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Published on 1 May 2004

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Current treatments for COPD

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Domenico Spina
PhD
Reader in Pharmacology
The Sackler Institute of Pulmonary Pharmacology
GKT School of Biomedical Science
King’s College London
London
UK
E:domenico.spina@kcl.ac.uk

Chronic obstructive pulmonary disease (COPD) is a slowly developing disease characterised by a gradual loss in lung function. The patient can suffer from chronic cough, excess mucus production and exercise intolerance. The inexorable rise in morbidity and mortality paints a rather depressing picture for the economic and societal cost of this smoking- related disease and highlights the need to adopt smoking cessation strategies. Although there is currently no therapeutic modality, apart from smoking cessation, that can halt the decline in lung function observed in COPD, a number of pharmacological agents are available that can improve the quality of life in susceptible individuals.

Pharmacological treatment of COPD
COPD, a disease characterised by airflow obstruction, is partly reversible and progressively deteriorates. Individuals who suffer from COPD have reduced lung function (as expressed by forced expiratory volume in 1 sec [FEV1]) and exacerbation of symptoms (including cough and mucus secretion). Due to the nature of this disease, patients can suffer from a diminished capacity to undertake physical exertion and have a poor quality of life. Smoking and exposure to indoor pollution are major factors in the morbidity of this disease. At the cellular level, these insults directly trigger resident cells (such as alveolar macrophages) within the lung, which then promote the recruitment of other inflammatory cells, such as neutrophils, to the lung. It is also likely that these insults increase the oxidant burden within the lung, which in turn can activate inflammatory cells. If the inflammation is present in large and/or small airways, then airflow obstruction is a consequence of mucus hypersecretion due to increase in the number and activity of mucus-secreting cells. Damage to the epithelium impairs the mucociliary response that clears bacteria and mucus. Physiologically, this can promote cough, expectoration and increased resistance to expiratory flow. If the inflammation is located in the peripheral airways, destruction of alveolar tissue occurs and is thought to be a consequence of the high protease burden within the lung. This leads to loss in alveolar integrity and loss in lung elastic recoil, which, at the physiological level, is characterised by dyspnoea, impaired gas exchange, airflow limitation and exercise intolerance.(1–3)

A limited number of drug treatments are available for this disease. Smoking cessation should be encouraged, as it is the only form of “treatment” that has been shown to reduce the progression of this disease.(4) However, this can be difficult for a majority of smokers because of the addictive properties of nicotine. The availability of highly selective nicotinic antagonists would be useful in this context. Therefore, the recent finding that antidepressant bupropion given for a short period improves the likelihood of smoking abstinence is of interest.(5,6)

The airway obstruction observed in COPD is a consequence of a narrowing of the airways due to several factors, including loss in elastic recoil, mucus secretion and cholinergic vagal tone. Bronchodilator drugs can improve airflow obstruction, but the poorly reversible nature of the obstruction in this disease means that only variable increases in baseline FEV1 will be demonstrated. However, the benefit to the patient comes in the form of an increase in ventilation at a lower functional residual capacity; in addition, reduction of the hyperinflation improves the capacity to exercise. There are two major classes of bronchodilator drugs used in the treatment of COPD.

Anticholinergic drugs
Anticholinergic drugs, including ipratropium bromide, oxitropium bromide and tiotropium bromide, antagonise the actions of acetylcholine release from parasympathetic nerves that innervate the lung. As a consequence, airway smooth muscle relaxation and inhibition of mucus secretion are desirable beneficial actions. Muscarinic (M)(2) receptors are found on the terminal ending of parasympathetic nerves, and activation of these receptors leads to a reduction in the release of acetylcholine from parasympathetic nerves. In contrast, activation of M(3) receptors on effector cells, such as airway smooth muscle cells, leads to contraction. It would be desirable to selectively antagonise the actions of acetylcholine at M(3) but not M(2) receptors, as the latter act through a negative feedback mechanism to limit the release of acetylcholine from parasympathetic terminals. Ipratropium bromide is a nonselective antagonist that is nonetheless effective in the treatment of COPD.(7) However, its short duration of action necessitates medication on a regular basis. In contrast, tiotropium bromide has affinity for both receptor subtypes, but appears to rapidly dissociate from M(2) receptors while remaining firmly bound to the M(3) receptor. Consequently, this drug has been marketed as a once-daily treatment. A number of recent studies have shown that tiotropium bromide significantly improves lung function, reduces symptoms, increases quality of life and reduces exacerbation rates.(8–10)

beta(2)-adrenoceptor agonists
Relaxation of airway smooth muscle can also be induced by beta(2)-adrenoceptor agonists, of which salbutamol, salmeterol and formoterol are examples. Coupling of beta(2)-adrenoceptors with G protein activates the effector protein adenylyl cyclase, leading to a rise in intracellular levels of cyclic AMP, which, in turn, activates protein kinase A and ultimately leads to the relaxation of airway smooth muscle. Both salmeterol and formoterol are superior to salbutamol in terms of duration of action and, as such, improve lung function, reduce symptoms and increase the quality of life in COPD.(10) Shorter-acting drugs such as salbutamol offer the advantage of providing rapid bronchodilator relief and, therefore, are commonly prescribed as rescue medication during an exacerbation of disease. Unlike anticholinergic drugs, beta(2)-adrenoceptor agonists do not inhibit mucus secretion; however, they improve mucociliary clearance and inhibit neutrophil function,(11–13) although to what extent these actions contribute to the clinical efficacy of this drug class is not clear at present. The difference in bronchodilator mechanism between anticholinergic and beta(2)-adrenoceptor agonists suggests that combination therapy is appropriate for the management of COPD,(1) and recent findings show that a combination therapy consisting of long-acting beta(2)-adrenoceptor agonists and tiotropium bromide could be used.(14)

Other drug classes
Theophylline has also been used in the treatment of COPD, but its usefulness is limited because of the greater side-effects associated with this drug. Theophylline can relax airway smooth muscle, albeit at high concentrations. It has been proposed that theophylline elevates cyclic AMP within cells following inhibition of phosphodiesterase (PDE). However, this drug is a weak PDE inhibitor, and it is not surprising that the doses required for bronchodilation result in side-effects such as nausea and emesis. Interestingly, theophylline also documents antineutrophilic activity and, therefore, could potentially exert some anti-inflammatory action in COPD. Whether the action of theophylline can be improved is currently under investigation with the development of highly potent PDE4 inhibitors for the potential treatment of COPD.(15,16)

The utility of glucocorticosteroids in COPD is a controversial issue. Glucocorticosteroids had either a minimal effect(17) or showed a beneficial effect on exacerbation of the disease. (18,19) This discordance in the literature may relate to the severity of the disease, as the beneficial action of glucocorticosteroids was observed in individuals who had an FEV1 value of <50% of that predicted. Glucocorticosteroids are anti-inflammatory drugs and might potentially be disease-modifying. However, these drugs do not appear to influence the long-term decline in lung function in COPD.(17,19–21)

Conclusion
The current agents used in COPD treat only the underlying symptoms and do not inhibit the processes that lead to the destruction of the alveoli. However, improvements in the duration of action of bronchodilator drugs have significantly improved the treatment of this disease.

The potential for combination therapy will also benefit patients. As our understanding of the molecular events leading to the destruction of alveolar tissue increases, we will be in a better position to develop newer therapies for treating COPD.

References

  1. Am J Respir Crit Care Med 2001;163:1256-76.
  2. Annu Rev Med 2003;54:113-29.
  3. Lancet 2003;362:1053-61.
  4. BMJ 1977;1:1645-8.
  5. Am J Med 2004;116:151-7.
  6. Trends Pharmacol Sci 2004;25:42-8.
  7. Pulm Pharmacol Ther 1997;10: 129-44.
  8. Eur Respir J 2002;19:217-24.
  9. Eur Respir J 2002;19:209-16.
  10. Chest 2004;125:249-59.
  11. Eur Respir J  1998;11:86-90.
  12. Eur Respir J 1999;14:363-9.
  13. Chest 2001;120:258-70.
  14. Pulm Pharmacol Ther 2004;17:35-9.
  15. Am J Respir Crit Care Med 2002;165:1371-6.
  16. Am J Respir Crit Care Med 2003;167:813-8.
  17. Lancet 1999;353:1819-23.
  18. Am J Respir Crit Care Med 2002;165:1592-6.
  19. BMJ 2000;320: 1297-303.
  20. N Engl J Med 2000;343:1902-9.
  21. N Engl J Med 1999;340:1948-53.

Resources
European Respiratory Society
W:ww.ersnet.org
Global Initiative for COPD
W:www.goldcopd.com
American Lung Association
W:www.lungusa.org/diseases/index_profilerc.html

Events
American Thoracic Society (ATS) Annual Congress
Orlando, FL, USA. 21–26 May 2004
European Respiratory Society (ERS) Annual Congress
Glasgow, UK. 4–8 September 2004



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