Loperamide

Loperamide
Clinical data
Pronunciation /loʊˈpɛrəmaɪd/
Trade names Imodium, others[1]
AHFS/Drugs.com Monograph
MedlinePlus a682280
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
Routes of
administration		 by mouth
ATC code
Legal status
Legal status
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
Synonyms R-18553
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
ECHA InfoCard 100.053.088
Chemical and physical data
Formula C29H33ClN2O2
Molar mass 477.037 g/mol (513.506 with HCl)
3D model (JSmol)
 NYesY (what is this?)  (verify)

Loperamide, sold under the brand name Imodium among others,[1] is a medication used to decrease the frequency of diarrhea.[2] It is often used for this purpose in gastroenteritis, inflammatory bowel disease, and short bowel syndrome. It is not recommended for those with blood in the stool. The medication is taken by mouth.[2]

Common side effects include abdominal pain, constipation, sleepiness, vomiting, and a dry mouth. It may increase the risk of toxic megacolon.[2] Loperamide's safety in pregnancy is unclear, but there is no evidence of harm.[3] It appears to be safe in breastfeeding.[4] It is an opioid with no significant absorption from the gut and does not cross the blood brain barrier when used at normal doses.[5] It works by slowing the contractions of the intestines.[2]

Loperamide was first made in 1969 and used medically in 1976.[6] It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.[7] Loperamide is available as an inexpensive generic medication.[2][8] The wholesale cost in the developing world is about US$0.004 to US$0.04 per dose.[9] In August 2016, the US retail cost is about US$0.31 per dose.[10]

Medical uses

Loperamide is effective for the treatment of a number of types of diarrhea.[11] 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.[12]

Loperamide is often compared to diphenoxylate. Recent studies suggest that loperamide is more effective and has lower neural side effects.[13][14][15]

Side effects

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%).[16] 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.[17] The most frequent symptoms of loperamide overdose are drowsiness, vomiting and abdominal pain or burning.[18]

High doses may result in heart problems such as abnormal heart rhythms.[19]

Contraindications

Treatment should be avoided in the presence of high fever or if the stool is bloody. Treatment is not recommended for people that could have negative 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 as a primary treatment.[12] 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 people with liver failure due to reduced first pass metabolism.[20] Additionally, caution should be used when treating people 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.[21]

Children

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.[22] A review 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.[23] In 1990, all formulations for children of the antidiarrheal loperamide were banned in Pakistan.[24]

Pregnancy and breast feeding

Loperamide is not recommended in the UK for use during pregnancy nor by nursing mothers.[25] 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.[26] 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.[27] Loperamide can be present in breast milk, and is not recommended for breast feeding mothers.[21]

Drug interactions

Loperamide is a substrate of P-glycoprotein; therefore, the concentration of loperamide will increase when given with a P-glycoprotein inhibitor.[16] Common P-glycoprotein inhibitors include quinidine, ritonavir, and ketoconazole, among others.[28] Loperamide is capable of decreasing the absorption of some other drugs. As an example, when saquinavir concentrations can decrease by half when given with loperamide.[16]

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 other opioids, antihistamines, antipsychotics, and anticholinergics.[29]

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. Loperamide works like morphine, decreasing the activity of the myenteric plexus, which decreases the tone of the longitudinal and circular smooth muscles of the intestinal wall.[30][31] This increases the time material stays in the intestine, allowing more water to be absorbed from the fecal matter. Loperamide also decreases colonic mass movements and suppresses the gastrocolic reflex.[32]

Loperamide's circulation in the bloodstream is limited in two ways. Efflux by P-glycoprotein in the intestinal wall reduces passage of loperamide, and the fraction of drug crossing is then further reduced through first pass metabolism by the liver.[33][34] Loperamide metabolizes into an MPTP-like compound, but is unlikely to exert neurotoxicity.[35]

Blood–brain barrier

Efflux by P-glycoprotein also prevents circulating loperamide from effectively crossing the blood–brain barrier, affecting the central nervous system.[36] Concurrent administration of P-glycoprotein inhibitors such as quinidine potentially allows loperamide to cross the blood–brain barrier and produce central morphine-like effects. Loperamide taken with quinidine was found to produce respiratory depression, indicative of central opioid action.[37]

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.[38][39]

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.[40]

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).[41]

The first clinical on loperamide were published in 1973 in the Journal of Medicinal Chemistry[42] with the inventor being one of the authors. The trial name for it was "R-18553".[43] Loperamide oxide has a different research code: R-58425.[44]

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.[45]

In 1973, Janssen started to promote loperamide under the brand name Imodium. In December 1976, Imodium got FDA approval.[46]

During the 1980s, Imodium became the best-selling prescription antidiarrheal in the United States.[47]

In March 1988, McNeil Pharmaceutical began selling loperamide as the OTC product under the brand name Imodium A-D.[48]

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) were registered in Pakistan and reported by World Health Organization.[49] 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).[50]

In the late 1980s, prior to the expiration of US patent on 30 January 1990,[47] McNeil company started to develop Imodium Advanced containing loperamide and simethicone for treating both diarrhea and gas. In March 1997 the company patented such combination.[51] The drug was approved in June 1997 by the FDA as Imodium Multi-Symptom Relief in the form of a chewable tablet.[52]

In November 1993, loperamide was launched as an orally disintegrating tablet based on Zydis technology.[53][54] Imodium Instant Melts from Johnson & Johnson is currently the only loperamide available in the form of orally disintegrating tablets.[55][56]

In 2013, loperamide in the form of 2 mg tablets was added to WHO Model List of Essential Medicines.[57]

Society and culture

Cost

It is sold as a generic medication and is not very expensive.[2][8] The wholesale cost in the developing world is about US$0.004 to US$0.04 a dose.[9] In August 2016, the US retail cost is about US$0.31 per dose.[10] In 2016 Imodium was one of the biggest selling branded over-the-counter medications sold in Great Britain, with sales of £32.7 million.[58]

Brand names

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

Recreational use

Loperamide has typically been deemed to have a relatively low risk of misuse.[59] In 2012, there were no reports of loperamide abuse.[60]

In 2015, however, case reports of extremely high-dose loperamide resulting in opioid misuse were published.[61][62]

In 2016, several clinical reports of severe cardiotoxicity due to high-dose loperamide abuse, including two deaths, were published.[63][64][65] The authors of one of the reports have called for the FDA to limit the availability of loperamide for public safety reasons, in an analogous manner to restrictions put on the sales of pseudoephedrine, to be sold only in limited amounts.[66]

See also

References

  1. 1 2 3 Drugs.com International brands for loperamide Page accessed Sept 4, 2015
  2. 1 2 3 4 5 6 7 "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. ISBN 9780199697397.
  7. ↑ "WHO Model List of Essential Medicines (19th List)" (PDF). World Health Organization. April 2015. Retrieved 8 December 2016.
  8. 1 2 Hamilton, Richard J. (2013). Tarascon pocket pharmacopoeia (14 ed.). [Sudbury, Mass.]: Jones & Bartlett Learning. p. 217. ISBN 9781449673611.
  9. 1 2 "Loperamide HCL". International Drug Price Indicator Guide. Retrieved 26 August 2015.
  10. 1 2 "NADAC (National Average Drug Acquisition Cost) Loperamide". Centers for Medicare and Medicaid Services. Retrieved 16 April 2016. Loperamide 2mg Capsule ... 0.33803 [USD] ... 03/23/2016
  11. ↑ Hanauer, S. B. (Winter 2008). "The Role of Loperamide in Gastrointestinal Disorders". Reviews in Gastroenterological Disorders. 8 (1): 15–20. PMID 18477966.
  12. 1 2 "Loperamide". Retrieved 14 May 2016.
  13. ↑ Miftahof, Roustem (2009). Mathematical Modeling and Simulation in Enteric Neurobiology. World Scientific. p. 18. ISBN 9789812834812.
  14. ↑ 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.
  15. ↑ Zuckerman, Jane N. (2012). Principles and Practice of Travel Medicine. John Wiley & Sons. p. 203. ISBN 9781118392089.
  16. 1 2 3 http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/017694s050lbl.pdf
  17. ↑ "Epocrates Page Not Found". Retrieved 14 May 2016.
  18. ↑ 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. PMID 9022646. doi:10.3109/15563659709001159.
  19. ↑ "Safety Alerts for Human Medical Products - Loperamide (Imodium): Drug Safety Communication - Serious Heart Problems With High Doses From Abuse and Misuse". www.fda.gov. Retrieved 12 June 2016.
  20. ↑ "rxlist.com". 2005.
  21. 1 2 "Drugs@FDA: FDA Approved Drug Products". Retrieved 14 May 2016.
  22. ↑ "Imodium (Loperamide Hydrochloride) Capsule". DailyMed. NIH.
  23. ↑ Li ST, Grossman DC, Cummings P (2007). "Loperamide therapy for acute diarrhea in children: systematic review and meta-analysis". PLOS Medicine. 4 (3): e98. PMC 1831735 Freely accessible. PMID 17388664. doi:10.1371/journal.pmed.0040098.
  24. ↑ "E-DRUG: Chlormezanone". Essentialdrugs.org. Archived from the original on 26 July 2011.
  25. ↑ "Medicines information links - NHS Choices". Retrieved 14 May 2016.
  26. ↑ "Drugs@FDA: FDA Approved Drug Products". Retrieved 14 May 2016.
  27. ↑ Einarson, A.; et al. (2000). "Prospective, controlled, multicentre study of loperamide in pregnancy". Canadian journal of gastroenterology. 14 (3): 185–187. PMID 10758415.
  28. ↑ "Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers". Retrieved 14 May 2016.
  29. ↑ "Epocrates Page Not Found". Retrieved 14 May 2016.
  30. ↑ "DrugBank: Loperamide". Retrieved 14 May 2016.
  31. ↑ "Loperamide Hydrochloride Drug Information, Professional". Retrieved 14 May 2016.
  32. ↑ Katzung, B. G. (2004). Basic and Clinical Pharmacology (9th ed.). ISBN 0-07-141092-9.
  33. ↑ Lemke, Thomas L.; Williams, David A. (2008). Foye's Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. p. 675. ISBN 9780781768795.
  34. ↑ Dufek, Matthew B.; Knight, Beverly M.; Bridges, Arlene S.; Thakker, Dhiren R. (2013-03-01). "P-glycoprotein increases portal bioavailability of loperamide in mouse by reducing first-pass intestinal metabolism". Drug Metabolism and Disposition: The Biological Fate of Chemicals. 41 (3): 642–650. ISSN 1521-009X. PMID 23288866. doi:10.1124/dmd.112.049965.
  35. ↑ Kalgutkar, Amit S.; Nguyen, Hang T. (2004-09-01). "Identification of an N-Methyl-4-Phenylpyridinium-Like Metabolite of the Antidiarrheal Agent Loperamide in Human Liver Microsomes: Underlying Reason(s) for the Lack of Neurotoxicity Despite the Bioactivation Event". Drug Metabolism and Disposition. 32 (9): 943–952. ISSN 0090-9556. PMID 15319335.
  36. ↑ Upton, RN (Aug 2007). "Cerebral uptake of drugs in humans.". Clinical and experimental pharmacology & physiology. 34 (8): 695–701. PMID 17600543. doi:10.1111/j.1440-1681.2007.04649.x.
  37. ↑ 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. PMID 11014404. doi:10.1067/mcp.2000.109156.
  38. ↑ Yanagita, T.; Miyasato, K.; Sato, J. (1979). "Dependence Potential of Loperamide Studied in Rhesus Monkeys". NIDA Research Monograph. 27: 106–113. PMID 121326.
  39. ↑ 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.
  40. ↑ "DEA "Orange Book" Lists of Scheduling Actions" (PDF). DEA Office of Diversion Control. U.S. Department of Justice. February 2016. Retrieved April 17, 2016.
  41. ↑ Florey, Klaus (1991). Profiles of Drug Substances, Excipients and Related Methodology, Volume 19. Academic Press. p. 342. ISBN 9780080861142.
  42. ↑ Stokbroekx RA, Vandenberk J, Van Heertum AH, Van Laar GM, Van der Aa MJ, Van Bever WF, Janssen PA (1973). "Synthetic Antidiarrheal Agents. 2,2-Diphenyl-4-(4'-aryl-4'-hydroxypiperidino)butyramides". Journal of Medicinal Chemistry. 16 (7): 782–786. PMID 4725924. doi:10.1021/jm00265a009.
  43. ↑ Schuermans V, Van Lommel R, Dom J, Brugmans J (1974). "Loperamide (R 18 553), a novel type of antidiarrheal agent. Part 6: Clinical pharmacology. Placebo-controlled comparison of the constipating activity and safety of loperamide, diphenoxylate and codeine in normal volunteers". Arzneimittelforschung. 24: 1653–7. PMID 4611432.
  44. ↑ https://www.ebi.ac.uk/chembl/compound/inspect/CHEMBL2105114
  45. ↑ P. Mainguet; R. Fiasse (1977). "Double-blind placebo-controlled study of loperamide (Imodium) in chronic diarrhoea caused by ileocolic disease or resection" (PDF). Gut (journal) (18): 575–579. Archived from the original (PDF) on 5 September 2014. Retrieved 2014-09-05.
  46. ↑ "IMODIUM FDA Application No.(NDA) 017694". Food and Drug Administration. 1976. Archived from the original on 5 September 2014. Retrieved 2014-09-05.
  47. 1 2 McNeil-PPC, Inc., Plaintiff, v. L. Perrigo Company, and Perrigo Company, Defendants, 207 F. Supp. 2d 356 (E.D. Pa. June 25, 2002).
  48. ↑ "IMODIUM A-D FDA Application No.(NDA) 019487". Food and Drug Administration. 1988. Archived from the original on 5 September 2014. Retrieved 2014-09-05.
  49. ↑ "Loperamide: voluntary withdrawal of infant fomulations" (PDF). WHO Drug Information Vol. 4, No. 2, 1990. 1990. pp. 73–74. Archived from the original (PDF) on 6 September 2014. 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.
  50. ↑ 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. pp. 130–131. ISBN 92-1-130230-7.
  51. ↑ "Treatment of diarrhea and flatulence in gastrointestinal disorders US 5612054 A". 1997. Archived from the original on 2014-09-05. Retrieved 2014-09-05.
  52. ↑ "IMODIUM MULTI-SYMPTOM RELIEF FDA Application No.(NDA) 020606". Food and Drug Administration. 1997. Archived from the original on 5 September 2014. Retrieved 2014-09-05.
  53. ↑ "Scherer announces launch of another product utilizing its Zydis technology". PR Newswire Association LLC. 1993-11-09. Retrieved 2014-08-30.
  54. ↑ 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.
  55. ↑ 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.
  56. ↑ Nayak, Amit Kumar; Manna, Kaushik (2011). "Current developments in orally disintegrating tablet technology" (PDF). Journal of Pharmaceutical Education and Research, Vol 2, Issue No. 1, June 2011. Archived from the original (PDF) on 6 September 2014. Retrieved 2014-09-05.
  57. ↑ "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)" (PDF). World Health Organization. 2013. Archived from the original (PDF) on 5 September 2014. Retrieved 2014-09-05. Other medicines added were: loperamide
  58. ↑ "A breakdown of the over-the-counter medicines market in Britain in 2016". Pharmaceutical Journal. 28 April 2017. Retrieved 29 May 2017.
  59. ↑ Baker, DE (2007). "Loperamide: a pharmacological review.". Reviews in gastroenterological disorders. 7 Suppl 3: S11–8. PMID 18192961.
  60. ↑ Mediators and Drugs in Gastrointestinal Motility II: Endogenous and Exogenous Agents. Springer Science & Business Media. 6 December 2012. pp. 290–. ISBN 978-3-642-68474-6.
  61. ↑ MacDonald, R; Heiner, J; Villarreal, J; Strote, J (2 May 2015). "Loperamide dependence and abuse.". BMJ case reports. 2015: bcr2015209705. PMID 25935922. doi:10.1136/bcr-2015-209705.
  62. ↑ Dierksen, Jennifer; Gonsoulin, Morna; Walterscheid, Jeffrey P. (2015). "Poor Manʼs Methadone". The American Journal of Forensic Medicine and Pathology. 36 (4): 268–270. ISSN 0195-7910. doi:10.1097/PAF.0000000000000201.
  63. ↑ Eggleston, William; Clark, Kenneth H.; Marraffa, Jeanna M. (2016). "Loperamide Abuse Associated With Cardiac Dysrhythmia and Death". Annals of Emergency Medicine. ISSN 0196-0644. PMID 27140747. doi:10.1016/j.annemergmed.2016.03.047.
  64. ↑ Mukarram, O.; Hindi, Y.; Catalasan, G.; Ward, J. (2016). "Loperamide Induced Torsades de Pointes: A Case Report and Review of the Literature". Case Reports in Medicine. 2016: 1–3. ISSN 1687-9627. doi:10.1155/2016/4061980.
  65. ↑ Wightman, Rachel Sarah; Hoffman, Robert S; Howland, Mary Ann; Rice, Brian; Biary, Rana; Lugassy, Daniel (2016). "Not your regular high: cardiac dysrhythmias caused by loperamide". Clinical Toxicology. 54 (5): 454–458. ISSN 1556-3650. PMID 27022002. doi:10.3109/15563650.2016.1159310.
  66. ↑ Ben Guarino (4 May 2016). "Abuse of diarrhea medicine you know well is alarming physicians". The Washington Post. Retrieved 8 May 2016.
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