Diphenoxylate

Last updated

Diphenoxylate
Diphenoxylat.svg
Diphenoxylate molecule ball.png
Clinical data
Other namesR-1132, NIH-756
AHFS/Drugs.com Monograph
Routes of
administration
Oral
Drug class Opioid
Antidiarrheal
ATC code
Legal status
Legal status
  • AU:S3 (OTC, packs of up to 8x tablets combined with Atropine) & S4 (Rx Only, as S3 but larger pack sizes) & S8 (Controlled, all other preparations)
  • BR: Class A1 (Narcotic drugs) [1]
  • CA: Schedule I
  • DE:Prescription only (Anlage II for higher doses)if combined with atropine sulphate
  • UK: Class A
  • US: Schedule II (alone) and V (with atropine)
Pharmacokinetic data
Protein binding 74–95%
Elimination half-life 12–14 hours
Identifiers
  • ethyl 1-(3-cyano-3,3-diphenylpropyl)-4-phenylpiperidine-4-carboxylate
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.011.837 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C30H32N2O2
Molar mass 452.598 g·mol−1
3D model (JSmol)
  • N#CC(c1ccccc1)(c2ccccc2)CCN4CCC(c3ccccc3)(C(=O)OCC)CC4
  • InChI=1S/C30H32N2O2/c1-2-34-28(33)29(25-12-6-3-7-13-25)18-21-32(22-19-29)23-20-30(24-31,26-14-8-4-9-15-26)27-16-10-5-11-17-27/h3-17H,2,18-23H2,1H3 Yes check.svgY
  • Key:HYPPXZBJBPSRLK-UHFFFAOYSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Diphenoxylate is a centrally active opioid drug of the phenylpiperidine series that is used as a combination drug with atropine for the treatment of diarrhea. Diphenoxylate is an opioid and acts by slowing intestinal contractions; the atropine is present to prevent drug abuse and overdose. It should not be given to children due to the risk that they will stop breathing and should not be used in people with Clostridioides difficile infection.

Contents

Medical use

Diphenoxylate is used to treat diarrhea in adults; it is only available as a combination drug with a subtherapeutic dose of atropine to prevent abuse. [2]

It should not be used in children due to the risk of respiratory depression. [2] It does not appear harmful to a fetus but the risks have not been fully explored. [2]

It should not be taken with other central depressants like alcohol, as they can increase its risks. [2]

It should not be used for people with diarrhea caused by an infection, for example with Clostridioides difficile infection, since the slowing of peristalsis can prevent clearing of the infectious organism. [2]

Adverse effects

The drug label (in some jurisdictions) has warnings with regard to the risk of respiratory depression, anticholinergic toxicity and opioid overdose, the risk of dehydration and electrolyte imbalance that people with severe diarrhea always run, and toxic megacolon in people with ulcerative colitis. [2]

Other adverse effects include numbness in the hands and feet, euphoria, depression, lethargy, confusion, drowsiness, dizziness, restlessness, headache, hallucinations, edema, hives, swollen gums, itchiness, vomiting, nausea, loss of appetite, and stomach pain. [2]

Pharmacology

Diphenoxylate is rapidly metabolized to difenoxin; it is eliminated mostly in feces but also in urine. [2]

Like other opioids, diphenoxylate acts by slowing intestinal contractions, 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; the atropine is an anticholinergic and is present to prevent drug abuse and overdose. [3]

History and chemistry

Diphenoxylate was first synthesized by Paul Janssen at Janssen Pharmaceutica in 1956 as part of a medicinal chemistry investigation of opioids. [4]

Diphenoxylate is made by combining a precursor of normethadone with norpethidine. Loperamide (Imodium) and bezitramide are analogs. [5] Like loperamide, it has a methadone-like structure and a piperidine moiety. [6]

Society and culture

Pricing

In 2017 Hikma Pharmaceuticals raised the price of its liquid formulation of generic diphenoxylate-atropine in the US by 430%, from $16 to $84.00. [7]

Regulation

In the United States, drugs containing diphenoxylate combined with atropine salts are classified as Schedule V controlled substances. [8] [2] (Diphenoxlate by itself is a Schedule II controlled substance.)

It is on Schedule III of the Single Convention on Narcotic Drugs, only in forms that contain, according to the Yellow List: "not more than 2.5 milligrams of diphenoxylate calculated as base and a quantity of atropine sulfate equivalent to at least 1 per cent of the dose of diphenoxylate". [9]

Research

Diphenoxylate and atropine have been studied in small trials as a treatment for fecal incontinence; it appears to be less efficacious and have more adverse effects when compared with loperamide or codeine. [10]

Related Research Articles

An anti-diarrheal drug is any medication which provides symptomatic relief for diarrhea.

<span class="mw-page-title-main">Atropine</span> Anticholinergic medication used as antidote for nerve agent poisoning

Atropine is a tropane alkaloid and anticholinergic medication used to treat certain types of nerve agent and pesticide poisonings as well as some types of slow heart rate, and to decrease saliva production during surgery. It is typically given intravenously or by injection into a muscle. Eye drops are also available which are used to treat uveitis and early amblyopia. The intravenous solution usually begins working within a minute and lasts half an hour to an hour. Large doses may be required to treat some poisonings.

<span class="mw-page-title-main">Hyoscyamine</span> Tropane alkaloid

Hyoscyamine is a naturally occurring tropane alkaloid and plant toxin. It is a secondary metabolite found in certain plants of the family Solanaceae, including henbane, mandrake, angel's trumpets, jimsonweed, the sorcerers' tree, and Atropa belladonna. It is the levorotary isomer of atropine and thus sometimes known as levo-atropine.

<span class="mw-page-title-main">Loperamide</span> Medicine used to reduce diarrhea

Loperamide, sold under the brand name Imodium, among others, is a medication of the opioid receptor agonist class used to decrease the frequency of diarrhea. It is often used for this purpose in irritable bowel syndrome, inflammatory bowel disease, short bowel syndrome Crohn's disease and ulcerative colitis. It is not recommended for those with blood in the stool, mucus in the stool, or fevers. The medication is taken by mouth.

<i>Clostridioides difficile</i> infection Disease caused by C. difficile bacteria

Clostridioides difficile infection, also known as Clostridium difficile infection, is a symptomatic infection due to the spore-forming bacterium Clostridioides difficile. Symptoms include watery diarrhea, fever, nausea, and abdominal pain. It makes up about 20% of cases of antibiotic-associated diarrhea. Antibiotics can contribute to detrimental changes in gut microbiota; specifically, they decrease short-chain fatty acid absorption which results in osmotic, or watery, diarrhea. Complications may include pseudomembranous colitis, toxic megacolon, perforation of the colon, and sepsis.

<span class="mw-page-title-main">Opioid</span> Psychoactive chemical

Opioids are a class of drugs that derive from, or mimic, natural substances found in the opium poppy plant. Opioids work in the brain to produce a variety of effects, including pain relief. As a class of substances, they act on opioid receptors to produce morphine-like effects.

Anticholinergics are substances that block the action of the acetylcholine (ACh) neurotransmitter at synapses in the central and peripheral nervous system.

<span class="mw-page-title-main">Pethidine</span> Opioid analgesic

Pethidine, also known as meperidine and sold under the brand name Demerol among others, is a fully synthetic opioid pain medication of the phenylpiperidine class. Synthesized in 1938 as a potential anticholinergic agent by the German chemist Otto Eisleb, its analgesic properties were first recognized by Otto Schaumann while working for IG Farben, in Germany. Pethidine is the prototype of a large family of analgesics including the pethidine 4-phenylpiperidines, the prodines, bemidones, and others more distant, including diphenoxylate and analogues.

<span class="mw-page-title-main">Tacrine</span> Chemical compound

Tacrine is a centrally acting acetylcholinesterase inhibitor and indirect cholinergic agonist (parasympathomimetic). It was the first centrally acting cholinesterase inhibitor approved for the treatment of Alzheimer's disease, and was marketed under the trade name Cognex. Tacrine was first synthesised by Adrien Albert at the University of Sydney in 1949. It also acts as a histamine N-methyltransferase inhibitor.

<span class="mw-page-title-main">Oxymorphone</span> Opioid analgesic drug

Oxymorphone is a highly potent opioid analgesic indicated for treatment of severe pain. Pain relief after injection begins after about 5–10 minutes, after oral administration it begins after about 30 minutes, and lasts about 3–4 hours for immediate-release tablets and 12 hours for extended-release tablets. The elimination half-life of oxymorphone is much faster intravenously, and as such, the drug is most commonly used orally. Like oxycodone, which metabolizes to oxymorphone, oxymorphone has a high potential to be abused.

<span class="mw-page-title-main">Toxidrome</span> Syndrome caused by a dangerous level of toxins

A toxidrome is a syndrome caused by a dangerous level of toxins in the body. It is often the consequence of a drug overdose. Common symptoms include dizziness, disorientation, nausea, vomiting and oscillopsia. It may indicate a medical emergency requiring treatment at a poison control center. Aside from poisoning, a systemic infection may also lead to one. Classic toxidromes are presented below, which are variable or obscured by co-ingestion of multiple drugs.

<span class="mw-page-title-main">Travelers' diarrhea</span> Stomach and intestinal infection

Travelers' diarrhea (TD) is a stomach and intestinal infection. TD is defined as the passage of unformed stool while traveling. It may be accompanied by abdominal cramps, nausea, fever, headache and bloating. Occasionally bloody diarrhea may occur. Most travelers recover within three to four days with little or no treatment. About 12% of people may have symptoms for a week.

Diphenoxylate/atropine, also known as co-phenotrope, is a combination of the medications diphenoxylate and atropine, used to treat diarrhea. It should not be used in those in whom Clostridioides difficile infection is a concern. It is taken by mouth. Onset is typically within an hour.

<span class="mw-page-title-main">Colestyramine</span> Pharmaceutical drug

Colestyramine (INN) or cholestyramine (USAN) is a bile acid sequestrant, which binds bile in the gastrointestinal tract to prevent its reabsorption. It is a strong ion exchange resin, which means it can exchange its chloride anions with anionic bile acids in the gastrointestinal tract and bind them strongly in the resin matrix. The functional group of the anion exchange resin is a quaternary ammonium group attached to an inert styrene-divinylbenzene copolymer.

<span class="mw-page-title-main">Difenoxin</span> Chemical compound

Difenoxin is an opioid drug used, often in combination with atropine, to treat diarrhea. It is the principal metabolite of diphenoxylate.

<span class="mw-page-title-main">Opioid overdose</span> Toxicity due to excessive consumption of opioids

An opioid overdose is toxicity due to excessive consumption of opioids, such as morphine, codeine, heroin, fentanyl, tramadol, and methadone. This preventable pathology can be fatal if it leads to respiratory depression, a lethal condition that can cause hypoxia from slow and shallow breathing. Other symptoms include small pupils and unconsciousness; however, its onset can depend on the method of ingestion, the dosage and individual risk factors. Although there were over 110,000 deaths in 2017 due to opioids, individuals who survived also faced adverse complications, including permanent brain damage.

<span class="mw-page-title-main">Fidaxomicin</span> Antibiotic

Fidaxomicin, sold under the brand name Dificid among others, is the first member of a class of narrow spectrum macrocyclic antibiotic drugs called tiacumicins. It is a fermentation product obtained from the actinomycete Dactylosporangium aurantiacum subspecies hamdenesis. Fidaxomicin is minimally absorbed into the bloodstream when taken orally, is bactericidal, and selectively eradicates pathogenic Clostridioides difficile with relatively little disruption to the multiple species of bacteria that make up the normal, healthy intestinal microbiota. The maintenance of normal physiological conditions in the colon may reduce the probability of recurrence of Clostridioides difficile infection.

Antimotility agents are drugs used to alleviate the symptoms of diarrhea. These include loperamide (Imodium), bismuth subsalicylate (Pepto-Bismol), diphenoxylate with atropine (Lomotil), and opiates such as paregoric, tincture of opium, codeine, and morphine. In diarrhea caused by invasive pathogens such as Salmonella, Shigella, and Campylobacter, the use of such agents has generally been strongly discouraged, though evidence is lacking that they are harmful when administered in combination with antibiotics in Clostridioides difficile cases. Use of antimotility agents in children and the elderly has also been discouraged in treatment of EHEC due to an increased rate of hemolytic uremic syndrome.

Bezlotoxumab, sold under the brand name Zinplava, is a human monoclonal antibody designed for the prevention of recurrence of Clostridioides difficile infections. Bezlotoxumab binds to Clostridioides difficile toxin B.

<i>Clostridioides difficile</i> Species of bacteria

Clostridioides difficile is a bacterium known for causing serious diarrheal infections, and may also cause colon cancer. It is known also as C. difficile, or C. diff, and is a Gram-positive species of spore-forming bacteria. Clostridioides spp. are anaerobic, motile bacteria, ubiquitous in nature and especially prevalent in soil. Its vegetative cells are rod-shaped, pleomorphic, and occur in pairs or short chains. Under the microscope, they appear as long, irregular cells with a bulge at their terminal ends. Under Gram staining, C. difficile cells are Gram-positive and show optimum growth on blood agar at human body temperatures in the absence of oxygen. C. difficile is catalase- and superoxide dismutase-negative, and produces up to three types of toxins: enterotoxin A, cytotoxin B and Clostridioides difficile transferase. Under stress conditions, the bacteria produce spores that are able to tolerate extreme conditions that the active bacteria cannot tolerate.

References

  1. Anvisa (31 March 2023). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 4 April 2023). Archived from the original on 3 August 2023. Retrieved 16 August 2023.
  2. 1 2 3 4 5 6 7 8 9 "US label: Diphenoxylate hydrochloride and atropine sulfate tablets" (PDF). FDA. 12 February 2018. For label updates see FDA index page for NDA 012462
  3. Stern J, Ippoliti C (November 2003). "Management of acute cancer treatment-induced diarrhea". Seminars in Oncology Nursing. 19 (4 Suppl 3): 11–6. doi:10.1053/j.soncn.2003.09.009. PMID   14702928.
  4. Florey K (1991). Profiles of Drug Substances, Excipients and Related Methodology, Volume 19. Academic Press. p. 342. ISBN   9780080861142.
  5. Casy AF, Parfitt RT (2013). Opioid Analgesics: Chemistry and Receptors. Springer Science & Business Media. p. 312. ISBN   9781489905857.
  6. Patrick GL (2013). An Introduction to Medicinal Chemistry. OUP Oxford. p. 644. ISBN   9780199697397.
  7. Crow D (20 August 2017). "Hikma hikes price of US medicines by up to 430%" . Financial Times. Archived from the original on 11 December 2022. Retrieved 10 May 2018.
  8. "Diphenoxylate". MedlinePlus. 15 April 2018. Retrieved 10 May 2018.
  9. "Yellow List: List of Narcotic Drugs Under International Control, 50th Edition" (PDF). International Narcotics Control Board. 2011. p. 8. Retrieved 10 May 2018.
  10. Omar MI, Alexander CE (June 2013). "Drug treatment for faecal incontinence in adults". The Cochrane Database of Systematic Reviews. 2013 (6): CD002116. doi:10.1002/14651858.CD002116.pub2. PMC   7098421 . PMID   23757096. Open Access logo PLoS transparent.svg