Loperamide

Development and Regulatory History

• Origin and Approval: Loperamide was synthesized in 1969 and introduced medically in 1976. It became available over-the-counter (OTC) in 1988.

Medical Applications

• FDA-Approved Uses:
  1. Traveler’s Diarrhea: Quick relief for transient episodes of diarrhea while traveling.
  2. Irritable Bowel Syndrome (IBS): Used to manage symptoms of diarrhea predominant IBS.
  3. Acute Nonspecific Diarrhea: For sudden onset diarrhea without a specific cause in patients aged two years and older.
  4. Reducing Ileostomy Output: Helps to decrease the volume of discharge from an ileostomy.
• Off-label Uses:
  • Chemotherapy-Induced Diarrhea: Used to manage diarrhea caused by cancer treatment, particularly with agents like irinotecan and neratinib.

Mechanism of Action

• Opioid Receptor Activity: Loperamide functions primarily as a mu-opioid receptor agonist in the gastrointestinal tract, reducing motility and increasing the absorption of electrolytes and water.
• Blood-Brain Barrier: At therapeutic levels, loperamide does not cross the blood-brain barrier due to P-glycoprotein efflux. However, at toxic levels, inhibition of P-glycoprotein allows loperamide to cross into the central nervous system and cause opioid-like effects.

Pharmacokinetics

• Absorption and Metabolism: Loperamide has a peak plasma time of 4 to 5 hours, with a bioavailability of less than 1% due to extensive first-pass metabolism in the liver. It’s metabolized predominantly via CYP2C8 and CYP3A4 into desmethylloperamide, which has minimal opioid activity.
• Elimination: Primarily excreted in the bile and thus in the feces, with minimal renal excretion.

Dosage and Administration

• Forms Available: Tablets, capsules, and orodispersible tablets, as well as oral solutions.
• Dosing Guidelines:
  • Adults: Start with a 4 mg dose for acute diarrhea, followed by 2 mg after each unformed stool. Daily maximum is 8 mg for OTC use and 16 mg under prescription.
  • Chronic Use: Typically 2 mg twice daily.
  • Special Cases: Higher dosages or adjusted timing for cases like chemotherapy-induced diarrhea.

Special Populations

• Pediatrics: Not recommended for children under two years of age. Dosage adjustments based on weight for older children.
• Pregnancy and Lactation: Generally advised to avoid due to insufficient data on safety. Loperamide is detectable in breast milk.
• Renal and Hepatic Impairment: No dosage adjustment necessary for renal impairment. Caution advised in hepatic impairment due to altered drug metabolism.

Adverse Effects and Toxicity

• Common Side Effects: Include constipation, nausea, dizziness, and drowsiness.
• Serious Adverse Effects
  • Toxic megacolon – increase the risk of developing toxic megacolon by Reduced Motility, Increased Risk of Distension with the slowed transit of intestinal contents and Impaired Reflexes by increasing the tone of the anal sphincter
  • Necrotizing enterocolitis
  • Stevens-Johnson syndrome
  • Toxic epidermal necrolysis
  • Syncope
  • QT/QTc interval prolongation, torsades de pointed, ventricular tachycardia
  • Other ventricular arrhythmias and/or cardiac arrest
• Toxicity Management: Includes monitoring and possibly the use of naloxone for opioid-like central nervous system effects.

Contraindications

• patients less than two years old
• patients with acute ulcerative colitis
• patients with bloody diarrhea/diarrhea associated with bacterial enterocolitis such as that caused by Salmonella, Shigella, or C. difficile – primarily due to concerns about exacerbating underlying conditions that require different treatment strategies.
  • the combination with antibiotics is likely to be safe in the setting of mild febrile dysentery¹

Toxicity

1. Opioid-like Effects from High Doses or Drug Interactions:
   • When taken in excess or with p-glycoprotein inhibitors, loperamide can mimic opioid effects such as euphoria, miosis, central nervous system depression, and respiratory depression.
2. Treatment of Overdose:
   • Primary treatment is supportive care.
   • Naloxone can be administered via intranasal bolus, intravenous bolus, or infusion for respiratory depression.
   • Continuous monitoring is necessary for at least 24 hours post-naloxone due to its shorter half-life compared to loperamide.
3. Cardiac Toxicity Risks:
   • Large doses can cause severe cardiac conduction issues.
   • Continuous cardiac monitoring is advised, along with an immediate ECG.
4. Management of Cardiac Conduction Abnormalities:
   • If QRS widening is observed, administer sodium bicarbonate, either in boluses or as an infusion.
   • For QTc prolongation, correct electrolyte imbalances (magnesium, potassium, phosphate), and consider isoproterenol or transcutaneous pacing if needed.
5. Cardiac Arrest Protocol:
   • Follow standard ACLS (Advanced Cardiac Life Support) guidelines for treatment.

1. Wingate D, Phillips SF, Lewis SJ, et al. Guidelines for adults on self-medication for the treatment of acute diarrhoea. Aliment Pharmacol Ther 2001;15:773–82. Search PubMed ↩︎