Diphenoxylate
1776481
225356258
2008-07-13T07:11:28Z
Nono64
2313206
Drug Enforcement Administration : "DEA" link correction
{{drugbox
| IUPAC_name = ethyl 1-(3-cyano-3,3-diphenyl-propyl)- 4-phenyl-piperidine-4-carboxylate
| image = Diphenoxylat.svg
| CAS_number = 915-30-0
| ATC_prefix = A07
| ATC_suffix = DA01
| ATC_supplemental =
| PubChem = 13505
| smiles = C1=CC=CC(=C1)C(C2=CC=CC=C2)(C#N)CCN3CCC(CC3)(C(=O)OCC)C4=CC=CC=C4
| DrugBank = APRD00366
| C=30 | H=32 | N=2 | O=2
| molecular_weight = 452.587 g/mol
| bioavailability =
| protein_bound = 74-95%
| metabolism =
| elimination_half-life = 12-14 hours
| pregnancy_category =
| legal_US = Schedule II
| legal_status =
| routes_of_administration =
}}
'''Diphenoxylate''' ('''Lomotil®, Co-phenotrope''' and others) is an [[opioid]] agonist used for the treatment of [[diarrhoea]] 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 therefore stop the formation of loose and liquid stools. It is the main active ingredient in the [[anti-propulsive]]/[[anti-peristaltic]] medication [[Lomotil]]®, which also contains [[atropine]] as noted below. Lomotil® is the prototype of a small subfamily of opioids including [[difenoxin]] and [[diphenoxylic acid]] (both are also active metabolites of diphenoxylate produced in the human body) and loperamide, which unlike the other three work exclusively in the intestines because it does not cross the [[blood-brain barrier]] Diphenoxylate was discovered at [[Janssen Pharmaceutica]] in [[1956]]. It is a congener to the [[narcotic]] [[pethidine]] of which the common brand names are [[Dolantin]]® and [[Demerol]]® amongst others. Other somewhat more distant relatives include [[alphaprodine]] (Nisentil®) and [[piritramide]] (Dipidolor®).
===Actions and Use===
Diphenoxylate works by decreasing the speed and amplitude of wave-live movements of the intestines (peristalsis) therefore allowing the body time to remove moisture from the intestinal contents and consolidate waste product into a dense solid form rather than loose and watery as is diarrhoea.
Similar to loperamide and difenoxin preparations, the usual protocol is to take a loading dose (usually two tablets or the quantity of liquid containing 5 mg of diphenoxylate) and then the standard dose of one tablet every 3 to 4 hours ''prn'' over a time period not to exceed 48 hours unless so ordered by the physician. Long-term intermittent ''prn'' users should contact their physician if the need for it arises more than was usual at the outset of therapy as [[tolerance]] to diphenoxylate can occur. Those taking it in large quantities or continuously over an extended period should taper down the dose on a schedule devised by the physician and/or pharmacist.
===Related Drugs===
Diphenoxylate is metabolised in the body to yield [[difenoxin]], another centrally-acting antidiarrhoeal which is 250 to 400 per cent the strength of diphenoxylate via the oral route and is also able to be manufactured and is distributed as [[Motofen]]®, (1 mg difenoxin/25 µg atropine) which was introduced in the United States in the late 1990s after being discovered in 1970 at Janssen.
The Diphenoxylate-Loperamide subfamily of gastrointestinal drugs works directly on opioid receptors, which can be found in the intestine, brain, and spinal cord. Diphenoxylate itself crosses the [[blood-brain barrier]]. This being the case, this medication is potentially habit-forming and can generate significant tolerance if taken continously for a protracted period. Physical dependence is most common particularly at high doses and/or when long-time usage is involved. The CNS penetration of diphenoxylate makes it an agent which can cause [[euphoria]] and other changes which could over time lead to a morbid seek orientation for the drug in the user. Because of this, diphenoxylate is manufactured and marketed as a combination drug with [[atropine]]
([[Lomotil]]®, [[Pfizer]]). Lomotil® was used during the [[Apollo program]], as was pethidine.<ref>[http://lsda.jsc.nasa.gov/books/apollo/S2ch1.htm W. Royce Hawkins, M.D., John F. Zieglschmid, M.D., Clinical aspects of crew health]</ref><ref>[http://history.nasa.gov/SP-4029/Apollo_18-42_Apollo_Medical_Kits.htm Apollo Medical Kits]</ref>
===Inclusion of Atropine===
The atropine additive strategy is designed to discourage use of the drug in a manner inconsistent with its labelling and physician and manufacturer instructions; in theory, the [[anticholinergic]] effect of atropine will produce severe weakness and nausea if standard dosage is exceeded, and at the time diphenoxylate was introduced in the United States a number of manufacturers used this strategy with oral forms of [[morphine]], [[methadone]] (also using [[scopolamine]]), [[oxycodone]] and others. Currently, the only other narcotic produced in the United States to use this strategy is Motofen® ([[difenoxin]] 1 mg with 25 µg atropine sulphate).
The 25 µg of atropine present in each 2½ mg Lomotil® tablet is <sup>1</sup>/<sub>40</sub> of the standard therapeutic dose of atropine via the oral route for normal anticholinergic uses, and some long term ''prn'' users of Lomotil® or related drugs for [[Irritable Bowel Syndrome]] who are particularly sensitive to the atropine content (especially in terms of Lomotil® turning diarrhoea into painful constipation) none the less have been known to place the tablets on a piece of blotter paper, put a drop of distilled water on them and wait for the tablet to begin to break down and then scrape up the solids to be taken to stop diarrhoea. Another strategy which also can help with other elements of IBS is to simply take a lower dose and stretch it out (potentiate it) by taking it along with certain antihistamines such as [[promethazine]], [[cyclizine]], [[hydroxyzine]], [[meclizine]], or [[cyproheptadine]], with promethazine and hydroxyzine being the most common. Taking it on top of plain Kaopectate can also be helpful.
For those sensitive to atropine and other tropane alkaloids, Lomotil® and Motofen® can result in painful constipation and exacerbate the cyclic form of Irritable Bowel Syndrome. It is also possible to reduce the atropine content of Motofen® tablets by placing tablets on a piece of blotter paper, covering with a drop of distilled water and scraping up the solids as the tablet breaks down. It is also possible to use lower doses of Motofen® by combining it with hydroxyzine, promethazine, or related antihistamines. As is the case with almost all other opioids, [[depressants]] like [[carisoprodol]], [[meprobamate]], [[cyclobenzaprine]], and [[glutethimide]] also boost diphenoxylate. All of the above should be carefully monitored by a physician when used.
===Use In Irritable Bowel Syndrome===
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 loperamide; thus, diarrhoea and cramping which does not respond to belladonna derivatives and non-centrally-acting soothing and/or stool-dessicating agents are often treated with conservative doses of codeine, especially where [[paregoric]] and/or [[laudanum]] are not currently in general use.
Diarrhoea accompanied by significant cramping or intestinal cramping alone may benefit from either adding another smooth-muscle agent to the protocol such as [[dicycloverine]], [[papaverine]], or [[orphenadrine]] (which accomplishes several things at once since it is an antihistamine as noted above). Such cases may also benefit from a switch to [[paregoric]], [[laudanum]], powdered or granulated [[opium]], or B&O (i.e. Belladonna & Opium) Suppositories as all of the above include many drugs which work together and have non-narcotic alkaloids like papaverine and other components like oils, waxes, resins &c. which work elsewhere in the body. [[Pantopon]] (Opium Alkaloids Hydrochlorides) and similar preparations have much of the advantages of whole opium in injectable form
===Regulation===
As noted below, diphenoxylate is listed in national controlled-substances and drugs laws such as pure diphenoxylate being in Annex/Schedule/List II of the [[Single Convention on Narcotic Drugs]] of 1961 and also in similarly numbered schedules of laws passed to implement the Convention such as the Canadian Controlled Substances Act and the Betäubungsmittelgesetz in Germany and the Suchtgiftverordnung of Austria. This level of regulation is also implemented in the Misuse of Drugs Act of 1971 (UK), the French opium law of 31. December 1970, and royal decrees and laws passed by practically all other countries in Europe, the Pacific Rim, South Asia and the Middle East
In many cases, Lomotil® type preparations with extra active ingredients are over the counter and/or subject to provincial and/or municipal control or minimal national oversight; the schedule numbers vary by country.
This medication is classified as a [[Schedule V]] under the United States' Comprehensive Drug Abuse Control & Prevention Act of 1970 aka [[Controlled Substances Act]] (CSA) (21 U.S.C. § 801 et. seq.) by the [[Food and Drug Administration]] (FDA) and the [[Drug Enforcement Administration]] (DEA) in the United States when used in preparations. When diphenoxylate is used alone, it is classified as a [[Schedule II]]; having one or more other active ingredients makes it Schedule V. As such, diphenoxylate/atropine tablets are under state and local control and where allowed by state law, can be obtained by signing a log book and the customer can receive up to 48 units (tablets or capsules) in any 48-hour period, much like the 4 fl. oz. limit on [[codeine]], [[dihydrocodeine]], dionine ([[ethylmorphine]]), and [[opium]] cough syrups and [[gastrointestinal drugs]].
The other Schedule V narcotics, all of which may be obtained in some states without prescription as noted in this article, are cough syrups containing low amounts of [[codeine]], [[ethylmorphine]], and [[dihydrocodeine]] and dilute formulations of opium such as Parepectolin®. Very dilute syrups of [[hydrocodone]] containing three or more other active ingredients were also Schedule V and often available without prescription until rescheduling to Schedule III circa or about 1990.
As for the rest of the family, in the United States difenoxin & atropine tablets are Schedule IV and therefore federally controlled and require a prescription, loperamide is unscheduled and not on prescription, and diphenoxylic acid is classified as a form of diphenoxylate. Other Schedule IV narcotics also include [[butorphanol]] nasal spray, [[pentazocine]], [[propoxyphene]]-based mixtures and others of the same type. Unscheduled narcotics and opioid agonists include [[loperamide]] (OTC), [[nalbuphine]] (Rx), [[tramadol]] (Rx), and [[dextromethorphan]] (OTC).
As an example of the degree of regulation at the federal level, the most commonly-known Schedule IV drug of any type is Valium as well as nearly all other [[benzodiazepines]], whereas Schedule III contains [[Vicodin]]® ([[hydrocodone]] bitartrate), and Schedule II contains [[cocaine]], [[secobarbital]], [[methamphetamine]], [[methylphenidate]], all forms of [[morphine]] and derivatves like [[Dilaudid]]® ([[hydromorphone]] hydrochloride), [[oxymorphone]], and [[oxycodone]]. Examples of a legitimate medical drug which are generally illegal (Schedule I) would include the morphine derivatives Vilan® ([[nicomorphine]] HCl), Paramorfan® ([[dihydromorphine]] HCl) and the synthetics Ketodur® ([[ketobemidone]]), Dipidolor® ([[piritramide]]), and Palfium® ([[dextromoramide]]).
A Schedule V purchase involves the customer having to sign a dispensary log after presenting proper identification to the pharmacist; the Schedule V ledger lists transactions going back two years and must have pages that are difficult to remove and usually pre-numbered. This schedule devolves control over the drugs therein to state and local governments, so in states where it cannot be bought over the counter it may or may not require the duplicate, triplicate, or quintuplicate narcotic prescription order form defined by state law.
Narcotic preparations for gastrointestinal problems tend to be the more available of the narcotics; other narcotics for pain like the [[Tylenol With Codeine]] series, (even No. 1 and other combination products with the same quantity and therefore narcotic content number (7½ or 8 mg, i.e. <sup>1</sup>/<sub>8</sub> of a grain of [[codeine]] phosphate per tablet) are more restricted and therefore all Schedule III.
Whilst Lomotil® is [[Schedule V]], in some states it may not be available without prescription as it is classified as requiring a prescription order under the general prescription law for other reasons including the atropine content and the dangers of improper use not unlike [[antibiotics]], [[insulin]], [[corticosteroids]] and the like. This is the same as the regulation of Donnagel PG some states, when it was available, it was a prescription drug because of the belladonna content; the stimulant [[pyrovalerone]] is another Schedule V but prescription-only drug.
==References==
<references/>
* Merlo M, Brown CH, The effect of diphenoxylate hydrochloride on diarrhea, Am J Gastroenterol. 1960 Dec;34:625-30.
* Kasic AM, Treatment of diarrhea in irritable colon, including preliminary observations with a new antidiarrheal agent, diphenoxylate hydrochloride (Lomotil), Am J Gastroenterol. 1961 Jan;35:46-9.
{{opioids}}
{{Antidiarrheals, intestinal anti-inflammatory/anti-infective agents}}
[[Category:Antidiarrhoeals]]
[[Category:Opioids]]
[[Category:Nitriles]]
[[Category:Piperidines]]
[[de:Diphenoxylat]]