Montuschi 3) other types of medication (vaccines, antibiotics, α1- antitrypsin augmentation therapy, mucolytic agents, antioxidants, immunoregulators, antitussives and vasodilators). These drugs will be presented in the order in which they would normally be prescribed for the treatment of patients with COPD, based on the level of severity of the disease. Current knowledge on inhibitors of phosphodiesterase type 4 (PDE4), a new class of drugs for COPD which are in the late phase III of clinical development (Lipworth 2005), will be presented. However, it must be emphasized that each treatment regimen needs to be patient-speciﬁc as the relationship between the severity of symptoms and the severity of lung function is inﬂuenced by other factors, such as the frequency and severity of exacerbations, the presence of complications, the presence of respiratory failure, the presence of other diseases, and general health status. Treatment of stable chronic obstructive pulmonary disease Bronchodilators Bronchodilators are currently the mainstay of the treatment of COPD (GICOPD 2001). Bronchodilators are selective short-acting β2-agonists such as salbutamol, metaproterenol, terbutaline, bambuterol, pirbuterol, isoetharine, bitolterol and fenoterol or selective long-acting β2-agonists such as salmeterol and formoterol; anticholinergic antimuscarinic agents such as ipratropium bromide, oxitropium bromide and tiotropium bromide, and methylxanthines such as theophylline. Short- and long-acting β2-agonists and antimuscarinic agents are generally administered by inhalation (aerosol, dry-powder or nebuliser solution). Bronchodilator therapy is most frequently delivered by pressurized metered-dose inhalers (MDIs) or dry-powder inhalers (DPIs). Because of the lower bioavailability in asthma patients, the dose delivered by DPIs should be doubled compared with that of MDIs (RS 2003); while a study comparing ipratropium bromide delivered by MDIs and by DPIs in COPD patients found that there was no difference between these two types of inhalers (Cuvelier et al 2002). The use of a spacer device to improve drug delivery proves particularly useful for patients who have poor inhalation technique. In a study on patients with COPD, inhalation of salbutamol through MDIs with spacer and dry-powder inhalers produced similar bronchodilating effects (Ikeda et al 1999). However, further studies are necessary to establish deposition in the respiratory tract 410 and the dose-effect relationship of drugs delivered by different inhalers in patients with COPD, as these are important factors in the choice of dosage. Short-acting β2-agonists such as salbutamol and terbutaline are also available for oral or parenteral delivery. Theophylline is generally administered orally, mostly frequently in controlled release preparations which prolong the pharmacological effect of the drug, even if they do not significantly eliminate the interindividual variability of the bioavailability. For chronic administration, bronchodilators are the mainstay of treatment of COPD as they prevent and improve symptoms (Chrystyn et al 1988; Vathenen et al 1988; Gross et al 1989; Rennard 2004). One of the main therapeutic effects of bronchodilators, at least in severe COPD, is improvement in the emptying of the lungs during expiration. This causes a reduction in dynamic hyperinﬂation at rest and during exercise with consequent improvement in exercise tolerance (Belman et al 1996). However, it is not easy to predict the extent of this improvement based on an increase in forced expiratory volume in one second (FEV1) after a short period of bronchodilatory therapy (Berger and Smith 1988; Hay et al 1992). The evaluation of the efﬁcacy of bronchodilators is generally based on questionnaires concerning symptom variation. COPD may require inhalation of a short-acting β2-agonist on demand or, when airways obstruction is more severe, chronic administration of an antimuscarinic agent by inhalation or a long-acting β2-agonist (RS 2003). Selective β -agonists 2 There are no signiﬁcant differences between the various β2-agonists as far as selectivity for β2-adrenoceptors is concerned, with the exception of metaproterenol and iso-etharine, which are less selective (Undem and 1 2001). Short-acting β2-agonists have a bronchodilatory effect within 1 to 5 minutes and which lasts for up to 4 hours (Rennard 2004). Long-acting inhaled β2-adrenergic agonists such as salmeterol and formoterol have a prolonged bronchodilatory effect for approximately 12 hours. Unlike salmeterol which has a slow onset of action, formoterol has a rapidly occurring bronchodilatory effect similar to that of short- acting β2-agonists (Undem and Lichtenstein 2001; Rennard 2004). Selective β2-agonists mainly work by stimulating the β2-adrenoceptors on the airway smooth muscle cells. The formation of the drug-receptor complex activates a stimulatory protein (Gs) which binds to guanosine triphosphate (GTP) with activation of the adenylate cyclase which leads to an increase in intracellular cyclic adenosine International Journal of COPD 2006:1(4)