Acetylcysteine

N-acetyl-L-cysteine (NAC), the active ingredient in acetylcysteine exerts an intense mucolytic-fluidizing 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 other secretions.

Acetylcysteine has been shown to dramatically reduce the viscosity and tenacity of sputum. The liquifying action is due to the presence of a free sulphydryl group which opens up disulphide bonds present in mucus. This pharmacological action of acetylcysteine is of benefit to patients suffering from ocular mucus abnormality. This combined with the emollient properties of hypromellose, ensures lubrication and soothing relief for dry eye syndrome.

Furthermore, acetylcysteine exerts a direct antioxidant action, having a free thiol (-SH) nucleophilic group that is able to interact directly with electrophilic groups of oxidant radicals. Of particular interest is the recent finding that acetylcysteine protects α1-antitrypsin enzyme inhibiting elastase from inactivation by hypochlorous acid (HOCl), a powerful oxidant agent produced by the myeloperoxidase enzyme of activated phagocytes. Due to its molecular structure, acetylcysteine can readily cross cell membranes. Inside the cell, NAC is deacetylated to L-cysteine, an amino acid essential 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. It is the most important protective intracellular mechanism against oxidant radicals, both exogenous and endogenous, as well as toward numerous cytotoxic substances.

These features make Acetylcysteine particularly suitable for the treatment of acute and chronic affections of the respiratory system, characterised by thick, viscous mucous and mucopurulent secretions.

There is no evidence on the efficacy and safety of mucolytics including acetylcysteine in acute bronchitis.

Oral administration

Absorption

Following oral administration, acetylcysteine is rapidly and almost completely absorbed and metabolised in the liver to cysteine (the pharmacologically active metabolite), diacetylcysteine, cysteine and further mixed disulphides.

Distribution

Due to the high first-pass effect, the bioavailability of orally administered acetylcysteine is very low (approximately 10%). In humans, maximum plasma concentrations are achieved after 1-3 hours with the maximum plasma concentration of the metabolite cysteine in the range of approximately 2µmol/l. The protein binding of Acetylcysteine was determined to be about 50%.

Biotransformation

Acetylcysteine and its metabolites occur in three different forms in the organism: partially in free form, partially bound to proteins via labile disulphide bonds and partially as incorporated amino acid. Acetylcysteine is excreted almost exclusively in the form of inactive metabolites (inorganic sulphates, diacetylcysteine) via the kidneys. The plasma half-life of Acetylcysteine is approximately 1 hour and is mainly determined by the rapid hepatic biotransformation. Impaired hepatic function therefore leads to prolonged plasma half-lives of up to 8 hours.

Elimination

Pharmacokinetic studies with intravenous administration of acetylcysteine revealed a distribution volume of 0.47 l/kg (in total) or 0.59 l/kg (reduced acetylcysteine); the plasma clearance was determined to be 0.11 l/h/kg (in total) and 0.84 l/h/kg (reduced acetylcysteine), respectively. The elimination half-life after intravenous administration is 30-40 minutes while excretion follows three-phase kinetics (alpha, beta and terminal gamma phase).

Acetylcysteine crosses the placenta and is detected in cord blood. No information is available regarding excretion in breast milk.

No knowledge is available concerning the behaviour of acetylcysteine at the blood-brain barrier in humans.

IV administration

Following intravenous administration of acetylcysteine using the standard 20-hour intravenous regimen, plasma levels of 300 to 900mg/l have been reported to occur shortly after the start of the infusion, falling to 11 to 90mg/l at the end of the infusion period. Elimination half-lives of 2 to 6 hours have been reported after intravenous dosing, with 20 to 30% of the administered dose being recovered unchanged in the urine.

Metabolism appears to be rapid and extensive. There is no information on whether acetylcysteine crosses the blood-brain barrier or the placenta, or whether it is excreted in breast milk.

Topical instillation into the conjunctival sac

No specific work has been carried out on the pharmacokinetic properties of acetylcysteine when used as a topical preparation for the eye. Acetylcysteine reduces the viscosity and tenacity of mucus in the eye. This, combined with the emollient properties of hypromellose, ensures lubrication and soothing relief for dry eye syndromes.

Acute toxicity studies in rats and mice, by oral, intraperitoneal and intravenous administration showed acetylcysteine to be of low toxicity. LD₅₀ values greater than 7 g/kg in mice and 6 g/kg in rats have been reported. Chronic toxicity studies with acetylcysteine in rats at doses up to 2000 mg/kg/day and dogs at doses up to 300 mg/kg/day for periods up to 52 weeks demonstrate that acetylcysteine is well tolerated, even at higher doses. In reproductive toxicity studies in rats and rabbits, the oral administration of doses up to 2000 mg/kg/day did not show changes in reproductive capacity, teratogenic effects or peri/postnatal toxicity.