Loperamide
Loperamide
Generic Name
Loperamide
Mechanism
- G‑protein coupled μ‑opioid receptor agonist primarily acting in the myenteric plexus of the gut.
- Inhibits cyclic‑AMP synthesis → reduced chloride secretion in enterocytes → decreased luminal fluid.
- Decreases intestinal transit time by:
- Enhancing colonic smooth‑muscle tone.
- Increasing rectoanal inhibitory reflex (RAIR) duration.
- Does not cross the blood‑brain barrier at therapeutic doses, limiting CNS opioid effects.
Pharmacokinetics
| Parameter | Typical Value (oral) | Notes |
| Absorption | 55–75 % bioavailability | Rapid first‑pass hepatic metabolism |
| Distribution | Large volume (~3 L/kg) | Primarily bound (>90 %) to intestinal tissue |
| Metabolism | CYP3A4 and CYP2C8 → inactive metabolites | Minor contribution to systemic exposure |
| Elimination | 80 % fecal excretion (biliary), 20 % renal | Half‑life ~4 h; terminal phase 20–24 h |
| Drug Interactions | Strong CYP3A4 inhibitors ↑ plasma conc. | Avoid co‑administration with quinidine or ketoconazole |
Indications
- Acute, non‑gastrointestinal enteropathogenic diarrhea (e.g., traveler's, viral, bacterial, or NSAID‑associated).
- Chronic diarrhea associated with inflammatory bowel disease (IBD) when symptomatic control is needed.
- Adjunct for symptomatic relief in other dysmotility conditions (e.g., diverticulitis, pancreatitis‑related diarrhea).
Contraindications
- Contraindicated:
- Severe ischemic colitis (risk of perforation).
- Perianal abscess, fistula, or other inflammatory perirectal disease.
- Warnings:
- Cardiac conduction: High doses (>8 mg/day) or CYP3A4 inhibition can precipitate QTc prolongation and torsades de pointes.
- Liver disease: Metabolism impaired; use with caution.
- Pregnancy/Breastfeeding: Category B; insufficient human data, use only if benefits outweigh risks.
- Adolescent use: No established safety; avoid in under 12 yrs without specialist guidance.
Dosing
| Form | Adult Dose | Pediatric Guidance (6–12 yrs) | Max Daily Dose |
| Immediate‑release tablets | 4 mg initial → 2 mg q6‑h PRN | 1.5 mg initial → 0.75 mg q6‑h PRN | 16 mg/day |
| Delayed‑release tablets | 2‑4 mg after each loose stool | 0.5‑1 mg after each loose stool | 8 mg/day |
• First dose: 4 mg (or 2 mg in sensitive patients) to rapidly reduce peristalsis.
• Subsequent doses: 2 mg every 6 h as needed; do not exceed 16 mg/day.
• Administration: Oral, with or without food.
• Special populations: Renal or hepatic impairment → use lowest effective dose; monitor for accumulation.
Adverse Effects
Common (≥1 %):
• Constipation
• Abdominal cramping
• Dry mouth
Serious (rare <0.1 %):
• Severe constipation → megacolon, fecal impaction
• Cardiac arrhythmias (QTc prolongation, torsades de pointes) at supra‑therapeutic doses
• Allergic reactions (rash, urticaria)
• Hepatotoxicity (rare hepatic enzyme elevations)
Monitoring
- Baseline ECG if underlying cardiac disease or when co‑administered with QT‑prolonging agents.
- Liver function tests in chronic users, especially with other hepatotoxic medications.
- Renal function if dosing >16 mg/day or with polypharmacy.
- Patient education on signs of constipation and arrhythmia (palpitations, syncope).
Clinical Pearls
1. “Loperamide is not a systemic opioid.”
• It never achieves adequate CNS concentrations; however, overdose can bypass hepatic barriers and cause CNS depression.
2. “CYP3A4 inhibitors are loperamide's biggest villain.”
• Co‑administer with ketoconazole, clarithromycin, or grapefruit juice → risk of cardiotoxicity.
3. “Use the lowest effective dose."
• For chronic diarrhea in IBD, consider 4 mg/day maintenance to minimize constipation risk.
4. “Not a stool softener.”
• Loperamide increases stool firmness; for diarrheal stool in malabsorption, combine with loperamide + a mild laxative.
5. “Avoid in diverticulitis”
• Reduced peristalsis may worsen colonic intraluminal pressure → perforation.
6. “Monitor QTc when dose >8 mg/day.”
• Use 12‑lead ECG in patients receiving polypharmacy with other QT‑extending drugs.
7. “Keep patients hydrated.”
• Though it reduces fluid loss, aggressive dehydration can precipitate constipation and worsen hepatic congestion, especially in elderly.
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• Key Takeaway: Loperamide is a potent, gut‑specific opioid agonist that effectively manages diarrheal symptoms while sparing CNS effects. Careful dosing, attention to drug interactions, and monitoring cardiac parameters are essential to maximize safety and efficacy.