Loperamide

Loperamide

Loperamide
Systematic (IUPAC) name
4-[4-(4-Chlorophenyl)-4-hydroxypiperidin-1-yl]-N,N-dimethyl-2,2-diphenylbutanamide
Clinical data
Pronunciation
Trade names Imodium, others[1]
AHFS/Drugs.com
MedlinePlus
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
Legal status
Routes of
administration
oral, inhaled
Pharmacokinetic data
Bioavailability 0.3%
Protein binding 97%
Metabolism Liver (extensive)
Biological half-life 9-14 hours[2]
Excretion Faeces (30-40%), urine (1%)
Identifiers
CAS Registry Number  Y
34552-83-5 (with HCl)
ATC code A07
A07 (oxide)
PubChem CID:
IUPHAR/BPS
DrugBank  N
ChemSpider  Y
UNII  Y
KEGG  Y
ChEBI  N
ChEMBL  Y
Synonyms R-18553
Chemical data
Formula C29H33ClN2O2
Molecular mass 477.037 g/mol (513.506 with HCl)
 N   

Loperamide, sold under the brand name Imodium among others,[1] is a medication used to decrease the frequency of health system.[7] It is sold as a generic medication and is not very expensive.[2][8] Wholesale the cost is about 0.004 to 0.04 USD a dose.[9] In the United States it is about 0.20 USD a dose.[2]

Contents

  • Medical uses 1
  • Side effects 2
  • Drug interactions 3
  • Mechanism of action 4
    • Blood–brain barrier 4.1
  • History 5
  • Society and culture 6
    • Cost 6.1
    • Brand names 6.2
  • References 7
  • External links 8

Medical uses

Loperamide is effective for the treatment of a number of types of diarrhea.[10] 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.[11]

Loperamide is often compared to diphenoxylate. Recent studies suggest that loperamide is more effective and has lower neural side effects.[12][13][14]

Side effects

Treatment should be avoided in the presence of high E. coli O157:H7 or salmonella, loperamide is contraindicated as a primary treatment.[11] 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.[15] 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.[16]

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.[17] 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.[18] In 1990, all pediatric formulations of the antidiarrheal loperamide were banned in Pakistan.[19]

Loperamide is not recommended in the UK for use during pregnancy nor by nursing mothers.[20] 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.[21] 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.[22] Loperamide can be present in breast milk, and is not recommended for breast feeding mothers.[16]

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%).[23] 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.[24] The most frequent symptoms of loperamide overdose are drowsiness, vomiting and abdominal pain or burning.[25]

Drug interactions

Loperamide is a substrate of P-glycoprotein, therefore the concentration of Loperamide will increase when given with a P-Glycoprotein inhibitor.[23] Common P-Glycoprotein inhibitors include quinidine, ritonavir, and ketoconazole, among others.[26] 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.[23]

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, other opioids, antihistamines, antipsychotics, and anticholinergics.[27]

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; 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.[28][29] 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.[30]

Blood–brain barrier

Loperamide is subject to efflux by P-glycoprotein. This mechanism effectively prevents loperamide from crossing the blood-brain barrier and so shields the CNS from exposure (and thus risk of CNS tolerance/dependence).[31]

Concurrent administration of P-glycoprotein inhibitors such as quinidine could potentially allow loperamide to cross the blood–brain barrier. Quinidine with loperamide was found to produce respiratory depression, indicative of central opioid action.[32]

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.[33][34]

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)

History

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).[35]

The first clinical on loperamide were published in 1973 in the Journal of Medicinal Chemistry[36] with the inventor being one of the authors.

The trial against placebo was conducted from December 1972 to February 1974, its results being published in 1977 in Gut journal, an edition of British Society of Gastroenterology.[37]

The drug was patented in the USA in 1973.[38][39]

In 1973 Janssen started to promote loperamide under the brand name Imodium.

In December 1976 Imodium got FDA approval.[40]

During the 1980s, Imodium became the best-selling prescription antidiarrheal in the United States.[41]

In March 1988 McNeil Pharmaceutical began selling loperamide as the OTC product under the brand name Imodium A-D.[42]

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

  • Imodium Website
  • Imodium UK Website

External links

  1. ^ a b c Drugs.com International brands for loperamide Page accessed Sept 4, 2015
  2. ^ a b c d e f g h i "Loperamide Hydrochloride". The American Society of Health-System Pharmacists. Retrieved Aug 25, 2015. 
  3. ^ "Prescribing medicines in pregnancy database". Australian Government. 3 March 2014. Retrieved 22 April 2014. 
  4. ^ "Loperamide use while Breastfeeding". Retrieved 26 August 2015. 
  5. ^ "loperamide hydrochloride". NCI Drug Dictionary. Retrieved 26 August 2015. 
  6. ^ Patrick, Graham L. (2013). An introduction to medicinal chemistry (Fifth edition. ed.). Oxford: Oxford University Press. p. 644.  
  7. ^ "WHO Model List of Essential Medicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014. 
  8. ^ a b Hamilton, Richard J. (2013). Tarascon pocket pharmacopoeia (14 ed.). [Sudbury, Mass.]: Jones & Bartlett Learning. p. 217.  
  9. ^ a b "Loperamide HCL". International Drug Price Indicator Guide. Retrieved 26 August 2015. 
  10. ^ Hanauer, S. B. (Winter 2008). "The Role of Loperamide in  
  11. ^ a b http://www.drugs.com/pro/loperamide.html
  12. ^ Miftahof, Roustem (2009). Mathematical Modeling and Simulation in Enteric Neurobiology. World Scientific. p. 18.  
  13. ^ 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.  
  14. ^ Zuckerman, Jane N. (2012). Principles and Practice of Travel Medicine. John Wiley & Sons. p. 203.  
  15. ^ "rxlist.com". 2005. 
  16. ^ a b http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label_ApprovalHistory
  17. ^ "Imodium (Loperamide Hydrochloride) Capsule". DailyMed. NIH. 
  18. ^ 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.  
  19. ^ "E-DRUG: Chlormezanone". Essentialdrugs.org. 
  20. ^ http://www.nhs.uk/medicine-guides/pages/MedicineOverview.aspx?condition=Diarrhoea&medicine=imodium
  21. ^ http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label_ApprovalHistory#labelinfo
  22. ^ Einarson, A.; et al. (2000). "Prospective, controlled, multicentre study of loperamide in pregnancy". Canadian journal of gastroenterology 14 (3): 185–187.  
  23. ^ a b c http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/017694s050lbl.pdf
  24. ^ https://online.epocrates.com/noFrame/showPage.do;jsessionid=FB4C4C42205138677A3F9E475E6C6299?method=drugs&MonographId=44&ActiveSectionId=5
  25. ^ 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.  
  26. ^ http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/ucm093664.htm#PgpTransport
  27. ^ https://online.epocrates.com/noFrame/showPage.do?method=drugs&MonographId=44&ActiveSectionId=4
  28. ^ http://www.drugbank.ca/drugs/DB00836
  29. ^ http://www.drugs.com/mmx/loperamide-hydrochloride.html
  30. ^ Katzung, B. G. (2004). Basic and Clinical Pharmacology (9th ed.).  
  31. ^ Upton, RN (Aug 2007). "Cerebral uptake of drugs in humans.". Clinical and experimental pharmacology & physiology 34 (8): 695–701.  
  32. ^ 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.  
  33. ^ Yanagita, T.; Miyasato, K.; Sato, J. (1979). "Dependence Potential of Loperamide Studied in Rhesus Monkeys". NIDA Research Monograph 27: 106–113.  
  34. ^ 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.  
  35. ^ Florey, Klaus (1991). Profiles of Drug Substances, Excipients and Related Methodology, Volume 19. Academic Press. p. 342.  
  36. ^ 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.  
  37. ^ P. Mainguet, R. Fiasse (1977). "Double-blind placebo-controlled study of loperamide (Imodium) in chronic diarrhoea caused by ileocolic disease or resection".  
  38. ^ "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. 
  39. ^ "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. 
  40. ^ "IMODIUM FDA Application No.(NDA) 017694".  
  41. ^ a b McNeil-PPC, Inc., Plaintiff, v. L. Perrigo Company, and Perrigo Company, Defendants, 207 F. Supp. 2d 356 (E.D. Pa. June 25, 2002).
  42. ^ "IMODIUM A-D FDA Application No.(NDA) 019487".  
  43. ^ "Loperamide: voluntary withdrawal of infant fomulations". WHO Drug Information Vol. 4, No. 2, 1990. 1990. pp. 73–74. Archived from the original (PDF) 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. 
  44. ^ Consolidated List of Products Whose Consumption And/or Sale Have Been Banned, Withdrawn, Severely Restricted Or Not Approved by Governments, 8th Issue.  
  45. ^ "Treatment of diarrhea and flatulence in gastrointestinal disorders US 5612054 A". 1997. Archived from the original on 2014-09-05. Retrieved 2014-09-05. 
  46. ^ "IMODIUM MULTI-SYMPTOM RELIEF FDA Application No.(NDA) 020606".  
  47. ^ "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. 
  48. ^ 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.  
  49. ^ 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. 
  50. ^ 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 (PDF) on 2014-09-05. Retrieved 2014-09-05. 
  51. ^ "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)".  

References

Loperamide was originally marketed Imodium, and there are many generic brands[1]

Brand names

It is as a generic medication and is not very expensive.[2][8] Wholesale the cost is about 0.004 to 0.04 USD a dose.[9] In the United States it is about 0.20 USD a dose.[2]

Cost

Society and culture

In 2013 loperamide in the form of 2 mg tablets has been added to WHO Model List of Essential Medicines.[51]

In November 1993 loperamide has been launched as an orally disintegrating tablet based on Zydis technology.[47][48] Imodium Instant Melts from Johnson & Johnson is currently the only loperamide available in the form of orally disintegrating tablets.[49][50]

In the late 1980s prior to the expiration of US Patent in January 30, 1990,[41] 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.[45] The drug has been approved in June 1997 by FDA as Imodium Multi-Symptom Relief in the form of a chewable tablet.[46]

[44] 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).[43]