Continuing Education Activity

Diphenoxylate/atropine combination is a medication used in the management and treatment of diarrhea. It is in the antimotility class of drugs. This activity describes the indications, action, and contraindications for Diphenoxylate/Atropine as a valuable agent in treating acute and chronic diarrhea. This activity will highlight the mechanism of action, adverse event profile, and other vital factors, including dosing, monitoring, relevant interactions pertinent for members of the healthcare team in managing patients with diarrhea and related conditions.

Objectives:

• Identify the mechanism of action of diphenoxylate/atropine.
• Describe the adverse effects of diphenoxylate/atropine.
• Review the appropriate monitoring of diphenoxylate/atropine.
• Summarize interprofessional team strategies for improving care coordination and communication to advance diphenoxylate/atropine and improve outcomes.

Indications

Diphenoxylate is an active ingredient of commonly available antimotility agents. Its indication is for the treatment of diarrhea in adults and children 13 years or older or as add-on therapy in managing acute non-infectious diarrhea. These conditions include diarrhea-predominant-irritable bowel syndrome, ulcerative colitis, and Crohn disease, which have not responded to other medications.[1] It is mainly used in a short-term course only but is a possible therapeutic consideration for chronic diarrhea. Long-term use requires the close supervision of a physician as its prolonged use may lead to dependence.[2]

Mechanism of Action

Diphenoxylate is an opioid agonist that acts on the presynaptic opioid receptors (predominantly mu receptors) in the enteric nervous system. The enteric nervous system is comprised of two components: the myenteric plexus and submucosal plexus. The myenteric plexus lies between the circular and longitudinal smooth muscles of the bowel wall and controls segmental contractions, i.e., peristaltic movements of the gut. The submucosal plexus controls the secretions of fluid and electrolytes in the lumen of the intestine. By acting on the presynaptic opioid receptors, it blocks the release of acetylcholine in the synaptic cleft and hence inhibits the motility and secretory action of the enteric nervous system. This action leads to a decrease in segmental contractions and prolongation of gastrointestinal transit time. Diphenoxylate reduces the epithelial secretion of fluid and electrolytes and enhances active absorption by mild action on delta receptors.

It does not have analgesic effects of morphine at standard doses, but it can lead to CNS effects, like euphoria, at higher doses. The drug can have misuse potential if used for a prolonged time and classified as a Schedule II drug under the Food and Drug Administration when used alone. Atropine is added in a fixed dose of 0.025 mg; it is a competitive inhibitor of acetylcholine receptors to prevent patients from misusing diphenoxylate. Atropine produces anticholinergic side effects like nausea/bloating/tachycardia/dryness of mouth/eyes when ingested at higher doses. These adverse effects are unpleasant for the patient and discourage overdosing. The combination medication is Schedule V.

Administration

Diphenoxylate hydrochloride/atropine sulfate combination is available as the fixed-dose composition of 2.5 mg/0.025 mg. Diphenoxylate/atropine is available in both tablet and liquid preparation. Only the liquid preparation can be administered to children, and not the tablets. A maximum of eight tablets, i.e., 20 mg of diphenoxylate, can be administered in 24 hours. The dose is the same for children between 13 to 17 years. There is not enough evidence available specifying the safety of diphenoxylate/atropine in children <13 yrs. However, the drug is contraindicated in children < 6yrs due to severe complications. Using medicine in quantities of more than 20 mg is associated with symptoms related to toxicity.

 The initial dose of 20 mg can be administered for the initial control of symptoms and then reduced to a lower maintenance dose as per individual requirements. Clinical improvement after administration usually occurs within 48 hours. If there is no improvement seen within ten days of maximum dosing, further drug administration is unlikely to make a difference.

The preparation of diphenoxylate hydrochloride is insoluble in commonly available aqueous media. This property precludes the self-administration of the drug. A dose of 100 to 300 mg/day, or the equivalent of 40 to 120 tablets, administered over 50 to 70 days, can produce opioid withdrawal symptoms if the patient stops the drug abruptly.

Adverse Effects

Children: Diphenoxylate/atropine can cause respiratory and CNS depression in children <6 years.

Toxicity: At higher doses, it can present with anticholinergic side effects like hyperthermia, tachycardia, urinary retention, flushing, dryness of the skin and mucous membranes, confusion, headache, or opioid side effects like respiratory depression.

Electrolyte imbalance: The drug can worsen dehydration and electrolyte imbalance in patients with pre-existing electrolyte imbalance. Therefore the electrolyte imbalance needs correction before administration of the drug.

Gastrointestinal complications:  Diphenoxylate/atropine can precipitate GI complications, including sepsis and prolonged diarrhea, when administered in patients with infectious diarrhea.[3] This effect is because of the prolongation of GI transit time and decreased GI motility, which leads to bacterial overgrowth and release of enterotoxins into the bloodstream, creating a septic shock-like picture.

Toxic Megacolon: This drug can precipitate toxic megacolon in patients with acute ulcerative colitis. Due to decreased motility, the physiological secretions might get accumulated in the bowel leading to distension. The colon is already fragile in ulcerative colitis and is prone to rupture.[4]

Drug Interactions: Diphenoxylate crosses the blood-brain barrier and causes central side effects like depression,  sedation/drowsiness, numbness of extremities, euphoria, malaise/lethargy, confusion,  dizziness, restlessness, headache, hallucination. Therefore its use requires caution in patients already taking drugs with CNS activity such as barbiturates, benzodiazepines, antipsychotics, antihistamines, or MAO inhibitors.

Allergic reactions: Patients can develop allergic reactions like anaphylaxis, urticaria, angioneurotic edema,  swelling of the gums, pruritus. Clinicians should not administer the drug to patients with previous episodes of an allergic reaction.

Rare: As its main action is on the enteric nervous system, higher doses can cause paralytic ileus, pancreatitis.[5]

The adverse effects listed above have been organized based on severity and not on frequency.

Contraindications

Contraindications

1. Patients who have known hypersensitivity to diphenoxylate or atropine.
2. Patients with obstructive jaundice. Due to mu receptor agonism, diphenoxylate leads to constriction of the sphincter of Oddi, which leads to the worsening of symptoms of obstructive disease.
3. Children <6 yrs should not be administered diphenoxylate/atropine tablets owing to the high risk of severe CNS/respiratory depression.[6][7]
4. Diarrhea associated with pseudomembranous colitis (Clostridium difficile) or enterotoxin-producing bacteria due to the risk of gastrointestinal complications like sepsis and prolonged/worsened diarrhea.[8]

Cautions

1. Patients with electrolyte imbalance as the drug decrease GI motility, potentially leading to fluid retention and aggravating electrolyte imbalance & dehydration.
2. Patients with advanced hepatorenal disease, which can precipitate hepatic coma.
3. Other CNS depressants - Diphenoxylate/atropine can potentiate CNS depression when used with other drugs like barbiturates/benzodiazepines/tranquilizers/anxiolytics/antipsychotics/general anesthetics/alcohol.
4. Patients with infectious diarrhea - Diphenoxylate/atropine can lead to gastrointestinal complications like sepsis/ prolonged or worsening diarrhea by decreasing GI motility and enhancing bacterial overgrowth and release of enterotoxins. These organisms include toxigenic E.coli/Salmonella/Shigella/Clostridium difficile induced pseudomembranous colitis.[9]
5. Patients with acute ulcerative colitis are at risk of developing toxic megacolon. Therefore the drug has to be withdrawn if any signs of abdominal distension appear. 
6. In theory, the administration of diphenoxylate/atropine in patients taking monoamine oxidase inhibitors can precipitate hypertensive crisis. This effect occurs as the chemical structure of diphenoxylate hydrochloride is similar to meperidine hydrochloride.

Monitoring

Diphenoxylate is a Schedule V controlled substance classified by the Food and Drug Administration and has minimal abuse potential.[10][11] Monitoring is essential in patients who require a long-term course of the medication. Diphenoxylate's chemical structure is similar to meperidine, which is a potent opioid analgesic. This property is linked to dependence with prolonged use of diphenoxylate/atropine and requires clinician supervision. 

Close monitoring is essential in patients with diarrhea associated with ulcerative colitis as this medication increases the risk of toxic megacolon. Any symptom suggestive of toxic megacolon like abdominal distension/decreased bowel sounds should prompt withdrawal of the drug. This drug is withheld in patients with diarrhea associated with electrolyte imbalance until it's corrected as it can precipitate dehydration. The initial and maximum dosage administered in 24 hours is 20 mg, i.e., eight tablets.[12] Clinicians should monitor for symptoms of overdose in patients receiving higher doses of diphenoxylate/atropine, which can present as mild dryness of mucous membranes or severe such as respiratory and CNS depression.

Toxicity

Overdose can be life-threatening. The presentation can be delayed for up to 30 hours since the drug decreases gastric emptying and hence takes time to reach toxic levels in the blood. Symptoms vary from anticholinergic to opioid toxidromes, like respiratory depression, tachypnea, coma, delirium, lethargy, hyperthermia, tachycardia, dryness of mucous membranes, mydriasis or miosis, encephalopathy, seizures. The respiratory depression might correlate with the accumulation of difenoxin, which is an active metabolite of diphenoxylate. The recommended treatment for toxicity is naloxone if the patient exhibits respiratory depression. Considerations may be given for gastric lavage and administration of activated charcoal if indicated.

Close monitoring for 24 hours is advisable in significant overdose or those with concerning symptoms. Naloxone is a pure mu (opioid) receptor antagonist which reverses the opioid toxicity effects caused by diphenoxylate toxicity. Recurrent episodes of respiratory depression require repeated doses of naloxone or infusion.[13]

Enhancing Healthcare Team Outcomes

Managing diphenoxylate/atropine overdose requires an interprofessional team of healthcare professionals that includes nursing, laboratory technologists, pharmacists, and clinicians/mid-level practitioners in different specialties. Without proper management, the morbidity and mortality from diphenoxylate/atropine overdose are high. The moment the triage nurse obtains a history of suspected diphenoxylate/atropine overdose, the emergency department clinician and the assigned nurse are responsible for coordinating the care, which includes the following:

• Ordering and obtaining drug levels in the serum and or urine
• Monitor the patient for signs and symptoms of respiratory depression.
• Consider treatments to help limit the absorption of the drug in the body.
• Consult with the pharmacist about the use of activated charcoal and naloxone.
• Consult with a toxicologist and nephrologist on further management, which may include dialysis.
• Consult with the radiologist about imaging tests to ensure that the patient has not swallowed any drug packages.
• Consult with the intensivist about ICU care and monitoring while in hospital.

The management of diphenoxylate/atropine overdose does not stop in the emergency department. Once the patient stabilizes, one has to determine how and why the patient overdosed. Consult with a mental health counselor if this was an intentional act and assess risk factors for-self harm. Further, the possibility of addiction and withdrawal symptoms have to be a consideration. Only by working as an interprofessional team can the morbidity of diphenoxylate/atropine overdose be decreased. Initial short-term data reveal that the use of naloxone can be life-saving. The long-term outcomes for detoxification and drug rehabilitation remain guarded.