Racecadotril, also known as acetorphan, is an antidiarrheal medication which acts as a peripheral enkephalinase inhibitor. Unlike other

opioid Opioids are substances that act on opioid receptors to produce morphine-like effects. Medically they are primarily used for pain relief, including anesthesia. Other medical uses include suppression of diarrhea, replacement therapy for opioid use ...

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, Russia and the Czech Republic) 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 Thiorphan is the active metabolite of the antidiarrheal racecadotril (acetorphan). It prevents the degradation of endogenous enkephalins by acting as an enkephalinase inhibitor Inhibitor or inhibition may refer to: In biology * Enzyme inhib ...

is the active metabolite of racecadotril, which exerts the bulk of its inhibitory actions on enkephalinases.

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 Constipation is a bowel dysfunction that makes bowel movements infrequent or hard to pass. The stool is often hard and dry. Other symptoms may include abdominal pain, bloating, and feeling as if one has not completely passed the bowel moveme ...

and flatulence. Several guidelines have recommended racecadotril use in addition to oral rehydration treatment in children with acute diarrhea.

Contraindications

Racecadotril has no contraindications apart from known

hypersensitivity Hypersensitivity (also called hypersensitivity reaction or intolerance) refers to undesirable reactions produced by the normal immune system, including allergies and autoimmunity. They are usually referred to as an over-reaction of the immune ...

to the substance.Mediq.ch
racecadotril. Accessed 2019-12-30. 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 Hereditary fructose intolerance (HFI) is an inborn error of fructose metabolism caused by a deficiency of the enzyme aldolase B. Individuals affected with HFI are asymptomatic until they ingest fructose, sucrose, or sorbitol. If fructose is inges ...

glucose-galactose malabsorption Glucose-galactose malabsorption is a rare condition in which the cells lining the intestine cannot take in the sugars glucose and galactose, which prevents proper digestion of these molecules and larger molecules made from them. Glucose and gala ...

and saccharase deficiency, as it contains sugar.

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 Erythema multiforme (EM) is a skin condition that appears with red patches evolving into target lesions, typically on both hands. It is a type of erythema possibly mediated by deposition of immune complexes (mostly IgM-bound complexes) in the ...

, and erythema nodosum.

Overdose

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

Interactions

No interactions in humans have been described. Combining racecadotril with an ACE inhibitor can theoretically increase the risk for angioedema. Racecadotril and its main metabolites neither inhibit nor induce the liver enzymes CYP1A2,

CYP2C9 Cytochrome P450 family 2 subfamily C member 9 (abbreviated CYP2C9) is an enzyme protein. The enzyme is involved in metabolism, by oxidation, of both xenobiotics, including drugs, and endogenous compounds, including fatty acids. In humans, the pro ...

, CYP2C19, CYP2D6, and

CYP3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine. It oxidizes small foreign organic molecules ( xenobiotics), such as toxins or drugs, so that they can be removed from ...

. They also do not induce UGT enzymes. This means that racecadotril has a low potential for pharmacokinetic interactions.

Pharmacology

Mechanism of action

Enkephalin An enkephalin is a pentapeptide involved in regulating nociception in the body. The enkephalins are termed endogenous ligands, as they are internally derived and bind to the body's opioid receptors. Discovered in 1975, two forms of enkephal ...

s are

peptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. ...

s produced by the body that act on

receptors with preference for the δ subtype. Activation of δ receptors inhibits the enzyme

adenylyl cyclase Adenylate cyclase (EC 4.6.1.1, also commonly known as adenyl cyclase and adenylyl cyclase, abbreviated AC) is an enzyme with systematic name ATP diphosphate-lyase (cyclizing; 3′,5′-cyclic-AMP-forming). It catalyzes the following reaction: :A ...

, decreasing intracellular levels of the messenger molecule

cAMP Camp may refer to: Outdoor accommodation and recreation * Campsite or campground, a recreational outdoor sleeping and eating site * a temporary settlement for nomads * Camp, a term used in New England, Northern Ontario and New Brunswick to descri ...

. The

active metabolite An active metabolite is an active form of a drug after it has been processed by the body. Metabolites of drugs An active metabolite results when a drug is metabolized by the body into a modified form which continues to produce effects in the body ...

of racecadotril,

thiorphan Thiorphan is the active metabolite of the antidiarrheal racecadotril (acetorphan). It prevents the degradation of endogenous enkephalins by acting as an enkephalinase inhibitor Inhibitor or inhibition may refer to: In biology * Enzyme inhib ...

, inhibits

enkephalinase Enkephalinases are enzymes that degrade endogenous enkephalin opioid peptides. They include: * Aminopeptidase N (APN) * Neutral endopeptidase (NEP) * Dipeptidyl peptidase 3 (DPP3) * Carboxypeptidase A6 (CPA6) * Leucyl/cystinyl aminopeptidase ( ...

enzymes in the

intestinal epithelium The intestinal epithelium is the single cell layer that form the luminal surface (lining) of both the small and large intestine (colon) of the gastrointestinal tract. Composed of simple columnar epithelial cells, it serves two main functi ...

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 The small intestine or small bowel is an organ (anatomy), organ in the human gastrointestinal tract, gastrointestinal tract where most of the #Absorption, absorption of nutrients from food takes place. It lies between the stomach and large intes ...

without influencing basal secretion. Racecadotril also has no influence on the time substances, bacteria or virus particles stay in the intestine.

Pharmacokinetics

Racecadotril is rapidly absorbed after oral administration and reaches C_max within 60 minutes. Food delays C_max 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 Biological half-life (also known as elimination half-life, pharmacologic half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the b ...

, measured from enkephalinase inhibition, is three hours. Thiorphan is further metabolized to inactive metabolites such as the methyl thioether and the methyl

sulfoxide In organic chemistry, a sulfoxide, also called a sulphoxide, is an organosulfur compound containing a sulfinyl () functional group attached to two carbon atoms. It is a polar functional group. Sulfoxides are oxidized derivatives of sulfides. E ...

. Both active and inactive metabolites are excreted, mostly via the kidney (81.4%), and to a lesser extent via the feces (8%).

Society and culture

Brand names

In France, Portugal and Spain it is sold as ''Tiorfan'' and in Italy as ''Tiorfix''. In India it is available as ''Redotril'' and ''Enuff''.

References

External links

* {{Portal bar , Medicine Enkephalinase inhibitors Antidiarrhoeals Propionamides Carboxylate esters Acetate esters Thioesters Benzyl esters