|Systematic (IUPAC) name|
|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 is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.
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).
In 1973 Janssen started to promote loperamide under the brand name Imodium.
During the 1980s, Imodium became the best-selling prescription antidiarrheal in the United States.
In the 1980s there also existed loperamide 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 6 deaths) has been registered in Pakistan and reported by World Health Organization. In the following years (1990-1991) products containing loperamide have been restricted for children use in a number of countries (ranging from 2 to 5 years of age).
In the late 1980s prior to the expiration of US Patent in January 30, 1990, McNeil company started to develop Imodium Advanced containing loperamide and simethicone for treating both diarrhea and flatulence. In March 1997 the company patented such combination. The drug has been approved in June 1997 by FDA as Imodium Multi-Symptom Relief in the form of a chewable tablet.
In November 1993 loperamide has been launched as an orally disintegrating tablet based on Zydis technology. Imodium Instant Melts from Johnson & Johnson is currently the only loperamide available in the form of orally disintegrating tablets.
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. 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.
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, 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.
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, and 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, 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; 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 on 17. July 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
- US National Cancer Institute, Drug Dictionary
- Stokbroekx, R. A.; Vanenberk, J.; Van Heertum, A. H. M. T.; Van Laar, G. M. L. W.; Van der Aa, M. J. M. C.; Van Bever, W. F. M.; Janssen, P. A. J. (1973). "Synthetic Antidiarrheal Agents. 2,2-Diphenyl-4-(4'-aryl-4'-hydroxypiperidino)butyramides". Journal of Medicinal Chemistry 16 (7): 782–786. doi:10.1021/jm00265a009. PMID 4725924.
- "WHO Model List of Essential Medicines". World Health Organization. October 2013. Retrieved 22 April 2014.
- Florey, Klaus (1991). Profiles of Drug Substances, Excipients and Related Methodology, Volume 19. Academic Press. p. 342. ISBN 9780080861142.
- P. Mainguet, R. Fiasse (1977). "Double-blind placebo-controlled study of loperamide (Imodium) in chronic diarrhoea caused by ileocolic disease or resection". Gut (journal) (18): 575–579. Archived from the original on 2014-09-05. Retrieved 2014-09-05.
- "2,2-diaryl-4-(4'-aryl-4'-hydroxy-piper-idino)-butyramides (US 3714159 A)". Google Patents. 1973. Archived from the original on 2014-09-05. Retrieved 2014-09-05.
- "2,2-diaryl-4-(4'-aryl-4'-hydroxy-piper-idino)-butyramides (US 3714159 A)". Espacenet. 1973. Archived from the original on 2014-09-05. Retrieved 2014-09-05.
- "IMODIUM FDA Application No.(NDA) 017694". Food and Drug Administration. 1976. Archived from the original on 2014-09-05. Retrieved 2014-09-05.
- McNeil-PPC, Inc., Plaintiff, v. L. Perrigo Company, and Perrigo Company, Defendants, 207 F. Supp. 2d 356 (E.D. Pa. June 25, 2002).
- "IMODIUM A-D FDA Application No.(NDA) 019487". Food and Drug Administration. 1988. Archived from the original on 2014-09-05. Retrieved 2014-09-05.
- "Loperamide: voluntary withdrawal of infant fomulations". WHO Drug Information Vol. 4, No. 2, 1990. 1990. p. 73-74. Archived from the original on 2014-09-06. Retrieved 2014-09-06. "The leading international supplier of this preparation, Johnson and Johnson, has since informed WHO that having regard to the dangers inherent in improper use and overdosing, this formulation (Imodium Drops®), was voluntarily withdrawn from Pakistan in March 1990. The company has since decided not only to withdraw this preparation worldwide but also to remove all syrup formulations from countries where WHO has a programme for control of diarrhoeal diseases. The company has since decided not only to withdraw this preparation worldwide but also to remove all syrup formulations from countries where WHO has a programme for control of diarrhoeal diseases."
- Consolidated List of Products Whose Consumption And/or Sale Have Been Banned, Withdrawn, Severely Restricted Or Not Approved by Governments, 8th Issue. United Nations. 2003. p. 130-131. ISBN 92-1-130230-7.
- "Treatment of diarrhea and flatulence in gastrointestinal disorders US 5612054 A". 1997. Archived from the original on 2014-09-05. Retrieved 2014-09-05.
- "IMODIUM MULTI-SYMPTOM RELIEF FDA Application No.(NDA) 020606". Food and Drug Administration. 1997. Archived from the original on 2014-09-05. Retrieved 2014-09-05.
- "Scherer announces launch of another product utilizing its Zydis technology". PR Newswire Association LLC. 1993-11-09. Archived from the original on 2014-08-30. Retrieved 2014-08-30.
- Rathbone, Michael J.; Hadgraft, Jonathan; Roberts, Michael S. (2002). "The Zydis Oral Fast-Dissolving Dosage Form". Modified-Release Drug Delivery Technology. CRC Press. p. 200. ISBN 9780824708696. Retrieved 2014-08-26.
- Rajendra Awasthi et al. (2013). "Fast Disintegrating Drug Delivery Systems: A Review with Special Emphasis on Fast Disintegrating Tablets". Journal of Chemotherapy and Drug Delivery, 05/2013. Retrieved 2014-08-30.
- Nayak, Amit Kumar; Manna, Kaushik (2011). "Current developments in orally disintegrating tablet technology". Journal of Pharmaceutical Education and Research, Vol 2, Issue No. 1, June 2011. Archived from the original on 2014-09-05. Retrieved 2014-09-05.
- "The Selection and Use of Essential Medicines: Report of the WHO Expert Committee, 2013 (including the 18th WHO Model List of Essential Medicines and the 4th WHO Model List of Essential Medicines for Children)". World Health Organization. 2013. Archived from the original on 2014-09-05. Retrieved 2014-09-05. "Other medicines added were: loperamide"
- Hanauer, S. B. (Winter 2008). "The Role of Loperamide in Gastrointestinal Disorders". Reviews in Gastroenterological Disorders 8 (1): 15–20. PMID 18477966.
- Miftahof, Roustem (2009). Mathematical Modeling and Simulation in Enteric Neurobiology. World Scientific. p. 18. ISBN 9789812834812.
- Benson, Al; Chakravarthy, A.; Hamilton, Stanley R. et al., eds. (2013). Cancers of the Colon and Rectum: A Multidisciplinary Approach to Diagnosis and Management. Demos Medical Publishing. p. 225. ISBN 9781936287581.
- Zuckerman, Jane N. (2012). Principles and Practice of Travel Medicine. John Wiley & Sons. p. 203. ISBN 9781118392089.
- Butler, T. (October 2008). "Loperamide for the Treatment of Traveler's Diarrhea: Broad or Narrow Usefulness?". Clinical Infectious Diseases 47 (8): 1015–1016. doi:10.1086/591704. PMID 18781871.
- "rxlist.com". 2005.
- "Imodium (Loperamide Hydrochloride) Capsule". DailyMed. NIH.
- Li, Su-Ting T., David C. Grossman, and Peter Cummings (2007). "Loperamide therapy for acute diarrhea in children: systematic review and meta-analysis". PLoS medicine 4 (3): e98. doi:10.1371/journal.pmed.0040098. PMC 1831735. PMID 17388664.
- "E-DRUG: Chlormezanone". Essentialdrugs.org.
- Einarson, A., et al. (2000). "Prospective, controlled, multicentre study of loperamide in pregnancy". Canadian journal of gastroenterology 14 (3): 185–187. PMID 10758415.
- Litovitz, T; Clancy, C; Korberly, B; Temple, AR; Mann, KV (1997). "Surveillance of loperamide ingestions: an analysis of 216 poison center reports.". Journal of toxicology. Clinical toxicology 35 (1): 11–9. doi:10.3109/15563659709001159. PMID 9022646.
- "USMLE-Rx". Step 1 Qmax. MedIQ Learning, LLC. 2014.
- Katzung, B. G. (2004). Basic and Clinical Pharmacology (9th ed.). ISBN 0-07-141092-9.[page needed]
- Upton, RN (Aug 2007). "Cerebral uptake of drugs in humans.". Clinical and experimental pharmacology & physiology 34 (8): 695–701. doi:10.1111/j.1440-1681.2007.04649.x. PMID 17600543.
- Sadeque, A. J.; Wandel, C.; He, H.; Shah, S.; Wood, A. J. (September 2000). "Increased Drug Delivery to the Brain by P-glycoprotein Inhibition". Clinical Pharmacology and Therapeutics 68 (3): 231–237. doi:10.1067/mcp.2000.109156. PMID 11014404.
- Yanagita, T.; Miyasato, K.; Sato, J. (1979). "Dependence Potential of Loperamide Studied in Rhesus Monkeys". NIDA Research Monograph 27: 106–113. PMID 121326.
- Nakamura, H.; Ishii, K.; Yokoyama, Y. et al. (November 1982). "[Physical Dependence on Loperamide Hydrochloride in Mice and Rats]". Yakugaku Zasshi (in Japanese) 102 (11): 1074–1085. PMID 6892112.