|Systematic (IUPAC) name|
|Pregnancy cat.||B3 (AU) C (US)|
|Legal status||Pharmacy Only (S2) (AU) OTC (CA) GSL (UK) OTC (US)|
|Excretion||Faeces (30-40%), urine (1%)|
34552-83-5 (with HCl)
|Mol. mass||477.037 g/mol (513.506 with HCl)|
|(what is this?)|
In most countries it is available generically and under brand names such as Lopex, Imodium, Dimor, Fortasec, Lopedium, Gastro-Stop and Pepto Diarrhea Control. It was developed at Janssen Pharmaceutica. It is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.
This includes control of acute nonspecific diarrhea, mild traveler's diarrhea, irritable bowel syndrome, chronic diarrhea due to bowel resection, and chronic diarrhea secondary to inflammatory bowel disease. It is also useful for reducing ileostomy output. Of note, Loperamide is not useful in preventing traveler's diarrhea.Off Label uses for loperamide also include chemotherapy induced diarrhea, especially related to irinotecan use. Loperamide should not be used in cases of bloody diarrhea, acute exacerbation of ulerative colitis, or bacterial enterocolitis.
Treatment should be avoided in the presence of high fever or if the stool is bloody (dysentery). It is of no value in diarrhea caused by cholera, Shigella or Campylobacter. Treatment is not recommended for patients that could suffer detrimental effects from rebound constipation. If there is a suspicion of diarrhea associated with organisms that can penetrate the intestinal walls, such as E. coli O157:H7 or salmonella, loperamide is contraindicated. 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 patients suffering from hepatic impairment due to reduced first pass metabolism. Additionally, caution should be used when treating patients with advanced HIV as there have been cases of both viral and bacterial toxic megacolon. If abdominal distension is noted, therapy with loperamide should be discontinued.
The use of loperamide in children under 2 years is not recommended. There have been rare reports of fatal paralytic ileus associated with abdominal distention. Most of these reports occurred in the setting of acute dysentery, overdose, and with very young children less than two years of age. A systematic review and meta-analysis examined control trials of loperamide in children under 12 years old, and found that serious adverse events occurred only in children under 3 years old. The study reported that the use of loperamide should be contraindicated in children under 3 years old, systemically ill, malnourished, moderately dehydrated, or have bloody diarrhea. In 1990, all pediatric formulations of the antidiarrheal loperamide were banned in Pakistan.
Loperamide is not recommended in the UK for use during pregnancy nor by nursing mothers. In the US, loperamide is classified by the FDA as pregnancy category C. Studies in rat models have shown no teratogenicity, but there have not been sufficient studies in humans.  One controlled, prospective study of 89 women exposed to loperamide during the first trimester 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 breast feeding mothers.
Adverse drug reactions (ADRs) 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, anaphylavis/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.
Loperamide is a substrate of P-Glycoprotein, therefore the concentration of Loperamide will increase when given with a P-Glycoprotein inhibitor. Common P-Glycoprotein inhibitors include quinidine, ritonavir, ketoconazole, among others. Loperamide is also capable of decreasing the concentration of other P-Glycoprotein substrates. As an example, when saquinavir concentrations can decrease by half when given with loperamide.
Loperamide is an anti-diarrheal agent which decreases intestinal movement. As such, when combined with other antimotility drugs, there is an increased risk of constipation. These drugs include, but are not limited to, opiates, antihistamines, anti psychotics, 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; by itself it does not affect the central nervous system. It works similarly to morphine, by decreasing the activity of the myenteric plexus, which in turn decreases the tone of the longitudinal and circular smooth muscles of the intestinal wall. This increases the amount of time substances stay in the intestine, allowing for more water to be absorbed out of the fecal matter. Loperamide also decreases colonic mass movements and suppresses the gastrocolic reflex.
Ability to cross the blood–brain barrier
It is a misconception that loperamide does not cross the blood–brain barrier. Loperamide does cross this barrier, although it is immediately pumped back out into non–central nervous system (CNS) circulation by P-glycoprotein. While this mechanism effectively shields the CNS from exposure (and thus risk of CNS tolerance/dependence) to loperamide, many drugs are known to inhibit P-glycoprotein and may thus render the CNS vulnerable to opiate agonism by loperamide.
Concurrent administration of P-glycoprotein inhibitors such as quinidine and its other isomer quinine (although much higher doses must be used), PPIs like omeprazole (Prilosec OTC) and even black pepper (piperine as the active ingredient) could potentially allow loperamide to cross the blood–brain barrier. It should however be noted that only quinidine with loperamide was found to produce respiratory depression, indicative of central opioid action.
Loperamide has been shown to cause a mild physical dependence during preclinical studies, specifically in mice, rats, and rhesus monkeys. Symptoms of mild opiate withdrawal have been observed following abrupt discontinuation of long-term therapy with loperamide.
When originally approved for medical use in the United States, loperamide was considered a narcotic and was put into Schedule II of the Controlled Substances Act 1970. It was transferred to Schedule V in the summer of 1977 and then decontrolled as of 3 November 1982. (source: Federal Register)
- Methylnaltrexone - a Mu opioid antagonist (in contrast to the Mu opioid agonist loperamide) that does not cross the blood brain barrier so as to not affect CNS
- Simethicone - an anti-gas frequently combined with loperamide in medications
- Traveler's diarrhea
- Activated carbon
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