Emerging role of long acting muscarinic antagonists for asthma

Abstract

Acetlycholine is involved in the control of airway smooth muscle constriction and in recruitment of inflammatory cells via neuronal and paracrine effects on muscarinic type 3 receptors. Long acting muscarinic antagonists (LAMA) are well established in guidelines for COPD but are not currently licensed for use in asthma. There are emerging data from key clinical trials to show that LAMA may confer bronchodilator effects and improved control when used in addition to inhaled corticosteroid (ICS) alone or in conjunction with long acting β-adrenoceptor agonists (LABA). Further studies in persistent asthmatic patients are required to evaluate ICS sparing effects of LAMA looking particularly at airway hyper-responsiveness and surrogate inflammatory markers, in addition to evaluation of possible synergy between LAMA and LABA when given together. Future possible development of combination inhalers comprising ICS/LAMA or ICS/LAMA/LABA will require long term studies looking at asthma control and exacerbations in both adult and paediatric patients.

Keywords: asthma; muscarinic antagonist; tiotropium; β-adrenoceptor.

Figure 1

In humans there is no direct sympathetic innervation of the smooth muscle, but β₂ADR (β₂) are available to circulating adrenaline. Pre-synaptically the sympathetic nerves lie close to the parasympathetic system and are thought to influence β₂ADR here. It is thought both β₂ADR and M₂ receptors are inhibitory to the release of acteylchoine (ACh) and that there is crosstalk between these receptor types (broken line). The M₂ receptor is stimulated by ACh to reduce further ACh secretion. This M₂ autoreceptor is thought to be defective in asthma and in response to viruses, hence this negative feedback is lost and there is increased airway hyperreactivity (AHR). Post-synaptically the muscarinic M₃ receptor is the main parasympathetic bronchoconstrictor mechanism. Although post-synaptic M₂ receptors are present their role is to prolong M₃ initiated bronchoconstriction by opposing the actions of β₂ADR. Hence the same receptors may have different actions pre- and post-synaptically exerting independent effects on AHR and airway tone respectively