Hidrasec Mechanism of Action

Pharmacotherapeutic group: Other antidiarrhoeals agent (intestinal antisecretory antidiarrhoeal agent). ATC code: A07XA04. (A: digestive system and metabolism).
Pharmacology: Pharmacodynamics: Racecadotril is a prodrug that must be hydrolysed to its active metabolite thiorphan, which is an inhibitor of enkephalinase, a cell membrane enzyme present in various tissues, including the intestinal epithelium.
This enzyme contributes to the hydrolysis of exogenous and endogenous peptides, such as enkephalins.
Racecadotril thus protects enkephalins from enzymatic degradation, thereby prolonging their action at enkephalinergic synapses in the small intestine and thus reducing hypersecretion.
Racecadotril is a pure intestinal antisecretory active substance. It decreases intestinal hypersecretion of water and electrolytes induced by cholera toxin or inflammation, with no effect on basal secretion. It exerts antidiarrhoeal activity of rapid onset without altering the intestinal transit time.
Capsule: Racecadotril does not trigger abdominal distension. During clinical trials, secondary constipation is observed at the same frequency in racecadotril and placebo groups.
In oral use, the activity of racecadotril remains peripheral without any effect on the central nervous system.
A randomized, crossover clinical study has shown that 100 mg racecadotril at the therapeutic dose (one capsule) or at a higher dose (4 capsules) does not induce QT/QTc prolongation in 56 healthy adult volunteers (unlike the effect observed with moxifloxacin, used as a positive control).
Granules for oral suspension: In two clinical studies performed in children, racecadotril reduced stool weight by 40% and 46%, respectively, within the first 48 hours.
A significant reduction in the duration of the diarrhoea and the need for rehydration was also observed.
A meta-analysis (9 randomised clinical trials, racecadotril versus placebo, in addition to oral rehydration solution) collected individual patient data from 1,384 boys and girls suffering from acute diarrhoea of varying severity, treated in an outpatient or hospitalized setting.
The mean age was 12 months (interquartile range: 6-39 months).
A total of 714 patients were less than 1 year and 670 patients were more than 1 year old. The mean weight ranged from 7.4 kg to 12.2 kg, depending on the study. The overall mean duration of diarrhoea after enrolment was 2.81 days in the placebo group and 1.75 days for racecadotril.
In oral use, the activity if racecadotril remains peripheral without any effect on the central nervous system.
A randomized, crossover clinical study has shown that 100 mg racecadotril at the therapeutic dose (one capsule) or at a higher dose (4 capsules) does not induce QT/QTc prolongation in 56 healthy adult volunteers (unlike the effect observed with moxifloxacin, used as a positive control).
Pharmacokinetics: Absorption: Following oral administration, racecadotril is rapidly absorbed. The activity on plasma enkephalinase appears from the thirtieth minutes onwards.
The bioavailability of racecadotril is not altered by food, but the peak activity is delayed by about one and a half hours.
Distribution: Following oral administration of 14C-labelled racecadotril in healthy volunteers, the concentration of racecadotril was about 200 times higher in plasma than in blood cells and about 3 times higher in plasma than in the total blood volume. Racecadotril does not significantly bind to blood cells.
In plasma, the mean apparent volume of distribution of 66.4 L/kg demonstrates moderate distribution of 14C in other tissues.
Ninety percent of the active metabolite of racecadotril, thiorphan, (RS)-N-(1-oxo-2-(mercaptomethyl)-3-phenylpropyl) glycine, is bound to plasma proteins, primarily albumin.
The pharmacokinetic properties of racecadotril are not altered during repeat-dose administration or in the elderly.
The intensity and duration of action of racecadotril are dose-related.
For a 100 mg dose, the duration of plasma enkephalinase inhibition is about 8 hours.
Capsules: Peak plasma enkephalinase activity occurs approximately 2 hours post-dose, corresponding to 75% inhibition for the dose of 100 mg/kg.
Granules for oral suspension: The peak concentration is reached within approximately 2.5 hours, corresponding to 90% inhibition of enzymatic activity for the administered dose of 1.5 mg/kg.
Metabolism: The biological half-life of racecadotril, as determined by plasma enkephalinase inhibition, is 3 hours.
Racecadotril is rapidly hydrolysed to thiorphan (RS)-N-(1-oxo-2-(mercaptomethyl)-3-phenylpropyl) glycine, its active metabolite, which is itself transformed into inactive metabolites S-methylthiorphan sulphoxide, S-methylthiorphan, 2-methanesulfinylmethyl propionic acid and 2-methylsulfanylmethyl propionic acid, which were all formed on greater than 10% systemic exposure to the parent compound.
Other minor metabolites have also been detected and quantified in urine and faecal matter.
Repeated administration of racecadotril does not induce accumulation within the body.
In vitro data show that racecadotril/thiorphan and its four major inactive metabolites have no significant action as inhibitors of the cytochrome CYP isoforms 3A4, 2D6, 2C9, 1A2 and 2C19.
In vitro data show that racecadotril/thiorphan and its four major inactive metabolites have no significant action as inducers of the cytochrome CYP isoforms (family 3A, 2A6, 2B6, 2C9/2C19, family 1A, 2E1) and enzymes that bind to glucuronyl transferase.
Racecadotril does not alter the protein binding of highly protein-bound products, such as tolbutamide, warfarin, niflumic acid, digoxin or phenytoin.
In patients with hepatic insufficiency (cirrhosis, Child-Pugh B), the kinetic profile of the metabolite shows the same T_max and T_1/2 and lower C_max (-65%) and areas under the curve (-29%), compared to healthy subjects.
In patients with severe renal insufficiency (creatinine clearance between 11 and 39 mL/min), the kinetic profile of the metabolite shows a lower C_max (-49%) and larger areas under the curve (+15%) and T_1/2 compared to healthy volunteers (creatinine clearance >70 mL/min).
In the paediatric population, the pharmacodynamic results are similar to those of the adult population, with C_max reached 2.5 hours post-dose. There is no accumulation after repeated doses every 8 hours for 7 days.
Excretion: Racecadotril is eliminated via its active and inactive metabolites. Elimination takes place mainly via the kidney (81.4%), and, to a lesser degree, via the faecal (around 8%). Excretion via the lungs is not significant (less than 1% of the dose).
Toxicology: Preclinical safety data: Four-week chronic toxicity studies performed in monkeys and dogs, useful for assessing the duration of treatment in humans, have not demonstrated any effect at dosages up to 1250 mg/kg/day and 200 mg/kg, corresponding to safety margins of 625 and 62 (compared to humans), respectively.
Racecadotril did not proved to be immunotoxic in mice treated for 1 month.
A longer duration of exposure (1 year) in monkeys showed generalised infections and reduced antibody responses to vaccinations (at a dose of 500 mg/kg/day) and no infection/immunosuppression at 120 mg/kg/day.
Similarly, in dogs treated at a dose of 200 mg/kg/day for 26 weeks, some infectious/immune reactions were detected. Their clinical significance is unknown: see Adverse Reactions.
No mutagenic or clastogenic effect of racecadotril was detected during standard tests in vivo and in vitro.
No carcinogenicity tests have been conducted, as treatment is short term.
Reproductive toxicity and development studies (pre-embryonic development and fertility, prenatal and postnatal development, embryo-foetal development studies) revealed no particular effect of racecadotril.
Other preclinical effects (such as severe, probably aplastic anaemia, increased diuresis, ketonuria, diarrhoea) were observed only at exposures well above the maximum human dose. Their clinical significance is not known.
A toxicity study conducted in juvenile rats showed no significant effect due to racecadotril at doses up to 160 mg/kg/day, corresponding to a dose 35 times higher than the recommended paediatric dose (e.g. 4.5 mg/kg/day).
Despite the immaturity of renal function in children less than 1 year old, higher exposure levels are not expected in this group.
Other safety pharmacology studies revealed no harmful effects on the central nervous system, the cardiovascular and respiratory functions.
In animals, racecadotril potentiates the effects of butylhyoscine on intestinal transit and the anticonvulsant effect of phenytoin.