Pharmacologic rationale underlying the therapeutic effects of tiotropium/olodaterol in COPD

Figures & data

Figure 1 Tiotropium: mechanism of bronchodilating action.

Notes: Tiotropium lastingly binds with high affinity to muscarinic M₃ receptors, thus preventing them from activating the signal transduction pathway involving Gq protein and phospholipase C (PLC). As a consequence, the synthesis of the intracellular second messenger inositol 1,4,5-trisphosphate (IP₃) is suppressed. Therefore, blockade of muscarinic M₃ receptors by tiotropium results in an effective inhibition of bronchoconstriction mediated by IP₃-dependent Ca²⁺ mobilization.

Figure 2 Olodaterol: mechanism of bronchodilating action.

Notes: Olodaterol persistently binds with high affinity and selectivity to β₂-adrenergic receptor (β₂-AR), thus forming a very stable ternary complex, also including G stimulatory (Gs) protein. The subsequent, long-lasting stimulation of adenylyl cyclase (AC) and sustained increase in the intracellular concentration of second messenger cyclic AMP (cAMP) are responsible for activation of cAMP-dependent protein kinase A (PKA). PKA phosphorylates several targets involved in inhibition of Ca²⁺ release, as well as in sequestration of Ca²⁺ into intracellular stores.

Table 1 LABA/LAMA fixed dose combinations

LABA	LAMA	Inhaler	Company
Olodaterol	Tiotropium	Respimat Soft Mist	Boehringer Ingelheim
Indacaterol	Glycopyrronium	Breezhaler	Novartis
Vilanterol	Umeclidinium	Ellipta	GlaxoSmithKline
Formoterol	Aclidinium	Genuair	Almirall

Abbreviations: LABA, long-acting β₂-adrenoceptor agonists; LAMA, long-acting muscarinic receptor antagonists.