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

opioid Opioids are a class of Drug, drugs that derive from, or mimic, natural substances found in the Papaver somniferum, opium poppy plant. Opioids work on opioid receptors in the brain and other organs to produce a variety of morphine-like effects, ...

medications used to treat diarrhea, which reduce intestinal motility, racecadotril has an antisecretory effect — it reduces the secretion of water and

electrolytes An electrolyte is a substance that conducts electricity through the movement of ions, but not through the movement of electrons. This includes most soluble salts, acids, and bases, dissolved in a polar solvent like water. Upon dissolving, t ...

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.

Medical uses

Racecadotril is used for the treatment of acute diarrhea in children and adults and has better tolerability than

loperamide Loperamide, sold under the brand name Imodium, among others,Drugs.co Page accessed 4 September 2015 is a medication of the opioid receptor agonist class used to decrease the frequency of diarrhea. It is often used for this purpose in irritable ...

, as it causes less

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

and

flatulence Flatulence is the expulsion of gas from the Gastrointestinal tract, intestines via the anus, commonly referred to as farting. "Flatus" is the medical word for gas generated in the stomach or bowels. A proportion of intestinal gas may be swal ...

. 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) is an abnormal physiological condition in which there is an undesirable and adverse immune response to an antigen. It is an abnormality in the immune system that causes Imm ...

to the substance.Mediq.ch
racecadotril. Accessed 2019-12-30. There is insufficient data for the therapy of chronic diarrhea, for patients with

renal In humans, the kidneys are two reddish-brown bean-shaped blood-filtering organs that are a multilobar, multipapillary form of mammalian kidneys, usually without signs of external lobulation. They are located on the left and right in the retrop ...

hepatic The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...

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.

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 Hives, also known as urticaria, is a kind of skin rash with red or flesh-colored, raised, itchy bumps. Hives may burn or sting. The patches of rash may appear on different body parts, with variable duration from minutes to days, and typically ...

angioedema Angioedema is an area of swelling (edema) of the lower layer of skin and tissue just under the skin or mucous membranes. The swelling may occur in the face, tongue, larynx, abdomen, or arms and legs. Often it is associated with hives, which are ...

, erythema multiforme, 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 Angiotensin-converting-enzyme inhibitors (ACE inhibitors) are a class of medication used primarily for the treatment of high blood pressure and heart failure. This class of medicine works by causing relaxation of blood vessels as well as a decr ...

can theoretically increase the risk for angioedema. Racecadotril and its main metabolites neither inhibit nor

induce Induce may refer to: * Induced consumption * Induced innovation * Induced character * Induced coma * Induced menopause * Induced metric * Induced path * Induced topology * Induce (musician), American musician * Labor induction Labor indu ...

the liver enzymes CYP1A2, CYP2C9, CYP2C19,

CYP2D6 Cytochrome P450 2D6 (CYP2D6) is an enzyme that in humans is encoded by the ''CYP2D6'' gene. ''CYP2D6'' is primarily expressed in the liver. It is also highly expressed in areas of the central nervous system, including the substantia nigra. CYP2 ...

, and

CYP3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine, which in humans is encoded by ''CYP3A4'' gene. It organic redox reaction, oxidizes small foreign organic molecules ( ...

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

Pharmacology

Mechanism of action

Enkephalins are

peptide Peptides are short chains of amino acids linked by peptide bonds. A polypeptide is a longer, continuous, unbranched peptide chain. Polypeptides that have a molecular mass of 10,000 Da or more are called proteins. Chains of fewer than twenty am ...

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. 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 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 In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. H ...

. 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 The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that regulates the transfer of solutes and chemicals between the circulatory system and the central nervous system ...

. 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 (elimination half-life, pharmacological 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 blood plasma. ...

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

thioether In organic chemistry, a sulfide (British English sulphide) or thioether is an organosulfur functional group with the connectivity as shown on right. Like many other sulfur-containing compounds, Volatile organic compound, volatile sulfides have ...

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%).

Society and culture

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.''

References

External links

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