BMS2047 Pharmacology - On Demand Lecture 1 - Cyclooxygenase PDF

Inflammation and Antiinflammatories Dr Penny Lympany [email protected] 28AY04 Cyclooxygenase as a drug target Lecture Bite 1 Cyclooxygenase Enzyme producing PGG2 and PGH2 COX-1: Constitutive, widespread Produces PGE2 in stomach – protective Subtype found in platelets – produces TXA2 for aggrega...

Inflammation and Antiinflammatories Dr Penny Lympany [email protected] 28AY04 Cyclooxygenase as a drug target Lecture Bite 1 Cyclooxygenase Enzyme producing PGG2 and PGH2 COX-1: Constitutive, widespread Produces PGE2 in stomach – protective Subtype found in platelets – produces TXA2 for aggregation Small hydrophobic channel – inhibited by small molecules COX-2: Inducible – synthesis of enzyme increased by cytokines Produces high levels of PGs in areas of inflammation Also found in endothelial cells – produces PGI2 to prevent aggregation – and in the CNS Larger channel – inhibited by drugs with bulky side groups which cannot enter COX-1 NSAIDS Non-steroidal anti-inflammatory drugs Non selective (Weak COX1) o Aspirin – irreversible covalent modification o Ibuprofen - reversible COX 1 selective o Ketorolac o Flurbiprofen COX 2 selective (generally reversible) o Celecoxib o Rofecoxib Side effects: GI bleeding, possible increased cardiovascular risk Paracetamol Not an anti-inflammatory drug Several proposed mechanisms of action COX 3 in CNS? Decrease nitrox oxide synthesis in spinal cord? Metabolite NAPQI inhibit neurotransmission? Antipyretic analgesic Extremely safe and well tolerated Given for wide range of conditions Liver toxicity Cyclooxygenase and NSAIDS Smith FG et al. (2012) Pharmaceuticals 5(11):1160-76. Cyclooxygenase and NSAIDS Don’t forget to:  Check out the case study  Look at the covid question and start to brainstorm how you would approach it. We will be looking at this next week in the tutorial sessions.  Spend time reflecting on your week, what questions you have and have you been productive with your time. To post on the discussion board click here References GENERAL: Rang & Dales Pharmacology (2016) 8th Edition, Elsevier. Neal (2016) Medical Pharmacology at a Glance 8th Edn (especially for revision) IN MORE DETAIL: Serhan, C., Chiang, N. & Van Dyke, T. (2008). Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators. Nat Rev Immunol 8, 349–361 https://doi.org/10.1038/nri2294 Ricciotti E, FitzGerald GA. (2011) Prostaglandins and inflammation. Arterioscler Thromb Vasc Biol. 31(5):986-1000. doi: 10.1161/ATVBAHA. Smith FG, Wade AW, Lewis ML, Qi W. (2012) Cyclooxygenase (COX) Inhibitors and the Newborn Kidney. Pharmaceuticals (Basel) 5(11):1160-76. doi: 10.3390/ph5111160. Murdoch JR, Lloyd CM. (2010) Chronic inflammation and asthma. Mutat Res. 690(1-2):24-39. doi: 10.1016/j.mrfmmm.2009.09.005. Farzam, K., Sabir, S. & O'Rourke, M.C. Antihistamines https://www.ncbi.nlm.nih.gov/books/NBK538188/