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SUPPLEMENT TO Journal of the association of physicians of india MAY 2013 VOL.

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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
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
physicians prescription. This class of medication acts by reducing airway phospholipases and by altering the biophysical properties
the irritation of cough receptors due to mucous accumulation and of mucous. The byproducts which accumulate as a result of this
by coughing up of this mucous. The sequelae of mucous hyper- inflammatory cascade includes neutrophil derived DNA and
secretion is airway obstruction, air flow limitation, ventilation filamentous actins (F-actin), dead or apoptotic cells, bacteria and
perfusion mismatch, and impairment of gas exchange.1,2 The cellular debris.7 All these factors together contribute to mucous
spectrum of diseases in which there is excessive sputum purulence and the material expectorated is termed as sputum.
production due to airway mucous hypersecretion include Drugs that are designed to specifically alter the viscoelastic
asthma, chronic obstructive pulmonary disease (COPD) or properties of mucous in addition to promoting clearance of
cystic fibrosis (CF). Slowing or paralysis of the mucociliary sputum are called mucoactive.
escalator will reduce mucous clearance and increase bacterial Mucoactive drugs can hence be classified as expectorants
colonization leading to repeated lower respiratory tract infection mucoregulators, mucolytic or mucokinetics based on their
and exacerbations of airways disease.3-6 The issue of mucous potential mechanism of action.
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
Mucolytics
contributes to bronchial hyper-responsiveness.3,5 Researchers Mucolytic can be classified into 2 categories classic
have further contemplated that chronic mucous hyper-secretion mucolytics depolymerise mucin glycoproteins and peptides
reflects lack of asthma control leading in turn to accelerated mucolytics: depolymerize DNA and F-actin polymer
loss of lung function and increased mortality. In summary, this networks.
results in airway obstruction, bacterial colonization and repeated Classic mucolytics: The prototype agent in this group is
infections and exacerbation. N-acetyl cysteine (NAC) which in addition to being a mucolytic
This mucous hypersecretion is a reflection of the inflammatory agent also has significant antioxidant and anti-inflammatory
process which is related to asthma, CF and COPD. Hence, it properties. Nebulized NAC when administered as an aerosol
would be important to develop drugs that address the airway dissociates mucin disulphide bonds and other disulphide
bond crossed linked gel component to reduce viscosity. Due
Table 1 : Theoretical requirements for pharmacotherapy of to its antioxidant effect this agent can also protect against free
airway mucus pathophysiology in asthma, COPD and CF radical damage.7,8-11 NAC decreased airway inflammation by
reducing lysozyme and lactoferrin concentrations in smokers,12
Overall Effect Component Effects* inhibiting neutrophils and monocytes chemotaxis and oxidative
Reduce viscosity (increase burst responses in vitro,13 reducing the activation and number
elasticity?) of neutrophils and macrophages in bronchoalveolar lavage and
Reduce DNA/filamentous actin smokers14,15 and by inhibiting the adherence of bacteria to ciliated
content of mucus (CF, COPD)
Facilitate mucus clearance (short-
Increase ciliary function
epithelial cells in vitro.16 There is good evidence of prove that
term relief of symptoms) oral NAC has stabilized disease in idiopathic pulmonary fibrosis
Induce cough
Facilitate release of tethered and may also reduce exacerbation rates in chronic bronchitis.17,18
goblet cell mucin (asthma) Other Mucolytics: Erdosteine and fudosteine: Erdosteine is an
Inhibit mucin secretion antioxidant with mucolytic properties and also reduces bacterial
Treat airway/pulmonary adhesiveness. A small randomized controlled trial showed fewer
inflammation exacerbations, reduced hospitalization time and improved
Reduce goblet cell number
quality of life in patients with COPD that were treated with
Reduce submucosal gland size
Inhibit plasma exudation erdosteine when compared with placebo;19 however, future
Reverse hypersecretory (asthma) trials will be necessary to confirm these findings. Fudosteine
phenotype (long-term benefit) Correct increased ratio of gland is a cysteine with greater bio-availability than NAC. It reduces
mucous cells to serous cells hypersecretion by down regulation of mucin gene expression.
(COPD)
Peptide Mucolytic: These bring down highly polymerized and
Reverse increased ratio of low-
charge glycoform MUC5B to
F-actin network that is characteristic of pus. Dornase alpha is a
MUC5AC (COPD) proteolytic enzyme that cleaves DNA polymers and is used in the
*
The relative importance of the individual component effects to airway long term treatment of mucous hypersecretion in CF.20 Dornase
mucus pathophysiology is unclear. Consequently, it may be unnecessary is used in children with CF with corresponding improvement
to meet all theoretical requirements, with inhibition of only certain in lung function and outcome.21 However these agents need to
aspects having important clinical benefit; COPD - chronic obstructive be evaluated further in clinical trial.
pulmonary disease; CF - cystic fibrosis; DNA - deoxyribonucleic acid;
Non Destructive Mucolytic: These agents disrupt polyionic
MUC - mucin gene product
oligosaccharide mucin network by a mechanism termed charge-
shielding. Dextran and heparin belong to this class. Preclinical
Consultant Pulmonologist, Fortis Hospital, Kolkata
*
24 SUPPLEMENT TO Journal of the association of physicians of india MAY 2013 VOL. 61

studies have demonstrated their efficacy.22-24 Larger clinical quantities of thick viscous secretion. This agent has not been
studies are however still to be undertaken. shown to be useful in randomized clinical trials.39,40
Ion Channel Modifiers
Current Recommendations for Clinical Tricyclic nucleotides (uridine triphosphate and adenosine
Use of Mucolytic Drugs triphosphate) regulate ion transport through P2 Y2 purinergic
Even though there is abundance of mucoactive drugs which receptors that increase intracellular calcium. Nebulized uridine
are available only a few are recommended for use in respiratory triphosphate aerosol in the presence or absence of amiloride
hypersecretory disease. For e.g. even though the National enhances mucociliary clearance in healthy subjects.41
Institute of Clinical Excellence (NICE) in the UK recommends
mucolytic therapy in the management of COPD, most guidelines Mucoregulators
do not recommend this form of treatment. Neither the BTS(25) Agents that interfere with DNA /F-actin network to regulate
nor the European Respiratory Society26 currently recommends mucous secretion are described as muco-regulatory agents. Their
mucolytic drugs in treatment. In Canada mucolytics are listed mechanism of action is wide ranging.
as one of a number of treatments under investigations and Carbocysteine is an antioxidant that has ability to restore
are not specifically recommended in disease management.27 the viscoelastic properties of mucous and provides anti-
The American Thoracic Society recommends mucokinetic inflammatory effects, in addition to providing protective effects
agents step 3 as an adjunct to bronchodilators when there is on respiratory cells. Carbocysteine is not thought to act directly
mild-to-moderate symptoms and also in severe exacerbations if upon the mucous structure but increases chloride transport
the sputum is very viscous.28 As far as asthma guidelines are across airway epithelium which might contribute towards its
concerned, the BTS does not mention mucolytics at all29 and the mucoregulatory action.42 The anti-inflammatory properties of
American Thoracic Society also makes no such recommendations Carbocysteine is by reduction of neutrophil infiltration into
regarding mucolytics or expectorants.30 the airway lumen,43 decreased levels of interleukin (IL 8, IL 6)
Theoretical Requirements for Effective Therapy of Airway and cytokine levels exhaled in chronic obstructive pulmonary
Mucus Hypersecretion: An agent which induces discharge or disease.44 It has been shown to be an effective and safe drug for
expulsion of mucous from the respiratory tract is called an the treatment of COPD in randomized clinical trials, reducing
expectorant. To facilitate this it typically requires the coughing the incidence of exacerbations and improving quality of life.35-
and sneezing action which loosens the mucous from the lungs 38
It should however be noted that in the PEACE (Preventive
or the upper respiratory tract. These events can be thought to be Effect of ACute Exacerbation) study that subjects were Chinese
protective because they might unplug obstructed large, medium (25% non smokers) who had limited access to other drugs
or small airways. This might improve alveolar aeration and that target exacerbation (e.g. long acting bronchodilators and
provide relief from neural irritation triggered by mechanical corticosteroids).35 Moreover, Carbocysteine has been shown to
properties of mucous plug or effects of their inflammatory improve oxidative stress and chronic inflammation associated
components. This will help in reducing the effort of breathing with severe chronic diseases in particular advanced cancer and
and improve dyspnoea. Some frequently used expectorants are cancer related syndrome both alone and in combination with
discussed in summary below: other anti oxidant drugs.30,39,40
Hypertonic Saline Anticholinergic Agents
Aerosol using hypertonic saline (saline, urea, or ascorbic Anticholinergic medications reduce glandular output and
acid) has been thought to induce ciliary motility, proteolysis sputum volume.45-47 This secretory response is mediated via M3
and mucous liquefaction There have been quite a few studies muscarinic receptors expressed on sub-mucosal airway cells.
which have proven the efficacy of long term use of inhaled The various agents include atropine, ipratropium, scopolamine,
hypertonic saline in improving lung function in patients with glycopyrrolate and tiotropium. Atropine blocks mucociliary
CF. Inhaled mannitol has been shown to be beneficial in non CF clearance of gel, but not the mucous sol phase. In contrast,
bronchiectasis.31-33 The meta-analysis of short term clinical studies ipratropium bromide does not appear to effect mucociliary
suggest nebulized hypertonic saline improved mucociliary transport.7
clearance in CF but was less effective than DNAase.34 Regardless Glucocorticoids
of the method used (saline or mannitol), this is an effective
These are potent anti inflammatory agents used in the
tool for the generation of sputum for diagnostic and research
management of acute exacerbation of asthma and COPD. They
purposes.31-33
have a definite influence on mucociliary clearance.48
Iodite Containing Compounds
Macrolide Antibiotics
These agents promote the secretion of airway fluid. Even
They have been used to treat a wide range of chronic
though these agents have long being used as expectorants their
inflammatory lung disorders. 48 These agents include
clinical use is controversial because of potential toxicity.7,35,36
Azithromycin, Clarithromycin and Erythromycin. They are
Iodinated glycerol, first introduced in 1915, reduces chest
thought to be standard care therapy for CF bronchiectasis and
discomfort and offers anti-tussive effects in patients with chronic
most recently COPD. These agents reduce sputum productions
bronchitis, without affecting dyspnoea or lung function.37
in severe purulent bronchitis, diffuse pan-bronchiolitis,
Domiodol increases secretion volume in adults with chronic
sinobronchial syndrome and otitis.49 Their long term safety in the
bronchitis.7,38
treatment of COPD especially on grounds of breeding resistance
Guaifenesin (Glyceryl Guaiacolate) to these antibiotics still needs to be addressed.50
This may help to reduce bronchial sputum surface tension. It
is mainly for symptomatic treatment of cough producing small
SUPPLEMENT TO Journal of the association of physicians of india MAY 2013 VOL. 61 25

Mucokinetics Use of MUCO Active Agents as Over


These agents act on cilia and increase mucociliary clearance. the Counter Medications (OTC) in
Mucokinetic medication includes bronchodilators, tricyclic
nucleotides and ambroxol. Surfactants also promote cough Cough
clearance of mucous by decreasing the surface adhesion between Studies
mucous and airway epithelium.51 i. Systematic review of randomized controlled trials of over
Bronchodilators the counter cough medications for acute cough in adults:
There is dispute regarding the activity of 2 adrenergic 15 trials involving 2166 participants that all the inclusion
agonists on mucociliary clearance.52-54 Some reports have shown criteria antihistamines seem to be no better then placebo. There
that salmeterol could restore secretory functions in CF airway was conflicting evidence on effectiveness of antitussives,
sub-mucosal glands serous cells,55 and that 2 adrenergic agonists expectorants, antihistamine decongestant, and other drug
can enhance mucociliary clearance in patients with airway combinations compared with placebo. The effect size was
reversibility.56 small and hence of doubtful clinical significance. The results
should be interpreted cautiously.58
Ambroxol
ii. Over the counter (OTC) medications for acute cough in
This agent is thought to stimulate surfactant and mucous
children and adults in the ambulatory setting. 26 trials
secretion, yet promoting normalization of mucous viscosity in
involving 4031 patients were included. In children studies
viscid secretions. A recent systematic review towards evidence
antitussives, antihistamines, antihistamine decongestants
of generalized benefit using ambroxol for a range of parameters
and antitussives bronchodilators combinations were no
including secretolytic activity (promoting mucous clearance),
more effective than placebo. The result of one trial favored
anti inflammatory and anti oxidant activity and exerts local
active treatment of mucolytics over the placebo. One trial
anesthetic effect.57
tested two pediatrics cough syrups and both preparation
Mucoactive drugs and their potential mechanisms of action showed a satisfactory response in 46% and in 56% of
Mucoactive drugs Potential mechanism of action children compared to 21% of children in the placebo group.
Expectorants: Increases secretion volume and/or A minority of studies reported adverse effects described at
Hypertonic saline hydration a low incidence such as nausea, vomiting, headache and
Guaifenesin Stimulates secretion and reduces drowsiness. The authors concluded that there was no good
mucus viscosity evidence for or against the effectiveness of OTC medications
Mucoregulators: Metabolism of mucus producing and acute cough.59
Carbocysteine cells, antioxidant and anti-
Anticholinergic agents inflammatory effects, modulates Mucoactive Drugs in Development
Glucocorticoids mucus production. Surfactant
Macrolide antibiotics Decreases secretion volume Thymosin 4
Reduces airway inflammation and
Dry powder mannitol
mucin secretion.
Reduces airway inflammation and Denufosol tetrasodium (INS37217 respiratory) for cystic fibrosis
mucin secretion Erdosteine
Mucolytics: Breaks disulphide bonds linking Heparin
N-Acetylcysteine mucin polymers
N-Acystelyn Antioxidant and anti-inflammatory Conclusion
Erdosteine effects. The review of available literature shows that expectorants,
Dornase alfa Increases chloride secretion and
mucolytics, and mucokinetic agents are unlikely to play anything
Gelsolin breaks disulphide bonds
Thymosin 4 Modulates mucus production and
other than a relatively minor role in symptom relief, reduction in
Dextran increases mucociliary transport exacerbations, or disease modification in asthma, COPD or CF.
Heparin Hydrolyses the DNA in mucus and In CF, the defect is in CF transmembrane-conductance
reduces viscosity in the lungs regulator. This will not be addressed by mucolytic therapy.
Severs actin filament cross-links
Severs actin filament cross-links COPD is caused by cigarette smoking or due to exposure to
Breaks hydrogen bonds and biomass fuel. Smoking cessation is the only intervention shown
increases secretion hydration to slow the decline in lung function. Many COPD patients are
Breaks both hydrogen and ionic asymptomatic until late in their condition, by which time they
bonds may have lost the greater proportion of their lung function. Like
Mucokinetics:- Improves cough clearance by most interventions in COPD, the introduction of mucokinetic
Bronchodilators increasing expiratory flow agents at this late stage is unlikely to influence the natural course
Surfactants Decreases sputum/mucus of illness. Introduction of mucolytic therapy at such a late stage
Ambroxol adhesiveness
is unlikely to significantly affect the decline in lung function.
Stimulates surfactant production and
inhibits neuronal sodium channels Similarly, in asthma, inhaled corticosteroids and 2 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

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