Current and Novel Bronchodilators in Respiratory Disease

Domenico Spina


Curr Opin Pulm Med 

In This Article

Muscarinic Antagonists

Tiotropium bromide is clinically effective in the management of COPD by improving baseline FEV1, reducing the frequency of exacerbations, and increasing the quality of life.[76] Consequently, other long-acting muscarinic antagonist (LAMAs) including glycopyrronium bromide,[77] aclidinium bromide[78] and umeclidinium bromide[79,80] are under clinical development (Table 4).[81,82,83,84] This drug class is not used in the treatment of asthma, although tiotropium bromide causes bronchodilation of a similar magnitude to salmeterol and is clinically effective in difficult to control asthma.[53,85,86]

There are five muscarinic receptor subtypes and their expression on airway smooth muscle cells (M3-receptor) and submucosal glands (M1-receptor) forms the basis for the beneficial action of this drug class in COPD, by virtue of antagonism of airway smooth muscle contraction and submucosal gland secretion by endogenously released acetylcholine, but with potential for side-effects via antagonism of cardiac M2-receptors. LAMAs are characterized as nonselective antagonists with similar affinities between muscarinic receptor subtypes but tend to dissociate more quickly from the M2-receptor versus M3-receptor (Table 4). The association rate constants are the same order of magnitude for all LAMAs, and therefore receptor kinetics does not explain the faster clinical onset of action of glycopyrronium bromide compared with tiotropium bromide despite being similarly effective in terms of improvement in lung function and exacerbation rate.[77] Aclidinium bromide (twice daily)[78] and umeclidinium bromide[79] are also characterized by slow onset of action.

The potentially quicker dissociation rate from the M2-receptor might confer an advantage allowing lung vagal prejunctional M2-autoreceptors and cardiac M2-receptors to remain functionally active thereby improving the benefit/risk ratio. Many studies have reported lengthy dissociation times for LAMAs from the M3-receptor that is proposed to explain once a day treatment and prolonged improvement in baseline lung function (Table 4). However, the calculated dissociation half-life for LAMAs appears to be dependent upon the binding conditions used in these assays (e.g. absence of Na+ ions under non-physiological conditions).[81] For example, a comparison of binding characteristics under physiological versus non-physiological conditions reveals an order of magnitude overestimation of the dissociation half-life of muscarinic antagonists from the receptor under the latter condition[81] (Table 4). Similarly, receptor kinetics does not explain why aclidinium bromide with a similar dissociation half-life as tiotropium bromide (under non-physiological conditions) requires twice daily treatment to achieve comparable bronchodilator activity as tiotropium bromide.[78] However, aclidinium bromide is an ester that is rapidly metabolized within minutes by plasma esterases and characterized by a pH-dependent instability in aqueous solution (hours) that might explain why twice daily dosing is required, with obvious advantages for limiting systemic side-effects.

Hence, onset of action and long duration of action is likely to be influenced by retention within the vicinity of receptor sites either via interaction with nonreceptor proteins, lipid membranes or rebinding as described for LABAs, rather than differences in receptor affinity and kinetics.[47] LAMAs including tiotropium, aclidinium and glycopyrronium bromide are inverse agonists with similar intrinsic activity as documented by their ability to inhibit the activation of the AP-1 gene in M3-receptor overexpressing Chinese hamster ovary cells; this is therefore unlikely to account for their long duration of action.[87] However, this mechanism could account for the anti-inflammatory effect of muscarinic antagonists reported in various in-vitro studies,[88] although the clinical relevance is not firmly established.

Clinical studies have reported the beneficial effect of combined use of LABAs and LAMAs for a number of variables including bronchodilation, rate of exacerbation, dyspnoea and symptom control.[80,89–91] Additional bronchodilation can be achieved particularly if some patients are not dosed optimally on monotherapy, and combination therapy offers the opportunity of reducing the dose of each bronchodilator but not at the expense of clinical effectiveness and potential to reduce the risk of adverse side-effects with high dose monotherapy.

Another approach has been the development of a dual acting muscarinic antagonist, β2-agonist (MABA) for once a day treatment as exemplified by GSK961081,[92] which offers the advantage of a molecule with a single pharmacokinetic profile and potential benefits concerning formulation of one as opposed to two separate molecules. This treatment could offer greater simplicity for patients undergoing triple therapy with combination LABA/LAMA/inhaled corticosteroid in COPD.