Source: European Medicines Agency (EU) Revision Year: 2016
Pharmacotherapeutic group: Cough and cold preparations, Mucolytics
ATC code: R05CB06
Ambroxol, a substituted benzylamine, is a metabolite of bromhexine. It differs from bromhexine by the absence of a methyl group and the introduction of a hydroxyl group in the para-trans position of the cyclohexyl ring. Although its mechanism of action has yet to be completely elucidated, mucolytic and secretomotor effects have been found in various investigations.
Action following oral administration commences after 30 minutes on average and persists for 6-12 hours depending on the extent of the single dose.
In preclinical investigations, it increases the proportion of serous bronchial secretion. The transport of mucus is thought to be promoted by the reduction of viscosity and the activation of the ciliated epithelium.
Ambroxol induces activation of the surfactant system by acting directly on the type II pneumocytes of the alveoles and the Clara cells in the region of the small airways.
It promotes the formation and outward transfer of surface-active material in the alveolar and bronchial region of the foetal and adult lungs. These effects have been demonstrated in cell cultures and in vivo on various species.
Following use of ambroxol, concentrations of the antibiotics amoxicillin, cefuroxime, erythromycin and doxycycline in the sputum and in the bronchial secretion are increased. To date, it has not been possible to surmise a clinical relevance from this.
Ambroxol is practically completely absorbed following oral administration. Tmax following oral administration is 1-3 hours. The absolute bioavailability of ambroxol on oral administration is reduced by approx. one third by a first-pass effect. Renally excreted metabolites (e.g. dibromo anthranilic acid, glucuronides) are formed in the process. Binding to plasma proteins is approx. 85% (80-90%). The terminal half-life in the plasma is 7-12 hours. The plasma halflife of the sum of ambroxol and its metabolites is approx. 22 hours.
Ambroxol crosses the placental barrier and passes into the cerebrospinal fluid and breast milk.
Excretion is 90% renal in the form of metabolites formed in the liver. Unchanged ambroxol accounts for less than 10 % of renal excretion.
Due to the high protein binding and the high volume of distribution, as well as the slow redistribution from the tissue to the blood, major elimination of ambroxol through dialysis or forced diuresis is not expected.
Clearance of ambroxol is diminished by 20-40% in severe hepatic diseases. In severe renal dysfunction, an accumulation of the metabolites of ambroxol must be expected.
Preclinical data based on conventional studies on the safety pharmacology, investigations on the toxicity following acute and repeated administration, genotoxicity and carcinogenicity show no particular risk for humans.
Investigations of reproductive toxicity on the rat and rabbit have produced no evidence of a teratogenic potential up to a dose of 3 g/kg body weight and 200 mg/kg body weight respectively. The peri- and postnatal development of rats was impaired only at a dose of 500 mg/kg. Fertility disturbances in rats were not observed at a dose of up to 1.5 g/kg.
Ambroxol clears the placental barrier and crosses into breast milk in animals.
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