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34. Loperamide Toxicity: “I’m in Love … I’m All Stopped Up”
Keywords
LoperamideBlood–brain barrierP-glycoproteinMultidrug efflux pumpPeripheral activityMesenteric plexusLarge intestineCase
Pertinent History
The patient arrived to the emergency department (ED) via EMS at 0600. He reported he took 400 tablets of loperamide at 2200 the previous evening in an attempt to get high. He awoke this morning with lightheadedness, right-sided abdominal pain, nausea, and dyspnea. The initial EKG by EMS was concerning for widened QRS and extremely prolonged QTc.
PMH
Depression, panic disorder
SH
Denies a history of illicit drug use, but states he has been taking loperamide to get high. He reports taking 100 tablets every 1–2 days for the past 2 months. Denies current tobacco use but has a history of smokeless tobacco.
Pertinent Physical Exam
BP 119/66, pulse 82, temperature 98.1 °F (36.7 °C), RR 17, SpO2 100%
Except as noted below, the findings of a complete physical exam are within normal limits.
Cardiovascular:
Normal rate, irregular rhythm. No murmur heard. Normal heart sounds.
Pertinent Diagnostic Testing
Test | Result | Units | Normal Range |
|---|---|---|---|
Sodium | 135 | mEq/L | 135–148 mEq/L |
Potassium | 2.9 ↓ | mEq/L | 3.5–5.5 mEq/L |
Chloride | 102 | mEq/L | 96–112 mEq/L |
Bicarbonate | 22 | mEq/L | 21–34 mEq/L |
BUN | 14 | mg/dL | 6–23 mg/dL |
Creatinine | 1.64 ↑ | mg/dL | 0.6–1.5 mg/dL |
Calcium | 8.4 ↓ | mg/dL | 8.6–10.5 mg/dL |
Phosphate | 5.0 ↑ | mg/dL | 2.2–4.6 mg/dL |
Magnesium | 1.5 ↓ | mg/dL | 1.6–2.6 mg/dL |
Salicylate | < 5 | mg/dL | <30.0 mg/dL |
Acetaminophen | <10 | mcg/mL | <32.0 mcg/mL |
Alcohol | 380 ↑ | mg/dL | <10 mg/dL |
Troponin | 0.01 | mg/dL | < 0.04 ng/dl |
EKG on Arrival
Plan
The patient arrived alert and oriented, but lightheaded. He was placed on a cardiac monitor, given IV fluids. Given the patient’s EKG with QRS widening and QT prolongation, he was given IV magnesium, IV calcium, and IV bicarbonate.
The poison center was contacted regarding the patient’s case. The patient’s symptoms, including cardiac dysrhythmias were felt to be consistent with massive loperamide overdose. As the patient was found to be hypokalemic and hypomagnesemic, these electrolytes were replaced. After speaking with the poison center, it was thought the widened QRS was primarily a potassium channel event and therefore would not respond to naloxone. The patient was admitted to the ICU.
Learning Points: Loperamide Overdose
Priming Questions
- 1.
How does loperamide work as an anti-diarrheal agent?
- 2.
How does loperamide toxicity present?
- 3.
How do you treat and stabilize a loperamide toxicity?
Introduction/Background
- 1.
Loperamide is a synthetic opioid, sold over the counter as an antidiarrheal agent. At therapeutic doses, it acts at the μ-opioid receptor to inhibit peristaltic activity of the mesenteric plexus of the large intestine [1].
- 2.
It has been considered low risk for abuse due to its peripheral activity and lack of central effects at therapeutic doses.
This is due to both the low bioavailability and active excretion at the blood–brain barrier by P-glycoprotein, a multidrug efflux pump [2].
Although this drug has been considered to have a wide margin of safety and considered low risk for abuse, there is growing evidence that misuse and abuse of loperamide for its opioid effects are growing.
A study looking at the National Poison Data System found a 91% increase in reported loperamide exposures from 2010 to 2015 [3].
Physiology/Pathophysiology
- 1.
Loperamide is a phenylpiperidine opioid, similar to meperidine. By stimulating μ-opioid receptors in the myenteric plexus, it acts to slow the intestinal transit time. The medication also possesses antisecretory properties and blocks intestinal calcium channels [2].
- 2.
It has been considered safe and low risk for abuse due in part to its low bioavailability.
Predominant metabolism is by intestinal and hepatic cytochrome P450 enzymes, which metabolize the drug to inactive metabolites [4].
Absorbed loperamide as well as its metabolites undergo biliary excretion.
- 3.
In addition to its low bioavailability, the presence of P-glycoprotein (P-gp) at the blood–brain barrier decreases this medication’s abuse potential. P-gp is a multidrug efflux pump that is found in several different areas of the body. Its importance in loperamide is due to its active role in limiting the passage of loperamide into the brain [5].
- 4.
There are several known drug interactions with loperamide which can influence its concentration within the blood and brain.
Because the low bioavailability of loperamide is in part due to its metabolism by cytochrome P450 enzymes, any inhibitor of these enzymes has the potential to increase bioavailability [2].
P-gp inhibitors also act to increase loperamide concentration by not only increasing the absorption of loperamide from the intestine but also by inhibiting efflux pumping of loperamide out of the brain.
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