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Loperamide


Loperamide

Article Author:
Nidhi Sahi
Article Author:
Rosalee Nguyen
Article Editor:
Cynthia Santos
Updated:
5/30/2020 2:52:50 PM
For CME on this topic:
Loperamide CME
PubMed Link:
Loperamide

Indications

Loperamide is an over-the-counter oral antidiarrheal agent made in 1969, first used medically in 1976 and became available without a prescription in 1988.[1] Initially, due to its opioid-like abuse potential, it was categorized as a Schedule V drug by the Federal Drug Administration (FDA).[2] Currently, loperamide has been FDA approved to treat various forms of diarrhea and has also been used off-label to treat the adverse effects of chemotherapy resulting in diarrhea. In recent years, there has been an increased interest in non-medical use of loperamide, ranging from self- management of opioid withdrawal symptoms as well as a means to induce euphoria, i.e., getting high. Recently, a new syndrome termed loperamide-induced cardiotoxicity has come to light.[3] Patients can present with different forms of potentially life-threatening dysrhythmias when using loperamide in toxic doses.

Medical use: The FDA approved loperamide for the treatment of various forms of diarrhea, including traveler’s diarrhea, irritable bowel syndrome associated with chronic diarrhea, acute nonspecific diarrhea in patients two years of age and older, and is indicated for reducing ileostomy output.[4] The off-label uses include the management of chemotherapy-related diarrhea.

Illicit drug use and self-medication use: In recent years, there has been a noticeable incline in the use and abuse of loperamide as a means of self-management of opioid withdrawal as well as an inexpensive method to induce euphoria, i.e., to achieve a euphoric state. Vakkalanka et al. found a 91% increase in reported loperamide exposures, including eight deaths, from 2010 to 2015 across Poison Control Centers in the United States.[5] Individuals have used loperamide as a means to self-medicate in an effort to decrease the withdrawal side effects of opioid dependence or slow the tapering process. Recently high dose loperamide has shown promise for such use.[6]

Mechanism of Action

Loperamide is a highly lipophilic synthetic phenylpiperidine opioid.[7] The peak plasma time is 4 to 5 hours, with a half-life of 7 to 19 hours.[8] It has a low bioavailability of < 1%, due to the first-pass metabolism. It has high protein binding and a large volume of distribution. Loperamide is extracted in the GI tract and metabolized in the liver by the cytochrome P450 pathway; it is metabolized in the liver via CYP2C8 and CYP3A4 to desmethylloperamide.[3] This pathway allows for decreased gastrointestinal uptake and thus enhanced elimination through bile excretion. At therapeutic doses, loperamide acts on the mu-opioid receptors directly on the circular and longitudinal intestinal muscles to decrease transition time, inhibit peristalsis, electrolyte loss, and increase rectal tone.[9] However, at higher doses, because loperamide is a substrate for P-glycoprotein, P-glycoprotein becomes inhibited, allowing loperamide to cross the blood-brain barrier and act on the central nervous system, producing central opioid effects and toxicity.[9]

Loperamide was also found to inhibit both the Na+ gated cardiac channels, which in turn prolongs the QRS complex as well as the hERG channel, which increases the QTc interval.[10] QRS and QTc prolongation both in turn can cause ventricular dysrhythmias, monomorphic and polymorphic ventricular tachycardia, torsade de pointes, ventricular fibrillation, Brugada syndrome, cardiac arrest, and death.

Administration

Loperamide is a mu- receptor agonist [4]. It is extracted in the liver and metabolized by CYP3A4, a cytochrome P450 enzyme [3]. It is then conjugated and excreted into the bile. At recommended doses, there is almost no active loperamide available in the systemic circulation.

Loperamide is available in different formulations, most commonly as tablets, capsules, and orodispersible tablets that melt on the tongue. The usual initial recommended dose for acute diarrhea such as traveler’s diarrhea is 4 mg starting dose, followed by 2 mg dosing after each unformed stool but not to exceed 8 mg per day for over the counter use and 16 mg per day with prescription use. For chronic use, the suggested dose is 2 mg BID. It is not recommended for children less than age 2.

Adverse Effects

Common Adverse Effects [4][6]

  • Dry mouth
  • Flatulence
  • Abdominal cramps
  • Nausea
  • Ileus
  • Constipation
  • Urinary retention
  • Dizziness
  • Drowsiness

Serious Adverse Effects [4][6][11][12]

  • Toxic megacolon
  • Necrotizing enterocolitis
  • Stevens-Johnson syndrome
  • Toxic epidermal necrolysis
  • Syncope
  • QT/QTc interval prolongation
  • Torsades de pointes
  • Ventricular tachycardia
  • Other ventricular arrhythmias
  • Cardiac arrest

Contraindications

Loperamide is contraindicated in patients less than two years old, acute ulcerative colitis, bloody diarrhea, and diarrhea associated with bacterial infections.[13]

Monitoring

When loperamide is taken in large quantities and/or with other drugs used that may alter its pharmacokinetic effects, such as p- glycoprotein inhibition, loperamide produces opioid-like symptoms. These include a sensation of euphoria, miosis, central nervous system depression, and respiratory depression. Treatment of loperamide overdose and toxicity is primarily supportive. Naloxone, including an intranasal naloxone bolus, intravenous naloxone bolus, or naloxone infusion, may be used in patients with respiratory depression.[14] As naloxone has a shorter half-life than loperamide, patents should be observed for at least 24 hours after the last naloxone use to ensure they do not deteriorate clinically.

Used, in high doses, loperamide can produce dysrhythmias and conduction abnormalities.[15] The patient should be on a cardiac monitor and an ECG obtained. If there is QRS widening, sodium bicarbonate may be given and can be repeated in boluses or given as an infusion.[16] If there are signs of QTc prolongation (QTc is considered prolonged if greater than 450 ms in males and 470 ms in females), electrolyte abnormalities (magnesium, potassium, phosphate) should be corrected, and isoproterenol or transcutaneous pacing may be an option.[17] Cardiac arrest is manageable using standard ACLS protocols.

Toxicity

Currently, loperamide remains available over the counter and easily accessible without a prescription.

Taken in large quantities, loperamide can cause systemic effects similar to opioid toxicity (central nervous system depression, respiratory depression) as well as lethal cardiac conduction abnormalities.[3]

Enhancing Healthcare Team Outcomes

Healthcare providers widely prescribe loperamide for different types of diarrhea. Pharmacists and physicians need to survey the potential for abuse and educate the patient of its potential toxicity in large doses. In September 2019, the FDA approved a new package size limitations and unit-dose packaging for certain over-the-counter loperamide products in an effort to improve patient safety. When prescribing or recommending loperamide, the clinician should have the nurse and/or pharmacist reiterate all safety and dosing issues to ensure proper use of the medication and to optimize patient safety, as patients may think that because of its OTC availability, that it does not represent any potential for misuse.


References

[1] Kaplan MA,Prior MJ,McKonly KI,DuPont HL,Temple AR,Nelson EB, A multicenter randomized controlled trial of a liquid loperamide product versus placebo in the treatment of acute diarrhea in children. Clinical pediatrics. 1999 Oct;     [PubMed PMID: 10544864]
[2] MacDonald R,Heiner J,Villarreal J,Strote J, Loperamide dependence and abuse. BMJ case reports. 2015 May 2;     [PubMed PMID: 25935922]
[3] Wu PE,Juurlink DN, Clinical Review: Loperamide Toxicity. Annals of emergency medicine. 2017 Aug;     [PubMed PMID: 28506439]
[4] Regnard C,Twycross R,Mihalyo M,Wilcock A, Loperamide. Journal of pain and symptom management. 2011 Aug;     [PubMed PMID: 21703817]
[5] Vakkalanka JP,Charlton NP,Holstege CP, Epidemiologic Trends in Loperamide Abuse and Misuse. Annals of emergency medicine. 2017 Jan;     [PubMed PMID: 27823872]
[6] Litovitz T,Clancy C,Korberly B,Temple AR,Mann KV, Surveillance of loperamide ingestions: an analysis of 216 poison center reports. Journal of toxicology. Clinical toxicology. 1997;     [PubMed PMID: 9022646]
[7] Killinger JM,Weintraub HS,Fuller BL, Human pharmacokinetics and comparative bioavailability of loperamide hydrochloride. Journal of clinical pharmacology. 1979 Apr;     [PubMed PMID: 438356]
[8] Heel RC,Brogden RN,Speight TM,Avery GS, Loperamide: a review of its pharmacological properties and therapeutic efficacy in diarrhoea. Drugs. 1978 Jan;     [PubMed PMID: 342229]
[9] Vandenbossche J,Huisman M,Xu Y,Sanderson-Bongiovanni D,Soons P, Loperamide and P-glycoprotein inhibition: assessment of the clinical relevance. The Journal of pharmacy and pharmacology. 2010 Apr;     [PubMed PMID: 20604828]
[10] Kang J,Compton DR,Vaz RJ,Rampe D, Proarrhythmic mechanisms of the common anti-diarrheal medication loperamide: revelations from the opioid abuse epidemic. Naunyn-Schmiedeberg's archives of pharmacology. 2016 Oct;     [PubMed PMID: 27530870]
[11] Teigeler T,Stahura H,Alimohammad R,Kalahasty G,Koneru JN,Ellenbogen M,Ellenbogen KA,Padala SK, Electrocardiographic changes in loperamide toxicity: Case report and review of literature. Journal of cardiovascular electrophysiology. 2019 Nov;     [PubMed PMID: 31432581]
[12] Spinner HL,Lonardo NW,Mulamalla R,Stehlik J, Ventricular tachycardia associated with high-dose chronic loperamide use. Pharmacotherapy. 2015 Feb;     [PubMed PMID: 25645123]
[13] Li ST,Grossman DC,Cummings P, Loperamide therapy for acute diarrhea in children: systematic review and meta-analysis. PLoS medicine. 2007 Mar 27     [PubMed PMID: 17388664]
[14] Eggleston W,Palmer R,Dubé PA,Thornton S,Stolbach A,Calello DP,Marraffa JM, Loperamide toxicity: recommendations for patient monitoring and management. Clinical toxicology (Philadelphia, Pa.). 2019 Nov 4;     [PubMed PMID: 31684751]
[15] Eggleston W,Clark KH,Marraffa JM, Loperamide Abuse Associated With Cardiac Dysrhythmia and Death. Annals of emergency medicine. 2017 Jan;     [PubMed PMID: 27140747]
[16] Lasoff DR,Schneir A, Ventricular Dysrhythmias from Loperamide Misuse. The Journal of emergency medicine. 2016 Mar;     [PubMed PMID: 26794455]
[17] Katz KD,Cannon RD,Cook MD,Amaducci A,Day R,Enyart J,Burket G,Porter L,Roach T,Janssen J,Williams KE, Loperamide-Induced Torsades de Pointes: A Case Series. The Journal of emergency medicine. 2017 Sep;     [PubMed PMID: 28755998]