|Diphenoxylate||Mu opiate receptor agonist|
|Atropine||Muscarinic acetylcholine receptors antagonist|
|Side effects||Nausea, abdominal pain, sleepiness, itchiness, confusion, headache|
|Defined daily dose||Not established|
Diphenoxylate/atropine, also known as co-phenotrope, is a combination of the medications diphenoxylate and atropine, used to treat diarrhea. It may be used for mild travelers' diarrhea but is not recommended for severe disease or if blood is present. It should not be used in those in whom Clostridioides difficile infection is a concern. It is taken by mouth. Benefits begin within an hour and last for up to 4 hours.
Common side effects include nausea, abdominal pain, sleepiness, itchiness, confusion, and headache. It may worsen disease in those with certain infections. There are concerns of abuse and respiratory depression with high doses. It is unclear if use in pregnancy is safe and use when breastfeeding it may result in side effects in the baby. It is an opioid that acts on the intestines to decrease contractions. The atropine is present to decrease the risk of misuse.
Diphenoxylate was first made in 1956. The combination was approved for medical use in the United States in 1960. It is available as a generic medication and over the counter. In the United States the wholesale cost per is dose is US$0.31. In 2017, it was the 353rd most commonly prescribed medication in the United States, with more than 700 thousand prescriptions. It is sold under the brand name Lomotil among others. The medication is in Schedule V in the United States.
It should not be used for people with diarrhea caused by an infection, for example with Clostridium difficile infection, since the slowing of peristalsis can prevent clearing of the infectious organism.
In adults if is started with 4 pills, after which 3 pill may be taken every 6 hours.
Absolute contraindications are:
- Allergy to diphenoxylate or atropine
- Diarrhea associated with pseudomembranous enterocolitis, diarrhea caused by antibiotic treatment, or diarrhea caused by enterotoxin-producing bacteria.
- Presence of jaundice
The drug label 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.
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.
Interactions with other drugs:
- Antidepressants (e.g. Elavil, Prozac)
- Monoamine oxidase inhibitors (e.g. Nardil, Parnate)
- Opioid analgesics
- Sedatives (e.g. Ambien, Sonata)
It may cause serious health problems when overdosed. Effects may include any of the following: convulsions, respiratory depression (slow or stopped breathing), dilated eye pupils, nystagmus (rapid side-to-side eye movements), erythema (flushed skin), gastrointestinal constipation, nausea, vomiting, paralytic ileus, tachycardia (rapid pulse), drowsiness and hallucinations. Symptoms of toxicity may take up to 12 hours to appear.
Mechanism of action
Diphenoxylate is anti-diarrheal and atropine is anticholinergic. A subtherapeutic amount of atropine sulfate is present to discourage deliberate overdosage. Atropine has no anti-diarrheal properties, but will cause tachycardia when overused. The medication diphenoxylate works by slowing down the movement of the intestines. In some cases it has been shown to ease symptoms of opiate withdrawal.
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.
Diphenoxylate is made by combining a precursor of normethadone with norpethidine. Loperamide (Imodium) and bezitramide are analogs.  Like loperamide, it has a methadone-like structure and a piperidine moiety.
Society and culture
As of 2018, the combination drug is marketed in the US and some other countries under the following brands: Atridol, Atrolate, Atrotil, Co-Phenotrope, Dhamotil, Dimotil, Intard, Logen, Lomanate, Lomotil, Lonox, and Reasec.
In the United States, drugs containing diphenoxylate combined with atropine salts are classified as Schedule V controlled substances. (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".
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