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Pharmacotherapeutic group: Syrup: mucolytics. ATC: R05CB01.
Pharmacology: Effervescent tab/Powd for oral soln: N-acetyl-L-cysteine (NAC), the active ingredient of FLUIMUCIL exerts an intense mucolytic action on mucous and mucopurulent secretions, by depolymerizing the mucoproteic complexes and the nucleic acids which confer viscosity to the vitreous and purulent component of the sputum and of other secretions.
Furthermore, NAC, exerts a direct antioxidant action, being provided with a free thiol (-SH nucleophillic) group, which is able to interact directly with the electrophilic groups of the oxidant radicals. Of particular interest is the recent demonstration that NAC protects the a1-antitrypsin, enzyme inhibitor of elastase, from the inactivation due to the action of hypochlorous add (HOCI), a powerful oxidant agent produced by the myeloperoxidase enzyme of activated phagocytes.
These features make FLUIMUCIL A particularly suitable for the treatment of acute and chronic affections of the respiratory system, characterized by thick and viscous mucous and mucopurulent secretions. Furthermore, the molecular structure permits the molecule to cross easily cellular membranes. Inside the cell, NAC is deacetylized, forming L-cysteine, an amino acid indispensable for glutathione synthesis (GSH).
GSH is a highly reactive tripeptide, found ubiquitously in the various tissues of animals and is essential for the maintenance of functional capacity as well as cellular morphological integrity, as it represents the most important protective, endocellular mechanism against oxidant radials, either of external or internal nature, as well as towards numerous cytotoxic substances.
NAC plays a role of primary importance in the maintenance of adequate GSH levels thus contributing to the cellular protection from harmful agents which, through progressive GSH depletion, would be able to express their cytotoxic action, as the case of acetaminophen poisoning.
Due to this mechanism of action, NAC is also indicated as a specific antidote in acetaminophen poisoning, in the course of a cyclophosphamide treatment and a haemorrhagic cystitis, (in the latter case it provides SH-groups necessary to inactivate acrolein, a toxic metabolite that affects the urinary mucosae, whilst not interfering with chemotherapy).
Syrup: Pharmacodynamics: N-acetyl-L-cysteine (NAC), the active substance of Fluimucil, has an intense mucolytic-fluidifying action on mucous and mucopurulent secretions. It depolymerises the mucoprotein complexes and the nucleic acids that confer viscosity to the glassy and purulent elements of the sputum and other secretions.
NAC, as such, also has a direct antioxidant action because it has a free nucleophilic thiol group (SH) that can interact directly with the electrophilic groups of oxidising radicals. The recent evidence showing that NAC protects α1-antitrypsin (an elastase-inhibiting enzyme) from inactivation by hypochlorous acid (HOCl), a powerful oxidising agent produced by the myeloperoxidase enzyme of activated phagocytes, is particularly interesting. The molecule's structure allows it to easily cross cellular membranes. Inside the cell, NAC is de-acetylated and L-cysteine becomes available - this amino acid is essential for glutathione synthesis (GSH).
GSH is a highly reactive tripeptide that is ubiquitously present in the various tissues of animals. It is essential for maintaining the cell's capacity to function and its morphological integrity, because it is the most important intra-cellular defense mechanism against oxidising radicals (endogenous or exogenous) and against many cytotoxic substances.
These activities make Fluimucil particularly suitable for treating acute and chronic infections of the airways characterised by thick, viscous mucous and mucopurulent secretions.
Pharmacokinetics: Effervescent tab/Powd for oral soln: Absorption: Acetylcysteine absorption after oral administration is rapid and complete.
The bioavailability of free acetylcysteine is only of 10%, due to a high first-pass metabolism.
After administration of a relatively high dose of 30 mg/kg body weight acetylcysteine, total acetylcysteine (free and bound) peak plasma concentration is about 67 nmol/ml, with a tmax of 0.75-1 hour.
After administration of 600 mg acetylcysteine in the form of tablets, the peak plasma concentration (Cmax) of total acetylcysteine (free and bound) amounts to 3.40 μg/ml (20.83 nmol/ml) with a tmax of 0.71 h (43 minutes). The AUC (area under the curve) is 10.06 μg*h/ml. The effect of food intake on systemic bioavailability after orally administered acetylcysteine has not been tested.
Distribution: Acetylcysteine is found in the body both in unchanged form and as oxidative metabolites, either in free form or reversibly bound to plasma proteins through disulfide bonds.
Acetylcysteine is mainly spread within the extracellular aqueous milieu. It is found mostly in the liver, kidneys, lungs and bronchial mucus.
Biotransformation: The metabolic process starts soon after the product administration: acetylcysteine is deacetylated in the intestinal wall through first-pass metabolism to L-cysteine, equally active, and then metabolized to inactive products.
Élimination: Approximately 30% of the administered dose is eliminated directly by renal excretion. The main metabolites are cystine and cysteine, but also small amounts of taurine and sulfates are excreted.
No studies concerning the elimination of the non-renally cleared fraction are available to date. After intravenous administration of 200 mg acetylcysteine in 6 subjects, an elimination half-life of 1.95 (0.95-3.57) hours for the reduced forms and of 5.58 (4.1-9.5) hours for total acetylcysteine was observed. After administration by oral route of a 400mg effervescent tablet (not identical to Fluimucil formulations), the half-life of total acetylcysteine amounts to 6.25 (4.59-10.6) hours.
Syrup: Absorption: In humans, acetylcysteine is completely absorbed after oral administration. Because of the gut wall metabolism and first-pass effect, the bioavailability of acetylcysteine taken orally is very low (approx. 10%). No differences were reported for the various pharmaceutical forms. In patients with various respiratory or cardiac diseases, the maximum plasma concentration (Cmax) is obtained between 2 to 3 hours after administration and the levels remain high over a period of 24 hours.
Distribution: Acetylcysteine is distributed both in the non-metabolized (20%) and the metabolized (active) (80%) form, and can mainly be found in the liver, kidneys, lungs, and bronchial secretions.
The volume of distribution of acetylcysteine ranges from 0.33 to 0.47 L/kg. Protein binding is about 50%, four hours after the dose and decreases to 20% at 12 h.
Acetylcysteine crosses the placenta.
Biotransformation: Acetylcysteine undergoes rapid and extensive metabolism in the gut wall and liver following oral administration.
The resulting compound, cysteine, is considered to be an active metabolite. Following this stage of transformation, acetylcysteine and cysteine share the same metabolic route.
Elimination: Renal clearance may account for about 30% of total body clearance. Following oral administration, the terminal half-life of total acetylcysteine is 6.25 (4.59 to 10.6) hours.
Linearity/non-linearity: The pharmacokinetics of acetylcysteine is proportional to the administered dose in the dose range between 200-3200 mg/m2 for area under the plasma concentration time curve (AUC) and Cmax.
Toxicology: Preclinical safety data: Syrup: Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and toxicity to reproduction and development.
In acute toxicity studies, the oral LD50 values were determined as 8 g/kg and >10 g/kg in mice and rats, respectively.
In prolonged administration for 12 weeks, a dose of 1 g/kg/day by the oral route was well tolerated in rats. In dogs, the oral administration of 300 mg/kg/day for a period of one year did not result in toxic reactions.
Acetylcysteine was considered to be non-genotoxic on the basis of in vitro and in vivo studies.
Reproductive studies were conducted in rats at oral doses of up to 2,000 mg/kg per day and in rabbits at oral doses of up to 1,000 mg/kg per day; they did not demonstrate any impairment in female fertility or harmful effects on the foetus due to acetylcysteine. In addition, the treatment of male rats with acetylcysteine at an oral dose of 250 mg/kg per day for 15 weeks did not affect the fertility or general reproductive performance of the animals.
