monophosphate (cAMP) levels which, in turn, activates a cAMP-dependant protein kinase (PKA) (Johnson and Coleman 1995). Activation of the latter causes myosin light chain kinase phosphorylation with a reduction in the afﬁnity of this enzyme for the calcium–calmodulin complex, a reduction in the formation of active myosin light chain kinase, a reduction in myosin phosphorylation and, ﬁnally, a reduction in the interaction of actin and myosin ﬁlaments with consequent bronchodilation. In addition, PKA stimulation causes a reduction in intracellular calcium ion levels because of increased extrusion of calcium from the cell, reduction in the entry of calcium into the cell, and increase in the uptake of calcium by the smooth endoplasmic reticulum, which is the site at which calcium ions are deposited within the cell. The reduction in the concentration of intracellular calcium causes a reduction in the formation of the calcium–calmodulin complex which produces the previously described effects. In addition to this main bronchodilation mechanism of selective β2-agonists, other mechanisms may, in theory, contribute to reducing airway obstruction. Stimulation of β2-adrenoceptors also increases potassium channel conduction with hyperpolarization and relaxation of the airway smooth muscle (Kume et al 1994). This effect is, in part, independent from the increase in cAMP levels (Kume et al 1994). The activation of ß2-receptors on inflammatory cells such as mast cells, basophils, eosinophils, neutrophils and lymphocytes cause an increase in cAMP levels and subsequent inhibition of the release of inﬂammatory mediators such as leukotrienes, histamine and cytokines (Hughes et al 1983; Barnes 1999). β2-agonists increase mucociliary clearance, decrease microvascular permeability and may inhibit phospholipase A2 with subsequent reduction in the synthesis of leukotrienes, prostaglandins and thromboxane A2, which are important inﬂammatory mediators (Seale 1988). The importance of these mechanisms on the therapeutic effect of β2-agonists in humans, particularly in COPD, is not known. Inhalation limits the absorption and therefore the systematic side effects of β2-agonists. However, only about 10% of the aerosol enters the respiratory tract while the remainder is swallowed and may be absorbed in the intestinal tract with consequent systemic side effects. Furthermore, aerosolized particles less than 1μm in diameter reach the alveoli and may be absorbed in the pulmonary capillaries. The main side effect of selective β2-agonists administered by inhalation at clinical doses is muscular tremor. However, this tends to diminish in intensity during International Journal of COPD 2006:1(4) Pharmacological treatment of COPD prolonged treatment. This phenomenon is known as drug tolerance. It is not know if drug tolerance is due to the down regulation of the β2-adrenoceptors on the muscle cytoskeleton or to adaptation phenomena in the central nervous system. Tachycardia is uncommon in clinical doses of β2-agonists administered by inhalation. The absorption of β2-agonists may cause tachycardia by stimulating the cardiac β1-adrenoceptors, particularly at higher doses when relative selectivity for β2-adrenoceptors is lost. Although there are fewer cardiac β2-adrenoceptors, their stimulation may also contribute to tachycardia (Undem and Lichtenstein 2001). This type of side effect is particularly relevant in patients with ischemic heart disease or pre- existing arrhythmias. In these patients, β2-agonists need to be administered with caution, even when inhaled. Bron- chodilation may cause ventilation/perfusion mismatch with a consequent drop in the arterial partial pressure of oxygen. This is generally transitory and of little importance. Other side effects of systemically delivered β2-agonists, such as hypokalemia, increase in the plasma concentrations of glucose, lactose, and free fatty acids are much less common when β2-agonists are delivered by inhalation. Antimuscarinic drugs Antimuscarinics are delivered in the same way as bronchodilators. Antimuscarinics are quaternary ammonium derivatives which, after inhalation, undergo <1% absorption from the pulmonary or gastrointestinal tract. The parasympathetic nervous system has a role in the regulation of the bronchial tone. Vagal ﬁbres activate nicotinic and M1 muscarinic receptors on the parasympathetic ganglia of the respiratory tract; short postganglionic ﬁbers release acetylcholine which stimulates the M3 muscarinic receptors on the airway smooth muscle cells with consequent increase in motility. In addition, the airway submucosal glands have M3 muscarinic receptors. M3 muscarinic receptor stimulation increases bronchial secretion. Inﬂammatory mediators such as eicosanoids, histamine, and bradykinin may further produce parasympathetic reﬂexes which partly explains their bronchoconstriction effect. Antimuscarinic bronchodilators are non-selective antagonists of cholinergic muscarinic receptors. Their effect on airway obstruction is mainly due both to M muscarinic 3 receptor antagonism in the airway smooth muscle cells, with consequent bronchodilation, and to M3 muscarinic receptor antagonism in the cells of the submucosal glands, with a reduction in the basal and stimulated cholinergic 411