The effect of ambroxol in the treatment of cough

Prepared by Dr. Laura Tamašauskienė

Introduction Cough is an important defense mechanism of the body (1). It is classified as acute, lasting less than 3 weeks, subacute, lasting from 3 to 8 weeks, and chronic, lasting more than 8 weeks (2). Acute cough is most commonly caused by acute upper respiratory tract infections (2). Subacute cough occurs after a respiratory tract infection. Chronic cough, associated with a lower quality of life, is usually a symptom of various chronic diseases - chronic obstructive pulmonary disease (COPD), asthma, rhinitis, gastroesophageal reflux (2, 3). Chronic cough can be caused by smoking and the use of certain medications (2). Chronic cough affects 9.6% of individuals worldwide (3). In Europe, this symptom affects 12.7% of individuals (3). Cough can be non-productive (dry) or productive (wet). For example, in gastroesophageal reflux disease, a chronic non-productive cough is typical (4). Chronic productive cough is characteristic of bronchiectasis, COPD, asthma (4). In acute upper respiratory tract infections, acute cough is initially non-productive, later becoming productive (5). Acute productive cough is typical in pneumonia and pertussis (5). Mucolytics are medications used to facilitate productive cough. These drugs liquefy mucus by breaking down mucopolysaccharide chains, making it easier to remove secretions from the respiratory tract (6). Early administration of mucolytics can stop the development of subacute cough (7). One of the representatives of this group of drugs is ambroxol. It is prescribed to liquefy mucus formed during productive cough in acute or chronic bronchial and lung diseases (8). Ambroxol is a metabolite of bromhexine. After taking this medication, the effect occurs on average after 30 minutes and lasts 6-12 hours depending on the size of the single dose (8). This article reviews the effect of ambroxol.

Anti-inflammatory effect of ambroxol Inflammation is the immune system's response to harmful stimuli. Inflammatory cells are activated at the site of inflammation, promoting the release of proteolytic enzymes, cytokines, nitric oxide, and superoxide anion (9). In inflamed tissues, inflammatory cells are activated by leukotrienes, granulocyte, and macrophage colony-stimulating factor. The physiological role of the inflammatory response is to eliminate harmful factors, but it is not always possible to avoid the effects of factors causing inflammation (e.g., allergens, tobacco smoke), leading to a prolonged process (9). This can lead to chronic inflammatory diseases. In acute diseases such as acute upper respiratory tract infection, the inflammatory response to the virus causes tissue damage and symptom manifestation (9). Many studies have analyzed the anti-inflammatory effect of ambroxol. In acute inflammation, chemoattractants and/or cytokines with these properties are the first to initiate the inflammatory response. One of the most important chemoattractants during acute inflammatory response (e.g., viral infection) is leukotriene B4 (LTB4). It promotes the functions of monocytes, macrophages, and neutrophils (9). Studies show that leukotriene B4 is also involved in the pathogenesis of COPD. In studies using an acute inflammation model, ambroxol effectively reduced the secretion of LTB4 from monocytes and neutrophils (9). There is data that ambroxol inhibits neutrophil response to various chemoattractants (9). Interleukins (IL) also play a significant role in the inflammatory response. One of them, IL-8, has a chemotactic effect on neutrophils and macrophages. Studies show that when ambroxol is administered, the secretion of IL-8 from bronchial epithelial cells decreases (9). Patients with COPD treated with ambroxol showed a decreased level of IL-8 in the blood and saliva after 10 days (9). Furthermore, based on scientific literature, ambroxol reduces the frequency of exacerbations of chronic bronchitis and/or COPD (9). Inflammatory processes involve not only neutrophils and monocytes but also other cells - basophils, eosinophils. They act in allergic diseases. These cells respond to cytokines produced by type 2 T helper cells (Th2) and mast cells - IL-4, IL-13, IL-5, as well as the mediator cysteinyl leukotriene, vasoactive peptides (e.g., histamine) (9). Studies have shown that ambroxol reduced the levels of cysteinyl leukotriene, IL-4, IL-13, and histamine, as well as the release of histamine from mast cells (9, 10). In patients with asthma, ambroxol reduced the sensitivity of the airways to methacholine when administered for 14 days at 90 mg (9). An in vitro study revealed a significant decrease in IL-1 secretion from macrophages and IL-2 secretion from peripheral blood mononuclear cells and bronchoalveolar lavage when ambroxol was administered (9). This drug reduced the secretion of gamma interferon. In a study with animals suffering from acute lung inflammation, ambroxol reduced the levels of IL-6 and tumor necrosis factor alpha (9, 10). Gibbs et al. demonstrated that ambroxol inhibits IgE-mediated histamine release from mast cells located in the skin (11). Antioxidant effect of ambroxol Studies have revealed that Ambroxol has a free radical-neutralizing effect (9, 10, 12). It is believed to protect against oxidative stress caused by tobacco smoke and other inhaled toxic substances (10). A study with laboratory animals showed that Ambroxol can protect the heart from cytotoxic agents (e.g., doxorubicin) induced lipid peroxidation (10). Ambroxol inhibits the breakdown of hyaluronic acid and the damage of alpha-1 antiproteinase caused by peroxynitrite and hypochlorous acid, as well as the production of superoxide anion, hydrogen peroxide, and nitric oxide (9). Most studies evaluating Ambroxol's antioxidant properties have been conducted with laboratory animals or in vitro. There are few studies in the scientific literature conducted with patients. Ambroxol has a high affinity for lung tissue, so its concentration in the lungs is about 20 times higher than in the blood serum. Ambroxol stimulates surfactant production in the respiratory tract (12). Antioxidants are found in the composition of surfactant. Therefore, by increasing the amount of surfactant, Ambroxol indirectly reduces oxidative stress in the lungs (12). The Effect of Ambroxol on the Penetration of Antibiotics into Lung Tissue Scientific studies provide data that Ambroxol can improve the penetration of antibiotics into lung tissue. In one study, 60 patients with LRTI producing purulent sputum were divided into 3 groups. They were treated with amoxicillin, erythromycin, or cefuroxime. Some patients were given Ambroxol (90 mg/day) with antibiotic therapy, while others received a placebo. The treatment lasted for 7 days. On days 1 and 7 of treatment, the concentration of antibiotics in blood serum and bronchial secretions was measured. The results showed that Ambroxol significantly increased the concentration of antibiotics in bronchial secretions compared to the placebo (13). In another study, patients with lower respiratory tract bacterial infection were treated with amoxicillin (1,500 mg/day) or a combination of amoxicillin (1,500 mg/day) and Ambroxol (90 mg/day). The results showed that in patients treated with the combination of Ambroxol and amoxicillin, the concentration of amoxicillin in plasma and sputum was significantly higher compared to the subjects who did not take Ambroxol. Additionally, patients taking Ambroxol recovered from fever more quickly (13). Wang et al., after conducting in vitro studies, found that treating Pseudomonas aeruginosa infection, ciprofloxacin's antibacterial activity increases when Ambroxol is administered concurrently (14). Summary Coughing is an important defense mechanism of the body. It is a common symptom of various diseases. Cough is classified by duration (acute, subacute, and chronic) and nature (productive and nonproductive). Mucolytics, such as Ambroxol, are prescribed to treat acute or chronic productive cough. It thins mucus by breaking down mucopolysaccharide chains, making it easier for secretions to be removed from the respiratory tract. Ambroxol effectively reduces coughing both in acute upper respiratory viral infections and chronic lower respiratory diseases (LRTIs). Scientific studies show that Ambroxol has a broader effect - it has anti-inflammatory and antioxidant properties. There is evidence that this drug reduces the frequency of exacerbations in LRTIs. Furthermore, when used with antibiotics, Ambroxol improves their penetration into lung tissue.

Publication "Internistas" No. 1, 2018.

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