Pharmacological mechanisms leading to synergy in fixed-dose dual bronchodilator therapy.

Long-acting β2 adrenoceptor agonists (LABAs) in combination with long-acting muscarinic antagonists (LAMAs) can elicit functional and clinical benefits in chronic obstructive pulmonary disease (COPD). LABA/LAMA combinations synergistically relax human isolated airways at the level of the medium and small bronchi. LABAs and LAMAs both modulate the bronchial tone via different pathways localized at the level of presynaptic parasympathetic fibers and airway smooth muscle cells. The exact nature of the interactions between these pathways is not completely understood, but there is cross-talk at many levels in airway smooth muscle cells that is also regulated by the activity of calcium-activated potassium channels and protein tyrosine kinases. While the synergy between LABAs and LAMAs is a class effect, some of the currently available fixed-dose combinations (FDCs) do not induce synergistic interaction because the individual components are not appropriately balanced in the combination. Concerns remain on the cardiovascular safety profile of LABA/LAMA FDCs.