Loperamide

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Loperamide
Loperamide.svg
Loperamide3Dan2.gif
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. B3 (AU) C (US)
Legal status Pharmacy Only (S2) (AU) OTC (CA) GSL (UK) OTC (US)
Routes oral, insufflation
Pharmacokinetic data
Bioavailability 0.3%
Protein binding 97%
Metabolism Hepatic (extensive)
Half-life 7-14 hours
Excretion Faeces (30-40%), urine (1%)
Identifiers
CAS number 53179-11-6 YesY
34552-83-5 (with HCl)
ATC code A07DA03
A07DA05 (oxide)
PubChem CID 3955
DrugBank DB00836
ChemSpider 3818 YesY
UNII 6X9OC3H4II YesY
KEGG D08144 YesY
ChEBI CHEBI:6532 N
ChEMBL CHEMBL841 YesY
Synonyms R-18553
Chemical data
Formula C29H33ClN2O2 
Mol. mass 477.037 g/mol (513.506 with HCl)
 N (what is this?)  (verify)

Loperamide /lˈpɛrəmd/, a piperidine derivative,[1] is an opioid drug used against diarrhoea resulting from gastroenteritis or inflammatory bowel disease. It was developed by Janssen Pharmaceutica in 1971.[2]

In most countries it is available generically and under brand names such as Lopex, Imodium, Dimor, Fortasec, Lopedium, Gastro-Stop and Pepto Diarrhea Control.[3] 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.[4]

Medical uses[edit]

Loperamide is effective for the treatment of a number of types of diarrhea.[5]

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 ulcerative colitis, or bacterial enterocolitis.[6]

Cautions[edit]

Treatment should be avoided in the presence of high fever or if the stool is bloody (dysentery).[7] It is of no value in diarrhea caused by cholera, Shigella or Campylobacter.[7] 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.[6][8] 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.[9] 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.[10]

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.[11] 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.[12] In 1990, all pediatric formulations of the antidiarrheal loperamide were banned in Pakistan.[13]

Loperamide is not recommended in the UK for use during pregnancy nor by nursing mothers.[14] 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.[15] 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.[16] Loperamide can be present in breast milk, and is not recommended for breast feeding mothers.[10]

Adverse effects[edit]

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%).[17] 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.[18] The most frequent symptoms of loperamide overdose are drowsiness, vomiting and abdominal pain or burning.[19]

Drug interactions[edit]

Loperamide is a substrate of P-Glycoprotein, therefore the concentration of Loperamide will increase when given with a P-Glycoprotein inhibitor.[17] Common P-Glycoprotein inhibitors include quinidine, ritonavir, and ketoconazole, among others.[20] 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.[17]

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.[21]

Recreational use[edit]

In recent times, "loperamide (which is available over the counter) has been used recreationally when combined with a g-glycoprotein inhibitor such as omeprazole."[22]

Mechanism of action[edit]

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; 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.[23][24] 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.[25]

Ability to cross the blood–brain barrier[edit]

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.[26]

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.[27]

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.[28][29]

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)

See also[edit]

References[edit]

  1. ^ US National Cancer Institute, Drug Dictionary
  2. ^ US Patent Janssen US3714159
  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. PMID 4725924. 
  4. ^ "WHO Model List of Essential Medicines". World Health Organization. October 2013. Retrieved 22 April 2014. 
  5. ^ Hanauer, S. B. (Winter 2008). "The Role of Loperamide in Gastrointestinal Disorders". Reviews in Gastroenterological Disorders 8 (1): 15–20. PMID 18477966. 
  6. ^ a b http://www.drugs.com/pro/loperamide.html
  7. ^ 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. 
  8. ^ http://www.peteducation.com/article.cfm?c=0+1303+1459&aid=1432
  9. ^ "rxlist.com". 2005. 
  10. ^ a b http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label_ApprovalHistory
  11. ^ "Imodium (Loperamide Hydrochloride) Capsule". DailyMed. NIH. 
  12. ^ 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. 
  13. ^ "E-DRUG: Chlormezanone". Essentialdrugs.org. 
  14. ^ http://www.nhs.uk/medicine-guides/pages/MedicineOverview.aspx?condition=Diarrhoea&medicine=imodium
  15. ^ http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label_ApprovalHistory#labelinfo
  16. ^ Einarson, A., et al. (2000). "Prospective, controlled, multicentre study of loperamide in pregnancy". Canadian journal of gastroenterology 14 (3): 185–187. PMID 10758415. 
  17. ^ a b c http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/017694s050lbl.pdf
  18. ^ https://online.epocrates.com/noFrame/showPage.do;jsessionid=FB4C4C42205138677A3F9E475E6C6299?method=drugs&MonographId=44&ActiveSectionId=5
  19. ^ 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. 
  20. ^ http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/ucm093664.htm#PgpTransport
  21. ^ https://online.epocrates.com/noFrame/showPage.do?method=drugs&MonographId=44&ActiveSectionId=4
  22. ^ "USMLE-Rx". Step 1 Qmax (in English). MedIQ Learning, LLC. 2014. 
  23. ^ http://www.drugbank.ca/drugs/DB00836
  24. ^ http://www.drugs.com/mmx/loperamide-hydrochloride.html
  25. ^ Katzung, B. G. (2004). Basic and Clinical Pharmacology (9th ed.). ISBN 0-07-141092-9. [page needed]
  26. ^ 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. 
  27. ^ 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. 
  28. ^ Yanagita, T.; Miyasato, K.; Sato, J. (1979). "Dependence Potential of Loperamide Studied in Rhesus Monkeys". NIDA Research Monograph 27: 106–113. PMID 121326. 
  29. ^ 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. 

External links[edit]