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SUPPLEMENT TO Journal of the association of physicians of india • MAY 2013 • VOL. 61
Role of Mucolytics in Wet Cough
Raja Dhar*
M
ucolytics or ‘cough syrup’ constitute the most common
medication used by a respiratory physician in India. In
this class, expectorants comprise the lions’ share of a general
physician’s prescription. This class of medication acts by reducing
the irritation of cough receptors due to mucous accumulation and
by coughing up of this mucous. The sequelae of mucous hypersecretion is airway obstruction, air flow limitation, ventilation
perfusion mismatch, and impairment of gas exchange.1,2 The
spectrum of diseases in which there is excessive sputum
production due to airway mucous hypersecretion include
asthma, chronic obstructive pulmonary disease (COPD) or
cystic fibrosis (CF). Slowing or paralysis of the mucociliary
escalator will reduce mucous clearance and increase bacterial
colonization leading to repeated lower respiratory tract infection
and exacerbations of airways disease.3-6 The issue of mucous
hypersecretion is however more relevant to COPD and its role
in asthma and CF is less well defined. It is hypothesized that in
asthma excess mucous not only causes airway plugging but also
contributes to bronchial hyper-responsiveness.3,5 Researchers
have further contemplated that chronic mucous hyper-secretion
reflects lack of asthma control leading in turn to accelerated
loss of lung function and increased mortality. In summary, this
results in airway obstruction, bacterial colonization and repeated
infections and exacerbation.
This mucous hypersecretion is a reflection of the inflammatory
process which is related to asthma, CF and COPD. Hence, it
would be important to develop drugs that address the airway
Table 1 : Theoretical requirements for pharmacotherapy of
airway mucus pathophysiology in asthma, COPD and CF
Overall Effect
Component Effects*
• Reduce viscosity (increase
elasticity?)
• Reduce DNA/filamentous actin
content of mucus (CF, COPD)
Facilitate mucus clearance (short• Increase ciliary function
term relief of symptoms)
• Induce cough
• Facilitate release of “tethered”
goblet cell mucin (asthma)
• Inhibit mucin secretion
• Treat airway/pulmonary
inflammation
• Reduce goblet cell number
• Reduce submucosal gland size
• Inhibit plasma exudation
(asthma)
Reverse hypersecretory
• Correct increased ratio of gland
phenotype (long-term benefit)
mucous cells to serous cells
(COPD)
• Reverse increased ratio of lowcharge glycoform MUC5B to
MUC5AC (COPD)
*
The relative importance of the individual component effects to airway
mucus pathophysiology is unclear. Consequently, it may be unnecessary
to meet all theoretical requirements, with inhibition of only certain
aspects having important clinical benefit; COPD - chronic obstructive
pulmonary disease; CF - cystic fibrosis; DNA - deoxyribonucleic acid;
MUC - mucin gene product
Consultant Pulmonologist, Fortis Hospital, Kolkata
*
mucous problem in these patients. The inflammatory processes
in these diseases results not only in the loss of respiratory
function, but also in the destruction of the surfactant layer by
airway phospholipases and by altering the biophysical properties
of mucous. The byproducts which accumulate as a result of this
inflammatory cascade includes neutrophil derived DNA and
filamentous actins (F-actin), dead or apoptotic cells, bacteria and
cellular debris.7 All these factors together contribute to mucous
purulence and the material expectorated is termed as sputum.
Drugs that are designed to specifically alter the viscoelastic
properties of mucous in addition to promoting clearance of
sputum are called “mucoactive”.
Mucoactive drugs can hence be classified as expectorants
mucoregulators, mucolytic or mucokinetics based on their
potential mechanism of action.
Mucolytics
Mucolytic can be classified into 2 categories “classic”
mucolytics depolymerise mucin glycoproteins and “peptides”
mucolytics: depolymerize DNA and F-actin polymer
networks. Classic mucolytics: The prototype agent in this group is
N-acetyl cysteine (NAC) which in addition to being a mucolytic
agent also has significant antioxidant and anti-inflammatory
properties. Nebulized NAC when administered as an aerosol
dissociates mucin disulphide bonds and other disulphide
bond crossed linked gel component to reduce viscosity. Due
to its antioxidant effect this agent can also protect against free
radical damage.7,8-11 NAC decreased airway inflammation by
reducing lysozyme and lactoferrin concentrations in smokers,12
inhibiting neutrophils and monocytes chemotaxis and oxidative
burst responses in vitro,13 reducing the activation and number
of neutrophils and macrophages in bronchoalveolar lavage and
smokers14,15 and by inhibiting the adherence of bacteria to ciliated
epithelial cells in vitro.16 There is good evidence of prove that
oral NAC has stabilized disease in idiopathic pulmonary fibrosis
and may also reduce exacerbation rates in chronic bronchitis.17,18
Other Mucolytics: Erdosteine and fudosteine: Erdosteine is an
antioxidant with mucolytic properties and also reduces bacterial
adhesiveness. A small randomized controlled trial showed fewer
exacerbations, reduced hospitalization time and improved
quality of life in patients with COPD that were treated with
erdosteine when compared with placebo;19 however, future
trials will be necessary to confirm these findings. Fudosteine
is a cysteine with greater bio-availability than NAC. It reduces
hypersecretion by down regulation of mucin gene expression.
Peptide Mucolytic: These bring down highly polymerized and
F-actin network that is characteristic of pus. Dornase alpha is a
proteolytic enzyme that cleaves DNA polymers and is used in the
long term treatment of mucous hypersecretion in CF.20 Dornase
α is used in children with CF with corresponding improvement
in lung function and outcome.21 However these agents need to
be evaluated further in clinical trial.
Non Destructive Mucolytic: These agents disrupt polyionic
oligosaccharide mucin network by a mechanism termed “chargeshielding”. Dextran and heparin belong to this class. Preclinical
24
SUPPLEMENT TO Journal of the association of physicians of india • MAY 2013 • VOL. 61
studies have demonstrated their efficacy.22-24 Larger clinical
studies are however still to be undertaken.
quantities of thick viscous secretion. This agent has not been
shown to be useful in randomized clinical trials.39,40
Current Recommendations for Clinical
Use of Mucolytic Drugs
Ion Channel Modifiers
Even though there is abundance of mucoactive drugs which
are available only a few are recommended for use in respiratory
hypersecretory disease. For e.g. even though the National
Institute of Clinical Excellence (NICE) in the UK recommends
mucolytic therapy in the management of COPD, most guidelines
do not recommend this form of treatment. Neither the BTS(25)
nor the European Respiratory Society26 currently recommends
mucolytic drugs in treatment. In Canada mucolytics are listed
as one of a number of treatments “under investigations” and
are not specifically recommended in disease management.27
The American Thoracic Society recommends mucokinetic
agents “step 3” as an adjunct to bronchodilators when there is
mild-to-moderate symptoms and also in severe exacerbations if
the sputum is very “viscous”.28 As far as asthma guidelines are
concerned, the BTS does not mention mucolytics at all29 and the
American Thoracic Society also makes no such recommendations
regarding mucolytics or expectorants.30
Tricyclic nucleotides (uridine triphosphate and adenosine
triphosphate) regulate ion transport through P2 Y2 purinergic
receptors that increase intracellular calcium. Nebulized uridine
triphosphate aerosol in the presence or absence of amiloride
enhances mucociliary clearance in healthy subjects.41
Mucoregulators
Agents that interfere with DNA /F-actin network to regulate
mucous secretion are described as muco-regulatory agents. Their
mechanism of action is wide ranging.
Theoretical Requirements for Effective Therapy of Airway
Mucus Hypersecretion: An agent which induces discharge or
expulsion of mucous from the respiratory tract is called an
expectorant. To facilitate this it typically requires the coughing
and sneezing action which loosens the mucous from the lungs
or the upper respiratory tract. These events can be thought to be
protective because they might unplug obstructed large, medium
or small airways. This might improve alveolar aeration and
provide relief from neural irritation triggered by mechanical
properties of mucous plug or effects of their inflammatory
components. This will help in reducing the effort of breathing
and improve dyspnoea. Some frequently used expectorants are
discussed in summary below:
Carbocysteine is an antioxidant that has ability to restore
the viscoelastic properties of mucous and provides antiinflammatory effects, in addition to providing protective effects
on respiratory cells. Carbocysteine is not thought to act directly
upon the mucous structure but increases chloride transport
across airway epithelium which might contribute towards its
mucoregulatory action.42 The anti-inflammatory properties of
Carbocysteine is by reduction of neutrophil infiltration into
the airway lumen,43 decreased levels of interleukin (IL 8, IL 6)
and cytokine levels exhaled in chronic obstructive pulmonary
disease.44 It has been shown to be an effective and safe drug for
the treatment of COPD in randomized clinical trials, reducing
the incidence of exacerbations and improving quality of life.3538
It should however be noted that in the PEACE (Preventive
Effect of ACute Exacerbation) study that subjects were Chinese
(25% non smokers) who had limited access to other drugs
that target exacerbation (e.g. long acting bronchodilators and
corticosteroids).35 Moreover, Carbocysteine has been shown to
improve oxidative stress and chronic inflammation associated
with severe chronic diseases in particular advanced cancer and
cancer related syndrome both alone and in combination with
other anti oxidant drugs.30,39,40
Hypertonic Saline
Anticholinergic Agents
Aerosol using hypertonic saline (saline, urea, or ascorbic
acid) has been thought to induce ciliary motility, proteolysis
and mucous liquefaction There have been quite a few studies
which have proven the efficacy of long term use of inhaled
hypertonic saline in improving lung function in patients with
CF. Inhaled mannitol has been shown to be beneficial in non CF
bronchiectasis.31-33 The meta-analysis of short term clinical studies
suggest nebulized hypertonic saline improved mucociliary
clearance in CF but was less effective than DNAase.34 Regardless
of the method used (saline or mannitol), this is an effective
tool for the generation of sputum for diagnostic and research
purposes.31-33
Anticholinergic medications reduce glandular output and
sputum volume.45-47 This secretory response is mediated via M3
muscarinic receptors expressed on sub-mucosal airway cells.
The various agents include atropine, ipratropium, scopolamine,
glycopyrrolate and tiotropium. Atropine blocks mucociliary
clearance of gel, but not the mucous sol phase. In contrast,
ipratropium bromide does not appear to effect mucociliary
transport.7
Iodite Containing Compounds
These agents promote the secretion of airway fluid. Even
though these agents have long being used as expectorants their
clinical use is controversial because of potential toxicity.7,35,36
Iodinated glycerol, first introduced in 1915, reduces chest
discomfort and offers anti-tussive effects in patients with chronic
bronchitis, without affecting dyspnoea or lung function.37
Domiodol increases secretion volume in adults with chronic
bronchitis.7,38
Guaifenesin (Glyceryl Guaiacolate)
This may help to reduce bronchial sputum surface tension. It
is mainly for symptomatic treatment of cough producing small
Glucocorticoids
These are potent anti inflammatory agents used in the
management of acute exacerbation of asthma and COPD. They
have a definite influence on mucociliary clearance.48
Macrolide Antibiotics
They have been used to treat a wide range of chronic
inflammatory lung disorders. 48 These agents include
Azithromycin, Clarithromycin and Erythromycin. They are
thought to be standard care therapy for CF bronchiectasis and
most recently COPD. These agents reduce sputum productions
in severe purulent bronchitis, diffuse pan-bronchiolitis,
sinobronchial syndrome and otitis.49 Their long term safety in the
treatment of COPD especially on grounds of breeding resistance
to these antibiotics still needs to be addressed.50
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SUPPLEMENT TO Journal of the association of physicians of india • MAY 2013 • VOL. 61
Mucokinetics
These agents act on cilia and increase mucociliary clearance.
Mucokinetic medication includes bronchodilators, tricyclic
nucleotides and ambroxol. Surfactants also promote cough
clearance of mucous by decreasing the surface adhesion between
mucous and airway epithelium.51
Bronchodilators
There is dispute regarding the activity of β2 adrenergic
agonists on mucociliary clearance.52-54 Some reports have shown
that salmeterol could restore secretory functions in CF airway
sub-mucosal glands serous cells,55 and that β2 adrenergic agonists
can enhance mucociliary clearance in patients with airway
reversibility.56
Ambroxol
This agent is thought to stimulate surfactant and mucous
secretion, yet promoting normalization of mucous viscosity in
viscid secretions. A recent systematic review towards evidence
of generalized benefit using ambroxol for a range of parameters
including secretolytic activity (promoting mucous clearance),
anti inflammatory and anti oxidant activity and exerts local
anesthetic effect.57
Mucoactive drugs and their potential mechanisms of action
Mucoactive drugs
Potential mechanism of action
Expectorants:
• Increases secretion volume and/or
• Hypertonic saline
hydration
• Guaifenesin
• Stimulates secretion and reduces
mucus viscosity
• Metabolism of mucus producing
Mucoregulators:
• Carbocysteine
cells, antioxidant and anti• Anticholinergic agents
inflammatory effects, modulates
• Glucocorticoids
mucus production.
• Decreases secretion volume
• Macrolide antibiotics
• Reduces airway inflammation and
mucin secretion.
• Reduces airway inflammation and
mucin secretion
• Breaks disulphide bonds linking
Mucolytics:
• N-Acetylcysteine
mucin polymers
• Antioxidant and anti-inflammatory
• N-Acystelyn
effects.
• Erdosteine
• Increases chloride secretion and
• Dornase alfa
• Gelsolin
breaks disulphide bonds
• Modulates mucus production and
• Thymosin β4
increases mucociliary transport
• Dextran
• Heparin
• Hydrolyses the DNA in mucus and
reduces viscosity in the lungs
• Severs actin filament cross-links
• Severs actin filament cross-links
• Breaks hydrogen bonds and
increases secretion hydration
• Breaks both hydrogen and ionic
bonds
Mucokinetics:• Improves cough clearance by
• Bronchodilators
increasing expiratory flow
• Surfactants
• Decreases sputum/mucus
• Ambroxol
adhesiveness
• Stimulates surfactant production and
inhibits neuronal sodium channels
Use of MUCO Active Agents as Over
the Counter Medications (OTC) in
Cough
Studies
i.
Systematic review of randomized controlled trials of over
the counter cough medications for acute cough in adults:
15 trials involving 2166 participants that all the inclusion
criteria antihistamines seem to be no better then placebo. There
was conflicting evidence on effectiveness of antitussives,
expectorants, antihistamine – decongestant, and other drug
combinations compared with placebo. The effect size was
small and hence of doubtful clinical significance. The results
should be interpreted cautiously.58
ii. Over the counter (OTC) medications for acute cough in
children and adults in the ambulatory setting. 26 trials
involving 4031 patients were included. In children studies
antitussives, antihistamines, antihistamine decongestants
and antitussives bronchodilators combinations were no
more effective than placebo. The result of one trial favored
active treatment of mucolytics over the placebo. One trial
tested two pediatrics cough syrups and both preparation
showed a “satisfactory response” in 46% and in 56% of
children compared to 21% of children in the placebo group.
A minority of studies reported adverse effects described at
a low incidence such as nausea, vomiting, headache and
drowsiness. The authors concluded that there was no good
evidence for or against the effectiveness of OTC medications
and acute cough.59
Mucoactive Drugs in Development
Surfactant
Thymosin β4
Dry powder mannitol
Denufosol tetrasodium (INS37217 respiratory) for cystic fibrosis
Erdosteine
Heparin
Conclusion
The review of available literature shows that expectorants,
mucolytics, and mucokinetic agents are unlikely to play anything
other than a relatively minor role in symptom relief, reduction in
exacerbations, or disease modification in asthma, COPD or CF.
In CF, the defect is in CF transmembrane-conductance
regulator. This will not be addressed by mucolytic therapy.
COPD is caused by cigarette smoking or due to exposure to
biomass fuel. Smoking cessation is the only intervention shown
to slow the decline in lung function. Many COPD patients are
asymptomatic until late in their condition, by which time they
may have lost the greater proportion of their lung function. Like
most interventions in COPD, the introduction of mucokinetic
agents at this late stage is unlikely to influence the natural course
of illness. Introduction of mucolytic therapy at such a late stage
is unlikely to significantly affect the decline in lung function.
Similarly, in asthma, inhaled corticosteroids and β2 agonists
are highly effective in improving symptoms and reducing risk
of death.
The question that arises is whether the finding of a statistically
significant effect of medication on mucociliary clearance or
cough clearance is of clinical relevance. Do we increase the risk
of Pneumonia by administering a drug which reduces mucus
26
SUPPLEMENT TO Journal of the association of physicians of india • MAY 2013 • VOL. 61
transport? On the flip side, does the administration of a drug
which promotes mucus clearance prevent pulmonary infections
and slow down the deterioration of lung function? Different
factors, such as the frequency of infective exacerbations, the
changes in lung function, the experience of dyspnoea and the
ease of expectoration, are studied. Further research, however, is
needed to establish more precisely the clinical benefit of a specific
agent in patients and to examine the exact relationship between
alterations in mucus transport induced by a certain drug and its
clinical impact on patients.
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