Mucolytics Bromhexine

A molecular dissection of the alkaloid vasicine (52) ultimately resulted in the expectorant and mucolytic agent bromhexine (54). The synthesis starts with displacement of halogen on 2-nitrobenzyl-bromide (53) by N-methyl cyclohexylamine, followed by Raney nickel and hydrazine reduction of the nitro group. Bromination in acetic acid then affords bromhexine. 

Certain alkaloids such as vasicine obtained from plant Adhatoda vasica act as potent expectorant and mucolytic agent. Bromhexine, a derivative of vasicine depolymerises mucopolysaccharides directly and by liberating lysosomal enzymes. Another compound acetylcysteine opens disulfide bonds in mucoproteins present in sputum and decrease its viscosity. Carbocisteine acts in same manner. 

Mucolytic Agents (Acetylcysteine). Mucolytics soften mucus and make it more fluid.They also have an intracellular effect on goblet cells during mucin Ibrmation, facilitating production and improving quality. Therefore they may be considered mucin hypersecretors. Bromhexine, tyloxapol, A -acetylcysteine, and methylcysteine are examples of mucolytic agents. 

Bromhexine hydrochloride (Bisolvan) is a bronchial mucolytic agent and secretagogue that may have a stimulating effect on tear secretion. Oral bromhexine and its derivative ambroxol have equivocal results in clinical trials and are associated with side effects of nausea, sweating, and rashes. 

Bromhexine is taken orally or by aerosol and reduces sputum viscosity as measured ex vivo. Although it is still used empirically by some physicians, there have been no controlled studies showing a significant improvement in clinical status or lung function. Administration by inhalation aerosol or nasal spray produces a local expectorant/ mucolytic effect (1). Inhaled bromhexine (Paxirasol) reduces the amount of sputum, but does not reduce symptoms (SEDA-17, 208). 

Mucolytlcs - The problems presented by thick, tenacious sputum are central to the treatment of chronic bronchitis. There Is an Important need for effective mucolytlcs, particularly orally effective congiounds. The mucolytic-expectorant bromhexine (I), N-cyclohexyl-N-methyl-(2-amlno-3,5-dlbromobenzyl)ammonium chloride, was shown earlier to fragment the acid mucopolysaccharide fibers In sputum, thereby decreasing sputum viscosity. 

As mentioned above, LiB H4 has been used very successfully for reduction of a tertiary amide to an amine. Whereas treatment in trial reactions of238 with LiBHLt in THF solution at 65 °C gave the benzyl alcohol, the outcome in methylene chloride as solvent was different. Namely, reduction of 238 with LiB H in CH2CI2 at 40 °C gave 239, the mucolytic agent bromhexine, in 43% yield with a specific activity of 54Ci/mmol . 

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