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Line 14: Line 14:
| legal_CA = OTC
| legal_CA = OTC
| legal_UK = GSL
| legal_UK = GSL
| legal_US = OTC HCl salt Rx only without HCl
| legal_US = OTC
| routes_of_administration = oral, insufflation
| routes_of_administration = oral, insufflation


Revision as of 13:21, 22 February 2013

Loperamide
Clinical data
Trade namesImodium
AHFS/Drugs.comMonograph
MedlinePlusa682280
Pregnancy
category
Routes of
administration		oral, insufflation
ATC code
Legal status
Legal status
Pharmacokinetic data
BioavailabilityNot significantly absorbed from the gut
Protein binding97%
Metabolismhepatic
Elimination half-life9.1 to 14.4 hours (average 10.8 hours)
Identifiers
  • 4-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]- N,N-dimethyl-2,2-diphenylbutanamide
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.053.088 Edit this at Wikidata
Chemical and physical data
FormulaC29H33ClN2O2
Molar mass477.037 g/mol (513.506 with HCl) g·mol−1
3D model (JSmol)
  • Clc1ccc(cc1)C4(O)CCN(CCC(c2ccccc2)(c3ccccc3)C(=O)N(C)C)CC4
  • InChI=1S/C29H33ClN2O2/c1-31(2)27(33)29(24-9-5-3-6-10-24,25-11-7-4-8-12-25)19-22-32-20-17-28(34,18-21-32)23-13-15-26(30)16-14-23/h3-16,34H,17-22H2,1-2H3 checkY
  • Key:RDOIQAHITMMDAJ-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Loperamide (/[invalid input: 'icon']loʊˈpɛrəmaɪd/; R-18553[clarification needed]), a synthetic 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]

Medical uses

Loperamide is effective for the treatment of a number of types of diarrhea.[4]

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 by decreasing the activity of the myenteric plexus, which, like morphine, decreases the tone of the longitudinal smooth muscles but increases the tone of 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.[5]

Crossing the blood–brain barrier

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.[6]

Many physicians and pharmacists believe that loperamide does not cross the blood–brain barrier. In fact, however, 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 addiction) to loperamide, many drugs are known to inhibit P-glycoprotein and may thus render the CNS vulnerable to opiate agonism by loperamide.[7]

Only when very high doses are taken does enough accumulate in the brain to produce typical opioid effects, lasting for a number of hours (just as typical opioids would).[8][9]

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.[10][11]

Contraindications

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.[12] In 1990, all pediatric formulations of the antidiarrheal loperamide (Imodium and others) were banned in Pakistan.[13]

Treatment should be avoided in the presence of high fever or if the stool is bloody (dysentery).[14] It is of no value in diarrhea caused by cholera, Shigella or Campylobacter.[14] 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.[15][16]

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.[17]

Adverse effects

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.[18]

Hepatic

It is not recommended for use in hepatic failure since it can precipitate hepatic encephalopathy.[18]

Marketing in the developing world

In Pakistan, seven infants died in 1989 and 1990 after parents treated their babies' diarrhea with Imodium, a medicine sold by a subsidiary of Johnson & Johnson.[citation needed]

Since 1980, the World Health Organization has warned doctors of developing countries not to use Imodium because it can paralyze a child's intestines. For months a local doctor begged the company to pull the product from stores, but it didn't do so until a British television program broadcast footage of dying babies.[19]

See also

References

  1. ^ "Loperamide Hydrochloride." DailyMed.
  2. ^ US National Cancer Institute, Drug Dictionary
  3. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  4. ^ Hanauer, S. B. (2008 Winter). "The Role of Loperamide in Gastrointestinal Disorders". Reviews in Gastroenterological Disorders. 8 (1): 15–20. PMID 18477966. {{cite journal}}: Check date values in: |date= (help)
  5. ^ Katzung, B. G. (2004). Basic and Clinical Pharmacology (9th ed.). ISBN 0-07-141092-9.[page needed]
  6. ^ Sadeque, A. J.; Wandel, C.; He, H.; Shah, S.; Wood, A. J. (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  7. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 17600543 , please use {{cite journal}} with |pmid= 17600543 instead.
  8. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  9. ^ Sklerov, J.; Levine, B.; Moore, K. A.; Allan, C.; Fowler, D. (2005). "Tissue Distribution of Loperamide and N-desmethylloperamide Following a Fatal Overdose". Journal of Analytical Toxicology. 29 (7): 750–754. PMID 16419413. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  10. ^ Yanagita, T.; Miyasato, K.; Sato, J. (1979). "Dependence Potential of Loperamide Studied in Rhesus Monkeys". NIDA Research Monograph. 27: 106–113. PMID 121326.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  11. ^ Nakamura, H.; Ishii, K.; Yokoyama, Y.; et al. (1982). "[Physical Dependence on Loperamide Hydrochloride in Mice and Rats]". Yakugaku Zasshi (in Japanese). 102 (11): 1074–1085. PMID 6892112. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  12. ^ "Imodium (Loperamide Hydrochloride) Capsule". DailyMed. NIH.
  13. ^ "E-DRUG: Chlormezanone". Essentialdrugs.org.
  14. ^ a b Butler, T. (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. {{cite journal}}: Unknown parameter |month= ignored (help)
  15. ^ http://www.drugs.com/pro/loperamide.html
  16. ^ http://www.peteducation.com/article.cfm?c=0+1303+1459&aid=1432
  17. ^ "rxlist.com". 2005.
  18. ^ a b Bichner, F., ed. (2010). Australian Medicine Handbook. Adelaide: Australian Medicine Handbook Pty Ltd.
  19. ^ Scanlan, Christopher (1991-06-09). "America's Deadly Exports -- Trade Of Toxic Products Abroad Is A Windfall For U.S. Companies". The Seattle Times.
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