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Mucolytics and their role in the fight against COPD

Marie Thompson
RN RM NARTC Asthma/COPD
Practice Nurse
Newtownstewart

Chronic obstructive pulmonary disease (COPD) is one of the most common and important respiratory diseases in primary care. It is currently the fifth leading cause of death in the world,(1) and it is feared it may become the third by 2020.(2) In the UK alone, approximately 30,000 people die from this disease each year.(3) COPD is an underdiagnosed and undertreated killer.(4) The National Collaborating Centre for Chronic Conditions estimated in 2004 that there were 900,000 diagnosed cases of COPD in the UK, but that this could just be the tip of the iceberg, with an estimated 1.5 million sufferers.(4)
The principal cause of COPD is cigarette smoking.(5) One in 5 smokers develops COPD, and 3 in 5 have suffered at least one symptom of early COPD.(6,7) Occupational exposures, such as to excessive amounts of dust, can also lead to COPD.(8) An increased prevalence of COPD is also seen in areas of air pollution (particularly sulphur dioxide [SO(2)] and particles),(9) and areas of poverty/low socioeconomic status.(3) Alpha1-antitrypsin deficiency is a genetic imperfection, present in 1 in 2,500 people worldwide,(10) that results in the failure of the liver to express the alpha1-antitrypsin enzyme and can lead to cirrhosis of the liver and chronic emphysema. It accounts for 1-2% of all COPD cases.(11)

Symptoms of COPD
Typical symptoms of COPD are shortness of breath and wheezing on exertion, chronic cough, and an increase in phlegm production.(12) These can lead to more severe problems, particularly in older people, such as extreme mucus hypersecretion, respiratory infections and related cardiovascular conditions.(13)
A chronic productive cough is usually the first symptom of COPD. At first this may be intermittent, but it then develops to a daily occurrence. The cough is usually at its worst in the mornings, but the condition can become so advanced that symptoms are present throughout the day. However, unlike asthma, a patient with COPD is seldom woken at night. Morning cough and chest tightness are usually relieved by expectorating the mucus. The production of sputum is common, but in some cases COPD may develop without a cough.
Patients tend to seek medical help when their cough becomes more frequent and breathlessness on exertion develops; at this stage their disease is usually advanced. However, lack of awareness among the general population means that many people with COPD remain undiagnosed - approximately 40% of all sufferers.(4)
 
Diagnosis and treatment
A simple 15-minute appointment is usually sufficient to identify a COPD patient. Spirometry by a trained professional is the preferred lung function test in COPD and gives the most accurate diagnosis. This is often coupled with the patient's clinical history, which can give an indication of a history of asthma or reveal exposure to risk factors.
All COPD patients should be treated according to the British Thoracic Society (BTS)/National Institute for Clinical Excellence (NICE) guidelines for COPD,(14) revised in February 2004. These guidelines include guidance on the use of mucolytic therapy.

Mucolytics
Mucociliary dysfunction occurs when cilia in the bronchi are impaired as a result of COPD and exacerbations. This leads to hypersecretion of mucus and difficulty in expelling it from the lungs. This causes sputum to pool in the lungs, producing an ideal breeding ground for bacteria and often resulting in infection.
Mucolytics have existed as far back as 1955.(15) They were used mainly in France in the treatment of bronchitis and sinusitis. The first English trial (R Vaughan Hudson, 1960; unpublished) was carried out by 40 GPs.(15) A total of 208 patients with chronic bronchitis were started on a course of methylcysteine hydrochloride (mecysteine) for 21 days: 138 patients (66%) showed a reduction in cough and sputum, while in 18% of patients cough and sputum were completely eliminated.(15) Some limited work into the efficacy of ­mucolytics followed this trial in the subsequent years.
However, in 1985, mucolytics were blacklisted in the UK as a cost-cutting venture by the Department of Health. They were perceived to be of little therapeutic value owing to a lack of clinical data. They remained available on private prescription and indicated for patients under 18 undergoing a tracheostomy.
In 2001, more supporting evidence became available following a Cochrane review that summarised 23 clinical trials of oral mucolytics and established their benefits for treatment of COPD.(16) The review was conducted to determine whether treatment with mucolytics reduced the frequency of exacerbation or days of illness in people with chronic bronchitis or COPD. It demonstrated that "mucolytic drugs have a modest but significant effect on exacerbation rates in people with chronic bronchitis and COPD". The overall reduction in exacerbations was 29%, based on a reduction from 2.7 exacerbations per patient annually to 1.91 exacerbations. Also, the use of mucolytic therapy reduced the number of illness days experienced per month by 0.56 per patient.(16) Following the publication of this review, mucolytics were reintroduced onto the reimbursement list in February 2003.

Mode of action
Mucolytics act by breaking some of the chemical bonds between the molecules in mucus. Cysteine-based mucolytics accomplish this by cleaving crosslinks that hold the proteins in sputum together. This makes the bronchial mucus less viscous (thick and sticky) and thus easier to cough up.(17)

Management of patients
The NICE guidelines recommend that mucolytic therapy be considered in patients with a chronic ­productive cough, and continued if symptomatic improvement is seen.(14)
COPD patients who may benefit from mucolytics are those with a history of a productive cough. They can be easily identified from the COPD register, but asking a few basic questions can usually determine the suitability of a patient for mucolytic therapy, such as:

  • Does the patient have a morning cough?
  • How long does it take to cough up the phlegm?
  • How does the patient feel after expectorating?

If the patient finds it difficult to expectorate but experiences relief when they do, they will generally benefit from a mucolytic. These answers will also indicate how troublesome and difficult it is for some patients to expectorate.
There are two mucolytics available in the UK for prescribing: mecysteine (Visclair; Ranbaxy Lab­oratories) and carbocysteine (Mucodyne; Beacon Pharmaceuticals) - see Table 1 for a comparison of their properties. Our respiratory clinic uses mecysteine for 25 COPD patients.

[[NIP21_table1_28]]

A review of symptomatic improvement should take place after one month of treatment. The following criteria are used to review a patient on mucolytic therapy:

  • Is the medication working without causing side-effects?
  • Is the patient able to manage the therapy?
  • Are the patient's symptoms improving?

If all these conditions are met, treatment should be continued and reviewed annually.
Some patients may experience seasonal symptoms of chronic cough and sputum. These patients should also try the treatment for a month and review it. If the trial results in improved symptoms, repeat the treatment for the duration of the troublesome period in the years that follow.

Conclusion
In summary, regular and appropriate use of muco­lytics can help to reduce exacerbations and improve the daily management of cough-related symptoms for patients with COPD. The exacerbations that do occur may not be as severe and the benefit may be greater in those with more severe disease.(16) This therapy represents a cost-effective solution to problems with expectoration in productive cough and can dramatically improve a patient's quality of life.

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References

  1. World Health Organization.The global burden of disease. Geneva: WHO; 2003.
  2. Murray CJL, Lopez AD. Alternative projections of mortality and disability by cause 1990-2020: global burden of disease study. Lancet 1997;349;1498-504.
  3. British Thoracic Society COPD Consortium. The burden of lung disease: a statistics report from the British Thoracic Society. 2001. Available from URL:?http://www.brit-thoracic.org.uk/copd
  4. National Collaborating Centre for Chronic Conditions. Chronic ­obstructive pulmonary disease: national clinical guideline on management of chronic obstructive pulmonary disease in adults and secondary care. Thorax 2004;59 Suppl I:1-232.
  5. Siafakas NM, Vermiere P, Pride NB, et al. Optimal assessment and ­management of chronic obstructive pulmonary disease (COPD).Eur Respir J 1995;8:1398-420.
  6. Nihlén U, Montnémery P, Lindholm LH, Löfdahl C. Detection of chronic obstructive pulmonary disease (COPD) in primary health care: role of ­spirometry and respiratory symptoms. Scand J Primary Health Care 1999;17:232-7.
  7. British Thoracic Society COPD Consortium. Awareness of COPD: a quantitative study among the general public (MORI poll). 2001. Available from URL: http://www.brit-thoracic. org.uk/copd
  8. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease. Executive Summary. 2004. Available from URL: http://www.goldcopd.com
  9. Barnes PJ. Chronic obstructive pulmonary disease. N Engl J Med 2000;343:269-80.
  10. Genetics Home Reference. Alpha-1 antitrypsin deficiency. US National Library of Medicine. 2004. Available from URL: http://ghr.nlm.nih.gov
  11. Lomas DA, Mahadeva R. a1-anti-trypsin polymerization and the serpinopathies: pathobiology and prospects for therapy. J Clin Invest 2002;110:1585-90.
  12. Skrepnek GH, Skrepnek SV. Epidemiology, clinical and economic burden, and natural history of chronic obstructive pulmonary disease and asthma. Am J Management Care 2004;10:S129-38.
  13. Pistelli R, Lange P, Miller DL. Determinants of prognosis of COPD in the elderly: mucus hypersecretion, infections, cardiovascular comorbidity. Eur Respir J 2003;21:10s-14.
  14. BTS/NICE. Chronic obstructive pulmonary disease: management of chronic obstructive pulmonary disease in adults in primary and secondary care.  2004. Available from URL: http://www. nice.org.uk
  15. Palmer KNV, Geake MR, Brass W. Clinical trial of methylcysteine hydrochloride in chronic bronchitis. BMJ 1962;1:280-2.
  16. Poole PJ, Black PN. Oral mucolytic drugs for exacerbations of chronic obstructive pulmonary disease: ­systematic review. BMJ 2001;322:1-6.
  17. Aylward M, Bater PA, Davies DE, et al. Clinical therapeutic evaluation of methylcysteine hydrochloride in patients with chronic obstructive ­bronchitis: a balanced double-blind trial with placebo control.Curr Med Res Opin 1978;5:461-71.
  18. Ranbaxy Laboratories. Visclair: summary of product characteristics. London: Ranbaxy Laboratories; 2003.
  19. Beacon Pharmaceuticals. Mucodyne information for the patient. Kent: Beacon Pharmaceuticals; 2002.

Resources
British Thoracic Society COPD Consortium
W:www.brit-thoracic.org.uk/copd/
National Institute for Clinical Excellence
W:www.nice.org.uk