BMS2047 Pharmacology Introduction PDF

Inflammation and Antiinflammatories Introduction Dr Penny Lympany [email protected] 28AY04 Learning outcomes To describe and explain the process and effects of inflammation To identify and evaluate the role of cyclooxygenase, prostaglandins, leukotrienes, histamine and steroids in combatting in...

Inflammation and Antiinflammatories Introduction Dr Penny Lympany [email protected] 28AY04 Learning outcomes To describe and explain the process and effects of inflammation To identify and evaluate the role of cyclooxygenase, prostaglandins, leukotrienes, histamine and steroids in combatting inflammation To describe and explain the receptor systems for Prostaglandins Leukotrienes Histamine Steroids To discuss the causes and effects of gout and its treatment – case study To discuss the uses of DMARDS to treat rheumatoid arthritis To describe and explain the physiology of asthma and the drugs which can relieve its symptoms So where does this fit? Revision of past module material – Immunology Respiratory Link to Covid assessment question Link to future modules e.g. BMS3099 In summary Inflammation – Mobilises defensive cells Limits spread of pathogens Kills pathogens Initiates repair Phase 1 – exudation of plasma fluid containing mediators Phase 2 – neutrophils Phase 3 – monocytes – differentiate to macrophages Clearance through lymphatic system Antiinflammatory mediators Acute inflammation Tissue Damage Histamine Release of mediators Recruitment of immune cells Prostaglandins Bradykinin/ Nitric oxide Inflammation 5 cardinal signs of inflammation:  heat  redness  swelling  pain  loss of function These can be explained by the following concepts: ▪ Vasodilation increases blood flow to the area ▪ Extravasation of leukocytes into the surrounding tissue (basement membrane integrity is compromised, allowing proteins to leak out too). ▪ Proteins in the extra cellular fluid (ECF) leads to water moving into ECF by osmosis. ▪ Release of prostaglandins and histamine activate neurons → pain Inflammatory mediators 1. Attract leukocytes 2. Leukocytes remove the problem… 3. Acute inflammation aims to recruit cells to aid healing mainly by chemotaxis, attraction of leukocytes to the damage site. 4. Frequent and repetitive release of inflammatory mediators can lead to chronic inflammation which may eventually lead to fibrosis of the tissue. Serhan et al (2008) Nat Rev Immunol 8, 349–361 Prostaglandins The Arachidonic acid pathway Inflammation Phospholipid Phosphlipase A2 PGD2 PGE2 PGI2 Arachidonic acid Cyclooxygenase (COX) Prostaglandin G2 Cyclooxygenase (COX) PGF2 Thromboxane A2 Prostaglandin H2 The Arachidonic Acid pathway cont. Cyclooxygenase reaction Peroxidase reaction Prostaglandins cause: Vasodilation Pain Fever Prostaglandin Receptors Prostaglandin Receptors Summary  They are all G-protein coupled receptors (GPRCs)  Most of them regulate cAMP  PGE2 has the greatest number of receptors:  2x Gs  1x Gi/q  1x Gq Homeostatic and inflammatory functions  PGI2 receptor is Gs coupled  One receptor means same action in all tissues where it is expressed  Multiple receptors means different actions in different tissues. Leukotrienes Leukotriene Synthesis Leukotrienes cause: - Bronchoconstriction - Increase in vascular permeability - Chemotaxis Cysteinyl Leukotrienes Mayatepek & Flock (1998) THE LANCET 352: 1514–17 Leukotriene Receptors Leukotriene Receptors Summary  They are all G-protein coupled receptors (GPRCs)  On cells that surround the tissues where leukotrienes are made.  All cells express B2 receptor  No homeostatic function, only inflammation but a broad response Don’t forget to:  Check out the case studies  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. 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/