Racecadotril, also known as acetorphan, is an
antidiarrheal
An anti-diarrhoeal drug (or anti-diarrheal drug in American English) is any medication which provides symptomatic relief for diarrhoea.
Types
* Electrolyte solutions, while not true antidiarrhoeals, are used to replace lost fluids and salts in ac ...
medication which acts as a peripheral
enkephalinase inhibitor
An enkephalinase inhibitor is a type of enzyme inhibitor which inhibits one or more members of the enkephalinase class of enzymes that break down the endogenous enkephalin opioid peptides. Examples include racecadotril, ubenimex (bestatin), RB-1 ...
.
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 us ...
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 medium containing ions that is electrically conducting through the movement of those ions, but not conducting electrons. This includes most soluble salts, acids, and bases dissolved in a polar solvent, such as water. Upon di ...
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 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 September 4, 2015 is a medication used to decrease the frequency of diarrhea. It is often used for this purpose in inflammatory bowel disease and short bowel syn ...
, 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 movement ...
and
flatulence
Flatulence, in humans, is the expulsion of gas from the 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 swallowed environm ...
.
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 s ...
to the substance.
[Mediq.ch](_blank)
racecadotril. Accessed 2019-12-30.
There is insufficient data for the therapy of chronic diarrhea, for patients with
renal
The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; blood ...
or
hepatic
The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it i ...
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 ing ...
,
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 galac ...
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, 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 does not leave any long-lasti ...
,
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 ...
,
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 s ...
, and
erythema nodosum
Erythema nodosum (EN) is an inflammatory condition characterized by inflammation of the fat cells under the skin, resulting in tender red nodules or lumps that are usually seen on both shins. It can be caused by a variety of conditions, and typi ...
.
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 hypertension, high blood pressure and heart failure. They work by causing relaxation of blood vessels as well as a decrease i ...
can theoretically increase the risk for angioedema.
Racecadotril and its main metabolites neither inhibit nor
induce the liver enzymes
CYP1A2
Cytochrome P450 1A2 (abbreviated CYP1A2), a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the human body. In humans, the CYP1A2 enzyme is encoded by the ''CYP1A2'' gene.
Function
...
,
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 prote ...
,
CYP2C19
Cytochrome P450 2C19 (abbreviated CYP2C19) is an enzyme protein. It is a member of the CYP2C subfamily of the cytochrome P450 mixed-function oxidase system. This subfamily includes enzymes that catalyze metabolism of xenobiotics, including some p ...
,
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.
CYP2D ...
, 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 t ...
. They also do not induce
UGT enzymes.
This means that racecadotril has a low potential for
pharmacokinetic
Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to determining the fate of substances administered ...
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 enkephali ...
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.
A ...
s produced by the body that act on
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 us ...
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, 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 in the gastrointestinal tract where most of the absorption of nutrients from food takes place. It lies between the stomach and large intestine, and receives bile and pancreatic juice through the p ...
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
Cmax 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
The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that prevents solutes in the circulating blood from ''non-selectively'' crossing into the extracellular fluid of ...
. 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 bl ...
, measured from enkephalinase inhibition, is three hours.
Thiorphan is further metabolized to inactive metabolites such as the methyl
thioether
In organic chemistry, an organic 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 sulfides have foul odors. A sul ...
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''.
See also
*
Ecadotril
Ecadotril is a neutral endopeptidase inhibitor ((NEP) EC 3.4.24.11) and determined by the presence of peptidase family M13 as a neutral endopeptidase inhibited by phosphoramidon. Ecadotril is the (''S'')-enantiomer of racecadotril. NEP-like enzy ...
, the (''S'')-enantiomer of racecadotril
*
D/DL-Phenylalanine
*
RB-101
RB-101 is a drug that acts as an enkephalinase inhibitor, which is used in scientific research.
RB-101 is a prodrug which acts by splitting at the disulfide bond once inside the brain, to form two selective enzyme inhibitors and blocking both ty ...
References
External links
*
{{Portal bar , Medicine
Enkephalinase inhibitors
Antidiarrhoeals
Propionamides
Carboxylate esters
Acetate esters
Thioesters
Benzyl esters