PM 719 Pharmacology II Chapter 18 Eicosanoids PDF

PM 719 Pharmacology II Chapter 18 Eicosanoids, Prostaglandins, Thromboxanes, Leukotrienes, DRUGS: **alprostadil indomethacin** **misoprostol dinoprostone** **corticosteroids misoprostol** **aspirin omega-3-fatty acids** **ibuprofen** Eicosanoids = polyunsaturated long-chain fatty acids produ...

PM 719 Pharmacology II Chapter 18 Eicosanoids, Prostaglandins, Thromboxanes, Leukotrienes, DRUGS: **alprostadil indomethacin** **misoprostol dinoprostone** **corticosteroids misoprostol** **aspirin omega-3-fatty acids** **ibuprofen** Eicosanoids = polyunsaturated long-chain fatty acids produced in a wide range of tissues, highly bioactive the eicosanoids are the mediators of inflammation, redness etc. Prostanoids = prostaglandins, thromboxane, prostacyclin **Arachidonic Acid (AA):** AA is the major starting material for the synthesis of eicosanoids. AA is found in all cell membranes, the enzyme **phospholipase A~2~,** removes AA AA then undergoes enzymatic synthesis to form the following: [Substrate Enzyme Product ] AA Cytochrome P450 epoxyeicostrienoic acids (EETs) AA Lipoxygenase (LOX) **leukotrienes**, lipoxins AA Cyclooxygenase (COX) **prostaglandins**, **prostacyclin**, **thromboxane** (items in bold are the big deals in this chapter) **Products of the Cyclooxygenase (COX) Enzymes:** COX-1 found in most cells, makes prostanoids that are housekeeping, beneficial to the body (protect gastric lining, protect kidney function etc. COX-2 inducible enzyme, expression requires a stimulus, (stress, growth factors, makes prostanoids that cause inflammation, etc. Note: a bit over simplified but good enough to make the point. The division between "good" by COX-1 and "bad" by COX-2 is more complex with a significant overlap on which one makes good vs bad. **Prostaglandins** Named PGE~1~, PGH~2~ etc. etc. etc. The letters, A, B, G, H etc. define the substituents in the pentane ring The subscript counts the number of double bonds in the side chain (see Fig 18-1 pg 339) **Prostaglandins as drugs:** **alprostadil** a PGE~1~ used to relax smooth muscle and for some types of **misoprostol** a PGE~1~ derivative, cytoprotective prostaglandin used to prevent peptic ulcer **Products of Lipoxygenase (LOX)** LOX produced from AA leukotrienes, LOX found mostly in white cells Leukotrienes are mediators of inflammation in asthma, cardiovascular disease etc. **Biological Effects of Prostaglandins (PG) and Thromboxanes (TX):** Vascular Smooth Muscle: TXA potent vasoconstrictor PG promote vasodilation GI Smooth Muscle: mixed effects of contraction and relaxation Airways Smooth Muscle: PG relax and some PGs and TXs constrict, this will have major importance in the asthma chapter coming up Platelets: dose related but PG induce aggregation (low dose aspirin used to inhibit platelet aggregation by inhibition of PG synthesis in platelets) Kidney: PGs required and beneficial for a wide range of kidney function, chronic inhibition of the kidney COX enzyme with loss of beneficial PGs can lead to kidney damage CNS Fever: major role of PGs which are inhibited by the antipyretics, aspirin and acetaminophen Inflammation: PGE~2~ and PGI~2~ are the major prostaglandins (PGs) associated with inflammation Both above promote blood flow into the injury and produce Bone: PGs promote bone remodeling **Biological Effects of Lipooxygenase and Cytochrome P450 Derived Metabolites** Leukotrienes Play an important role in white cell function and immune response They activate white cells and promote inflammation **Inhibition of Eicosanoid Synthesis:** **Corticosteroids** The gold standard for eicosanoid synthesis mostly through inhibition of the [phospholipase enzyme that removes AA from cell walls] NSAIDs Non-steroidal anti-inflammatory drugs, like **aspirin**, **ibuprofen**, **Clinical Pharmacology:** Abortion PGE~2~ and PGF~2a~ promote uterine contraction and induce abortion **dinoprostone** a PGE analog used for this purpose GI System **misoprostol**, a PGE analog used to prevent aspirin (NSAID) induced peptic ulcer, drug taken po **Dietary Manipulation of Arachidonic Acid (AA) Metabolism:** Linoleic acid from sunflower and corn oils in the diet can act as alternative for the substrate AA, however the eicosanoids produced are biologically inactive. Cold water fish oils contain omega-3-fatty acids which act exactly as above. Caned sardines etc.