Introduction 

Ambroxol (Figure 1) (trans-4-(2-amino-3,5-dibrombenzylamino)-cyclohexanol), an active metabolite of bromhexine (2,4-dibromo-6-{[cyclohexyl (methyl)amino]methyl}aniline), is a widely used muco-active agent [1-2]. It is used to facilitate the removal of mucus from the airways and decrease mucus tenacity associated with a variety of respiratory diseases including episodes of acute upper respiratory tract infection [1]. Ambroxol hydrochloride is reported as having multiple clinically relevant actions including reduction of mucus viscosity, stimulation of airway surfactant secretion [3], anti-inflammation [4] and analgesia [5-7].

Therapeutic indications of Ambroxol hydrochloride

Prophylaxis of respiratory distress syndrome

Stimulation of foetal lung maturation and prophylaxis of respiratory distress syndrome in pregnancies where:

? spontaneous preterm delivery during weeks 28-34 is imminent;

? elective preterm delivery during weeks 28-34 is indicated as a result of foetal or maternal emergencies such as Rh incompatibility, diabetes or pre-eclampsia.

Ambroxol hydrochloride (Mucosolvan) concentrate for solution for infusion can also be used up to week 36 of pregnancy in cases where lung maturation has been shown by amniocentesis to be inadequate.

Pharmacodynamic properties

Ambroxol hydrochloride, a substituted benzylamine, is a metabolite of bromhexine. It differs from bromhexine in that a methyl group is absent and a hydroxyl group is present at the para-trans position on the cyclohexyl ring. Although its mechanism of action has not yet been fully elucidated, ambroxol hydrochloride has been shown to have mucolytic and secretomotor properties in various studies.

Ambroxol hydrochloride (Mucosolvan) concentrate for solution for infusion stimulates the formation and supply of surfactant in the alveoli and bronchioles by virtue of its effect on type II alveolar cells and Clara cells, as shown in morphological studies and metabolic studies on surfactant. It promotes histologically and biochemically detectable foetal lung maturation as well as improving respiratory physiological parameters such as lung compliance. Clinically, this results in an improvement in spontaneous breathing and a reduction in ventilatory requirements in immature neonates. The ability of ambroxol hydrochloride concentrate for solution for infusion to modify surfactant is due to regulatory effects on surfactant biosynthesis and metabolism. Because of the physiological mechanisms involved, these effects only become apparent after a certain time. Three to five days' treatment is likely to be required for clinically detectable lung maturity to be achieved. In vitro, ambroxol hydrochloride significantly reduces cytokine release from both circulating and tissue-bound mononuclear and polymorphonuclear cells. Ambroxol hydrochloride has additionally been shown to have antioxidant properties in a number of preclinical studies.

Pharmacokinetic properties

The pharmacokinetics of 1000 mg ambroxol  hydrochloride administered as an intravenous infusion over 2 h were investigated in pregnant women. Peak drug levels, which were achieved at the end of the infusion, were 3.7 ± 1.4 μg/ml. An infusion carried out over 4 h is therefore associated with peak blood levels of 2.7 μg/ml, which decline to ca. 0.5 μg/ml 12 h after the start of the infusion and to 0.2 μg/ml after 24 h. Repeated once-daily infusions administered over several days resulted in only moderate accumulation (by a factor of 1.6) in an intra-individual comparison. The percentage of ambroxol hydrochloride which is bound to plasma proteins is ca. 90% in adults and 60 - 70% in neonates. Ambroxol hydrochloride crosses the placenta and reaches the foetal lung. On account of its lipophilic and hydrophilic structural elements, ambroxol hydrochloride is readily distributed in various tissues. The large distribution volume indicates higher concentrations in tissue than in plasma; it has been shown, for instance, that concentrations of the drug in lung tissue exceed those in plasma by a factor of ≥ 17. Studies in human liver microsomes have shown that CYP3A4 is the predominant isoform responsible for the metabolism of ambroxol. Otherwise, the drug is metabolised primarily in the liver by phase II reactions (glucuronide conjugation) and cleavage to dibromoanthranilic acid, which accounts for 8 - 10% of the dose; other metabolites are also formed in small quantities. All of these metabolites are predominantly (80 - 90%) excreted in the urine. It has been shown that, following intravenous administration, 4.6% of a dose is excreted in the urine as unchanged ambroxol whilst 35.6% is excreted in the urine as conjugated drug. In pregnant women, the terminal half-life was found to be ca. 7 h. Clearance in pregnant women was 857 ± 300 ml/min.

References

[1] M. Malerba, B. Ragnoli, Ambroxol in the 21st century: pharmacological and clinical update, Expert Opin. Drug Metab. Toxicol. 4 (8) (2008) 1119-1129.

[2] D. Paleari, G.A. Rossi, G. Nicolini, D. Olivieri, Ambroxol: a multifaceted molecule with additional therapeutic potentials in respiratory disorders of childhood, Expert Opin. Drug Discovery. 6 (11) (2011) 1203-1214.

[3] J. Germouty, J.L. Jirou-Najou, Clinical e?cacy of ambroxol in the treatment of bronchial stasis. Clinical trial in 120 patients at two different doses, Respiration 51 (Suppl. 1) (1987) 37–41.

[4] K.M. Beeh, et al., Antiinflammatory properties of ambroxol, Eur. J. Med. Res. 13 (2008) 557-562.

[5] C. de Mey, et al., Efficacy and safety of ambroxol lozenges in the treatment of acute uncomplicated sore throat, Arztl. Forsch. 58 (1) (2008) 557-568.

[6] Gaida et al., Ambroxol, a Nav 1.8-preferring Na+ channel blocker, effectively suppresses pain symptoms in animal models of chronic, neuropathic and inflammatory pain, Neuropharmacology 49 (2005) 1220-1227.

[7] J.D. Hull, R.A. Lyon, In vitro pharmacology of ambroxol: Potential serotonergic sites of action. Life Sci. 197 (2018) 67-72.