Pathways

Vinblastine (also named Velban) is a natural alkaloid isolated from Vinca rosea, originally from Catharanthus (vinca) roseus. Vinblastine is used as chemotherapy medication such as an antimitotic agent. It is used as a treatment of breast cancer, testicular cancer, neuroblastoma, Hodgkin's and non-Hodgkins lymphoma, mycosis fungoides, histiocytosis and Kaposi's sarcoma. Its antitumor activity is thought to be due primarly to inhibition of mitosis at metaphase through interaction its interaction with tubulin (microtubules). Vinblastine binds specifically to microtubular proteins (tubulin) of the mitotic spindle, leading to crystallization of the microtubules (not dynamic anymore). In consequence, there is a mitotic arrest leading to the cell death. The disarray of microtubules induces two proteins; cellular tumor antigen p53 and cyclin dependent kinase inhibitor p21. The latter protein works to inhibit cyclin dependent kinases in the cell, which disrupt the phosphorylation of the apoptosis inhibitor Bcl-2. Bcl-2 suppresses apoptosis by regulating permeability of the mitochondrial membrane, but is unable to do so due to the interrupted phosphorylation. The former protein, p53, acts on BAK and BAX to enact conformational changes, creating pores in the mitochondrial membrane that allow the exit of cytochrome c. Cytochrome c further activates capsases in the cell, which cleave essential cellular proteins. In this way, p53 and p21 work alongside each other to promote apoptosis and terminate unhealthy cells.

Vincristine is a vinca alkaloid isolated from Vinca rosea. It is used as an antineoplastic agent in many cancer treatments (acute leukemia, malignant lymphoma, Hodgkin's disease, acute erythraemia, and acute panmyelosis). This drug is often chosen as part of polychemotherapy because of its lack of significant bone–marrow suppression and its unique clinical toxicity (neuropathy). The mechanism of vincristine is the inhibition of microtubule dynamics that would cause mitotic arrest and eventual cell death. As a microtubule destabilizing agent, Vincristine stimulates mitotic spindle destruction and microtubule depolymerization at high concentrations. At lower clinically relevant concentrations, vincristine can block mitotic progression. Unlike the taxanes, which bind poorly to soluble tubulin, vincristine can bind both soluble and microtubule-associated tubulin. To be able to stabilize the kinetics of microtubule, vincristine rapidly and reversibly bind to soluble tubulin which can increase the affinity of tubulin by the induction of conformational changes of tubulin. Vincristine binds to beta-tubulin subunits at the positive end of microtubules at a region called the Vinca-binding domain. The binding between vincristine and soluble tubulin decreases the rate of microtubule dynamics (lengthening and shortening) and increases the duration of the attenuated state of microtubules. Therefore, the proper assembly of the mitotic spindle could be prevented; and the tension at the kinetochores of the chromosomes could be reduced. Subsequently, chromosomes can not progress to the spindle equator at the spindle poles. Progression from metaphase to anaphase is blocked and cells enter a state of mitotic arrest. The cells may then undergo one of several fates. The tetraploid cell may undergo unequal cell division producing aneuploid daughter cells. Alternatively, it may exit the cell cycle without undergoing cell division, a process termed mitotic slippage or adaptation. These cells may continue progressing through the cell cycle as tetraploid cells (Adaptation I), may exit G1 phase and undergo apoptosis or senescence (Adaption II), or may escape to G1 and undergo apoptosis during interphase (Adaptation III). Another possibility is cell death during mitotic arrest. Alternatively, a mitotic catastrophe may occur and cause cell death. Vinca alkaloids are also thought to increase apoptosis by increasing concentrations of p53 (cellular tumor antigen p53) and p21 (cyclin-dependent kinase inhibitor 1) and by inhibiting Bcl-2 activity. Increasing concentrations of p53 and p21 lead to changes in protein kinase activity. Phosphorylation of Bcl-2 subsequently inhibits the formation of Bcl-2-BAX heterodimers. This results in decreased anti-apoptotic activity. Like other vinca alkaloids, Vincristine may also interfere with 1) amino acid, cyclic AMP, and glutathione metabolism, 2) calmodulin-dependent Ca2+-transport ATPase activity, 3) cellular respiration, and 4) nucleic acid and lipid biosynthesis.

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.