Diphenoxylate

Usage

• Diphenoxylate is prescribed for the symptomatic treatment of acute and chronic diarrhea. It is not effective against diarrhea caused by bacterial toxins or infections.
• Pharmacological Classification: Antidiarrheal, Opioid Agonist (although used for its antimotility effects rather than analgesic properties)
• Mechanism of Action: Diphenoxylate slows down the movement of the intestines (peristalsis) by acting on opioid receptors in the gut, thus reducing the frequency of bowel movements. The atropine sulfate component is added in a subtherapeutic dose to discourage abuse.

Alternate Names

• Diphenoxylate hydrochloride and atropine sulfate
• Brand Names: Lomotil, Lofeneoxal, Beamotil

How It Works

• Pharmacodynamics: Diphenoxylate acts on mu-opioid receptors in the gastrointestinal tract, inhibiting peristalsis and increasing intestinal transit time. It also increases intestinal water absorption and reduces electrolyte secretion, leading to firmer stools. Atropine, although present in small amounts, contributes to antidiarrheal action through anticholinergic effects (reducing intestinal motility and secretions).
• Pharmacokinetics:
  • Absorption: Well-absorbed orally. The peak plasma concentration of its active metabolite, diphenoxylic acid, is reached in about 2 hours.
  • Metabolism: Diphenoxylate is rapidly metabolized in the liver to diphenoxylic acid, which is the primary active form.
  • Elimination: Excreted primarily in the feces via biliary elimination, with a smaller portion excreted in urine.
• Mode of Action: Binds to mu-opioid receptors in the myenteric plexus of the intestinal wall, inhibiting acetylcholine release and reducing smooth muscle contractions, which slows intestinal motility.
• Receptor Binding/Enzyme Inhibition/Neurotransmitter Modulation: Mu-opioid receptor agonist. Atropine acts as a muscarinic acetylcholine receptor antagonist.
• Elimination Pathways: Primarily hepatic metabolism followed by biliary excretion.

Dosage

Standard Dosage

Adults:

• Initial: 5 mg (2 tablets or 10 mL liquid) four times daily.
• Maintenance: After initial control, reduce to individual needs (as low as 5 mg once daily).
• Maximum: Do not exceed 20 mg of diphenoxylate per day.

Children:

• 2-12 years: Use liquid formulation only. Initial: 0.3-0.4 mg/kg/day of diphenoxylate divided into four doses. Adjust based on weight, nutritional status, and degree of dehydration. Do not use tablets in children under 13.
• Under 2 years: Not recommended.

Special Cases:

• Elderly Patients: Start with a lower dose due to increased sensitivity to drug effects (especially anticholinergic effects and potential respiratory depression). Close monitoring is required.
• Patients with Renal Impairment: Use with caution; dosage adjustment may be necessary.
• Patients with Hepatic Dysfunction: Use with caution due to potential for impaired metabolism and accumulation; dosage adjustment may be needed.
• Patients with Comorbid Conditions: Use with caution in patients with glaucoma, obstructive uropathy, or severe colitis.

Clinical Use Cases

Diphenoxylate is not indicated for use in clinical situations such as intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations. It is solely indicated for the management of diarrhea.

Dosage Adjustments

Dose adjustments may be required in cases of renal or hepatic impairment, advanced age, or other comorbid conditions. Individualized dosing based on patient response and tolerability is important.

Side Effects

Common Side Effects:

• Nausea, vomiting
• Abdominal discomfort, bloating, cramping
• Drowsiness, dizziness
• Dry mouth

Rare but Serious Side Effects:

• Respiratory depression
• Paralytic ileus, toxic megacolon
• Pancreatitis
• Atropine toxicity (tachycardia, hyperthermia, urinary retention)

Long-Term Effects:

• Dependence with prolonged high-dose use is possible due to opioid agonist activity.

Adverse Drug Reactions (ADR):

• Anaphylaxis, angioedema
• Severe allergic reactions

Contraindications

• Hypersensitivity to diphenoxylate or atropine.
• Diarrhea caused by infections (e.g., C. difficile, invasive bacteria)
• Obstructive jaundice
• Pseudomembranous colitis
• Children under 2 years of age

Drug Interactions

• CNS depressants (alcohol, barbiturates, benzodiazepines): Additive sedative effects.
• Monoamine oxidase inhibitors (MAOIs): Potential for hypertensive crisis.
• Anticholinergic drugs: Additive anticholinergic effects.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: C (animal studies show potential risk; human studies inadequate). Use only if clearly needed.
• Breastfeeding: Diphenoxylate is excreted in breast milk and may cause adverse effects in nursing infants. Use with caution.

Drug Profile Summary

• Mechanism of Action: Opioid agonist acting on intestinal mu-opioid receptors to slow motility.
• Side Effects: Nausea, vomiting, drowsiness, dizziness, dry mouth, constipation. Rarely, respiratory depression, toxic megacolon.
• Contraindications: Hypersensitivity, infectious diarrhea, obstructive jaundice, children under 2 years.
• Drug Interactions: CNS depressants, MAOIs, anticholinergics.
• Pregnancy & Breastfeeding: Use with caution. Category C.
• Dosage: Adults: 5 mg QID initially, then reduce. Max 20mg/day. Children: 0.3-0.4 mg/kg/day divided QID (liquid only).
• Monitoring Parameters: Frequency and consistency of bowel movements, hydration status, respiratory rate, and mental status.

Popular Combinations

Diphenoxylate is typically not used in combination with other antidiarrheals. Electrolyte and fluid replacement therapy may be indicated in conjunction with diphenoxylate.

Precautions

• General Precautions: Monitor for signs of atropine toxicity, dehydration, and respiratory depression, especially in children and the elderly.
• Specific Populations: Avoid use in children under 2. Use with caution in the elderly and those with renal or hepatic impairment.
• Lifestyle Considerations: Avoid alcohol and other CNS depressants. Use caution when driving or operating machinery due to potential drowsiness.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Diphenoxylate?

A: Adults: 5 mg four times daily initially, reduced to as low as 5 mg daily once diarrhea is controlled. Maximum: 20 mg/day. Children (2-12 years): 0.3-0.4 mg/kg/day in divided doses (liquid formulation only).

Q2: How does Diphenoxylate work?

A: It acts on opioid receptors in the gut to slow intestinal motility and reduce the frequency of bowel movements.

Q3: What are the common side effects of Diphenoxylate?

A: Nausea, vomiting, drowsiness, dizziness, dry mouth, abdominal discomfort, and constipation.

Q4: When is Diphenoxylate contraindicated?

A: In cases of infectious diarrhea, obstructive jaundice, children under 2 years of age, and hypersensitivity to the drug.

Q5: Can Diphenoxylate be used during pregnancy?

A: Pregnancy Category C. Use only if clearly needed and weigh the potential risks and benefits.

Q6: Does Diphenoxylate interact with other medications?

A: Yes. It can interact with CNS depressants (alcohol, barbiturates), MAOIs, and other anticholinergic drugs.

Q7: How long should Diphenoxylate be used?

A: Use for the shortest duration necessary to control symptoms. Discontinue if diarrhea persists for more than 48 hours in acute cases or 10 days in chronic cases with maximum dosage.

Q8: What are the signs of Diphenoxylate overdose?

A: Dry mouth, flushing, hyperthermia, tachycardia, lethargy, pinpoint pupils, respiratory depression, and coma.

Q9: What should patients be advised regarding Diphenoxylate use?

A: Avoid alcohol and other CNS depressants. Do not exceed the recommended dosage. Use caution while driving or operating machinery. Maintain adequate hydration and follow a bland diet during treatment.

Q10: Is diphenoxylate addictive?

A: While the atropine is included to reduce the likelihood, chronic use of high doses can lead to opioid dependence. Discontinuation should be gradual in these cases.