullivan R, et al. Cardiac conduction disturbance after loperamide abuse.. 2014;52(9):952-957. 10. J Anal Toxicol. 2016;40(8):677-686. PubMed] Bishop-Freeman S, Feaster M, Beal J, et al. Loperamide-Related Deaths in North Carolina.. 2016;40(8):677-686. 11. Ann Emerg Med. 2017;69(1):83-86. PubMed] Eggleston W, Clark K, Marraffa J. Loperamide Abuse Associated With Cardiac Dysrhythmia and Death.. 2017;69(1):83-86. 12. J Am Pharm Assoc (2003). 2017;57(2S):S63-S67. PubMed] Swank K, Wu E, Kortepeter C, McAninch J, Levin R. Adverse event detection using the FDA post-marketing drug safety surveillance system: Cardiotoxicity associated with loperamide abuse and misuse.. 2017;57(2S):S63-S67. 13. Clin Toxicol (Phila). 2015;53(5):495-496. PubMed] Eggleston W, Nacca N, Marraffa J. Loperamide toxicokinetics: serum concentrations in the overdose setting.. 2015;53(5):495-496.