Difenoxin
Encyclopedia
Difenoxin is a 4-phenylpiperidine
derivative that is related to the opioid
analgesic
drug pethidine
(meperidine) and more distantly related to alphaprodine and piritramide
, and it is an active metabolite of the anti-diarrhoea drug diphenoxylate
. Difenoxin et al. have a high peripheral/central actions ratio, working primarily on various opioid receptors in the intestines. Difenoxin was developed in 1970 in Belgium at Janssen Pharmaceutica.
(Imodium) is also closely related to difenoxin in chemical structure but does not cross the blood-brain barrier
as does difenoxin, and the combination drug diphenoxylate hydrochloride with atropine sulphate (Lomotil) is the prototype of this four-member subfamily of the synthetic opioid receptor
agonists and sub-category of opioid anti-diarrhoeals. Pethidine
was serendipitiously discovered in research during the 1930s on gastrointestinal drugs to serve as alternatives to belladonna and opium
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. codeine
, morphine
, dihydrocodeine
, paregoric
, laudanum
and opium
. The parent of the three above-mentioned pethidine-related anti-diarrhoeals is diphenoxylic acid, which can also be manufactured and used pharmaceutically.
drug by itself (Lyspafen) in the USA. It has been approved for use in the late 1990s in the form of Motofen (difenoxin HCl and atropine tablets and elixir) which like Lomotil
is a less-restrictive category Schedule IV
on account of the adulterant; one difference is that the diphenoxylate and atropine formulation is Schedule V
. Atropine is present in each doseage unit in the amount of 25 µg, or 1/40 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 loperamide
and paregoric
.
; thus, diarrhoea and cramping which does not respond to belladonna derivatives and non-centrally-acting soothing and/or stool-desiccating agents are often treated with conservative doses of codeine
, especially where paregoric
and/or laudanum
are not currently in general use.
Difenoxin also has some sedative
and analgesic
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.
Piperidine
Piperidine is an organic compound with the molecular formula 5NH. This heterocyclic amine consists of a six-membered ring containing five methylene units and one nitrogen atom...
derivative that is related to the opioid
Opioid
An opioid is a psychoactive chemical that works by binding to opioid receptors, which are found principally in the central and peripheral nervous system and the gastrointestinal tract...
analgesic
Analgesic
An analgesic is any member of the group of drugs used to relieve pain . The word analgesic derives from Greek an- and algos ....
drug pethidine
Pethidine
Pethidine or meperidine Pethidine (INN) or meperidine (USAN) Pethidine (INN) or meperidine (USAN) (commonly referred to as Demerol but also referred to as: isonipecaine; lidol; pethanol; piridosal; Algil; Alodan; Centralgin; Dispadol; Dolantin; Mialgin (in Indonesia); Petidin Dolargan (in Poland);...
(meperidine) and more distantly related to alphaprodine and piritramide
Piritramide
Piritramide is a synthetic opioid analgesic with a potency 0.65 to 0.75 times that of morphine. A common starting dose is 15 mg IV, equivalent to 10 mg of morphine hydrochloride. Piritramide is commonly used for the treatment of postoperative pain...
, and it is an active metabolite of the anti-diarrhoea drug diphenoxylate
Diphenoxylate
Diphenoxylate is an opioid agonist used for the treatment of diarrhea that acts by slowing intestinal contractions and peristalsis allowing the body to consolidate intestinal contents and prolong transit time, thus allowing the intestines to draw moisture out of them at a normal or higher rate and...
. Difenoxin et al. have a high peripheral/central actions ratio, working primarily on various opioid receptors in the intestines. Difenoxin was developed in 1970 in Belgium at Janssen Pharmaceutica.
Related compounds
LoperamideLoperamide
Loperamide , a synthetic piperidine derivative, is an opioid drug used against diarrhea resulting from gastroenteritis or inflammatory bowel disease. In most countries it is available generically and under brand names such as Lopex, Imodium, Dimor, Fortasec, and Pepto Diarrhea Control...
(Imodium) is also closely related to difenoxin in chemical structure but does not cross the blood-brain barrier
Blood-brain barrier
The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...
as does difenoxin, and the combination drug diphenoxylate hydrochloride with atropine sulphate (Lomotil) is the prototype of this four-member subfamily of the synthetic opioid receptor
Opioid receptor
Opioid receptors are a group of G protein-coupled receptors with opioids as ligands. The endogenous opioids are dynorphins, enkephalins, endorphins, endomorphins and nociceptin. The opioid receptors are ~40% identical to somatostatin receptors...
agonists and sub-category of opioid anti-diarrhoeals. Pethidine
Pethidine
Pethidine or meperidine Pethidine (INN) or meperidine (USAN) Pethidine (INN) or meperidine (USAN) (commonly referred to as Demerol but also referred to as: isonipecaine; lidol; pethanol; piridosal; Algil; Alodan; Centralgin; Dispadol; Dolantin; Mialgin (in Indonesia); Petidin Dolargan (in Poland);...
was serendipitiously discovered in research during the 1930s on gastrointestinal drugs to serve as alternatives to belladonna and opium
Opium
Opium is the dried latex obtained from the opium poppy . Opium contains up to 12% morphine, an alkaloid, which is frequently processed chemically to produce heroin for the illegal drug trade. The latex also includes codeine and non-narcotic alkaloids such as papaverine, thebaine and noscapine...
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. codeine
Codeine
Codeine or 3-methylmorphine is an opiate used for its analgesic, antitussive, and antidiarrheal properties...
, morphine
Morphine
Morphine is a potent opiate analgesic medication and is considered to be the prototypical opioid. It was first isolated in 1804 by Friedrich Sertürner, first distributed by same in 1817, and first commercially sold by Merck in 1827, which at the time was a single small chemists' shop. It was more...
, dihydrocodeine
Dihydrocodeine
Dihydrocodeine, also called DHC, Drocode, Paracodeine and Parzone and known by the brand names of Synalgos DC, Panlor DC, Panlor SS, Contugesic, New Bron Solution-ACE, Huscode, Drocode, Paracodin, Codidol, Didor Continus, Dicogesic, Codhydrine, Dekacodin, DH-Codeine,...
, paregoric
Paregoric
Paregoric, or camphorated tincture of opium, also known as tinctura opii camphorata, is a medication known for its antidiarrheal, antitussive, and analgesic properties.-History:...
, laudanum
Laudanum
Laudanum , also known as Tincture of Opium, is an alcoholic herbal preparation containing approximately 10% powdered opium by weight ....
and opium
Opium
Opium is the dried latex obtained from the opium poppy . Opium contains up to 12% morphine, an alkaloid, which is frequently processed chemically to produce heroin for the illegal drug trade. The latex also includes codeine and non-narcotic alkaloids such as papaverine, thebaine and noscapine...
. The parent of the three above-mentioned pethidine-related anti-diarrhoeals is diphenoxylic acid, which can also be manufactured and used pharmaceutically.
Legal status
Difenoxin is a Schedule IControlled Substances Act
The Controlled Substances Act was enacted into law by the Congress of the United States as Title II of the Comprehensive Drug Abuse Prevention and Control Act of 1970. The CSA is the federal U.S. drug policy under which the manufacture, importation, possession, use and distribution of certain...
drug by itself (Lyspafen) in the USA. It has been approved for use in the late 1990s in the form of Motofen (difenoxin HCl and atropine tablets and elixir) which like Lomotil
Lomotil
The drug combination diphenoxylate/atropine is a popular oral anti-diarrheal in the United States, manufactured by Pfizer. Its UK BAN generic name is co-phenotrope....
is a less-restrictive category Schedule IV
Controlled Substances Act
The Controlled Substances Act was enacted into law by the Congress of the United States as Title II of the Comprehensive Drug Abuse Prevention and Control Act of 1970. The CSA is the federal U.S. drug policy under which the manufacture, importation, possession, use and distribution of certain...
on account of the adulterant; one difference is that the diphenoxylate and atropine formulation is Schedule V
Controlled Substances Act
The Controlled Substances Act was enacted into law by the Congress of the United States as Title II of the Comprehensive Drug Abuse Prevention and Control Act of 1970. The CSA is the federal U.S. drug policy under which the manufacture, importation, possession, use and distribution of certain...
. Atropine is present in each doseage unit in the amount of 25 µg, or 1/40 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 loperamide
Loperamide
Loperamide , a synthetic piperidine derivative, is an opioid drug used against diarrhea resulting from gastroenteritis or inflammatory bowel disease. In most countries it is available generically and under brand names such as Lopex, Imodium, Dimor, Fortasec, and Pepto Diarrhea Control...
and paregoric
Paregoric
Paregoric, or camphorated tincture of opium, also known as tinctura opii camphorata, is a medication known for its antidiarrheal, antitussive, and analgesic properties.-History:...
.
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 loperamideLoperamide
Loperamide , a synthetic piperidine derivative, is an opioid drug used against diarrhea resulting from gastroenteritis or inflammatory bowel disease. In most countries it is available generically and under brand names such as Lopex, Imodium, Dimor, Fortasec, and Pepto Diarrhea Control...
; thus, diarrhoea and cramping which does not respond to belladonna derivatives and non-centrally-acting soothing and/or stool-desiccating agents are often treated with conservative doses of codeine
Codeine
Codeine or 3-methylmorphine is an opiate used for its analgesic, antitussive, and antidiarrheal properties...
, especially where paregoric
Paregoric
Paregoric, or camphorated tincture of opium, also known as tinctura opii camphorata, is a medication known for its antidiarrheal, antitussive, and analgesic properties.-History:...
and/or laudanum
Laudanum
Laudanum , also known as Tincture of Opium, is an alcoholic herbal preparation containing approximately 10% powdered opium by weight ....
are not currently in general use.
Difenoxin also has some sedative
Sedative
A sedative or tranquilizer is a substance that induces sedation by reducing irritability or excitement....
and analgesic
Analgesic
An analgesic is any member of the group of drugs used to relieve pain . The word analgesic derives from Greek an- and algos ....
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.