Salmeterol is a long acting beta-2 adrenergic receptor agonists used to treat asthma and COPD. Beta-2 agonists are G protein linked second messengers. It can be found under the brand names Advair, Airduo, Serevent, and Wixela. This drug is to be inhaled alongside corticosteroids to be most effective. It is useful for the prevention of exercise induced bronchospasm and airflow obstruction. Salmeterol can bind to both active and exo sites on the beta-2 adrenergic receptor; the saligenin moiety binds to the active site and the hydrophilic tail binds to leucine residues in the exo site almost irreversibly, leading to the long duration of action seen with Salmeterol. A single dose can last 12 hours. The result of taking this drug is relaxation of the bronchial smooth muscles causing bronchodilator and increased airflow. Once Salmeterol is administered and it binds to the beta-2 adrenergic receptor, the G protein signalling cascade begins. The alpha and beta/gamma subunits of the G protein separate and GDP is replaced with GTP on the alpha subunit. This alpha subunit then activates adenylyl cyclase which converts ATP to cAMP. cAMP then activates protein kinase A (PKA) which in turn phosphorylates targets and inhibits MLCK through decreased calcium levels causing muscle relaxation. PKA can phosphorylate certain Gq-coupled receptors as well as phospholipase C (PLC) and thereby inhibit G protein-coupled receptor (GPCR) -PLC-mediated phosphoinositide (PI) generation, and thus calcium flux. PKA phosphorylates the inositol 1,4,5-trisphosphate (IP3) receptor to reduce its affinity for IP3 and further limit calcium mobilization. PKA phosphorylates myosin light chain kinase (MLCK) and decreases its affinity to calcium calmodulin, thus reducing activity and myosin light chain (MLC) phosphorylation. PKA also phosphorylates KCa++ channels in ASM, increasing their open-state probability (and therefore K+ efflux) and promoting hyperpolarization. Since myosine light chain kinase is not activated, Serine/threonine-protein phosphatase continues to dephosphorylate myosin LC-P, and more cannot be synthesized so myosin remains unbound from actin causing muscle relaxation. This relaxation of the smooth muscles in the lungs causes the bronchial airways to relax which causes bronchodialation, making it easier to breathe. Some risks and side effects of Salmeterol include monotherapy, hypokalemia, hypoglycemia, seizures, headache, tremor, and fatigue. Salmeterol is administered via respiratory inhalation.

Salmeterol Pathway References