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Revision as of 15:06, 15 November 2011 editBeetstra (talk | contribs)Edit filter managers, Administrators172,031 edits Script assisted update of identifiers for the Chem/Drugbox validation project (updated: 'ChEMBL', 'CAS_number').← Previous edit Latest revision as of 03:05, 1 February 2024 edit undoInternetArchiveBot (talk | contribs)Bots, Pending changes reviewers5,384,806 edits Rescuing 1 sources and tagging 0 as dead.) #IABot (v2.0.9.5 
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{{Short description|Chemical compound}}
{{further|]}}
{{Drugbox {{Drugbox
| Verifiedfields = changed
| verifiedrevid = 460785433
| IUPAC_name = 1-(3-cyano-3,3-diphenylpropyl)-4-phenylpiperidine-4-carboxylic acid | IUPAC_name = 1-(3-cyano-3,3-diphenylpropyl)-4-phenylpiperidine-4-carboxylic acid
| image = Difenoxin.svg | image = Difenoxin.svg
| image2 = Difenoxin-3D-balls.png
| width = 180 | width = 180


Line 10: Line 13:
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --> | pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
| pregnancy_US = <!-- A / B / C / D / X --> | pregnancy_US = <!-- A / B / C / D / X -->
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 --> | legal_AU = S8
| legal_BR = A1
⚫ | legal_CA = <!-- Schedule I -->
| legal_BR_comment = <ref>{{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=] |language=pt-BR |publication-date=2023-04-04}}</ref>
⚫ | legal_US = Schedule IV
⚫ | legal_CA = Schedule I
⚫ | legal_US = Schedule I
| legal_US_comment = (by itself); Schedule IV-V (with atropine)
| legal_DE = Prescription only (] for higher doses)
| legal_DE_comment = if combined with atropine sulphate


<!--Identifiers--> <!--Identifiers-->
| index2_label = HCl
| CAS_number = <!-- blanked - oldvalue: 35607-36-4 -->
| CAS_number_Ref = {{cascite|correct|CAS}}
| CAS_number = 28782-42-5
| CAS_number2_Ref = {{cascite|correct|CAS}}
| CAS_number2 = 35607-36-4
| UNII_Ref = {{fdacite|correct|FDA}}
⚫ | UNII = 3ZZ5BJ9F2Q
| UNII2_Ref = {{fdacite|correct|FDA}}
| UNII2 = VQZ63K01IW
| IUPHAR_ligand = 7592
| ATC_prefix = A07 | ATC_prefix = A07
| ATC_suffix = DA04 | ATC_suffix = DA04
| PubChem = 34328 | PubChem = 34328
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB01501 | DrugBank = DB01501
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 31620 | ChemSpiderID = 31620
| UNII_Ref = {{fdacite|correct|FDA}} | KEGG_Ref = {{keggcite|correct|kegg}}
⚫ | UNII = 3ZZ5BJ9F2Q
| KEGG = D03809 | KEGG = D03809
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 4534 | ChEBI = 4534
| ChEMBL_Ref = {{ebicite|changed|EBI}}
| ChEMBL = <!-- blanked - oldvalue: 1201321 -->
| ChEMBL = 1201321

<!--Chemical data-->
| C=28 | H=28 | N=2 | O=2 | C=28 | H=28 | N=2 | O=2
| molecular_weight = 424.53 g/mol
| smiles = C(CCN1CCC(CC1)(C(O)=O)C2=CC=CC=C2)(C3=CC=CC=C3)(C4=CC=CC=C4)C#N | smiles = C(CCN1CCC(CC1)(C(O)=O)C2=CC=CC=C2)(C3=CC=CC=C3)(C4=CC=CC=C4)C#N
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C28H28N2O2/c29-22-28(24-12-6-2-7-13-24,25-14-8-3-9-15-25)18-21-30-19-16-27(17-20-30,26(31)32)23-10-4-1-5-11-23/h1-15H,16-21H2,(H,31,32) | StdInChI = 1S/C28H28N2O2/c29-22-28(24-12-6-2-7-13-24,25-14-8-3-9-15-25)18-21-30-19-16-27(17-20-30,26(31)32)23-10-4-1-5-11-23/h1-15H,16-21H2,(H,31,32)
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = UFIVBRCCIRTJTN-UHFFFAOYSA-N | StdInChIKey = UFIVBRCCIRTJTN-UHFFFAOYSA-N
| synonyms = Difenoxin, Motofen | synonyms = Difenoxin, Motofen
}} }}


'''Difenoxin''' ('''Motofen''', '''R-15403''') is an ] drug used, often in combination with ], to treat diarrhea.<ref name=2004rev>{{cite journal | vauthors = Scarlett Y | title = Medical management of fecal incontinence | journal = Gastroenterology | volume = 126 | issue = 1 Suppl 1 | pages = S55-63 | date = January 2004 | pmid = 14978639 | doi = 10.1053/j.gastro.2003.10.007 | s2cid = 39136903 | url = http://cdr.lib.unc.edu/downloads/2n49tb24t }}</ref> It is the principal metabolite of ].<ref name=WHO>{{cite web |author1=United Nations Department of Economic and Social Affairs |title=Consolidated List of Products Whose Consumption and/or Sale Have Been Banned, Withdrawn, Severely Restricted or not Approved by Governments |url=https://www.un.org/esa/coordination/CL12.pdf |publisher=United Nations |access-date=5 November 2020 |location=New York |date=2005 |page=109}}</ref><ref name=Katzung>{{cite book | vauthors = Katzung BG, Masters SB, Trevor AJ |title=Basic and Clinical Pharmacology |publisher=McGraw-Hill Medical |location=New York |year=2012 |edition=12th|isbn=9780071764025 }}</ref>{{rp|558}}
'''Difenoxin''' ('''Motofen''', '''R-15403''') is a 4-]] derivative that is related to the ] ] drug ] (meperidine) and more distantly related to ] and ], and it is an active metabolite of the anti-] drug ]. Difenoxin et al. have a high peripheral/central actions ratio, working primarily on various ] in the intestines.<ref>Jackson LS, Stafford JE. The evaluation and application of a radioimmunoassay for the measurement of diphenoxylic acid, the major metabolite of diphenoxylate hydrochloride (Lomotil), in human plasma. ''Journal of Pharmacological Methods''. 1987 Nov;18(3):189-97.</ref> Difenoxin was developed in 1970 in Belgium at Janssen Pharmaceutica.


It was first approved in the US in 1978<ref>{{cite web |title=Drugs@FDA: FDA-Approved Drugs |url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=017744 |website=www.accessdata.fda.gov |access-date=5 November 2020}}</ref> and in 1980 in the former West Germany.<ref>{{cite book | vauthors = Sittig M | title = Pharmaceutical Manufacturing Encyclopedia | volume = 1-2 | edition = 2nd | publisher = William Andrew Publishing/Noyes | date = 1988 | isbn = 9780815511441 }}</ref>{{rp|485}}
==Related compounds==
] ('''Imodium''') is also closely related to difenoxin in chemical structure but does not cross the ] as does difenoxin, and the combination drug diphenoxylate hydrochloride with atropine sulphate (Lomotil) is the prototype of this four-member subfamily of the synthetic ] ] and sub-category of opioid anti-diarrhoeals. ] was serendipitiously discovered in research during the 1930s on gastrointestinal drugs to serve as alternatives to ] and ] derivatives, but the anti-diarrhoeal effects of pethidine are less than those of this subclass and equivalent contstipating doses of pethidine have prominent central actions. Therefore, with difenoxin and related drugs, the ratio of GI effects to central narcotic effects is particularly high, which makes it an attractive alternative in the minds of many to the other opioids used for diarrhoea, viz. ], ], ], ], ] and ] . The parent of the three above-mentioned pethidine-related anti-diarrhoeals is ], which can also be manufactured and used pharmaceutically.


Difenoxin crosses the blood brain barrier and induces some euphoria; it is often sold with or administered with atropine to reduce the potential for abuse and overdose.<ref name=2004rev/>
⚫ ==Legal status==
Difenoxin is a ] drug by itself (Lyspafen) in the ].<ref>http://www.deadiversion.usdoj.gov/schedules/orangebook/orangebook.pdf</ref> It has been approved for use in the late 1990s in the form of Motofen (difenoxin HCl and atropine tablets and elixir) which like ] is a less-restrictive category ] on account of the adulterant; one difference is that the diphenoxylate and atropine formulation is ]. Atropine is present in each doseage unit in the amount of 25&nbsp;µg, or <sup>1</sup>/<sub>40</sub> of the therapeutic dose. Many other countries have been using this combination product for many years as a second-line centrally-acting and/or opioid-agonist anti-diarrhoeal, betwixt ] and ].<ref>Innocenti P, Rossi L, Bombardieri G. Clinical effectiveness of difenoxine in patients with acute and chronic diarrhea. (Italian). ''Bollettino Chimico Farmaceutico''. 1983 Dec;122(12):64S-68S.</ref>


== Available forms ==
⚫ ==Side effects==
Diarrhoea resulting from cyclic or diarrhoea-predominant IBS may not be optimally treated with diphenoxylate or difenoxin, and may not respond to a meaningful degree to ]; thus, diarrhoea and cramping which does not respond to ] derivatives and non-centrally-acting soothing and/or stool-desiccating agents are often treated with conservative doses of ], especially where ] and/or ] are not currently in general use.


The abuse-deterring effects of atropine when used as an adulterant are reasonably effective in reducing the combination's potential for recreational use. It combines the mechanisms of ] and ] (the two more commonly used abuse-deterring agents) by increasing the likelihood of the overdose resulting in harmful and/or fatal ] (as does paracetamol), in addition to reliably producing unpleasant side-effects which "spoil" the opioid euphoria and discourage abusers from overdosing again following their initial experience (as does naloxone). This does not deter the use of single doses of difenoxin to potentiate another opiate, the anticholingeric activity of a single tablet is actually likely to increase the pleasurable effects of opioid use in a manner similar to combining one or more opioids with ].
Difenoxin also has some ] and ] effects as with other opioids, but diphenoxylate itself is a relatively weak analgesic, and difenoxin has similarly limited analgesic effects, although it is a potent anti-diarrheal drug. Research suggests that additional non-opioid mechanisms may also be involved in the action of difenoxin, explaining its strong anti-diarrheal effects despite only limited opioid action.<ref>De Luca A, Coupar IM. Difenoxin and loperamide: studies on possible mechanisms of intestinal antisecretory action. ''Naunyn Schmiedebergs Archives of Pharmacology''. 1993 Feb;347(2):231-7.</ref>

⚫ == Side effects ==

At high doses there are strong CNS effects and the atropine at such high doses causes typical ], such as ], ], and ]. Excessive use or overdose causes constipation and can promote development of ] as well as classic symptoms of overdose including potentially lethal respiratory depression.<ref name=2004rev/> In the 1990s its use in children was restricted in many countries due to the CNS side effects, which included anorexia, nausea and vomiting, headache, drowsiness, confusion, insomnia, dizziness, restlessness, euphoria and depression.<ref name=WHO/>

== Mechanism of action ==

Difenoxin has a high peripheral/central actions ratio, working primarily on various ] in the intestines.<ref>{{cite journal | vauthors = Jackson LS, Stafford JE | title = The evaluation and application of a radioimmunoassay for the measurement of diphenoxylic acid, the major metabolite of diphenoxylate hydrochloride (Lomotil), in human plasma | journal = Journal of Pharmacological Methods | volume = 18 | issue = 3 | pages = 189–97 | date = November 1987 | pmid = 3682841 | doi = 10.1016/0160-5402(87)90069-6 }}</ref> Although it is capable of producing significant central effects at high doses, doses within the normal therapeutic range generally do not notably impair cognition or ], resulting in therapeutic activity roughly equatable to that of ]. Increased dosages result in more prominent central opioid effects (and anticholingeric effects when the formulation also contains a ]). It therefore offers limited advantages over more potent anti-diarrheal opioid options (ex. ]) when treating intractable cases of diarrhea which fail to respond to normal or moderately increased difenoxin doses, and may in fact be harmful in such circumstances if the formulation used also contains atropine or ].

⚫ == Legal status ==

Difenoxin is a ] drug by itself in the US; the combination with atropine is in the less-restrictive category ] on account of the adulterant (the practice of making opioids more easily available by including an abuse-deterring adulterating agent is standard practice in the United States). Pure difenoxin, in Schedule I, has a quota of 50 grammes, and an ACSCN of 9168. The combination of difenoxin and atropine, in Schedule IV, has the DEA ACSCN of 9167 and being in Schedule IV is not assigned an aggregate annual manufacturing quota.<ref>{{cite web | work = DEA | url = http://www.deadiversion.usdoj.gov/schedules/orangebook/orangebook.pdf | title = Lists of Scheduling Actions, Controlled Substances, Regulated Chemicals (Orange Book) | date = May 2016 | access-date = 2011-01-24 | archive-date = 2016-04-17 | archive-url = https://web.archive.org/web/20160417085648/http://www.deadiversion.usdoj.gov/schedules/orangebook/orangebook.pdf | url-status = dead }}</ref>


== References == == References ==
{{reflist}} {{Reflist|30em}}


{{Antidiarrheals, intestinal anti-inflammatory/anti-infective agents}} {{Antidiarrheals, intestinal anti-inflammatory/anti-infective agents}}
{{Opioidergics}}


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