Introduction
Loperamide is a synthetic opioid receptor agonist classified as an antidiarrheal medication. First approved by the FDA in 1976, it acts primarily on the gastrointestinal tract to reduce diarrhea symptoms. Unlike most opioids, loperamide has limited central nervous system effects due to poor blood-brain barrier penetration and is subject to P-glycoprotein efflux. It is available as both prescription and over-the-counter formulations in various forms including tablets, capsules, and liquid.
Mechanism of Action
Loperamide exerts its antidiarrheal effects through μ-opioid receptor agonism in the myenteric plexus of the intestinal wall. This action results in:
- Decreased peristalsis and increased intestinal transit time
- Enhanced anal sphincter tone
- Reduced gastrointestinal secretions
- Increased water and electrolyte absorption
The drug has minimal affinity for other opioid receptors (δ and κ) and demonstrates negligible analgesic activity at therapeutic doses due to its limited CNS penetration.
Indications
FDA-Approved Indications:- Symptomatic control of acute nonspecific diarrhea
- Reduction of stool volume in patients with ileostomies
- Management of chronic diarrhea associated with inflammatory bowel disease
- Traveler's diarrhea (as adjunctive therapy)
- Diarrhea-predominant irritable bowel syndrome
Dosage and Administration
Adults (Acute Diarrhea):- Initial dose: 4 mg (2 capsules or 20 mL liquid)
- Maintenance: 2 mg after each loose stool
- Maximum: 16 mg/day (prescription) or 8 mg/day (OTC)
- Initial: 4-8 mg/day in divided doses
- Maintenance: Individualized, typically 4-8 mg/day
- Maximum: 16 mg/day
- Hepatic impairment: Use with caution; consider reduced dosing
- Renal impairment: No dosage adjustment needed
- Elderly: Initiate at lower end of dosing range
- Pediatrics:
- 2-5 years: 1 mg three times daily (max 3 mg/day) - 6-8 years: 2 mg twice daily (max 4 mg/day) - 9-11 years: 2 mg three times daily (max 6 mg/day) - ≥12 years: Adult dosing
Pharmacokinetics
Absorption: Poorly absorbed from GI tract (<1% systemic bioavailability) Distribution: Primarily confined to intestinal wall; 97% protein-bound Metabolism: Extensive hepatic metabolism via CYP3A4 and CYP2C8 Elimination: Half-life approximately 11 hours; excreted primarily in feces Onset of Action: 1-3 hours; duration 10-12 hoursContraindications
- Hypersensitivity to loperamide or any component
- Abdominal pain without diarrhea
- Acute ulcerative colitis
- Pseudomembranous colitis associated with broad-spectrum antibiotics
- Children <2 years old
Warnings and Precautions
Black Box Warning: Cardiac effects including QT prolongation, torsades de pointes, and other serious ventricular arrhythmias, syncope, and cardiac arrest have been reported with higher than recommended doses. Additional Precautions:- Avoid in patients with congenital long QT syndrome
- Use caution in patients with electrolyte imbalances
- Monitor for signs of toxic megacolon in acute colitis
- Risk of opioid withdrawal in patients with opioid dependence
- Potential for misuse and abuse at high doses
Drug Interactions
Major Interactions:- CYP3A4 inhibitors (ketoconazole, itraconazole, ritonavir): Increased loperamide levels
- CYP2C8 inhibitors (gemfibrozil): Increased loperamide levels
- QT-prolonging agents: Additive cardiac effects
- Opioid agonists: Potential for additive effects
- Anticholinergic agents: Additive constipating effects
- P-glycoprotein inhibitors: Increased systemic exposure
Adverse Effects
Common (≥1%):- Constipation (most frequent)
- Abdominal pain/discomfort
- Nausea
- Dizziness
- Dry mouth
- Cardiac arrhythmias (especially with overdose)
- Toxic megacolon
- Allergic reactions
- Paralytic ileus
- Opioid withdrawal symptoms (with abrupt discontinuation)
Monitoring Parameters
- Electrolytes (particularly potassium and magnesium)
- ECG monitoring in patients at risk for QT prolongation
- Bowel function and signs of constipation
- Hydration status
- Signs of cardiac arrhythmias (palpitations, syncope)
- Liver function in patients with hepatic impairment
Patient Education
- Take as directed; do not exceed recommended dosage
- Discontinue use if constipation develops
- Seek immediate medical attention for dizziness, fainting, or palpitations
- Maintain adequate fluid intake to prevent dehydration
- Avoid alcohol during therapy
- Do not use for more than 2 days unless directed by physician
- Store safely away from children
- Report any new medications to healthcare provider
References
1. FDA. (2018). Loperamide Drug Safety Communication. U.S. Food and Drug Administration. 2. Litovitz, T. L., et al. (2019). Loperamide abuse: Clinical features and cardiac complications. Journal of Medical Toxicology, 15(2), 134-138. 3. Goodman & Gilman's The Pharmacological Basis of Therapeutics, 13th Edition 4. Lexicomp Online, Loperamide Monograph 5. UpToDate. (2023). Loperamide: Drug information 6. Micromedex Solutions. (2023). Loperamide Detailed Drug Information 7. American Gastroenterological Association. (2021). Guidelines on Chronic Diarrhea Management 8. World Health Organization. (2019). Model List of Essential Medicines