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Pathway Description
Formoterol Action Pathway
Homo sapiens
Drug Action Pathway
Formoterol is a long acting beta-2 adrenergic receptor agonist that is used as a bronchodilator and to manage asthma and COPD. It can be used as well for prophylaxis against exercise induced bronchospasm. This drug is inhaled and can be recognized under the brand names Bevespi, Breyna, Duaklir, Foradil, Oxeze, Zenhale, and Symbicort. Formoterol both has a rapid onset and a long duration of action, demonstrating its efficiency. Formoterol is able to cause relaxation of the bronchial smooth muscles and opening of the airways through its binding to the beta-2 adrenergic receptors which causes G protein signalling cascade and activation of adenylyl cyclase. 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. It does have some degree of activity at beta-1 and beta-3 receptors, but the activity at beta-2 receptors is ~200 fold greater. Some side effects from using Formoterol may include nervousness, dry mouth, nausea, and headaches.
References
Formoterol Pathway References
Wishart DS, Feunang YD, Guo AC, Lo EJ, Marcu A, Grant JR, Sajed T, Johnson D, Li C, Sayeeda Z, Assempour N, Iynkkaran I, Liu Y, Maciejewski A, Gale N, Wilson A, Chin L, Cummings R, Le D, Pon A, Knox C, Wilson M: DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2018 Jan 4;46(D1):D1074-D1082. doi: 10.1093/nar/gkx1037.
Pubmed: 29126136
Billington CK, Penn RB: Signaling and regulation of G protein-coupled receptors in airway smooth muscle. Respir Res. 2003;4(1):2. Epub 2003 Mar 14.
Pubmed: 12648290
Anderson GP: Formoterol: pharmacology, molecular basis of agonism, and mechanism of long duration of a highly potent and selective beta 2-adrenoceptor agonist bronchodilator. Life Sci. 1993;52(26):2145-60. doi: 10.1016/0024-3205(93)90729-m.
Pubmed: 8099696
Bartow RA, Brogden RN: Formoterol. An update of its pharmacological properties and therapeutic efficacy in the management of asthma. Drugs. 1998 Feb;55(2):303-22. doi: 10.2165/00003495-199855020-00016.
Pubmed: 9506248
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