Montuschi parasympathetic activity with consequent reduction in airway obstruction. Unlike atropine, antimuscarinic bronchodilators do not have an inhibitory effect on mucociliary clearance. The reason for this difference is not known. The effectiveness of antimuscarinic drugs depends on the role that cholinergic vagal tone has in the pathophysiology of bronchial obstruction. Antimuscarinic bronchodilators are generally considered to be more effective for COPD than for asthma. This could be partly due to the different pathophysiological role of the parasympathetic vagal system in these two diseases. The aerosol inhalation of ipratropium has a maximum effect 30–60 minutes after administration; its duration of action is 3 to 6 hours, making administration of the drug necessary 3 to 4 times a day. Ipratropium generally produces the same moderate bronchodilation as obtained with maximum doses of β2-agonists (Undem and Lichenstein 2001). Oxitropium produces similar pharmacological effects to ipratropium and can be administered twice a day. Tiotropium bromide, a new long-acting anticholinergic drug, which can be administered just once a day, has similar or greater efﬁcacy compared with other bronchodilators (Calverley 2000) and is useful in combination with formoterol for COPD treatment (van Noord et al 2006). A randomized, prospective, double-blind, placebo-controlled, multicenter trial to assess whether adding salmeterol or salmeterol– fluticasone to chronic therapy with tiotropium would provide additional clinical beneﬁt to patients with moderate to severe COPD is currently being carried out (Aaron et al 2004). Tiotropium improves sleeping arterial oxygen saturation (McNicholas et al 2004) and, in combination with pulmonary rehabilitation, exercise tolerance in patients with COPD (Casaburi et al 2005). Tiotropium bromide is indicated in the maintenance treatment of COPD, but it is not effective in relieving acute bronchospasms. However, as is the case with asthmatic patients, some authors raised doubts about chronic administration of bronchodilators which could be associated with worsening COPD (van Schayck et al 1991). Because of their negligible absorption, antimuscarinics rarely cause systemic side effects and are generally well tolerated. Possible side effects include dry mouth, nausea, constipation, and headache (RS 2003). Antimuscarinic bronchodilators should be administered with caution in glaucoma, benign prostatic hypertrophy and urinary obstruction (RS 2003; Rennard 2004). Cases of acute angle-closure glaucoma have been reported with nebulized ipratropium, particularly when given with nebulized salbutamol. 412 Theophylline Theophylline, a methylxanthine, is one of the least expensive bronchodilators. Given its very low solubility in water, theophylline is administered intravenously as aminophylline. Aminophylline is a theophylline and ethylenediamine mixture, which is 20 times more soluble than theophylline alone. The bronchodilatory effect of theophylline is due both to relatively non-selective inhibition of cyclic neucleotide phosphodiesterases and to competitive antagonism of adenosine receptors (Barnes 2003). At least eleven phosphodiesterase isozymes have been identiﬁed (Soderling and Beavo 2000). The inhibition of phosphodiesterase isozymes type III and IV causes relaxation of the airway smooth muscle cells in vitro (Torphy et al 1993). Selective phosphodiesterase-4 inhibitors for COPD are currently in clinical trials (Lipworth 2005). Adenosine receptor antagonism also contributes to the brochodilatory effect of theophylline (Feoktistov et al 1998). In addition to bronchodilation, theophylline may have anti-inflammatory effects at lower plasma concentrations in the respiratory tract as shown by the reduction both in the number of neutrophils and in the interleukin-8 concentration in induced sputum from COPD patients, where the same effects cannot be obtained after inhalation of high glucocorticoid doses (Barnes 2003). In vitro studies have shown that low doses of theophylline may enhance the anti-inﬂammatory effect of corticosteroids and antagonize the “resistance” to corticosteroids caused by smoking in COPD patients by activating histone deacetylases (Barnes 2003, 2006). Theophylline is generally administered orally in conventional form or, more frequently, through sustained- release preparations or intravenously (like aminophylline) (Undem and Lichtenstein 2001). Sustained-release preparations are available for administration every 8, 12, or 24 hours. Intravenous administration of theophylline must be given very slowly, over at least a 20 minute period (RS 2003), because of the risk of serious toxic effects such as arrhythmias and convulsions. Inhalation of theophylline is not effective and intramuscular injection is not possible because of its irritant effect at the site of injection. Absorption of theophylline from conventional formulations is fast and complete with a plasma concentration peak within two hours of administration. Absorption of theophylline from sustained-release preparations has a large interindividual variability, for this reason, dosage must be changed to suit the individual patient. Theophylline is mainly eliminated by hepatic International Journal of COPD 2006:1(4)