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The pharmacologic approach to airway clearance: Mucoactive agents
Bruce K. Rubin, MEngr, MD, MBA, FRCPC
Professor and Vice-Chair of Pediatrics
Professor of Biomedical Engineering, Physiology and Pharmacology
Wake Forest University School of Medicine
Medical Center Blvd.
Winston-Salem, NC 27157-1081
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Rubin. Mucoactive medications. Page #
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Outline
1. Introduction
2. Expectorants
3. Medications that change the biophysical properties of secretions
3.1 Mucolytic agents
3.1.1 Classic mucolytics
3.1.2 Peptide Mucolytics
3.1.3 Nondestructive mucolytics
4. Mucokinetic agents
5. Cough clearance promotors
6. Mucoregulatory medications
7. Summary
1. Introduction
The airway mucosa responds to infection and inflammation in a variety of ways. This
response often includes surface mucous (goblet) cell and submucosal gland hyperplasia and
hypertrophy with mucus hypersecretion. Products of inflammation including neutrophil derived
DNA and filamentous actin (F-actin), effete cells, bacteria, and cell debris all contribute to
mucus purulence and, when this is expectorated it is called sputum. Mucoactive medications are
intended to serve one of two purposes; either to increase the ability to expectorate sputum or to
decrease mucus hypersecretion. Mucoactive medications have been classified according to their
proposed method of action (1). Sputum is expectorated mucus mixed with inflammatory cells,
cellular debris, polymers of DNA and F-actin, as well as bacteria. Mucus is usually cleared by
airflow and ciliary movement, and sputum is cleared by cough (2). In this review, I will discuss
each of these classes of medication, their proposed mechanism of action, and their potential use
in treating patients with chronic airways diseases associated with poor mucus clearance and with
mucus hypersecretion.
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2. Expectorants
Expectorants are defined as medications that are taken to improve the ability to
expectorate purulent secretions. This term is now taken to mean medications that increase airway
water or the volume of airway secretions. The most commonly used of these are simple
hydration including both bland aerosol administration and oral hydration, iodide containing
compounds such as SSKI or iodinated glycerol, glyceryl guaiacolate or guaifenesin, and the
more recently developed ion channel modifiers such as the P2Y2 purinergic agonists. Most of
these medications or maneuvers are ineffective at adding water to the airway and those that are
effective are also mucus secretagogues increasing the volume of both mucus and water in the
airways. Despite widespread use, iodinated compounds, guaifenesin, and simple hydration are
ineffective as expectorants (3). In fact, over-hydration has been shown to decrease airway mucus
clearance in some patients with chronic airway disease, particularly with acute asthma (4).
For many years, sputum induction using hyperosmolar saline inhalation has been used to
obtain specimens for the diagnosis of pneumonia. As summarized in the Cochrane Database, the
long term use of inhaled hyperosmolar saline improves pulmonary function in patients with
cystic fibrosis (CF) (5) and inhaled hyperosmolar saline or mannitol is beneficial in non-CF
bronchiectasis (6). Although this therapy is readily available and inexpensive, it has been
reported that hypertonic saline aerosol is not as effective as dornase alfa in the therapy of CF
lung disease (7).
Agents that increase transport across ion channels such as the CFTR chloride channel,
calcium dependent chloride channel, or agents that increase water transport across the airway
aquaporin water channels may increase the hydration of the periciliary fluid and so may aid
expectoration. These medications (including gene transfer vectors) are actively being
investigated. Early results using UTP to stimulate chloride secretion or amiloride to block
epithelial sodium channels were disappointing in that these did not produce a sustained
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improvement in pulmonary function in persons with CF (8) but newer P2Y2 chloride channel
activators appear to be more effective (9, 10).
In general, expectorant medications have not been consistently demonstrated to be
effective for the treatment of airway disease associated with mucus stasis or hypersecretion.
3. Medications that change the biophysical properties of secretions
The principal polymer component of normal airway mucus is mucin glycoprotein. The
mucin protein is heavily decorated with oligosaccharide side chains and the elongated
glycoproteins linearly polymerize and form a “tangled network” secondary structure. This
accounts for the gel structure of normal airway mucus. With chronic inflammation there is
thought to be hypersecretion of mucin although this has not been proven. In fact it has been
shown that there is mucus hyposecretion in the CF airway (11) and this may predispose the
airway to chronic infection with biofilm producing organisms. In sputum, a secondary polymer
network comprised of neutrophil derived DNA and F-actin also forms within the airway. This
DNA forms rigid polymer chains that copolymerize with cell wall associated actin (12). This
secondary polymer network is responsible for many of the abnormal properties of purulent
secretions.
3.1 Mucolytics
Mucolytic medications depolymerize either the mucin network (classic mucolytics) or the
DNA-actin polymer network (peptide mucolytics) and in so doing reduce the viscosity and
elasticity of airway secretions. Mucus has viscoelastic properties of both liquids (viscosity) and
solids (elasticity). Thus it is a gel and both the viscous (energy loss) and elastic (energy storage)
properties are essential for mucus spreading and clearance (13). Mucociliary clearance appears to
be dependent upon there being an optimal ratio of viscosity to elasticity (14). Mucolytic agents
have the potential to improve mucus rheology thus improving mucociliary or cough clearance,
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but these medications are also potentially able to over liquify secretions and this would decrease
clearance (15).
3.1.1 Classic Mucolytics
Classic mucolytics depolymerize the mucin glycoprotein oligomers by hydrolyzing the
disulfide bonds linking the mucin monomers. This is usually accomplished by free thiol
(sulfhydryl) groups hydrolyzing disulfide bonds attached to cysteine residues of the protein core.
The best known of these agents is N-acetyl L-cysteine (NAC) which is widely used for the
treatment of chronic bronchitis in Europe and Asia. There are few data available from placebo
controlled clinical trials of NAC or its derivatives, and these data do not demonstrate that NAC
improves mucus clearance or pulmonary function (16). The aerosol is available in the United
States but is often poorly tolerated by patients because of its sulfurous odor and because the pH
of 2.2 is associated with bronchospasm. NAC is an antioxidant and has been used to treat
acetaminophen overdose. The orally available compound is also available in Europe but despite
being a potent anti oxidant there are no data demonstrating that this medication is effective in the
treatment of chronic airway disease (17).
There are a number of similar compounds containing sulfhydryl groups that can
effectively depolymerize mucin polymers in vitro. Although many of these are better tolerated
than NAC, none have been clearly demonstrated to be effective in improving mucus clearance.
3.1.2 Peptide mucolytics
The mucin polymer network is essential for normal mucus clearance. It may be that the
classic mucolytics are generally ineffective because they are depolymerizing essential
components of the mucous gel. With airway inflammation and inflammatory cell necrosis, a
secondary polymer network develops in purulent secretions. In contrast to the mucin network,
this pathologic polymer gel serves no obvious purpose in airway protection or mucus clearance.
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The peptide mucolytics are designed specifically depolymerize the DNA polymer (dornase alfa)
or the F-actin network (e.g. gelsolin, thymosin beta 4).
Dornase alfa has seen wide acceptance as a peptide mucolytic for the treatment of cystic
fibrosis airway disease (18). When used as prescribed, its use is associated with improved
pulmonary function, decreased antibiotic use, and decreased hospitalization rate for many
patients with CF (19). For reasons that are not clear, this medication is not uniformly effective
for the treatment of CF airway disease and efficacy does not seem to be related to sputum DNA
content. There are limited and anecdotal data suggesting that dornase alfa may be effective in
treating some persons with non CF bronchiectasis including some patients with primary ciliary
dyskinesia (20). Although dornase alfa was not effective for the therapy of severe chronic
bronchitis, there are no published studies evaluating its potential efficacy in patients with milder
disease.
Both gelsolin and thymosin ß4 have been demonstrated to depolymerize the pathologic
DNA/F-actin network in CF sputum. These agents have never been studied in controlled clinical
trials.
3.1.3 Nondestructive mucolytics
Mucin is a polyionic tangled network and the charged nature of the oligosaccharide side
chains help to hold this network together as a gel. Several agents have been proposed that can
“loosen” this network by charge shielding. Such agents include low molecular weight dextran,
heparin, and other sugars or glycoproteins (21).
4. Mucokinetic agents
A mucokinetic medication is a drug that increases mucociliary clearance, generally by
acting on the cilia. Although a variety of medications such as tricyclic nucleotides, beta agonist
bronchodilators, and methylxanthines bronchodilators have all been demonstrated to increase
ciliary beat frequency, these agents have only a minimal effect on mucociliary clearance in
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patients with lung disease (22). The reason for this is probably a combination of factors including
the limited potential for efficacy in an airway with dysfunctional cilia or denuded of cilia. Most
of these agents are also mucus secretagogues which may paradoxically increase the burden of
airway secretions. Bronchodilator medications can also increase airway collapse in patients with
bronchomalacia by virtue of their ability to relax airway smooth muscle. Therefore, the only
persons for whom these medications are recommended are those who have improvement in
expiratory airflow following their use. Increased expiratory airflow can enhance the effectiveness
of cough (23). Thus bronchodilators might be better considered cough clearance promotors as
described below.
5. Cough clearance promotors
Cough becomes a major mechanism for mucus clearance when there is extensive ciliary
damage and mucus hypersecretion. Cough clearance depends on expiratory airflow, volume, and
force, and the biophysical properties of airway secretions. In general, decreasing the
viscoelasticity of airway secretions will not improve cough clearance unless this therapy also
releases mucus from adherent entanglements with cilia. As mucus becomes adherent to the
epithelium, it becomes far more difficult to expectorate. Patients who appear to benefit from
expectorants or mucolytic agents may do so by virtue of these medications releasing mucus from
epithelial attachment.
Agents that reduce the adhesivity of airway secretions and thus binding to the epithelium
are the abhesives. There is a thin layer of surfactant that serves to separate the periciliary fluid
and the cilia from the mucous layer permitting effective ciliary function and preventing secretion
adherence to the epithelium. With airway inflammation, there is extensive surfactant hydrolysis
by secretory phospholipases A2 (sPLA2) and the generation of lysophospholipids that appear to
increase mucus adhesivity (24). It has been shown that aerosolized surfactants are effective
abhesives and can significantly improve both cough clearability of secretions and pulmonary
function in patients with chronic bronchitis (25).
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Earlier generations of Venturi-driven jet nebulizers made it difficult to efficiently
aerosolize surfactant as this medication foams extensively and coats surfaces. Newer aerosol
delivery devices permit surfactant to be administered efficiently either as a dry powder or as a
wet aerosol. Studies are planned evaluating the potential effectiveness of surfactant for patients
with chronic airway diseases using some of these newer modes of drug delivery.
6. Mucoregulatory medications
Another approach to reducing the burden of airway secretions is to decrease
hypersecretion by goblet cells and submucosal glands. Medications that decrease mucus
hypersecretion are referred to as mucoregulatory medications. These medications include anti
inflammatory drugs such as corticosteroids which are effective at decreasing the inflammatory
stimulus that leads to mucus hypersecretion. Aerosolized indomethacin has also been used in
Japan to treat patients with diffuse panbronchiolitis who have impairment due to mucus
hypersecretion (26).
Anticholinergic medications are also extensively used as mucoregulatory medications.
Atropine is routinely given peri-operatively to prevent laryngospasm and to decrease mucus
secretion associated with endotracheal intubation. Atropine and its derivatives are
mucoregulatory medications in that they do not “dry” secretions but will decrease hypersecretion
that is mediated through M3 cholinergic mechanisms. The quaternary ammonium derivatives of
atropine including ipratropium bromide and tiotropium do not significantly cross the blood
airway barrier and as such, their use is not associated with typical systemic effects of
anticholinergic medications such as flushing or tachycardia. Ipratropium bromide is widely used
as a bronchodilator medication in patients with chronic bronchitis. Studies have also shown that
the long-term use of ipratropium is associated with a reduction in the volume of mucus secretion
in patients with chronic bronchitis (27). More specific M3 antagonists hold the promise of
improved mucoregulatory efficacy of this class of medications with less risk of adverse effects.
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Some of the more interesting of the mucoregulatory medications are the macrolide
antibiotics. These antibiotics were discovered 50 years ago and derivatives of erythromycin A
have been widely used for the treatment of bacterial infection. Since the mid 1960’s data have
been accumulating demonstrating that these medications also have immunomodulatory
properties. This means that they decrease hyperimmunity or inflammation to more normal and
beneficial levels. The mechanism for these properties appears to be different from that of the
corticosteroids. These immunomodulatory and mucoregulatory properties of macrolide
antibiotics have been exploited for the treatment of diffuse panbronchiolitis (DBP), a chronic
inflammatory airway disease with great morbidity and mortality when untreated. DPB is
primarily seen in Japan and Korea. Its etiology is unknown but the disease results in chronic
sinobronchitis with mucus hypersecretion and debilitation. Antibiotics and corticosteroids are
ineffective for the treatment of DPB. By virtue of their immunomodulatory and mucoregulatory
properties, the macrolide antibiotics have been demonstrated to be the most effective agents for
the treatment of DPB (28). Accumulating evidence suggests that the 14- and 15-membered
macrolides but not the 16 member macrolides, may also be highly effective for the therapy of CF
airway disease (29, 30). The mechanism of action of the macrolides as mucoregulatory agents is
under intensive study (31). It is anticipated that the development of macrolide medications
without antibiotic properties will significantly extend the spectrum of use of these medications.
7. Summary
Airway mucus hypersecretion and mucus retention is a significant problem for patient
with chronic airway disease. The burden of asthma, chronic bronchitis, bronchiectasis, CF, and
other airway diseases poses one of the most significant public health problems internationally.
Medications that can effectively improve mucus clearance would provide relief to millions of
persons around the world. Although many medications have been used clinically as mucoactive
therapy, there are few data to support any but a handful of these medications.
Rubin. Mucoactive medications. Page # 10
Table 1: Mucoactive agents
Mucoactive agent
Potential mechanisms of action
Expectorants
Hypertonic saline
Increases secretion volume and perhaps hydration
Classical mucolytics
N-acetylcysteine
Severs disulfide bond linking mucin oligomers
Nacystelyn
Increases chloride secretion and severs disulfide bonds
Peptide mucolytics
Dornase alfa
Hydrolyzes DNA polymer with reduction in DNA length
Gelsolin or Thymosin β4
Depolymerizes F-actin
Non-destructive mucolytics
Dextran
Breaks hydrogen bonds and increases secretion hydration
Low molecular weight heparin
May break both hydrogen and ionic bonds
Mucoregulatory agents
Anticholinergic agents
Decreases volume of stimulated secretions
Glucocorticoids
Decreases airway inflammation and mucin secretion
Indomethacin
Decrease airway inflammation
Macrolide antibiotics
Decreases airway inflammation and mucin secretion
Cough clearance promotors
Bronchodilators
Can improve cough clearance by increasing expiratory flow
Surfactants
Decreases sputum adhesiveness
Rubin. Mucoactive medications. Page # 11
Table 2 Airway targets for mucoactive medications
Rubin. Mucoactive medications. Page # 12
References
1. Rubin BK, Tomkiewicz RP, King M. Mucoactive agents: old and new. In: Wilmott RW, ed.
The Pediatric Lung. Basel: Birkhäuser Publishing, 1997:155-179.
2. Rubin BK and van der Schans CP. Eds. Therapy for Mucus Clearance Disorders. Biology of
the Lung Series, Claude Lenfant (NIH) Executive editor. Marcel Dekker. March 2004
3. Jager EG. Double-blind, placebo-controlled clinical evaluation of guaimesal in outpatients.
Clinical Therapeutics 1989;11:341-62.
4. Shim C, King M, Williams MH, Jr. Lack of effect of hydration on sputum production in
chronic bronchitis. Chest 1987;92:679-82.
5. Wark PA, McDonald V, Jones AP. Nebulised hypertonic saline for cystic fibrosis. Cochrane
Database Syst Rev. 2005;(3):CD001506
6. Wills P, Greenstone M. Inhaled hyperosmolar agents for bronchiectasis. Cochrane Database
Syst Rev. 2002;(1):CD002996).
7. Suri R, Metcalfe C, Lees B, et al. Comparison of hypertonic saline and alternate-day or daily
recombinant human deoxyribonuclease in children with cystic fibrosis: a randomised trial.
Lancet. 2001;20;358:1316-21
8. Graham A, Hashani A, Alton EW, et al. No added benefit from nebulized amiloride in patients
with cystic fibrosis. Eur Respir J 1993; 6:1243-48.
9. Noone PG, Hamblett N, Accurso F, et al. Safety of aerosolized INS 365 in patients with mild
to moderate cystic fibrosis: results of a phase I multi-center study. Pediatr Pulmonol.
2001;32:122-28.
10. Deterding R, Retsch-Bogart G, Milgram L, et al. Safety and tolerability of denufosol
tetrasodium inhalation solution, a novel P2Y2 receptor agonist: results of a phase 1/phase 2
multicenter study in mild to moderate cystic fibrosis. Pediatr Pulmonol. 2005;39:339-48.
11. Henke MO, Renner A, Huber RM, Seeds MC, Rubin BK. MUC5AC and MUC5B mucins
are decreased in cystic fibrosis airway secretions. Am J Respir Cell Mol Biol. 2004; 31:86-91.
Rubin. Mucoactive medications. Page # 13
12. Tomkiewicz RP, Kishioka C, Freeman J, Rubin BK. DNA and actin filament ultrastructure in
cystic fibrosis sputum. In: Baum G, ed. Cilia, Mucus and Mucociliary Interactions. New York:
Marcel Dekker, 1998:333-341.
13. King M, and Rubin BK. Mucus rheology: Relationship with transport. Chapter 7 in Airway
secretion: Physiological Bases for the Control of Mucus Hypersecretion. Ed. T. Takishima.
Marcel Dekker, Inc. New York. 1994 pp. 283-314.
14. Puchelle E, Zahm JM, Girard F, Bertrand A, Polu JM, Aug F, Sadoul P. Mucociliary
transport in vivo and in vitro. Relations to sputum properties in chronic bronchitis. Eur J Respir
Dis 1980; 61:254-264.
15. Rubin BK, MacLeod PM, Sturgess JM, King M. Recurrent respiratory infections in a child
with fucosidosis: Is the mucus too thin for effective transport? Pediatr Pulmonol 1991; 10:304-09
16. Grandjean EM, Berthet P, Ruffmann R, and Leuenberger P. Efficacy of oral long-term Nacetylcysteine in chronic bronchopulmonary disease: A meta-analysis of published double-blind,
placebo-controlled clinical trials. Clin Ther 2000; 22:209-221.
17. Decramer M, Rutten-van Molken M, Dekhuijzen PN, et al. Effects of N-acetylcysteine on
outcomes in chronic obstructive pulmonary disease (Bronchitis Randomized on NAC CostUtility Study, BRONCUS): A randomised placebo-controlled trial. Lancet. 2005;365:1552-60.
18. Laube BL, Auci RM, Shields DE, et al. Effect of rhDNase on airflow obstruction and
mucociliary clearance in cystic fibrosis. Am J Respir Crit Care Med 1996; 153:752-60.
19. Fuchs HJ, Borowitz DS, Christiansen DH, et al. Effect of aerosolized recombinant human
DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with
cystic fibrosis. N Engl J Med 1994; 331:637-42.
20. Rubin BK. Who will benefit from DNase? Pediatric Pulmonology 1999; 27:3-4.
21. Feng W, Garrett H, Speert DP, King M. Improved clearability of cystic fibrosis sputum with
dextran treatment in vitro. Am J Respir Crit Care Med 1998;157:710-714.
22. Isawa T, Teshima T, Hirano T, Ebina A, Konno K. Effect of oral salbutamol on mucociliary
clearance mechanisms in the lungs. Tohoku J Experimental Med 1986;150:51-61
Rubin. Mucoactive medications. Page # 14
23. King M, Brock G, Lundell C. Clearance of mucus by simulated cough. J Appl Physiol 1985;
58: 1776-82.
24. Hite RD, Seeds MC, Jacinto RB, Balasubramanian R, Waite M, Bass D. Hydrolysis of
surfactant-associated phosphotidylcholine by mammalian secretory phospholipases A2. Am J
Physiol 1998: 275 (Lung Cell Mol Physiol 19): L740-47.
25. Anzueto A, Jubran A, Ohar JA, et al. Effects of aerosolized surfactant in patients with stable
chronic bronchitis. A prospective randomized controlled trial. J Am Med Assoc 1997; 278:142631.
26. Tamaoki J, Chiyotani A, Kobayashi K, Sakai N, Kanemura T, Takizawa T. Effect of
indomethacin on bronchorrhea in patients with chronic bronchitis, diffuse panbronchiolitis, or
bronchiectasis. Am Rev Respir Dis 1992;145:548-52.
27. Tamaoki J, Chiyotani A, Tagaya E, Sakai N, Konno K. Effect of long term treatment with
oxitropium bromide on airway secretion in chronic bronchitis and diffuse panbronchiolitis.
Thorax 1994;49:545-48.
28. Shinkai M, Rubin BK. A global perspective on macrolide use. Japanese J Antibiotics
2005;58:129-32.
29. Shinkai M, Park CS, Rubin BK. Immunomodulatory effects of macrolide antibiotics. Clin
Pulm Med 2005;12:341-349.
30. Jaffé A, Bush A. Anti-inflammatory effects of macrolides in lung disease. Pediatric
Pulmonology 2001;31:464-73.
31. Rubin BK and Tamaoki J. Eds. Antibiotics as Anti-inflammatory and Immunomodulatory
Agents. Birkhäuser Verlag AG, Basel. November 2004.