Loperamide

Loperamide, commonly known by the brand name Imodium, is an opioid receptor agonist used to slow down diarrhea. It is taken orally and is frequently prescribed for diarrhea linked to conditions such as irritable bowel syndrome, inflammatory bowel disease, short bowel syndrome, Crohn’s disease, and ulcerative colitis.

Common side effects include abdominal pain, constipation, drowsiness, vomiting, and a dry mouth. There is a potential risk of toxic megacolon. Its safety during pregnancy is not fully established, though no evidence of harm has been found, and it appears safe for use while breastfeeding. At normal doses, this opioid is not significantly absorbed from the gut and does not cross the blood–brain barrier. It works by reducing the contractions of the intestines.

Loperamide was first synthesized in 1969 and entered medical use in 1976. It is included on the World Health Organization's List of Essential Medicines and is available as a generic drug. In 2023, it was the 276th most prescribed medication in the United States, with over 800,000 prescriptions.

**Medical uses** Loperamide is effective for treating several types of diarrhea. It is often compared to diphenoxylate; studies suggest loperamide works better and causes fewer neurological side effects.

**Side effects** The most common adverse effects are constipation (affecting 1.7–5.3% of users), dizziness (up to 1.4%), nausea (0.7–3.2%), and abdominal cramps (0.5–3.0%). Rare but serious side effects include toxic megacolon, paralytic ileus, angioedema, anaphylaxis or allergic reactions, toxic epidermal necrolysis, Stevens–Johnson syndrome, erythema multiforme, urinary retention, and heat stroke. Overdose symptoms typically include drowsiness, vomiting, and abdominal pain or burning. High doses can lead to heart problems such as abnormal heart rhythms.

**Contraindications** Loperamide should be avoided if there is a high fever or bloody stool. It is not recommended for people who might experience negative effects from rebound constipation. If diarrhea is suspected to be caused by organisms that can penetrate the intestinal wall—such as *E. coli* O157:H7 or *Salmonella*—loperamide should not be used as primary treatment. It is also not used in symptomatic *C. difficile* infections, as it raises the risk of toxin retention and toxic megacolon. Caution is needed in people with liver failure due to reduced first-pass metabolism, and in those with advanced HIV/AIDS, as cases of toxic megacolon have been reported. If abdominal distension occurs, treatment should be stopped.

**Children** A review of loperamide use in children under twelve found that serious adverse events only occurred in those under three years old. The study recommended that loperamide be contraindicated in children under three, as well as in those who are systemically ill, malnourished, moderately dehydrated, or have bloody diarrhea. In 1990, all pediatric formulations of loperamide were banned in Pakistan. In the UK, formulations for children under twelve are only available by prescription.

**Pregnancy and breastfeeding** In the UK, loperamide is not recommended during pregnancy or for nursing mothers. Studies in rats have shown no birth defects, but adequate human studies are lacking. One small prospective study of 89 women exposed to loperamide in the first trimester found no increased risk of malformations. Loperamide can appear in breast milk and is not recommended for breastfeeding mothers.

**Drug interactions** Loperamide is a substrate of P-glycoprotein, so its concentration rises when taken with a P-glycoprotein inhibitor, such as quinidine, ritonavir, or ketoconazole. It can also reduce the absorption of other drugs; for example, saquinavir levels can drop by half when given with loperamide. Because it slows intestinal movement, combining it with other antimotility drugs—like other opioids, antihistamines, antipsychotics, or anticholinergics—increases the risk of constipation.

**Mechanism of action** Loperamide is an opioid-receptor agonist that targets μ-opioid receptors in the myenteric plexus of the large intestine. It acts similarly to morphine, reducing the activity of the myenteric plexus, which lowers the tone of the longitudinal and circular smooth muscles in the intestinal wall. This prolongs the time material stays in the intestine, allowing more water to be absorbed from the stool. It also decreases colonic mass movements and suppresses the gastrocolic reflex. Its circulation in the bloodstream is limited in two ways: P-glycoprotein in the intestinal wall pumps it back out, and the fraction that does pass is further reduced by first-pass metabolism in the liver. Loperamide is metabolized into an MPTP-like compound, but it is unlikely to cause neurotoxicity.

**Blood–brain barrier** Efflux by P-glycoprotein also prevents circulating loperamide from crossing the blood–brain barrier effectively, so it generally only activates mu-opioid receptors in the peripheral nervous system. It currently scores one on the anticholinergic cognitive burden scale. If taken with P-glycoprotein inhibitors like quinidine, loperamide may cross the blood–brain barrier and produce central morphine-like effects. At high doses (over 70 mg), loperamide can saturate P-glycoprotein, overcoming this barrier.