Loperamide
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| Systematic (IUPAC) name | |
| 4-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]- N,N-dimethyl-2,2-diphenylbutanamide | |
| Clinical data | |
| Trade names | Imodium |
| AHFS/Drugs.com | monograph |
| MedlinePlus | a682280 |
| Pregnancy cat. | B[1] |
| Legal status | OTC (CA) GSL (UK) OTC (US) |
| Routes | oral, insufflation |
| Pharmacokinetic data | |
| Bioavailability | Not significantly absorbed from the gut |
| Protein binding | 97% |
| Metabolism | hepatic |
| Half-life | 9.1 to 14.4 hours (average 10.8 hours) |
| Identifiers | |
| CAS number | 53179-11-6  34552-83-5 (with HCl) |
| ATC code | A07DA03 A07DA05 (oxide) |
| PubChem | CID 3955 |
| DrugBank | DB00836 |
| ChemSpider | 3818 |
| UNII | 6X9OC3H4II |
| KEGG | D08144 |
| ChEBI | CHEBI:6532  |
| ChEMBL | CHEMBL841 |
| Synonyms | R-18553 |
| Chemical data | |
| Formula | C29H33ClN2O2 |
| Mol. mass | 477.037 g/mol (513.506 with HCl) |
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Loperamide /loʊˈpɛrəmaɪd/, a piperidine derivative,[2] is an opioid drug used against diarrhea resulting from gastroenteritis or inflammatory bowel disease. In most countries it is available generically and under brand names such as Lopex, Imodium, Dimor, Fortasec, Lopedium, and Pepto Diarrhea Control. It was developed at Janssen Pharmaceutica.[3]
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Medical uses[edit]
Loperamide is effective for the treatment of a number of types of diarrhea.[4]
Mechanism of action[edit]
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.[5][6] 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.[7]
Ability to cross the blood–brain barrier[edit]
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.[8]
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.[9]
When taken very high doses enough loperamid accumulates in the brain to produce typical opioid effects. These effects last a number of hours much like typical opioids do.[10][11]
However, 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.[12][13]
Contraindications[edit]
The use of loperamide (Imodium) 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.[14] In 1990, all pediatric formulations of the antidiarrheal loperamide (Imodium and others) were banned in Pakistan.[15]
Treatment should be avoided in the presence of high fever or if the stool is bloody (dysentery).[16] It is of no value in diarrhea caused by cholera, Shigella or Campylobacter.[16] 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.[17][18]
Loperamide treatment is not used in symptomatic C. difficile infections, as it increases the risk of toxin retention and precipitation of toxic megacolon.
Loperamide is not recommended in the UK for use during pregnancy nor by nursing mothers[19]
Loperamide should be administered with caution to patients suffering from hepatic impairment due to reduced first pass metabolism.[20]
Adverse effects[edit]
Adverse drug reactions (ADRs) associated with loperamide include abdominal pain and bloating, nausea, vomiting and constipation. Rare side-effects associated with loperamide are paralytic ileus, dizziness and rashes.[21]
Hepatic[edit]
It is not recommended for use in hepatic failure since it can precipitate hepatic encephalopathy.[21]
See also[edit]
- Gastroenteritis
- 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
References[edit]
- ^ "Loperamide Hydrochloride." DailyMed.
- ^ 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.
- ^ Hanauer, S. B. (2008 Winter). "The Role of Loperamide in Gastrointestinal Disorders". Reviews in Gastroenterological Disorders 8 (1): 15–20. PMID 18477966.
- ^ http://www.drugbank.ca/drugs/DB00836
- ^ http://www.drugs.com/mmx/loperamide-hydrochloride.html
- ^ Katzung, B. G. (2004). Basic and Clinical Pharmacology (9th ed.). ISBN 0-07-141092-9.[page needed]
- ^ 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.
- ^ Upton, R. N. (2007). "Cerebral Uptake of Drugs in Humans". Clinical and Experimental Pharmacology and Physiology 34 (8): 695–701. doi:10.1111/j.1440-1681.2007.04649.x. PMID 17600543.
- ^ Litovitz, T.; Clancy, C.; Korberly, B.; Temple, A. R.; Mann, K. V. (1997). "Surveillance of Loperamide Ingestions: An Analysis of 216 Poison Center Reports". Journal of Toxicology. Clinical Toxicology 35 (1): 11–19. PMID 9022646.
- ^ Sklerov, J.; Levine, B.; Moore, K. A.; Allan, C.; Fowler, D. (October 2005). "Tissue Distribution of Loperamide and N-desmethylloperamide Following a Fatal Overdose". Journal of Analytical Toxicology 29 (7): 750–754. PMID 16419413.
- ^ 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.
- ^ "Imodium (Loperamide Hydrochloride) Capsule". DailyMed. NIH.
- ^ "E-DRUG: Chlormezanone". Essentialdrugs.org.
- ^ a b 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.
- ^ http://www.drugs.com/pro/loperamide.html
- ^ http://www.peteducation.com/article.cfm?c=0+1303+1459&aid=1432
- ^ http://www.nhs.uk/medicine-guides/pages/MedicineOverview.aspx?condition=Diarrhoea&medicine=imodium
- ^ "rxlist.com". 2005.
- ^ a b Bichner, F., ed. (2010). Australian Medicine Handbook. Adelaide: Australian Medicine Handbook Pty Ltd.
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