Diphenoxylate Atropine

Diphenoxylate atropine is a fixed combination of diphenoxylate, a synthetic opioid related to pethidine, and a subtherapeutic dose of atropine. It is a second-line antidiarrhoeal for nonbloody diarrhoea. Atropine is present to discourage overdose, but overdose, particularly in young children, is dangerous.

Classification. Antidiarrhoeal; opioid agonist with antimuscarinic.

Mechanism. Diphenoxylate activates gut mu-opioid receptors, slowing peristalsis and increasing fluid absorption. At high doses it crosses into the CNS. Atropine adds antimuscarinic effects at overdose levels.

Pharmacodynamics. Onset 45 to 60 minutes; duration 3 to 4 hours. In overdose, effects can be delayed up to 12 to 30 hours.

Pharmacokinetics. Diphenoxylate is rapidly hydrolysed to its active metabolite diphenoxylic acid (difenoxine). Half-life of the active metabolite is about 12 hours; excretion is mainly faecal.

Adult oral doses unless stated. Doses refer to diphenoxylate, using tablets of 2.5 mg diphenoxylate with 0.025 mg atropine.

Acute and chronic nonbloody diarrhoea.

• Initial 5 mg (2 tablets) four times daily; maximum 20 mg daily.

• When diarrhoea is controlled, reduce to the lowest dose that maintains control; often 2.5 to 5 mg two to three times daily.

• If there is no improvement in 48 hours at the maximum dose, stop.

• Review need after a few days; avoid prolonged continuous use.

Chronic diarrhoea (for example short bowel and ileostomy). Use the lowest effective maintenance dose under specialist direction.

Children. Not advised under 12 years because of the risk of respiratory depression and toxicity. Contraindicated under 6 years. If used in specialist care for ages 6 to 12, give 0.3 to 0.4 mg/kg daily of diphenoxylate in four divided doses using an oral liquid.

Kidney and liver adjustment.

• Kidney impairment: use with caution.

• Liver impairment: use with caution in cirrhosis; avoid in severe disease or hepatic coma risk.

Contraindications.

• Obstructive jaundice; acute infectious or invasive diarrhoea (dysentery, pseudomembranous colitis, toxin-producing bacteria).

• Children under 6 years.

• Hypersensitivity.

• Concurrent MAO inhibitors (risk of hypertensive crisis).

Common adverse effects. Drowsiness, dizziness, nausea, dry mouth, constipation and headache.

Serious adverse effects.

• Respiratory depression, coma and death after overdose, particularly in young children; delayed onset requires prolonged observation.

• Toxic megacolon in inflammatory bowel disease.

• Paralytic ileus, urinary retention, tachycardia and anticholinergic toxicity.

• Dependence at high doses.

• Pancreatitis (rare).

Management of overdose.

• Give naloxone 0.4 to 2 mg IV in adults (0.01 mg/kg in children), repeated as needed.

• Observe for at least 24 to 48 hours, because respiratory depression can recur after naloxone wears off; use a naloxone infusion if needed.

• Support airway and ventilation; consider activated charcoal if within 1 hour of a large ingestion with a protected airway.

Major interactions.

• MAO inhibitors: hypertensive crisis; avoid.

• CNS depressants, alcohol, opioids, benzodiazepines: additive sedation and respiratory depression.

• Anticholinergic drugs: additive effects.

• Opioid antagonists (naltrexone): block effect.

Special groups.

• Pregnancy: avoid.

• Breastfeeding: avoid; metabolites enter milk.

• Children: avoid under 12 years; high risk in toddlers.

• Older adults: use the lowest dose; risk of ileus, confusion and retention.

• Down syndrome: increased sensitivity to atropine.

• Kidney impairment: caution.

• Liver impairment: caution; may precipitate hepatic coma.

• Controlled substance in some jurisdictions; check local rules.

Formulations. Tablets 2.5 mg diphenoxylate with 0.025 mg atropine; oral liquid in some markets.

Administration. Take with water. Use only the prescribed dose, and keep tablets out of reach of children. Continue oral rehydration solution.

Baseline. Exclude blood in stool, fever, recent antibiotics and inflammatory bowel disease. Review MAO inhibitor and sedative use.

Monitoring.

• Stool frequency, hydration and abdominal distension.

• Sedation, respiratory rate and pupil size, particularly in children and older adults.

• Review at 48 hours.

Therapeutic drug monitoring. Not applicable.

Stopping. Stop when stool is controlled, after 48 hours without improvement, or if distension, fever or blood appears. Taper after prolonged use to limit opioid withdrawal.

Referral and escalation. Admit for suspected overdose in any child or adult. Investigate persistent diarrhoea beyond 2 weeks.