Racecadotril

Overview

Racecadotril, also known as acetorphan, is an antidiarrheal medication which acts as a peripheral enkephalinase inhibitor. Unlike other opioid medications used to treat diarrhea, which reduce intestinal motility, racecadotril has an antisecretory effect — it reduces the secretion of water and electrolytes into the intestine. It is available in France (where it was first introduced in ~1990) and other European countries (including Germany, Italy, the United Kingdom, Spain, Portugal, Poland, Finland, Slovakia, Russia and Czechia) as well as most of South America and some South East Asian countries (including China, India and Thailand), but not in the United States. It is sold under the tradename Hidrasec, among others. Thiorphan is the active metabolite of racecadotril, which exerts the bulk of its inhibitory actions on enkephalinases.[1][2][3] WP

Uses, dosage and effects

Medical uses

Racecadotril is used for the treatment of acute diarrhea in children and adults and has better tolerability than loperamide, as it causes less constipation and flatulence. Several guidelines have recommended racecadotril use in addition to oral rehydration treatment in children with acute diarrhea.[4][5][6] WP

Risks and side effects

Contraindications

Racecadotril has no contraindications apart from known hypersensitivity to the substance.[7][8] WP

There is insufficient data for the therapy of chronic diarrhea, for patients with renal or hepatic failure, and for children under three months. Additional contraindications for the children's formulation are hereditary fructose intolerance, glucose-galactose malabsorption and saccharase deficiency, as it contains sugar.[5][7] WP

Side effects

The most common adverse effect is headache, which occurs in 1–2% of patients. Rashes occur in fewer than 1% of patients. Other described skin reactions include itching, urticaria, angioedema, erythema multiforme, and erythema nodosum.[5][7][8] WP

Overdose

No cases of overdose are known. Adults have tolerated 20-fold therapeutic doses without ill effects.[8] WP

Interactions

Interactions

No interactions in humans have been described. Combining racecadotril with an ACE inhibitor can theoretically increase the risk for angioedema.[7][8] WP

Racecadotril and its main metabolites neither inhibit nor induce the liver enzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. They also do not induce UGT enzymes. This means that racecadotril has a low potential for pharmacokinetic interactions.[8] WP

Pharmacology

Mechanism of action

Enkephalins are peptides produced by the body that act on opioid receptors with preference for the δ subtype. Activation of δ receptors inhibits the enzyme adenylyl cyclase, decreasing intracellular levels of the messenger molecule cAMP.[5][9] WP

The active metabolite of racecadotril, thiorphan, inhibits enkephalinase enzymes in the intestinal epithelium with an IC₅₀ of 6.1 nM, protecting enkephalins from being broken down by these enzymes. (Racecadotril itself is much less potent at 4500 nM.) This reduces diarrhea related hypersecretion in the small intestine without influencing basal secretion. Racecadotril also has no influence on the time substances, bacteria or virus particles stay in the intestine.[5][6][8] WP

Pharmacokinetics

Racecadotril is rapidly absorbed after oral administration and reaches Cₘₐₓ within 60 minutes. Food delays Cₘₐₓ by 60 to 90 minutes but does not affect the overall bioavailability. Racecadotril is rapidly and effectively metabolized to the moderately active S-acetylthiorphan the main active metabolite thiorphan, of which 90% are bound to blood plasma proteins. In therapeutic doses, racecadotril does not pass the blood–brain barrier. Inhibition of enkephalinases starts 30 minutes after administration, reaches its maximum (75–90% inhibition with a therapeutic dose) two hours after administration, and lasts for eight hours. The elimination half-life, measured from enkephalinase inhibition, is three hours.[5][6][7] WP

Thiorphan is further metabolized to inactive metabolites such as the methyl thioether and the methyl sulfoxide. Both active and inactive metabolites are excreted, mostly via the kidney (81.4%), and to a lesser extent via the feces (8%).[8] WP

Legal status

Brand names

In France, Portugal and Spain it is sold as Tiorfan and in Italy as Tiorfix, in Czechia and Slovakia as Enditril. In India it is available as Redotril and Enuff. In the Philippines it is sold as Hidrasec.[2] WP

Chemistry

Formula

C21H23NO4S PC

CAS number

81110-73-8 PC

Molar mass (g/mol)

385.5 PC

IUPAC name (computed by PubChem)

benzyl 2-[[2-(acetylsulfanylmethyl)-3-phenylpropanoyl]amino]acetate PC

SMILES

CC(=O)SCC(CC1=CC=CC=C1)C(=O)NCC(=O)OCC2=CC=CC=C2 PC

InChIKey

ODUOJXZPIYUATO-UHFFFAOYSA-N PC

PubChem CID

107751

Harm reduction information

No harm reduction data is on file for this compound yet. That means no dose, timing or combination data from PsychonautWiki or TripSit. Please don't guess a dose from similar compounds. If you have taken it and feel unwell, contact emergency services or a poison control center.

User reports

Pop culture

No references added yet.

Sources

1. Journal / agency Matheson AJ, Noble S. Racecadotril. Drugs. April 2000. doi:10.2165/00003495-200059040-00010 · PMID 10804038
2. Other Racecadotril. 13 December 2013
3. Journal / agency Spillantini MG, Geppetti P, Fanciullacci M, Michelacci S, Lecomte JM, Sicuteri F. In vivo 'enkephalinase' inhibition by acetorphan in human plasma and CSF. European Journal of Pharmacology. June 1986. doi:10.1016/0014-2999(86)90094-4 · PMID 3015640
4. Journal / agency Fischbach W, Andresen V, Eberlin M, Mueck T, Layer P. A Comprehensive Comparison of the Efficacy and Tolerability of Racecadotril with Other Treatments of Acute Diarrhea in Adults. Frontiers in Medicine. 2016. doi:10.3389/fmed.2016.00044 · PMID 27790616 · PMC5064048
5. Other Arzneistoff-Profile. 1982
6. Journal / agency Eberlin M, Mück T, Michel MC. A comprehensive review of the pharmacodynamics, pharmacokinetics, and clinical effects of the neutral endopeptidase inhibitor racecadotril. Frontiers in Pharmacology. 2012. doi:10.3389/fphar.2012.00093 · PMID 22661949 · PMC3362754
7. Other Mediq.ch: racecadotril. Accessed 2019-12-30
8. Other Austria-Codex. 2019
9. Journal / agency Cumming P, Marton J, Lilius TO, Olberg DE, Rominger A. A Survey of Molecular Imaging of Opioid Receptors. Molecules. November 2019. doi:10.3390/molecules24224190 · PMID 31752279 · PMC6891617

Text and values on this page are quoted from Wikipedia (CC BY-SA 4.0), PubChem (public domain). Each value links to the exact revision it came from.