Loperamide

Loperamide is a peripherally acting mu-opioid receptor agonist that slows gut transit and increases fluid absorption. It is the usual symptomatic treatment for acute noninfectious diarrhoea and chronic diarrhoea, but it must not be used in invasive diarrhoea. Overdose and misuse cause serious cardiac toxicity.

Classification. Antidiarrhoeal; opioid receptor agonist (peripheral).

Mechanism. Acts on mu-opioid receptors of the myenteric plexus to reduce propulsive peristalsis and increase anal sphincter tone. It also reduces intestinal secretion. P-glycoprotein efflux keeps it out of the brain at normal doses.

Pharmacodynamics. Onset within 1 hour; effect lasts 4 to 6 hours. Increases stool consistency and reduces frequency.

Pharmacokinetics. Oral bioavailability under 1% because of extensive first-pass metabolism. Protein binding 95%. Half-life 9 to 14 hours.

Metabolism. Hepatic oxidative N-demethylation via CYP3A4 and CYP2C8, with P-glycoprotein transport. Excreted mainly in faeces.

Adult oral doses unless stated.

Acute diarrhoea (nonbloody, afebrile).

• 4 mg initially, then 2 mg after each loose stool.

• Maximum 16 mg daily (12 mg daily for self-treatment).

• Use for no more than 48 hours.

• Maintain oral rehydration.

Chronic diarrhoea (for example irritable bowel syndrome with diarrhoea, short bowel, ileostomy, bile acid diarrhoea, radiotherapy diarrhoea).

• 2 mg two to four times daily, or 4 mg twice daily.

• Titrate to the lowest dose that controls symptoms; maximum 16 mg daily.

• Doses may be taken before meals to reduce post-meal urgency.

Chemotherapy-induced diarrhoea. 4 mg at the first loose stool, then 2 mg every 2 hours until 12 hours free of diarrhoea (or 4 mg every 4 hours at night); maximum 16 mg daily. Admit if severe, bloody, febrile or with neutropenia.

Paediatric dosing. Not advised for acute diarrhoea under 12 years in most settings, because of the risk of ileus and CNS depression. Where labelled:

• Age 4 to 7 years: 1 mg up to four times daily for up to 3 days.

• Age 8 to 11 years: 2 mg up to four times daily for up to 3 days.

• Age 12 years and over: adult dose, up to 5 days.

• Under 4 years: contraindicated.

Kidney and liver adjustment.

• Kidney impairment: no adjustment.

• Severe liver impairment: use with caution; reduced first-pass metabolism increases systemic exposure.

Contraindications.

• Acute dysentery (blood in stool, fever); acute ulcerative colitis; pseudomembranous or antibiotic-associated colitis; bacterial enterocolitis from invasive organisms.

• Ileus, constipation or abdominal distension where inhibited peristalsis must be avoided.

• Children under 4 years.

• Hypersensitivity.

Common adverse effects. Constipation, abdominal cramp, nausea, flatulence, dizziness and dry mouth.

Serious adverse effects.

• Cardiac toxicity with overdose, misuse or interacting drugs: QT prolongation, torsades de pointes, ventricular arrhythmia and cardiac arrest.

• CNS depression and respiratory depression in overdose, particularly in children.

• Toxic megacolon in inflammatory bowel disease or infective colitis.

• Paralytic ileus, urinary retention and angioedema.

Major interactions.

• P-glycoprotein and CYP3A4 or CYP2C8 inhibitors (quinidine, verapamil, ritonavir, saquinavir, itraconazole, ketoconazole, clarithromycin, erythromycin, gemfibrozil): raise loperamide levels, which increases cardiac risk; avoid or use the lowest dose.

• QT prolonging drugs (antimalarials such as artemether-lumefantrine, quinine and chloroquine; macrolides; fluoroquinolones; antipsychotics; ondansetron): additive risk.

• Oral desmopressin: raised levels; monitor sodium.

• Opioids and anticholinergics: additive constipation and ileus risk.

Management of overdose.

• Give naloxone 0.4 to 2 mg IV, repeated as needed, then an infusion if effect fades; loperamide acts for longer than naloxone.

• Observe for at least 24 to 48 hours, with continuous ECG monitoring and correction of potassium and magnesium.

• Treat torsades with IV magnesium sulphate 2 g and overdrive pacing or isoprenaline as directed by cardiology.

Special groups.

• Pregnancy: avoid in the first trimester if possible; limited data; short use acceptable thereafter.

• Breastfeeding: small amounts enter milk; short courses are acceptable.

• Children: restricted; high risk of toxicity.

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

• Kidney impairment: no adjustment.

• Liver impairment: caution.

• Regional: sold without prescription in many markets; do not use in suspected cholera, dysentery or febrile diarrhoea, where rehydration and treatment of the cause come first.

Formulations. Capsules and tablets 2 mg; orodispersible tablets 2 mg; oral liquid 1 mg in 5 mL.

Administration. Swallow capsules with water. Orodispersible tablets dissolve on the tongue. Always continue oral rehydration solution.

Baseline. Exclude blood in stool, fever, recent antibiotics and inflammatory bowel disease. Review interacting drugs and QT risk. ECG in cardiac disease or when high doses are used.

Monitoring.

• Stool frequency, hydration and abdominal distension.

• ECG when doses exceed 16 mg daily, with interacting drugs or in cardiac disease.

• Review at 48 hours.

Therapeutic drug monitoring. Not applicable.

Stopping. Stop when stool is formed, after 48 hours without improvement, or if blood, fever, distension or severe pain develops.

Referral and escalation. Investigate persistent diarrhoea beyond 2 weeks: stool cultures, faecal calprotectin, coeliac serology, thyroid function and colonoscopy for red flags. Admit for dehydration, bloody diarrhoea, fever or suspected toxic megacolon.