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](_blank)
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
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 ...
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
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. 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''.
See also
*
Ecadotril, the (''S'')-enantiomer of racecadotril
*
D/DL-Phenylalanine
*
RB-101
References
External links
*
{{Portal bar , Medicine
Enkephalinase inhibitors
Antidiarrhoeals
Propionamides
Carboxylate esters
Acetate esters
Thioesters
Benzyl esters