Editing Loperamide (section)

==Mechanism of action==
[[File:Loperamide 3D ball.png|thumb|Ball-and-stick model of loperamide molecule]]
Loperamide is an opioid-receptor [[agonist]] and acts on the [[Mu Opioid receptor|μ-opioid receptors]] in the [[myenteric plexus]] of the large intestine. It works like [[morphine]], decreasing the activity of the myenteric plexus, which decreases the tone of the longitudinal and circular [[smooth muscle]]s of the intestinal wall.<ref>{{cite web|url=http://www.drugbank.ca/drugs/DB00836|title=DrugBank: Loperamide|access-date=14 May 2016|url-status=live|archive-url=https://web.archive.org/web/20160510135146/http://www.drugbank.ca/drugs/DB00836|archive-date=10 May 2016}}</ref><ref>{{cite web|url=https://www.drugs.com/mmx/loperamide-hydrochloride.html|title=Loperamide Hydrochloride Drug Information, Professional|access-date=14 May 2016|url-status=live|archive-url=https://web.archive.org/web/20160503123442/http://www.drugs.com/mmx/loperamide-hydrochloride.html|archive-date=3 May 2016}}</ref> This increases the time material stays in the intestine, allowing more water to be absorbed from the fecal matter. It also decreases colonic mass movements and suppresses the [[gastrocolic reflex]].<ref>{{ cite book | vauthors = Katzung BG | title = Basic and Clinical Pharmacology | edition = 9th | year = 2004 | publisher = Lange Medical Books/McGraw Hill | isbn = 978-0-07-141092-2 }}{{Page needed|date=September 2010}}</ref>

Loperamide's circulation in the bloodstream is limited in two ways. Efflux by P-glycoprotein in the intestinal wall reduces the passage of loperamide, and the fraction of drug crossing is then further reduced through [[First pass effect|first-pass metabolism]] by the liver.<ref>{{cite book|url=https://books.google.com/books?id=R0W1ErpsQpkC|title=Foye's Principles of Medicinal Chemistry| vauthors = Lemke TL, Williams DA |date=2008|publisher=Lippincott Williams & Wilkins |isbn=9780781768795 |pages = 675 |url-status=live |archive-url= https://web.archive.org/web/20170908145128/https://books.google.com/books?id=R0W1ErpsQpkC |archive-date=8 September 2017 }}</ref><ref>{{cite journal | vauthors = Dufek MB, Knight BM, Bridges AS, Thakker DR | title = P-glycoprotein increases portal bioavailability of loperamide in mouse by reducing first-pass intestinal metabolism | journal = Drug Metabolism and Disposition | volume = 41 | issue = 3 | pages = 642–50 | date = March 2013 | pmid = 23288866 | doi = 10.1124/dmd.112.049965 | df = dmy-all | s2cid = 11014783 }}</ref> Loperamide metabolizes into an [[MPTP]]-like compound, but is unlikely to exert [[neurotoxicity]].<ref>{{cite journal | vauthors = Kalgutkar AS, Nguyen HT | title = 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 | journal = Drug Metabolism and Disposition | volume = 32 | issue = 9 | pages = 943–52 | date = September 2004 | doi = 10.1016/S0090-9556(24)02977-5 | pmid = 15319335 | url = http://dmd.aspetjournals.org/content/32/9/943 | url-status = live | archive-url = https://web.archive.org/web/20170908145128/http://dmd.aspetjournals.org/content/32/9/943 | df = dmy-all | archive-date = 8 September 2017 | url-access = subscription }}</ref>

===Blood–brain barrier===
Efflux by P-glycoprotein also prevents circulating loperamide from effectively crossing the blood-brain barrier,<ref>{{cite journal | vauthors = Upton RN | title = Cerebral uptake of drugs in humans | journal = Clinical and Experimental Pharmacology & Physiology | volume = 34 | issue = 8 | pages = 695–701 | date = August 2007 | pmid = 17600543 | doi = 10.1111/j.1440-1681.2007.04649.x | s2cid = 41591261 }}</ref> so it can generally only agonize mu-opioid receptors in the [[peripheral nervous system]], and currently has a score of one on the anticholinergic cognitive burden scale.<ref>{{cite web |url=http://www.agingbraincare.org/uploads/products/ACB_scale_-_legal_size.pdf |title=Anticholinergic Cognitive Burden Scale |access-date=23 September 2017 |archive-url=https://web.archive.org/web/20180307142553/http://www.agingbraincare.org/uploads/products/ACB_scale_-_legal_size.pdf |archive-date=7 March 2018 |url-status=dead }}</ref> Concurrent administration of P-glycoprotein inhibitors such as [[quinidine]] potentially allows loperamide to cross the blood-brain barrier and produce central morphine-like effects. At high doses (>70mg), loperamide can saturate P-glycoprotein (thus overcoming the efflux) and produce euphoric effects.<ref>{{cite journal | vauthors = Antoniou T, Juurlink DN | title = Loperamide abuse | journal = CMAJ | volume = 189 | issue = 23 | pages = E803 | date = June 2017 | pmid = 28606977 | pmc = 5468105 | doi = 10.1503/cmaj.161421 }}</ref> Loperamide taken with quinidine was found to produce respiratory depression, indicative of central opioid action.<ref>{{cite journal | vauthors = Sadeque AJ, Wandel C, He H, Shah S, Wood AJ | title = Increased drug delivery to the brain by P-glycoprotein inhibition | journal = Clinical Pharmacology and Therapeutics | volume = 68 | issue = 3 | pages = 231–7 | date = September 2000 | pmid = 11014404 | doi = 10.1067/mcp.2000.109156 | s2cid = 38467170 }}</ref>

High doses of loperamide have 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.<ref>{{cite journal | vauthors = Yanagita T, Miyasato K, Sato J | title = Dependence potential of loperamide studied in rhesus monkeys | journal = NIDA Research Monograph | volume = 27 | pages = 106–13 | year = 1979 | pmid = 121326 }}</ref><ref>{{cite journal | vauthors = Nakamura H, Ishii K, Yokoyama Y, Motoyoshi S, Suzuki K, Sekine Y, Hashimoto M, Shimizu M | title = [Physical dependence on loperamide hydrochloride in mice and rats] | language = ja | journal = Yakugaku Zasshi | volume = 102 | issue = 11 | pages = 1074–85 | date = November 1982 | pmid = 6892112 | doi = 10.1248/yakushi1947.102.11_1074 | doi-access = free }}</ref>