Pediatric Respirology and Critical Care Medicine

REVIEW ARTICLE
Year
: 2020  |  Volume : 4  |  Issue : 4  |  Page : 54--57

An overview of mucoactive agents


Li-Sang Hsu1, Yung-Feng Huang2, Yee Husan Chiou1, Bao-Ren Nong3,  
1 Department of Pediatrics, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
2 Fu Jen Catholic University Hospital, Taishan District, Taiwan; Department of Pediatrics, National Defense Medical Center, Tri-Service General Hospital, Taipei, Taiwan
3 Department of Pediatrics, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan; Department of Pediatrics, National Defense Medical Center, Tri-Service General Hospital, Taipei, Taiwan

Correspondence Address:
Bao-Ren Nong
Department of Pediatrics, Kaohsiung Veterans General Hospital, No. 386, Dajhong 1st Road, Zuoying Dist., Kaohsiung City.
Taiwan

Abstract

Mucus production of the respiratory tract is our first defense against microbes and allergens. However, overproduction of the sputum and difficulty with airway clearance could lead to many respiratory tract diseases. Mucoactive agents are medications that either change the properties of the sputum or decrease its production. This article aims to provide an overview of common mucoactive agent.



How to cite this article:
Hsu LS, Huang YF, Chiou YH, Nong BR. An overview of mucoactive agents.Pediatr Respirol Crit Care Med 2020;4:54-57


How to cite this URL:
Hsu LS, Huang YF, Chiou YH, Nong BR. An overview of mucoactive agents. Pediatr Respirol Crit Care Med [serial online] 2020 [cited 2021 Dec 3 ];4:54-57
Available from: https://www.prccm.org/text.asp?2020/4/4/54/320780


Full Text



 Introduction



Our airway epithelium defends against the inhaled irritants such as dusts, microbes, and allergens. The first defense is the production of mucus, by goblet cells lining the surface epithelium, and seromucous gland beneath the mucosal epithelium. The mucus is composed of water, carbohydrates, proteins (glycoprotein), and lipids (surfactant) and forms a thin film on the surface of the airways. Normally, the mucus entraps the foreign debris, microbes, and dust and clears them from the airway by ciliary movement, termed mucociliary clearance. Rhythmic vibrations of the cilia propel it toward the pharynx from where it is swallowed unnoticeably. However, when the mucus is produced excessively and changed in nature, mucociliary clearance is impaired. Cough becomes essential for airway clearance in this pathologic state. The expectorated mucus, along with microorganisms, cell debris, and other foreign particles, together formed the sputum.[1],[2],[3]

Medications that affect mucus properties and promote the clearance are said to be mucoactive. Mucoactive medications include expectorants, mucolytics, mucoregulatory drugs, and mucokinetic drugs. They can help expectorating the sputum or decrease mucus hypersecretion.[4] As these medications are used widely clinically, this review article aims to discuss the mechanism and efficacy of them [Table 1].{Table 1}

 Pathophysiology



The surface epithelium of intrapulmonary airways is composed of ciliated cells and secretory cells. Secretory cells release not only mucins but also antimicrobial molecules (e.g., defensins, lysozyme, and immunoglobulin A), immunomodulatory molecules (e.g., secretoglobins and cytokines), and protective molecules (e.g., trefoil proteins and heregulin). Submucosal gland is constituted of mucous cells and serous cells. Mucous cells secret mucin while serous cells secret proteoglycans and antimicrobial proteins.[5]

Normal mucus consists of 97% water and 3% solids (mucins, nonmucin proteins, salts, lipids, and cellular debris). There are two mechanisms for the expulsion of mucus from the airway – mucociliary clearance and cough clearance. The efficacy of mucus clearance is determined by the viscous and elastic properties of mucus. Healthy mucus has low viscosity and elasticity, whereas pathologic mucus has higher viscosity and elasticity (which may contains up to 15% solids) and is less easily cleared. Impaired mucus clearance results in the accumulation of mucus, which in turn may lead to infection and inflammation by providing an environment for microbial growth.[5]

 Expectorants



The efficiency of mucus clearance depends on an adequate volume of airway surface liquid.[6] Airway surface dehydration may increase the adhesivity of secretions to the epithelium of airway and thus make it more difficult to expectorate.[7] Hydration is thought to aid sputum expectoration.[4] Expectorants can help expectorate purulent secretions, by increasing airway water or the volume of airway secretions. For example, hypertonic saline or dry powder mannitol acts through hydration of luminal secretions.

The inhalation of hypertonic saline produces an osmotic force and draws water from the interstitium to the airway surface layer[8] and therefore improves airway hydration and accelerates mucus transportability.[5],[7],[9] Inhalation of hypertonic saline promotes greater sputum expectoration than isotonic saline.[9] Inhaled hypertonic saline is generally safe and well tolerated, except for some mild adverse reactions, such as unpleasant salty taste, throat irritation, excessive coughing, or airway narrowing.[8] Immediate adverse reactions resolve rapidly. Cough typically decreases over time. Bronchodilator may be used before administration of hypertonic saline to prevent or minimize airway narrowing.[10] Addition of hyaluronic acid can decrease bronchospasm and balance water homeostasis in airways. The adverse reactions during inhalation are less frequent and milder in inhalation of hypertonic saline and hyaluronic acid than inhalation of hypertonic saline alone. Combination of hypertonic saline and hyaluronic acid is the preferred solution for treatment.[9]

Guaifenesin, or glyceryl guaiacolate ether, is an oral expectorant that is once thought to stimulate cholinergic muscarinic receptors via the vagus nerve in the gastric mucosa and therefore stimulate submucosal glands (also called gastropulmonary reflex).[11],[12] However, its precise mechanism of action has remained unclear.[12] Other studies found that guaifenesin reduces mucin production, decreases mucus viscoelasticity, and increases mucociliary transport.[13] Moreover, it has significant better efficacy in decreasing mucin production, mucus viscosity, and elasticity, and increasing mucociliary clearance rate, than N-acetyl cysteine (NAC) or ambroxol.[14] It is approved by the US Food and Drug Administration as an effective expectorant with a good safety profile.[15] It is also sold as over-the-counter cold and cough medicines. Recently, an extended-release formulation of guaifenesin was launched. It combines immediate-release guaifenesin with an extended-release feature, to provide sustained blood levels for 12h. Studies revealed that it improves cough and other discomfort related with excess mucus.[16] It is also shown to have safe and well tolerated.[11]

Ambroxol is a mucoactive agent that increases bronchial secretions,[17] stimulates ciliary activity,[18] activates the surfactant system of the lung,[19] and owns antioxidative/anti-inflammatory activities[20] in animal models. Ambroxol has been used for years, and early studies showed that it improves respiratory symptoms, such as ease of expectoration, phlegm loosening, and decrease in sputum volume and sputum viscosity, in adults.[21],[22] In studies regarding children with acute respiratory disease, both ambroxol and acetyl cysteine (NAC) were effective in improving symptoms (cough and expectoration), but ambroxol was either more effective or had a more rapid effect than NAC.[23],[24] In conclusion, its secretolytic and secretomotoric actions restore the physiological clearance mechanisms of the respiratory tract, and its clinical efficacy and safety in the management of acute and chronic lower respiratory diseases were well documented.[25]

 Classic Mucolytics



Mucolytics degrade the mucin polymers, deoxyribonucleic acid (DNA), fibrin, or filamentous actin (F-actin) in airway secretions and therefore decrease viscosity of the mucus.[4] Classic mucolytics, such as acetyl cysteine (NAC), hydrolyze the disulfide bonds of mucus proteins to decrease mucus viscosity, thereby facilitating its clearance.[26] However, studies reported no significant differences in sputum volume, ease of expectoration, and atelectasis between acetyl cysteine and placebo.[27] Oral acetyl cysteine is rapidly inactivated and does not appear in airway secretions. It is probably the reason why acetyl cysteine is effective in vitro but ineffective in vivo.[4] One study found aerosolized NAC to decrease sputum viscosity (subjective assessment), but there is no significant change in daily sputum volume or pulmonary function.[28] Due to lack of high-level evidence, routine use of aerosolized NAC to improve airway clearance is not recommended in hospitalized adult and pediatric patients without cystic fibrosis.[29]

 Peptide Mucolytics



Peptide mucolytics degrade polymers in the sputum, which are composed of DNA, F-actin polymers, and mucin gel.[30] Dornase alfa, a human recombinant DNase, digests extracellular DNA released during infection, which contributes to viscosity of exudates.[31] Several case reports demonstrated the use of dornase alfa in patients having status asthmaticus with mucus plugging and refractory to traditional therapy.[32],[33],[34],[35] However, in the setting of acute bronchiolitis or airway malacia with a respiratory tract infection in children, studies found no benefit in clinically meaningful outcomes with nebulized dornase alfa.[36],[37]

Thymosin β4 (Tβ4) is another peptide mucolytic that degrades F-actin. There was a direct relationship between actin filament length and sputum cohesivity. One study found that Tβ4 depolymerizes sputum actin in both a dose-dependent (between 0.3 and 3.0 µg/mL) and a time-dependent manner.[38] Synergy with Tβ4 and dornase alfa at a concentration of 1.5 µg/mL of each was also observed.[38]

 Mucoregulatory and Mucokinetic Agents



Mucoregulatory agents such as glucocorticosteroids and macrolide antibiotics own the anti-inflammatory activity. Anticholinergic drugs not only act as bronchodilator but also inhibit cholinergic nerve-induced mucus secretion. These medications therefore may reduce chronic mucus hypersecretion.[7]

Mucokinetic agents increase mucociliary clearance, generally by acting on the cilia.[4] These medications include β2-adrenoceptor agonist bronchodilators and surfactant. β2 agonists increase airflow and ciliary beat and therefore facilitate mucus movement. Surfactant reduces the adherence of mucus to the epithelium.[7]

 Summary



In both acute and chronic airway diseases, mucus hypersecretion and retention cause variable degrees of discomfort to the patients and therefore are a frequent complaint. Mucoactive agents hence play an important role in treating our patients, and it is important for us to understand the pathophysiology of mucus hypersecretion and the mechanisms of different types of mucoactive agents.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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