Loperamide, sold under the brand name Imodium, among others, is a medication of the opioid receptor agonist class used to decrease the frequency of diarrhea. It is often used for this purpose in irritable bowel syndrome, inflammatory bowel disease, short bowel syndrome, Crohn's disease, and ulcerative colitis. Loperamide is taken by mouth. Common side effects include abdominal pain, constipation, sleepiness, vomiting, and dry mouth. It may increase the risk of toxic megacolon. Loperamide's safety in pregnancy is unclear, but no evidence of harm has been found. It appears to be safe in breastfeeding. It is an opioid with no significant absorption from the gut and does not cross the blood–brain barrier when used at normal doses. It works by slowing the contractions of the intestines. Loperamide was first made in 1969 and used medically in 1976. It is on the World Health Organization's List of Essential Medicines. Loperamide is available as a generic medication. In 2023, it was the 276th most commonly prescribed medication in the United States, with more than 800,000 prescriptions.
Medical uses Loperamide is effective for the treatment of a number of types of diarrhea. Loperamide is often compared to diphenoxylate. Studies suggest that loperamide is more effective and has lower neural side effects.
Side effects Adverse drug reactions most commonly associated with loperamide are constipation (which occurs in 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 more serious, side effects include toxic megacolon, paralytic ileus, angioedema, anaphylaxis/allergic reactions, toxic epidermal necrolysis, Stevens–Johnson syndrome, erythema multiforme, urinary retention, and heat stroke. The most frequent symptoms of loperamide overdose are drowsiness, vomiting, and abdominal pain, or burning. High doses may result in heart problems such as abnormal heart rhythms.
Contraindications Treatment should be avoided in the presence of high fever or if the stool is bloody. Treatment is not recommended for people who could have negative effects from rebound constipation. If suspicion exists of diarrhea associated with organisms that can penetrate the intestinal walls, such as E. coli O157:H7 or Salmonella, loperamide is contraindicated as a primary treatment. Loperamide treatment is not used in symptomatic C. difficile infections, as it increases the risk of toxin retention and precipitation of toxic megacolon. Loperamide should be administered with caution to people with liver failure due to reduced first-pass metabolism. Additionally, caution should be used when treating people with advanced HIV/AIDS, as cases of both viral and bacterial toxic megacolon have been reported. If abdominal distension is noted, therapy with loperamide should be discontinued.
Children A review of loperamide in children under twelve years of age found that serious adverse events occurred only in children under three years of age. The study reported that the use of loperamide should be contraindicated in children who are under three years of age, systemically ill, malnourished, moderately dehydrated, or have bloody diarrhea. In 1990, all formulations of loperamide for children were banned in Pakistan. Formulations for children aged less than twelve years of age are only available via prescription in the UK.
Pregnancy and breast feeding Loperamide is not recommended in the United Kingdom for use during pregnancy or by nursing mothers. Studies in rat models have shown no teratogenicity, but sufficient studies in humans have not been conducted. One controlled, prospective study of 89 women exposed to loperamide during their first trimester of pregnancy showed no increased risk of malformations. This, however, was only one study with a small sample size. Loperamide can be present in breast milk and is not recommended for breastfeeding mothers.
Drug interactions Loperamide is a substrate of P-glycoprotein; therefore, the concentration of loperamide increases when given with a P-glycoprotein inhibitor. Common P-glycoprotein inhibitors include quinidine, ritonavir, and ketoconazole. Loperamide can decrease the absorption of some other drugs. As an example, saquinavir concentrations can decrease by half when given with loperamide. Loperamide is an antidiarrheal agent, which decreases intestinal movement. As such, when combined with other antimotility drugs, the risk of constipation is increased. These drugs include other opioids, antihistamines, antipsychotics, and anticholinergics.
Mechanism of action
Loperamide is an opioid-receptor agonist and acts on the μ-opioid receptors in the myenteric plexus of the large intestine. It works like morphine, decreasing the activity of the myenteric plexus, which decreases the tone of the longitudinal and circular smooth muscles of the intestinal wall. This increases the time material stays in the intestine, allowing more water to be absorbed from the fecal matter. It also decreases colonic mass movements and suppresses the gastrocolic reflex. Loperamide's circulation in the bloodstream is limited in two ways. Efflux by P-glycoprotein in the intestinal wall reduces the passage of loperamide, and the fraction of drug crossing is then further reduced through first-pass metabolism by the liver. Loperamide metabolizes into an MPTP-like compound, but is unlikely to exert neurotoxicity.
Blood–brain barrier Efflux by P-glycoprotein also prevents circulating loperamide from effectively crossing the blood-brain barrier, so it can generally only agonize mu-opioid receptors in the peripheral nervous system, and currently has a score of one on the anticholinergic cognitive burden scale. Concurrent administration of P-glycoprotein inhibitors such as quinidine potentially allows loperamide to cross the blood-brain barrier and produce central morphine-like effects. At high doses (>70mg), loperamide can saturate P-glycoprotein (thus overcoming the efflux) and produce euphoric effects. Loperamide taken with quinidine was found to produce respiratory depression, indicative of central opioid action. High doses of loperamide have been shown to cause a mild physical dependence during preclinical studies, specifically in mice, rats, and rhesus monkeys. Symptoms of mild opiate withdrawal were observed following abrupt discontinuation of long-term treatment of animals with loperamide.
Chemistry
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