Difenoxin

From Wikipedia, the free encyclopedia
Jump to: navigation, search
Difenoxin
Difenoxin.svg
Difenoxin-3D-balls.png
Systematic (IUPAC) name
1-(3-cyano-3,3-diphenylpropyl)-4-phenylpiperidine-4-carboxylic acid
Clinical data
AHFS/Drugs.com International Drug Names
Legal status
Legal status
  • AU: S8 (Controlled)
  • CA: Schedule I
  • DE: Anlage II (Prohibited)
  • US: Schedule I (by itself); Schedule IV (with atropine)
Identifiers
CAS Number 35607-36-4 N
ATC code A07DA04 (WHO)
PubChem CID 34328
IUPHAR/BPS 7592
DrugBank DB01501 YesY
ChemSpider 31620 YesY
UNII 3ZZ5BJ9F2Q YesY
KEGG D03809 YesY
ChEBI CHEBI:4534 YesY
ChEMBL CHEMBL1201321 N
Synonyms Difenoxin, Motofen
Chemical data
Formula C28H28N2O2
Molar mass 424.53 g/mol
 NYesY (what is this?)  (verify)

Difenoxin (Motofen, R-15403) is an opioid drug used, often in combination with atropine, to treat diarrhea.[1] It is the principal metabolite of diphenoxylate.[2][3]:558

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.[1] At high doses there are strong CNS effects and the atropine at such high doses causes typical anticholinergic side effects, such as anxiety, dysphoria, and delirium. Excessive use or overdose causes constipation and can promote development of megacolon.[1] 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.[2]

Difenoxin has a high peripheral/central actions ratio, working primarily on various opioid receptors in the intestines.[4] 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 proprioception, resulting in therapeutic activity roughly equatable to that of loperamide (Imodium). Increased dosages result in more prominent central opioid effects (and anticholingeric effects when the formulation also contains a tropane alkaloid). It therefor offers limited advantages over more potent anti-diarrheal opioid options (ex. morphine) 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 hyoscyamine.

Difenoxin is a Schedule I drug by itself in the US; the combination with atropine is in the less-restrictive category Schedule IV 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.[5]

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 naloxone and paracetamol (the two more commonly used abuse-deterring agents) by increasing the likelyhood of the overdose resulting in harmful and/or fatal sequelae (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 orphenadrine.

It was introduced by Cilag in 1980 in the former West Germany.[6]:485 It was first approved in the US in 1978.[7]

References[edit]

  1. ^ a b c Scarlett Y Medical management of fecal incontinence. Gastroenterology. 2004 Jan;126(1 Suppl 1):S55-63. PMID 14978639
  2. ^ a b Department of Economic and Social Affairs of the United Nations Secretariat Consolidated List of Products Whose Consumption and/or Sale Have Been Banned, Withdrawn, Severely Restricted or not Approved by Governments Twelfth Issue: Pharmaceuticals United Nations – New York, 2005. Page 109
  3. ^ Katzung, Bertram G.; et al. (2012). Basic and Clinical Pharmacology (12th ed.). New York: McGraw-Hill Medical. ISBN 9780071764025. 
  4. ^ 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. J Pharmacol Methods. 1987 Nov;18(3):189-97. PMID 3682841
  5. ^ DEA Lists of Scheduling Actions, Controlled Substances, Regulated Chemicals (Orange Book) May 2016
  6. ^ Sittig, M. Pharmaceutical Manufacturing Encyclopedia, Volumes 1-2 (2nd Edition). William Andrew Publishing/Noyes, 1988. ISBN 9780815511441
  7. ^ FDA Motofen: NDA 017744