Pathways

Orciprenaline is a beta-2 adrenergic agonist used to treat bronchospasm, asthma, and COPD. This drug is used exclusively as a bronchodilator. When taken, it acts on the smooth muscles in the bronchi causing a muscle relaxation or bronchodilation. It activates the beta-2 adrenergic receptors which then further stimulates intracellular adenylyl cyclase. Once Orciprenaline 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. Orciprenaline is a moderately selective agonist and can include side effects such as dizziness, headaches, nausea, sweating, and tremors.

Acemetacin is highly metabolized and degraded by esterolytic cleavage to form its major and active metabolite indometacin. Indomethacin is a nonsteroidal anti-inflammatory (NSAID) used for the symptomatic management of chronic musculoskeletal pain conditions and to induce closure of a hemodynamically significant patent ductus arteriosus in premature infants. This drug is not FDA, Canada or EMA approved. It has analgesic, antipyretic, and anti-inflammatory effects. It targets the prostaglandin G/H synthase-1 (COX-1) and prostaglandin G/H synthase-2 (COX-2) in the cyclooxygenase pathway. The cyclooxygenase pathway begins in the cytosol with phospholipids being converted into arachidonic acid by the action of phospholipase A2. The rest of the pathway occurs on the endoplasmic reticulum membrane, where prostaglandin G/H synthase 1 & 2 convert arachidonic acid into prostaglandin H2. Prostaglandin H2 can either be converted into thromboxane A2 via thromboxane A synthase, prostacyclin/prostaglandin I2 via prostacyclin synthase or prostaglandin E2 via prostaglandin E synthase. COX-2 is an inducible enzyme, and during inflammation, it is responsible for prostaglandin synthesis. It leads to the formation of prostaglandin E2 which is responsible for contributing to the inflammatory response by activating immune cells and for increasing pain sensation by acting on pain fibers. Indomethacin inhibits the action of COX-1 and COX-2 on the endoplasmic reticulum membrane. This reduces the formation of prostaglandin H2 and therefore, prostaglandin E2 (PGE2). The low concentration of prostaglandin E2 attenuates the effect it has on stimulating immune cells and pain fibers, consequently reducing inflammation and pain. Fever is triggered by inflammatory and infectious diseases. Cytokines are produced in the central nervous system (CNS) during an inflammatory response. These cytokines induce COX-2 production that increases the synthesis of prostaglandin, specifically prostaglandin E2 which adjusts hypothalamic temperature control by increasing heat production. Because indomethacin decreases PGE2 in the CNS, it has an antipyretic effect. In clinical trials, acemetacin exhibits better gastric tolerability compared to its active metabolite indometacin.

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.

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.

Mesalazine is a non-steroidal anti-inflammatory drug (NSAID) structurally related to the salicylates. This molecule is used to treat mild to moderately active ulcerative colitis. Mesalazine's mechanism of action is still not understood, but it is believed that the molecule has a topical anti-inflammatory effect on colonic epithelial cells. It targets the prostaglandin G/H synthase-1 (COX-1) and prostaglandin G/H synthase-2 (COX-2) in the cyclooxygenase pathway. The cyclooxygenase pathway begins in the cytosol with phospholipids being converted into arachidonic acid by the action of phospholipase A2. The rest of the pathway occurs on the endoplasmic reticulum membrane, where prostaglandin G/H synthase 1 & 2 convert arachidonic acid into prostaglandin H2. Prostaglandin H2 can either be converted into thromboxane A2 via thromboxane A synthase, prostacyclin/prostaglandin I2 via prostacyclin synthase, or prostaglandin E2 via prostaglandin E synthase. COX-2 is an inducible enzyme, and during inflammation, it is responsible for prostaglandin synthesis. It leads to the formation of prostaglandin E2 which is responsible for contributing to the inflammatory response by activating immune cells and for increasing pain sensation by acting on pain fibers. Mesalazine inhibits the action of COX-1 and COX-2 on the endoplasmic reticulum membrane. This reduces the formation of prostaglandin H2 and therefore, prostaglandin E2 (PGE2). The low concentration of prostaglandin E2 attenuates the effect it has on stimulating immune cells and pain fibers, consequently reducing inflammation and pain. Furthermore, mesalazine also inhibits arachidonate 5-lipoxygenase, diminishing the inflammatory processes (leukotriene biosynthesis) and the peroxisome proliferator-activated receptor gamma (inhibiting transcription factors; NF-kappa-B-mediated proinflammatory responses). Mesalazine is administered as an oral tablet or as a rectal suppository.

Arformoterol is a beta-2 adrenergic receptor agonist that is used as a bronchodilator to treat COPD and chronic bronchitis. It accomplishes this by upon inhalation of the drug by relaxing smooth muscles in the airways to improve breathing. It can be found under the brand name Brovana, and it has a 2 fold greater potency than racemic formoterol. Once arformoterol 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 side effects of using arformoterol can include chest pain, anxiety, blurred vision, and chills.

Indacaterol is an inhaled beta-2 adrenergic agonist that is both rapid onset and long acting. The purpose of this drug is to relax bronchial smooth muscle to help treat COPD, asthma, and chronic bronchitis by opening the airways. It can be found under the brand names Hirobriz, Onbrez, and Ultibro. Indacaterol is long acting due to its high affinity to lipid raft domains in airway membranes meaning that it slowly dissociates from receptors. The result of taking this drug is relaxation of the bronchial smooth muscles causing bronchodilator and increased airflow. Once Indacaterol is administered and it binds to and activates 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 side effects of using Indacaterol may include sore throat, runny nose, headache, nausea, and cough which is the most common side effect.

Olodaterol is a beta-2 adrenergic agonist that is long acting. It is used for the management of chronic bronchitis and COPD, but not asthma. It accomplishes this by mediating smooth muscle relaxation and bronchodilator via L-type calcium channels. It can be found under the brand names Inspiolto Respimat, Stiolto, and Striverdi Respimat. Olodaterol activates beta-2 adrenergic receptors in lungs when it binds, and this then causes the G protein to be activated and the G protein cascade to begin. Olodaterol is highly selective for the beta-2 adrenergic receptor. Once arformoterol 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 bronchodilation, making it easier to breathe. Some side effects of using olodaterol can include nasopharyngitis, upper respiratory tract infection, cough, dizziness, and rash.

Levosalbutamol is a beta-2 adrenergic receptor agonist that is used to treat COPD and asthma. It is a short acting drug that can be found under the brand name Xopenex. Levosalbutamol is inhaled, and works by relaxing the smooth muscle in bronchial tubes to increase air flow. Levosalbutamol is Gs coupled and relaxes the muscles through activation of adenylyl cyclase. Short-acting inhaled beta-2 agonists are used for acute symptomatic relief of bronchospasm and to prevent exercise-induced asthma (EIA). Once levosalbutamol 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. Inhibits the phosphorylation of myosin. 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 side effects of using levosalbutamol may include headache, dizziness, nausea, fatigue, and stomach pain.

Terbutaline is a beta-2 adrenergic receptor agonist that is used primarily as a bronchodilator. It can be found under the brand name Bricanyl and is an inhaled drug with a short duration. It is used for the prevention and reversal of bronchospasm and for treatment of asthma and bronchitis. Terbutaline relaxes the smooth muscles in the bronchioles by binding to the beta-2 adrenergic receptor and starting a G protein signalling cascade that activates adenylyl cyclase. Once terbutaline 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. Inhibits the phosphorylation of myosin. 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 side effects from use of terbutaline may include nervousness, drowsiness, weakness, nausea, and headache. Terbutaline may be administered via respiratory inhalation, oral tablets, or subcutaneous injections.