Loperamide (Imodium)

Generic Name: Loperamide hydrochloride
Brand Names: Imodium, Dioraleze, Lopex, Fortasec, Entrocalm
Drug Class: Antidiarrheal agent
Pharmacological Class: Peripheral μ-opioid receptor agonist
ATC Code: A07DA03
Regulatory Status: Over-the-counter (OTC) for short-term use; prescription for chronic cases or higher doses in some countries

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Mechanism of Action

Loperamide is a synthetic peripherally acting μ-opioid receptor agonist that targets opioid receptors in the myenteric plexus of the intestinal wall. Its key actions include:

• Inhibition of peristalsis and intestinal motility, leading to increased transit time

• Increased absorption of electrolytes and water by allowing prolonged contact between the luminal contents and the mucosa

• Enhanced tone of the anal sphincter, reducing urgency and incontinence

Unlike central opioids (e.g., morphine), loperamide does not significantly cross the blood-brain barrier, largely due to being a substrate for P-glycoprotein efflux pumps, hence minimizing CNS effects at therapeutic doses.

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Therapeutic Indications

1. Acute Diarrhea:

   • Symptomatic treatment in adults and children aged ≥12 (some regions ≥6)

   • Includes traveler’s diarrhea of non-invasive origin

2. Chronic Diarrhea:

   • For chronic diarrheal conditions, including inflammatory bowel disease (IBD), short bowel syndrome, or post-cholecystectomy diarrhea

3. Ileostomy Output Control (off-label):

   • Reduces volume and frequency of stool in ileostomy patients

4. Adjunct in Bowel Regulation:

   • Used to promote continence in conditions with fecal incontinence due to loose stool

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Formulations and Strengths

Oral Dosage Forms:

• Capsules or Tablets: 2 mg

• Orally Disintegrating Tablets (ODT): 2 mg

• Liquid Solution/Syrup: 1 mg/5 mL

• Chewable Tablets: Available in some formulations

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Dosage and Administration

Adults (≥18 years):

Acute Diarrhea:

• Initial dose: 4 mg (2 tablets/capsules)

• Followed by: 2 mg after each loose stool

• Maximum dose: 16 mg/day (prescription use); 8 mg/day (OTC use in most countries)

• Duration: Usually not recommended beyond 48 hours without medical evaluation

Chronic Diarrhea:

• Starting dose: 4 mg/day

• Titrate to effective dose: Usually 4–8 mg/day in divided doses

• Maximum: 16 mg/day

Pediatric Use:

• Children 6–12 years (varies by region):

  • 2 mg initially, then 1 mg after each loose stool

  • Max: 4–6 mg/day depending on weight/age

• Children <6 years:

  • Use only under strict medical supervision (risk of ileus and CNS effects)

• Children <2 years:

  • Contraindicated due to serious risk of respiratory and CNS toxicity

Geriatric Use:

• Start at lower doses due to increased sensitivity; monitor for CNS effects and constipation

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Pharmacokinetics

• Absorption: ~40%; extensive first-pass metabolism

• Time to peak plasma concentration: ~2.5 hours

• Plasma protein binding: ~97%

• Metabolism: Hepatic, via CYP3A4 and CYP2C8

• Half-life: 10–14 hours

• Elimination: Fecal (mostly unchanged); minimal urinary excretion

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Contraindications

• Hypersensitivity to loperamide or any excipients

• Acute dysentery (characterized by bloody stools and high fever)

• Pseudomembranous colitis associated with antibiotics (e.g., Clostridioides difficile)

• Bacterial enterocolitis due to invasive organisms (e.g., Salmonella, Shigella, Campylobacter)

• Abdominal distension or suspected ileus

• Children under 2 years

• Severe hepatic impairment (relative contraindication)

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Warnings and Precautions

1. CNS Effects (At High Doses):

   • May cause euphoria, stupor, or respiratory depression in overdose or abuse situations

2. QT Prolongation and Cardiac Toxicity:

   • High doses (>16 mg/day) or abuse associated with torsades de pointes, ventricular arrhythmia, and cardiac arrest

3. Risk of Toxic Megacolon:

   • Particularly in IBD or severe colitis; discontinue immediately if abdominal distension develops

4. Abuse Potential:

   • Though low at therapeutic doses, high doses (≥50 mg) have been abused for opioid-like effects

5. Hepatic Impairment:

   • Use cautiously due to risk of reduced clearance and CNS toxicity

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Adverse Effects

Common (≥1%):

• Constipation

• Nausea

• Abdominal cramps

• Dizziness

• Flatulence

Uncommon (<1%):

• Dry mouth

• Drowsiness

• Rash

• Fatigue

• Indigestion

Rare:

• Ileus

• Toxic megacolon

• Hypersensitivity reactions (urticaria, angioedema)

• Cardiac arrhythmias (with overdose)

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Drug Interactions

CYP3A4 and CYP2C8 Inhibitors:

• E.g., ketoconazole, ritonavir, quinidine → increase loperamide plasma levels, increasing risk of CNS and cardiac toxicity

P-glycoprotein Inhibitors:

• E.g., verapamil, cyclosporine → may allow CNS penetration

Opioids or CNS depressants:

• Additive CNS effects at high doses; not clinically relevant at therapeutic doses

Anticholinergics or other constipating agents:

• May increase risk of paralytic ileus

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Overdose

Symptoms:

• CNS depression (drowsiness, stupor, respiratory depression)

• Cardiac arrhythmias (prolonged QT, torsades de pointes)

• Urinary retention

• Constipation, ileus, nausea

Management:

• Activated charcoal (if within 1–2 hours)

• Naloxone: Antagonizes opioid-like effects; repeated doses may be required

• Cardiac monitoring (ECG for QT prolongation)

• Supportive care and ventilation if needed

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Monitoring Parameters

• Clinical response (stool frequency, consistency)

• Dehydration signs (particularly in pediatric patients)

• CNS signs in hepatic impairment

• ECG in suspected overdose or long-term high-dose use

• Abdominal distension in IBD patients

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Use in Pregnancy and Lactation

Pregnancy:

• Category B (US FDA): No evidence of teratogenicity in animals; limited human data. Use only if benefits outweigh potential risks.

Lactation:

• Small amounts may be excreted in breast milk. Generally considered safe for short-term use. Monitor infant for constipation or sedation.

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Patient Counseling Points

• Do not exceed the recommended dose

• Intended for short-term use only

• Maintain adequate fluid and electrolyte intake (oral rehydration therapy)

• Seek medical advice if diarrhea persists >48 hours or is accompanied by fever, blood in stool, or signs of dehydration

• Avoid operating machinery if dizziness or drowsiness occurs

• Do not use in children under 2 years without explicit medical instruction

• Store safely and securely to prevent accidental overdose

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Comparison with Other Antidiarrheals

Drug	Class	Mechanism	CNS Effects	Indicated for Infectious Diarrhea
Loperamide	Opioid receptor agonist	↓ Motility	Minimal (therapeutic doses)	No
Diphenoxylate + Atropine	Opioid derivative + anticholinergic	↓ Motility	Moderate sedation	No
Racecadotril	Enkephalinase inhibitor	↓ Intestinal secretion	None	Yes (some infectious cases)
Bismuth subsalicylate	Antisecretory	Unknown (mucosal protection)	Mild	Yes (traveler’s diarrhea)

Storage

• Store at room temperature (15–30°C)

• Protect from heat and moisture

• Keep out of reach of children