Author: M. Decramer

Author: V. Brusasco

The airway narrowing in chronic obstructive pulmonary disease (COPD) has often been misunderstood as being irreversible. However, a large proportion of patients with COPD do respond to bronchodilator agents with significant changes in lung function.

Unlike in asthma, abnormalities in airway smooth muscle structure or function are not believed to play a key role in COPD airway narrowing. Although there are only limited data suggesting that cholinergic tone may be increased in COPD, the well-documented efficacy of antimuscarinic agents in increasing airway calibre suggests that cholinergic tone represents the major reversible component of airflow obstruction in these patients. Airway wall thickening and loss of airway-to-parenchyma interdependence are nonreversible components of airflow obstruction in COPD that may amplify the effect of changes in airway smooth muscle tone. Thus, keeping airway smooth muscle tone to a minimum might offer patients long-lasting airway patency and protection against breathlessness, which is the major complaint of patients with COPD.

Receptor antagonism by anticholinergic agents can achieve effective relaxation of airway smooth muscle in COPD. According to a classical view of cholinergic receptor function and distribution, the ideal anticholinergic bronchodilator would be one that blocks both M1 and M3 receptors, which mediate airway smooth muscle contraction, but not the M2 receptor, stimulation of which reduces acetylcholine release from vagus nerve endings and prevents the airway smooth muscle from contracting by excessive increments.

Agents with such pharmacodynamic selectivity are not available, but effective and prolonged inhibition of airway smooth muscle tone has been obtained with tiotropium, which binds to all three major muscarinic receptor subtypes, but for much longer to M3 than to M2 receptors. Recent data show that long-term treatment with tiotropium for 1 yr helps sustain 24-h airway patency. This sustained effect may help to explain the improvements in both exacerbation rate and lung function observed in chronic obstructive pulmonary disease patients treated with tiotropium.

Author: D. E. O'Donnell

The physiological hallmark of chronic obstructive pulmonary disease (COPD) is expiratory flow limitation. However, it is the resultant air trapping and associated increases in lung volume (hyperinflation) that provide a mechanistic link between the physiological impairment and the characteristic symptoms of COPD, such as dyspnoea (breathlessness), exercise intolerance and reduced health-related quality of life (HRQoL).

During exercise, the negative consequences of hyperinflation are particularly apparent. Delayed lung emptying and increased end-expiratory lung volume are aggravated, and tidal volume cannot rise to meet the increased ventilatory demands. Dyspnoea intensity rises abruptly to intolerable levels, and further increases in ventilation can only be achieved by rapid breathing. This rebounds to cause greater hyperinflation in a vicious cycle. As a result, patients with COPD often prematurely stop or avoid activity, leading to deconditioning, increased dyspnoea, worsening of disease and, ultimately, reduced HRQoL.

The Global Initiative for Chronic Obstructive Lung Disease guidelines recommend long-acting bronchodilators as first-line maintenance treatment in COPD.

Once-daily tiotropium 18 µg, a long-acting anticholinergic agent with 24-h efficacy, has been consistently shown to relieve dyspnoea and improve exercise tolerance and health status. These improvements may allow patients with chronic obstructive pulmonary disease to increase their daily activities, thereby reversing the cycle of chronic inactivity and muscle deconditioning.

Author: R. Casaburi

Patients with chronic obstructive pulmonary disease (COPD) frequently suffer from exercise intolerance, leading to a reduced ability to participate in activities of daily life and, therefore, to a reduced health-related quality of life (HRQoL). An important determinant of exercise intolerance is the loss of muscle mass.

Although the mechanism for loss of muscle function is multi-factorial, deconditioning appears to play a primary role in many patients. COPD patients often have decreased fat-free mass compared with healthy counterparts and reduced muscle cross-sectional area. It seems, then, that a cycle of decline often characterises COPD, in which inactivity results in muscle weakness, which in turn acts as a further deterrent to exercise. Such deconditioning can be reversed by pulmonary rehabilitation, leading to significant improvements in exercise tolerance and HRQoL.

Recent research suggests that the effectiveness of pulmonary rehabilitation can be amplified with concomitant administration of tiotropium (a long-acting bronchodilator) or supplemental oxygen. This suggests that facilitating higher training work-rates can enhance the anabolic effects of training.

Patients should be encouraged to maintain activity levels in the follow-up period after training, in order to retain the benefits of rehabilitation.

Author: R. Rodríguez-Roisin

Patients with chronic obstructive pulmonary disease (COPD) frequently develop exacerbations, leading to major clinical and healthcare utilisation ramifications. Exacerbations, especially those that result in hospitalisation, are the main cost driver in COPD and frequent exacerbations are associated with increased mortality, impaired health-related quality of life (HRQoL) and perhaps a more rapid decline in lung function over time. Prevention and treatment of exacerbations is, therefore, an important goal of maintenance therapy in COPD.

The impact of tiotropium, a long-acting anticholinergic agent, on exacerbations and associated healthcare utilisation has been studied in five randomised, controlled clinical trials of ≥6 months' duration involving >5,000 patients.

Analyses of adverse events reports submitted during three long-term efficacy and safety trials showed that tiotropium significantly reduced the incidence of exacerbations and delayed the time to first exacerbation, compared with either placebo or the short-acting anticholinergic agent, ipratropium. More recent prospective data confirmed previous findings.

Collectively, the results of these studies support the role of tiotropium as maintenance therapy in chronic obstructive pulmonary disease, demonstrating that this agent can provide significant reductions in the incidence of exacerbations and associated healthcare utilisation.

Author: M. Decramer

Over the past decade, several large-scale clinical trials have been performed to assess the impact of pharmacological treatments on patient-centred outcomes such as dyspnoea, exercise tolerance, exacerbations and health-related quality of life (HRQoL) in patients with chronic obstructive pulmonary disease (COPD).

Tiotropium, a once-daily inhaled anticholinergic agent that works through prolonged muscarinic M3 receptor blockade, has consistently been shown to provide sustained improvements in lung function parameters. Furthermore, several prospective trials have shown that tiotropium improves exercise tolerance and augments the beneficial effects of pulmonary rehabilitation. Beyond these important physiological outcomes, tiotropium has been shown to reduce dyspnoea, decrease the frequency of exacerbations and improve HRQoL in studies of ≤1 yr in duration. Such improvements in patient-centred outcomes may allow patients to increase their activity levels, thereby interrupting the downward spiral of chronic inactivity that leads to physical deconditioning and further reductions in exercise tolerance.

Recently, combination therapies of two long-acting bronchodilators have been examined more closely regarding their potential to provide patients with superior symptom relief compared with that provided by single-agent therapy.

Because maintenance treatment with tiotropium provides consistent and sustained improvements in many relevant clinical outcomes of chronic obstructive pulmonary disease, it may reduce the progression of the disease. This hypothesis is being tested in the ongoing Understanding the Potential Long-term Impacts on Function with Tiotropium (UPLIFT) trial.