Loperamide

Mechanism

• It acts on μ-opioid receptors in the myenteric plexus. This reduces smooth muscle tone and propulsive motility, and it increases small-intestinal and mouth-to-cecum transit time.
• It raises anal sphincter tone.
• It has some antisecretory activity against cholera toxin and some E. coli toxins.
• It is about 40 to 50 times more potent than morphine as an antidiarrheal.
• At normal doses it penetrates the CNS poorly. P-glycoprotein (Pgp) efflux limits both its gut absorption and its entry into the brain. - Goodman & Gilman's The Pharmacological Basis of Therapeutics, p. 1115-1116

Pharmacokinetics

• Peak plasma levels occur 3 to 5 h after an oral dose.
• Half-life is about 11 h.
• It undergoes extensive hepatic metabolism.
• It comes as capsules, solution and chewable tablets.
• Rapid transit can limit absorption of tablets or capsules, so a liquid form may work better. - Fischer's Mastery of Surgery

Uses and dosing

• Acute diarrhea in adults: 4 mg first, then 2 mg after each loose stool, up to 16 mg/day (OTC labelling is lower, commonly 8 mg/day). Stop if there is no improvement within 48 h.
• Chronic diarrhea: usually 4 to 8 mg/day in divided doses.
• Traveler's diarrhea: effective alone or with antibiotics. Adding simethicone reduces time to formed stool. - ROSEN's Emergency Medicine
• Children: maximum daily doses are 3 mg for ages 2 to 5, 4 mg for ages 6 to 8, and 6 mg for ages 8 to 12. Do not use under age 2.
• Pregnancy: it is the preferred antidiarrheal. It is not known to be teratogenic, though one source links it with lower birthweight. - Yamada's Textbook of Gastroenterology
• It is more effective than diphenoxylate.

Adverse effects and cautions

• Common: constipation, abdominal cramps, bloating.
• Overdose: constipation, paralytic ileus, and CNS depression, especially in children.
• Toxic megacolon risk: use with great caution, if at all, in active colonic inflammatory bowel disease.
• Avoid in bloody diarrhea, high fever, or suspected invasive infection (e.g. C. difficile). This is general clinical practice, not from the passages I pulled.
• Boxed warning (FDA): exceeding recommended doses can cause torsades de pointes, cardiac arrest and death.

Misuse and cardiotoxicity

• It is nicknamed "the poor man's methadone." Misuse and suicide ingestions have risen since 2010.
• Misuse doses are about 50 to 300 mg, which is 20 to 150 times the therapeutic dose. At these doses it crosses into the CNS and causes euphoria and respiratory depression.
• Cardiac effects come from sodium and potassium channel blockade. They include QT prolongation, QRS widening, ventricular tachycardia and fibrillation. - Tintinalli's Emergency Medicine, p. 1277-1278
• Drug interactions: Pgp inhibitors (e.g. quinidine) and CYP inhibitors raise loperamide levels and CNS entry. Users take them on purpose to boost the effect. This interaction has caused life-threatening cardiotoxicity. - Goodman & Gilman, Box 9-1

• Give activated charcoal. It can be repeated because loperamide slows peristalsis.
• Give naloxone for respiratory depression. Standard doses (0.04 to 0.4 mg) are used, and repeat dosing may be needed because loperamide's effects are long-lasting.
• For a wide QRS from sodium channel blockade, the standard approach is sodium bicarbonate. The passage was cut off, so this is from general toxicology knowledge. Also correct electrolytes and monitor the ECG.

Regulatory context

Recent evidence check