What is the mechanism of action of Loperamide (Loperamide)?

From the Guidelines

Loperamide works primarily by binding to μ-opioid receptors in the myenteric plexus of the large intestine, reducing intestinal motility and increasing transit time, as stated in the 2017 guidelines for the diagnosis and management of infectious diarrhea 1. This action decreases the frequency of bowel movements and firms stool consistency. Unlike other opioids, loperamide has minimal central nervous system effects at therapeutic doses because it does not readily cross the blood-brain barrier, making it effective for diarrhea without causing sedation or respiratory depression.

Key Mechanisms of Action

• Reduces intestinal motility and increases transit time
• Enhances water and electrolyte absorption by slowing intestinal transit
• Reduces colonic mass movements and decreases fecal volume
• Inhibits the release of acetylcholine and prostaglandins, further contributing to its antidiarrheal effects The standard adult dosage is 4mg initially, followed by 2mg after each loose stool, not exceeding 16mg daily, as recommended in the 2018 ESMO clinical practice guidelines for diarrhea in adult cancer patients 1.

Important Considerations

• Effects typically begin within 1-3 hours and can last 24 hours
• While generally safe for acute diarrhea, loperamide should be used cautiously in bacterial enterocolitis, inflammatory bowel disease, and should be discontinued if symptoms persist beyond 48 hours
• It's contraindicated in patients with bloody diarrhea, high fever, or suspected bacterial infection requiring antibiotic treatment, as noted in the 2004 guidelines for the treatment of cancer treatment-induced diarrhea 1.

From the FDA Drug Label

In vitro and animal studies show that loperamide hydrochloride acts by slowing intestinal motility and by affecting water and electrolyte movement through the bowel. Loperamide binds to the opiate receptor in the gut wall Consequently, it inhibits the release of acetylcholine and prostaglandins, thereby reducing propulsive peristalsis, and increasing intestinal transit time. The mechanism of action of loperamide is through:

• Slowing intestinal motility
• Affecting water and electrolyte movement through the bowel
• Binding to the opiate receptor in the gut wall
• Inhibiting the release of acetylcholine and prostaglandins
• Reducing propulsive peristalsis
• Increasing intestinal transit time 2

From the Research

Mechanism of Action of Loperamide

• Loperamide works by decreasing peristalsis and fluid secretion, resulting in longer gastrointestinal transit time and increased absorption of fluids and electrolytes from the gastrointestinal tract 3.
• The mechanism of action of loperamide is primarily the retardation of small-intestinal transit, and the stimulation of anal sphincter pressure and of faecal continence 4.
• Loperamide also behaves as a calcium-calmodulin antagonist and as a calcium channel blocker, which might contribute to its antidiarrhoeal activity 4.
• Loperamide increases mucosal contact time, allowing more complete absorption of electrolytes and water 4.
• Studies in animals have demonstrated inhibitory effects of opiates and opioids, including loperamide, on fluid and electrolyte secretion induced by various secretagogues 4.

Key Features of Loperamide

• Loperamide is a phenylpiperidine derivative with a chemical structure similar to opiate receptor agonists such as diphenoxylate and haloperidol 3.
• Loperamide has minimal central nervous system effects due to its low oral absorption and inability to cross the blood-brain barrier 3.
• Loperamide is metabolized by the cytochrome P450 (CYP) system and is a substrate for the CYP3A4 isoenzyme 3.
• Concurrent administration with CYP3A4 inhibitors may elevate loperamide concentrations 3.

Efficacy and Safety of Loperamide

• Loperamide is a safe and effective antidiarrheal for the treatment of acute diarrhea 5, 6.
• Loperamide is more effective than other opiates or opioid drugs in the treatment of both infantile and adult diarrhoea of various causes 4.
• Loperamide lacks significant abuse potential when used at the recommended therapeutic dose 3, 5.
• However, loperamide has become notoriously known as the "poor man's methadone" for people with substance dependence due to the increase in loperamide overdoses from self-administered medication to treat opioid withdrawal symptoms 7.