What is the mechanism of action of racecadotril?

Racecadotril Mechanism of Action

Racecadotril works by inhibiting the enzyme neutral endopeptidase (enkephalinase), which prevents the breakdown of endogenous enkephalins in the intestinal wall, thereby reducing pathologic water and electrolyte hypersecretion into the gut lumen without affecting normal basal secretion or intestinal motility. 1, 2

Detailed Pharmacologic Mechanism

Enzymatic Inhibition and Active Metabolite

• Racecadotril is rapidly converted after oral administration into its active metabolite thiorphan, which acts as a potent inhibitor of neutral endopeptidase (NEP, EC 3.4.24.11) 1
• Thiorphan does not cross the blood-brain barrier, ensuring that its effects remain localized to the peripheral nervous system in the gut 1

Enkephalin Protection and Opioid Receptor Activation

• By inhibiting enkephalinase, racecadotril protects endogenous enkephalins (naturally occurring opioid peptides) from enzymatic degradation 2, 3
• The preserved enkephalins then activate peripheral opioid receptors (specifically delta-opioid receptors) in the intestinal mucosa 3
• This antisecretory effect was confirmed to be mediated through opioid receptors, as it was completely blocked by naloxone (an opioid antagonist) but not by phentolamine (an alpha-adrenergic blocker) in experimental studies 3

Selective Antisecretory Action

• Racecadotril selectively inhibits pathologic hypersecretion of water, sodium, and potassium into the intestinal lumen during diarrheal states (such as cholera toxin-induced secretion), while leaving basal physiologic absorption completely unchanged 3, 4
• In experimental models, racecadotril reduced cholera toxin-induced water secretion by approximately 50% (from 0.73 to 0.37 mL/min) and sodium secretion by 88% (from 125.0 to 14.7 μmol/min) 3

Key Distinction from Loperamide

• Unlike loperamide, which acts as a μ-opioid receptor agonist to reduce intestinal motility and prolong transit time 5, racecadotril does not affect gastrointestinal transit time or motility 1, 2
• This mechanistic difference provides a theoretical safety advantage: racecadotril does not slow intestinal transit, thereby avoiding the risk of bacterial proliferation, toxin accumulation, or toxic megacolon in inflammatory or invasive diarrheal conditions 6, 7

Clinical Implications of the Mechanism

Efficacy Profile

• The antisecretory mechanism translates to consistent clinical effectiveness in reducing stool weight and stool frequency in both animal models and human studies of acute diarrhea 1, 2
• Racecadotril demonstrated efficacy comparable to loperamide in direct comparative trials in adults and children with acute diarrhea 1, 2

Safety and Tolerability Advantages

• Because racecadotril does not affect motility, it causes significantly less rebound constipation after resolution of diarrhea compared to loperamide 2, 4
• The tolerability profile of racecadotril is similar to placebo, with fewer adverse gastrointestinal effects than loperamide 2, 4
• The lack of central nervous system effects (due to thiorphan not crossing the blood-brain barrier) eliminates concerns about sedation or addiction 1

Guideline Recognition

• The European Society for Medical Oncology (ESMO) provides Level III evidence with Grade A recommendation for using racecadotril interchangeably with loperamide for Grade 1 immunotherapy-induced diarrhea, specifically citing its antisecretory mechanism as a distinguishing feature 8, 7

Common Pitfalls and Caveats

• Despite the theoretical safety advantage of not affecting motility, a randomized trial of prophylactic racecadotril (100 mg three times daily for 15 days) in patients receiving irinotecan-based chemotherapy failed to demonstrate any effect on preventing diarrhea compared to placebo 8
• Some critical analyses question whether racecadotril's peripheral antisecretory selectivity and relative clinical efficacy are as robust as initially proposed, particularly noting that clinical efficacy was most clearly demonstrated in young infants who have 10-fold higher baseline plasma enkephalin concentrations than adults 9
• Racecadotril lacks specific evaluation in the context of travelers' diarrhea, whereas loperamide has strong guideline support and FDA-labeled indication for this condition 5, 6