Mucosolvan 24 Hrs Mechanism of Action

Pharmacology: Preclinically ambroxol hydrochloride, the active ingredient of Mucosolvan, has been shown to increase respiratory tract secretion. It enhances pulmonary surfactant production and stimulates ciliary activity. These actions result in improved mucus flow and transport (mucociliary clearance).
Improvement of mucociliary clearance has been shown in clinical pharmacologic studies. Enhancement of fluid secretion and mucociliary clearance facilitates expectoration and eases cough.
In patients suffering from COPD, long-term treatment (6 months) with Ambroxol hydrochloride (Mucosolvan) Retard Capsule 75 mg resulted in a significant reduction of exacerbations that became evident after 2 months of treatment. Patients in the Ambroxol hydrochloride (Mucosolvan) treatment group lost significantly fewer days through illness and had fewer days when they needed antibiotic therapy. Treatment with Ambroxol hydrochloride (Mucosolvan) Retard Capsule 75 mg also induced a statistically significant improvement of symptoms (difficulty of expectoration, cough, dyspnea, auscultatory signs) compared with placebo.
A local anaesthetic effect of ambroxol hydrochloride has been observed in the rabbit eye model which may be explained by the sodium channel blocking properties. It was shown in vitro that ambroxol hydrochloride blocks cloned neuronal sodium channels; binding was reversible and concentration-dependent.
Cytokine release from blood but also tissue bound mononuclear and polymorphonuclear cells was found to be significantly reduced by ambroxol hydrochloride in vitro.
In clinical studies in patients with sore throat, pharyngeal pain and redness was significantly reduced.
These pharmacological properties are in accordance with the ancillary observation in clinical efficacy studies for the treatment with ambroxol hydrochloride of upper respiratory tract symptoms that leads to rapid relief of pain and pain related discomfort in the ear-nose-trachea region upon inhalation.
Following the administration of ambroxol hydrochloride antibiotic concentrations (amoxicillin, cefuroxime, erythromycin) in bronchopulmonary secretions and in the sputum are increased.
Antiviral properties in in vitro studies and in animal models in in vitro studies in human tracheal epithelial cells a reduction of rhinovirus replication has been observed. In a mouse airway model, a reduction of Influenza A virus replication was observed with ambroxol pretreatment.
Pharmacokinetics: Absorption: Absorption of all immediate release oral forms of ambroxol hydrochloride is rapid and complete, with dose linearity in the therapeutic range. Maximum plasma levels are reached within 1 to 2.5 hours following oral administration of the immediate-release formulation and after a median of 6.5 hours for the slow release formulation. The absolute bioavailability after a 30 mg tablet was found to be 79%. The slow release capsule showed a relative availability of 95% (dose-normalized) in comparison to a daily dose of 60 mg (30 mg twice daily) administered as immediate-release tablet.
Distribution: Distribution of ambroxol hydrochloride from blood to tissue is rapid and pronounced, with the highest concentration of the active substance found in the lungs. The volume of distribution following oral administration was estimated to be 552 L. In the therapeutic range, plasma protein binding was found to be approximately 90%.
Metabolism and elimination: About 30% of an orally administered dose is eliminated via first pass metabolism. Ambroxol hydrochloride is primarily metabolized in the liver by glucuronidation and some cleavage to dibromanthranilic acid (approximately 10% of dose) aside from some minor metabolites.
Studies in human liver microsomes have shown that CYP3A4 is responsible for the metabolism of ambroxol hydrochloride to dibromanthranilic acid. Within 3 days of oral administration, approximately 6% of the dose is found in free form, while approximately 26% of the dose is recovered in a conjugated form in the urine.
Ambroxol hydrochloride is eliminated with a terminal elimination half-life of approximately 10 hours. Total clearance is in the range of 660 mL/min, with renal clearance accounting for approximately 8% of the total clearance. It has been estimated that the amount of dose excreted in urine after 5 days represents about 83% of total dose (radioactivity).
Pharmacokinetics in special populations: In patients with hepatic dysfunction elimination of ambroxol hydrochloride is reduced, resulting in approximately 1.3 to 2-fold higher plasma levels. Due to the high therapeutic range of ambroxol hydrochloride, dose adjustments are not necessary.
Others: Age and gender were not found to affect the pharmacokinetics of ambroxol hydrochloride to a clinically relevant extent, and thus there is no necessity for adjustment of dosage regimens. Food was not found to influence the bioavailability of ambroxol hydrochloride.
Toxicology: Ambroxol hydrochloride has a low index for acute toxicity. In repeated-dose studies, oral doses of 150 mg/kg/day (mouse, 4 weeks), 50 mg/kg/day (rat, 52 and 78 weeks), 40 mg/kg/day (rabbit, 26 weeks) and 10 mg/kg/day (dog, 52 weeks) were the no observed adverse effect levels (NOAELs).
No toxicological target organs were detected.
Four-week intravenous toxicity studies with ambroxol hydrochloride in rats (4, 16 and 64 mg/kg/day) and in dogs (45, 90 and 120 mg/kg/day (infusions 3 h/day)) showed no severe local and systemic toxicity including histopathology. All adverse effects were reversible.
Ambroxol hydrochloride was neither embryotoxic nor teratogenic when tested at oral doses up to 3000 mg/kg/day in rats and up to 200 mg/kg/day in rabbits. The fertility of male and female rats was not affected up to 500 mg/kg/day. The NOAEL in the peri- and post-natal development study was 50 mg/kg/ day. At 500 mg/kg/day, ambroxol hydrochloride was slightly toxic for dams and pups, as shown by a retarded body weight development and reduced litter size.
Genotoxicity studies in vitro (Ames and chromosome aberration test) and in vivo (mouse micronucleus test) did not reveal any mutagenic potential of ambroxol hydrochloride.
Ambroxol hydrochloride did not show any tumorigenic potential in carcinogenicity studies in mice (50, 200 and 800 mg/kg/day) and rats (65, 250 and 1000 mg/kg/day) when treated with a dietary admixture for 105 and 116 weeks, respectively.