What is the difference between racedotril and loperamide? Why is racedotril called an antisecretory?

When faced with a case of acute diarrhoea, clinicians often reach for anti-diarrhoeal agents, but not all drugs are created equal. Two options are loperamide, an opioid receptor agonist, and racedotril, an enkephalinase inhibitor. Though both reduce stool output, they differ in their mechanism of action, safety profile, and clinical applications.

Mechanism of Action

Loperamide is a peripherally acting µ (mu)-opioid receptor agonist. It slows intestinal transit by inhibiting peristalsis and increasing fluid and electrolyte absorption. Because it is efficiently extruded from the CNS by P-glycoprotein, it does not cross the blood–brain barrier to a significant extent at therapeutic doses, which limits central opioid effects.

Racedotril acts as an indirect opioid agonist by inhibiting enkephalinase (neutral endopeptidase), the enzyme that degrades endogenous enkephalins. This increases the availability of enkephalins, which preferentially act at δ (delta)-opioid receptors to reduce intestinal hypersecretion. Unlike loperamide, racedotril does not slow intestinal motility, a key therapeutic distinction.

Clinical Implications

Speed of Action:

  • Both drugs have a rapid onset, but racedotril preserves motility, which can be advantageous in children and in frail older adults where constipation, abdominal distension, or ileus pose risks.

Safety:

  • Loperamide may cause constipation and, rarely, paralytic ileus. At very high doses or misuse, it can cause QT prolongation, ventricular arrhythmias, and cardiac arrest.

  • Racedotril has fewer systemic effects, is generally well tolerated, and carries a lower risk of rebound constipation.

Use in Children:

  • Racedotril is approved for paediatric use in many countries.

  • Loperamide is contraindicated in children under 2 years of age, and its use should be cautious, or avoided entirely, in young children (with warnings often applying to those under 6 years) because of the risk of ileus and CNS toxicity.

When to Choose What? — Take-Home Message

Both agents are effective, but their therapeutic applications differ:

  • Racedotril provides secretion-focused control with a favourable safety profile, making it particularly useful in paediatrics, in the elderly, and in patients where slowing gut transit is undesirable.

  • Loperamide remains widely used for rapid symptomatic relief of acute diarrhoea in adults without significant risk factors.

Understanding the pharmacology behind these agents supports more rational, patient-centred decision-making in diarrhoea management.