Bronchodilators, receptors and cross-talk: Together is better?

The most widely used maintenance therapies in chronic obstructive pulmonary disease (COPD) are long-acting muscarinic antagonists (LAMAs), and a number of these drugs are now available in combination with long-acting β2-agonists (LABAs). LAMAs inhibit the parasympathetic muscarinic pathway, while LABAs, as sympathomimetics, reduce airway smooth muscle (ASM) tone. As well as directly controlling the constriction and relaxation of ASM, muscarinic and adrenergic receptors are found on inflammatory cells, and drugs that target these receptors may also reduce inflammation in COPD. Evidence suggests that the muscarinic and adrenergic pathways cross-talk at the level of neuronal input to the ASM via second-messenger pathways within ASM cells. Although the cross-talk is not completely understood, pharmacologically targeting both pathways in COPD can maximize bronchodilation. Combining LAMAs and LABAs demonstrated improved efficacy compared with the individual therapies and so, for greater convenience, several fixed-dose combinations for once-daily use have been developed. These fixed-dose combinations demonstrate improvements in both lung-function and patient-reported outcomes compared with well-established monotherapies, with similar tolerability profiles to the individual agents.