cisapride

{{Drugbox

| Verifiedfields = changed

| verifiedrevid = 460039920

| IUPAC_name = (±)-cis-4-amino-5-chloro-N-(1-[3-(4-fluorophenoxy)propyl]-3-methoxypiperidin-4-yl)-2-methoxybenzamide

| image = Cisapride.svg

| image_class = skin-invert-image

| width = 250px

| image2 = Cisapride 3D.png

| tradename = Prepulsid, Propulsid

| Drugs.com = {{drugs.com|pro|propulsid}}

| MedlinePlus = a694006

| pregnancy_AU = B1

| pregnancy_category =

| legal_AU = S4

| legal_BR = C1

| legal_BR_comment = {{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=2023-03-31 |title=RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |url-status=live |archive-url=https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |archive-date=2023-08-03 |access-date=2023-08-16 |publisher=Diário Oficial da União |language=pt-BR |publication-date=2023-04-04}}

| legal_UK = POM

| legal_US_comment = Withdrawn

| legal_status =

| routes_of_administration = By mouth (tablets), suspension

| bioavailability = 30-40%

| protein_bound = 97.5%

| metabolism = liver CYP3A4, intestinal

| elimination_half-life = 10 hours

| excretion = kidney, bile duct

| CAS_number_Ref = {{cascite|correct|??}}

| CAS_number = 81098-60-4

| ATC_prefix = A03

| ATC_suffix = FA02

| ATC_supplemental =

| PubChem = 2769

| IUPHAR_ligand = 240

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| DrugBank = DB00604

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID = 2667

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = UVL329170W

| KEGG_Ref = {{keggcite|correct|kegg}}

| KEGG = D00274

| ChEMBL_Ref = {{ebicite|changed|EBI}}

| ChEMBL = 1729

| C=23 | H=29 | Cl=1 | F=1 | N=3 | O=4

| smiles = Clc1cc(c(OC)cc1N)C(=O)NC3CCN(CCCOc2ccc(F)cc2)CC3OC

| StdInChI_Ref = {{stdinchicite|correct|chemspider}}

| StdInChI = 1S/C23H29ClFN3O4/c1-30-21-13-19(26)18(24)12-17(21)23(29)27-20-8-10-28(14-22(20)31-2)9-3-11-32-16-6-4-15(25)5-7-16/h4-7,12-13,20,22H,3,8-11,14,26H2,1-2H3,(H,27,29)

| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

| StdInChIKey = DCSUBABJRXZOMT-UHFFFAOYSA-N

}}

Cisapride is a gastroprokinetic agent, a drug that increases motility in the upper gastrointestinal tract. It acts directly as a serotonin 5-HT₄ receptor agonist and indirectly as a parasympathomimetic. Stimulation of the serotonin receptors increases acetylcholine release in the enteric nervous system. It has been sold under the trade names Prepulsid (Janssen-Ortho) and Propulsid (in the United States). It was discovered by Janssen Pharmaceuticals in 1980. In many countries, it has been either withdrawn from the market or had its indications limited due to incidence of serious cardiac side-effects.{{Cite web|title=Propulsid To Go Off Market - Warning|url=https://www.medicinenet.com/propulsid_to_go_off_market_-_warning/views.htm|access-date=2021-12-25|website=MedicineNet|language=en}} Propulsid was linked to children's deaths.{{Cite web|date=2000-12-20|title=PROPULSID: A Heartburn Drug, Now Linked to Children's Deaths|url=https://www.latimes.com/nation/la-122001propulsid-story.html|access-date=2021-12-25|website=Los Angeles Times|language=en-US}}

The commercial preparations of this drug are the racemic mixture of both enantiomers of the compound. The (+) enantiomer itself has the major pharmacologic effects and does not induce many of the detrimental side-effects of the mixture.{{US patent reference |number = 5955478 |y= 1999 |m= Sep |d= 21 | inventor = Gray NM, Young JW |title= Methods for treating gastrointestinal motility dysfunction using optically pre (+) cisapride }}

Medical uses

Cisapride has been used for the treatment of gastroesophageal reflux disease (GERD). There is no evidence it is effective for this use in children.{{cite journal | vauthors = Maclennan S, Augood C, Cash-Gibson L, Logan S, Gilbert RE | title = Cisapride treatment for gastro-oesophageal reflux in children | journal = The Cochrane Database of Systematic Reviews | issue = 4 | pages = CD002300 | date = April 2010 | volume = 2010 | pmid = 20393933 | doi = 10.1002/14651858.CD002300.pub2 | pmc = 7138252 | url = https://researchonline.lshtm.ac.uk/3792/1/3792.pdf }} It also increases gastric emptying in people with diabetic gastroparesis. Evidence for its use in constipation is not clear.{{cite journal | vauthors = Aboumarzouk OM, Agarwal T, Antakia R, Shariff U, Nelson RL | title = Cisapride for intestinal constipation | journal = The Cochrane Database of Systematic Reviews | issue = 1 | pages = CD007780 | date = January 2011 | pmid = 21249695 | doi = 10.1002/14651858.CD007780.pub2 }}

In many countries, it has been either withdrawn or had its indications limited because of reports of the side-effect long QT syndrome, which may cause arrhythmias. The U.S. Food and Drug Administration (FDA) issued a warning letter to doctors,{{cite web

|url = https://www.medscape.com/viewarticle/783710

|title = "Cardiac contraindications included in new FDA warnings about Propulsid"

|author =

|date = January 25, 2000

|publisher = medscape.com

|accessdate = 10 May 2021

}} and cisapride was voluntarily removed from the U.S. market on July 14, 2000. Its use in Europe has also been limited. It was banned in India and in the Philippines in 2011.{{cite web|url=http://cdsco.nic.in/html/drugsbanned.html|title=Drugs banned in India|publisher=Central Drugs Standard Control Organization, Dte.GHS, Ministry of Health and Family Welfare, Government of India|access-date=2013-09-17|url-status=dead|archive-url=https://web.archive.org/web/20150221053621/http://cdsco.nic.in/html/drugsbanned.html|archive-date=2015-02-21}}

Veterinary uses

Cisapride is still available in the United States and Canada for use in animals, and is commonly prescribed by veterinarians to treat megacolon in cats.

Cisapride is also commonly used to treat GI stasis in rabbits, sometimes in conjunction with metoclopramide (Reglan).

Kinetics

Oral bioavailability of cisapride is approximately 33%. It is inactivated primarily by hepatic metabolism by CYP3A4 with a half-life of 10 hours. The dose of the drug should be reduced in case of liver diseases.{{cite journal | vauthors = Hedner T, Hedner J, Gelin-Friberg A, Huang ML, Van de Poel S, Woestenborghs R, Van Peer A, Heykants J | title = Comparative bioavailability of a cisapride suppository and tablet formulation in healthy volunteers | journal = European Journal of Clinical Pharmacology | volume = 38 | issue = 6 | pages = 629–31 | date = 1990 | pmid = 2373139 | doi = 10.1007/bf00278595 | s2cid = 33641651 }}

Pharmacology and mechanism of action

As a prokinetic agent that increases gastrointestinal motility, cisapride acts as a selective serotonin agonist in the 5-HT₄ receptor subtype. Cisapride also relieves constipation-like symptoms by indirectly stimulating the release of acetylcholine, which acts on muscarinic receptors.