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Loperamide, sold under the brand name Imodium, among others,
Common side effects include abdominal pain, constipation, sleepiness, vomiting, and a dry mouth.
Loperamide was first made in 1969 and used medically in 1976.
1 Medical uses
2 Side effects
2.3 Pregnancy and breast feeding
3 Drug interactions
4 Mechanism of action
4.1 Blood–brain barrier
6 Society and culture
6.2 Brand names
6.3 Recreational use
7 See also
9 External links
Loperamide is effective for the treatment of a number of types of diarrhea. 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. Off-label uses for loperamide also include chemotherapy-induced diarrhea, especially related to irinotecan use.
Loperamide should not be used as the primary treatment in cases of bloody diarrhea, acute exacerbation of ulcerative colitis, or bacterial enterocolitis.
Loperamide is often compared to diphenoxylate. Recent studies suggest that loperamide is more effective and has lower neural 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%).
High doses may result in heart problems such as abnormal heart rhythms.
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 a 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.
The use of loperamide in children under 2 years is not recommended. Rare reports of fatal paralytic ileus associated with abdominal distention have been made. Most of these reports occurred in the setting of acute dysentery, overdose, and with very young children less than 2 years of age.
Pregnancy and breast feeding
Loperamide is not recommended in the UK for use during pregnancy or by nursing mothers.
Loperamide is a substrate of P-glycoprotein ; therefore, the concentration of loperamide will increase when given with a P-glycoprotein inhibitor.
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
Ball-and-stick model of loperamide molecule
Loperamide is an opioid -receptor agonist and acts on the μ-opioid receptors in the myenteric plexus of the large intestine. Loperamide 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.
Loperamide’s circulation in the bloodstream is limited in two ways. Efflux by P-glycoprotein in the intestinal wall reduces passage of loperamide, and the fraction of drug crossing is then further reduced through first-pass metabolism by the liver.
Efflux by P-glycoprotein also prevents circulating loperamide from effectively crossing the blood–brain barrier,
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 were observed following abrupt discontinuation of long-term treatment of animals 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 on 17 July 1977 and then decontrolled as of 3 November 1982.
Loperamide hydrochloride was first synthesized by Paul Janssen from Janssen Pharmaceutica in Beerse (Belgium), following previous discoveries of diphenoxylate hydrochloride (1956) and fentanyl citrate (1960).
The first clinical reports on loperamide were published in 1973 in the Journal of Medicinal Chemistry
The trial against placebo was conducted from December 1972 to February 1974, its results being published in 1977 in Gut, an edition of British Society of Gastroenterology.
In 1973, Janssen started to promote loperamide under the brand name Imodium. In December 1976, Imodium got US FDA approval.
During the 1980s, Imodium became the best-selling prescription antidiarrheal in the United States.
In March 1988, McNeil Pharmaceutical began selling loperamide as an over-the-counter drug under the brand name Imodium A-D.
In the 1980s, loperamide also existed in the form of drops (Imodium Drops) and syrup. Initially, it was intended for children’s usage, but Johnson & Johnson voluntarily withdrew it from the market in 1990 after 18 cases of paralytic ileus (resulting in six deaths) were registered in Pakistan and reported by World Health Organization.
In the late 1980s, prior to the expiration of US patent on 30 January 1990,
In November 1993, loperamide was launched as an orally disintegrating tablet based on Zydis technology.
In 2013, loperamide in the form of 2-mg tablets was added to WHO Model List of Essential Medicines.
Society and culture
It is sold as a generic medication and is not very expensive.
Loperamide was originally marketed as Imodium, and many generic brands are sold.
Loperamide has typically been deemed to have a relatively low risk of misuse.
In 2015, however, case reports of extremely high-dose loperamide resulting in opioid misuse were published.
Since 2015, several reports of sometimes-fatal cardiotoxicity due to high-dose loperamide abuse have been published.
Naloxegol, a peripheral-acting opioid antagonist, is indicated to reduce opioid induced constipation (OIC) without greatly affecting analgesia. As such, it can be considered the antithesis of the peripheral-acting opiate agonist loperamide.
Methylnaltrexone, another peripheral-acting opioid antagonist, is similar to Naloxegol (indicated to reduce OIC without greatly affecting analgesia).
Simethicone, combined with loperamide in some formulations, is an antifoaming agent used to reduce bloating, discomfort, or pain caused by excessive gas.
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