Exflem/Exflem 200 Mechanism of Action

Pharmacologic Classification: Mucolytic.
Pharmacology: Pharmacodynamics: Exflem: Mechanism of Action:  Acetylcysteine, the N-acetyl derivative of the naturally occurring amino acid, L-cysteine, is a mucolytic agent, an antidote for paracetamol poisoning and a sulfhydryl donor. Acetylcysteine has an intense mucolytic action on mucoid and mucopurulent secretions due to its ability to split disulfide bonds in mucous glycoprotein altering their configuration to improve flow characteristics thus reducing the viscosity of mucus. Acetylcysteine has antioxidant action because of its nucleophilic free thiol (-SH) group that directly interacts with electrophilic groups of the oxidative radicals. Acetylcysteine protects α1-antitrypsin (an enzyme that inhibits elastase) from inactivation by hypochlorous (HOCl) acid. Hypochlorous acid (HOCl) is a potent oxidative agent produced by the myeloperoxidase enzyme of activated phagocytes. These activities make acetylcysteine particularly appropriate for the treatment of acute and chronic conditions of the respiratory system characterized by mucoid and mucopurulent dense and viscous secretions.
Exflem 200 Pharmacodynamic properties: Acetylcysteine is a derivative of the amino acid cysteine. The efficacy of acetylcysteine is secretolytic and secretomotoric in the area of the bronchial tract. It is discussed that it splits off the interconnecting disulphide bonds between the mycopolysaccharide chains and that it has a depolymerizing effect on DNA-chains (in purulent mucus). Due to these mechanisms, the viscosity of mucus should be reduced.
An alternative mechanism of acetylcysteine is meant to be based on the capacity of its reactive SH group to bind chemical radicals and to detoxify then in this way.
Furthermore, acetylcysteine contributes to an increase in glutathione synthesis, which is important for the detoxification of noxae. This provides the explanation for its antidotal effect in paracetamol intoxication.
A protective effect on the frequency and severity of bacterial exacerbations - when acetylcysteine is administered prophylactically - is described in patients with chronic bronchitis/mucoviscidosis.
Pharmacokinetics: Exflem Bioavailability: Acetylcysteine is rapidly absorbed from the gastrointestinal tract and transported to the liver via the portal circulation, where it undergoes extensive first-pass metabolism. The oral bioavailability of acetylcysteine varies between 6 and 10%. Peak plasma concentrations are observed approximately 0.5 to 1 hour after oral doses of 200 to 600 mg. Acetylcysteine may be present in plasma as the parent compound or as various oxidized metabolites such as N-acetylcysteine, N,N-diacetylcysteine, and L-cysteine. L-cysteine itself is metabolized to glutathione, protein, taurine, and sulfate. Renal clearance may account for about 30% of total body clearance. The terminal half-life of total acetylcysteine is 6.25 hours after oral dosing.
Exflem 200 Following oral administration, acetylcysteine is rapidly and almost completely absorbed and metabolized in the liver to cysteine, the pharmacologically active metabolite, as well as to diacetylcystine, cystine and further mixed disulphides. Due to the high first-pass effect, the bioavailability of orally administered acetylcysteine is very low (approx. 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 approx. 2 μmol/l. The protein binding of acetylcysteine was determined to be about 50%.
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, diacetylcystine) 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.
Pharmacokinetic studies with intravenous administration of acetylcysteine revealed a distribution volume of 0.47 L/kg BW (in total) or 0.59 L/kg BW (reduced); the plasma clearance was determined to be 0.11 L/h/kg BW (in total) and 0.84 L/h/kg BW (reduced), respectively. The elimination half-life after i.v. administration is 30-40 minutes while excretion follows three-phase kinetics (α, β, and terminal δ phase).
Acetylcysteine crosses the placenta and is detectable in cord blood. No information is available regarding the excretion into breast milk.
No information is available concerning the behaviour of acetylcysteine at the blood-brain barrier in humans.
Exflem 200: Toxicology: Preclinical safety data: Acute toxicity: See Overdosage.
Chronic toxicity: Studies in various animal species (rat, dog) with a duration of up to one year did not show any pathological alterations.
Tumorigenic and mutagenic potential: No mutagenic effects of acetylcysteine are to be expected. An in vitro test was negative.
No studies of a tumorigenic potential of acetylcysteine have been carried out.
Reproductive toxicology: Embryotoxicity studies have been performed in pregnant rabbits and rats receiving oral doses of acetylcysteine during organogenesis. The dose was 250, 500 and 750 mg/kg in rabbits and 500-1,000 mg/kg in rats. No malformations were observed in any of the studies.
Fertility studies, perinatal and postnatal studies have been performed with oral acetylcysteine in rats. The results of these studies showed that acetylcysteine does not affect gonadal function, fertility rape, parturition, lactation or the development of newborn animals.
N-acetylcysteine passes the placenta in rats and was identified in amniotic fluid. The concentration of the metabolite L-cysteine in placenta and foetus is above the maternal plasma concentration for up to 8 hours after oral administration.