Presentation on theme: "Do you administer NSAIDs or steroids to these patients?"— Presentation transcript:
1 Do you administer NSAIDs or steroids to these patients? A 54-year-old woman presents to her family physician's office with a 2 week history of pain and numbness in her left handA 19-year-old man, lying flat on a stretcher and wearing a hard cervical collar, arrives in the Emergency RoomDo you administer NSAIDs or steroids to these patients?Eric NiederhofferSIU-SOM
2 Prostaglandin, Leukotriene, Lipoxin, and Thromboxane Synthesis Pathway overviewProstaglandin receptorsPathway detailsDifferential actions of cyclooxygenasesCOX-1 and COX-2 comparisonTissue comparisonRole of ω-3 fatty acids
3 Anti-inflammatory steroids Pathway OverviewLinoleic acidZileutonAnti-inflammatory steroidsGlucocorticoidsArachidonic acidNSAIDsaspirinProstaglandins (PG)Lipoxins (LX)LipoxygenaseLeukotrienes (LT)Prostaglandin H2 synthaseLipoxygenaseThromboxanes (TXA)Thromboxane A2 synthaseThere are series 1 prostaglandins derived from dihomo-γ-linolenic acid (DGLA; series 2 derived from arachidonic acid (AA); series 3 derived from eicosapentaenoic acid (EPA), start with α-linolenic acid (ALA)Series 3 (ω3) can interfere with (competitive) series 2 (ω6) production (decrease inflammation)ω6 from corn oil; ω3 from canola oil, engineered rapeseed oil, Krill oilPG: prostaglandins - PGG2, PGH2 (constriction), PGD2 (constriction or vasodilation), PGE1 (vasodilation), PGE2 (vasoconstriction/dilation), PGF2a (constriction), PGI2 (prostacyclin, dilation, inhibition of platelet adhesion)LT: leukotrienes - LTB4, LTC4, LTD4, LTE4 (multiple roles, microvascular vasoconstriction); zileuton inhibits 5-lipoxygenaseLX: lipoxins - LXA4, LXB4TBX: thromboxanes - TXA2 (constriction, platelet adhesion), TXB2 (constriction)NSAIDs: nonsteroidal anti-inflammatory drugs, aspirin, ibuprofen; anti-inflammatory steroids work by boosting levels of lipocortin (an annexin, Ca2+-dependent inhibitor protein/enzyme that inhibits phospholipase A2); lipocortin-1 = annexin-1. Salicylate directly activates AMP kinase.Most of the enzymes are located in the smooth endoplasmic reticulumBrain/nerves - PGD2, PGE2, and PGF2 Kidneys - PGE2 and PGI2 Lungs - PGD2Synovial cells - PGE2 and PGI2 when stimulated by interleukin-1 Vascular beds - PGE2 and PGI2 & PGH2 and TXA2COX-1 deficiency: Type 1 - complete absence in platelets; Type 2 - normal protein, impaired activity; bleeding disorders
5 Pathway Details (PG, TX, LT) IL-1 (inflammation)IL-1RMembrane phospholipidsAnti-inflammatory steroidsGlucocorticoids(mediated by lipocortin-Ca2+)Arachidonic acidPhospholipase A2(or PLC)LTA4NSAIDS (aspirin)PGG2LTC4Glutathione S-transferaseLTB4PGH2 synthaseCyclooxygenaseO2LTD4LTE4PGH22GSHGSSGPG hydroperoxidasePGJ2PGD2 synthaseTXA2TXA2 synthasePGD2PGI2 (PC)PGF2aPGE2IL: interleukin-1 IL-1R: interleukin-1 receptor. The pathway also activated by bradykinin with its receptorNSAIDS: nonsteroidal anti-inflammatory drugs, aspirin (irreversible inhibitor of COX-1), ibuprofen (lesser ratio of COX-1/COX-2)Acetaminophen (an analgesic, does not affect COX-1 or COX-2 but may indicate presence of a COX-3 or PCOX-1a or PCOX-1b isoforms that are not involved in PG synthesis but address fever and pain)PG: prostaglandin GSH: glutathione (reduced form)GSSG: glutathione disulfide (oxidized form) PC: PGI2 or prostacyclinPGE2 synthase is also denoted PG endoperoxidase E isomerase, microsomal form is key enzymePLA2: cytosolic associated with COX-1, secretory associated with COX-2PGH2 can rearrange to form levuglandin, which forms histone H4 adducts and destabilizes nucleosomesLeukotriene receptor antagonists – zafirlukast (DLT4 and ELT4); montelukast (DLT4)PGI2 synthasePGE2 synthasePGF2synthase
6 Pathway Details (LX) Arachidonic acid 15S-H(p)ETE 15S-ETT 15R-HETE 15-LOX5-LOX15S-H(p)ETE15S-ETTAirway epitheliaLeukocytes15R-HETE5-LOX15R-ETT15 epi-LXA415 epi-LXB4LTA412-LOX5-LOXLXA4LXB4PlateletsLeukocytesAcyl-COX-2AspirinEpitheliaEndotheliaMonocytesAnti-Inflammatory EffectsCOX: cyclooxygenase LOX: lipoxygenase HETE: hydroxyeicosatetraenoic acidLX: lipoxin LT: leukotriene ETT: epoxytetraeneThe production of LX and epi-LX are transcellular pathways. Epi-lipoxins are also referred to as aspirin-triggered lipoxins (ATL), which interact with ATL receptors (ATLR). ATLR also bind to small peptide derived signaling molecules involved in the immune response.
7 Differential Actions of Cyclooxygenases HousekeepingUnwanted side-effectsEndothelial integrityVascular patencyGastric mucosal integrityPGI2COX1ConstitutivePGE2TXA2BronchodilationRenal functionPlatelet functionNSAIDsPGE2PGF2aCOX2InducibleInflammatoryCOX: cyclooxygenase, COX1 constitutive (endoplasmic reticulum), COX2 inducible (perinuclear envelope), COX3 brainNSAIDs: nonsteroidal anti-inflammatory drugs, aspirin, ibuprofenPG: prostaglandins (PGI2 = prostacyclin, endothelial cells)TX: thromboxane (TXA2 = thromboxane, platelets)Acetaminophen is an analgesic.COX-1 and COX-2 serve identical functions in catalyzing the conversion of arachidonic acid to prostanoids. The specific prostanoid(s) generated in any given cell is determined by which distal enzymes in the prostanoid synthetic pathways are expressed. For example, stimulated human synovial cells synthesize small amounts of PGE2 and prostacyclin but not thromboxane or PGD or PGF2a. Following exposure to interleukin-1, synovial cells make considerably more PGE2 and prostacyclin, but they still do not synthesize PGD, TXB2 or PGF2a. The IL1-induced increase in PGE2 and prostacyclin is mediated through COX-2.Thus, while the species of prostanoid synthesized in a cell is dependent upon the specific distal synthetic enzyme(s) expressed, the amount synthesized is determined by the amount of COX —1 and —2 activities expressed. COX-1 is expressed in nearly all cells (except red cells) in their basal (unstimulated) state. COX-1 mediated production of thromboxane in platelets promotes normal clotting. And COX-1 mediated synthesis of prostaglandins in the kidney appears to be responsible for maintaining renal plasma flow in the face of vasoconstriction.Aspirin appears to have a role (through action of CREB) in increasing myelin-associated proteins in oligodendrocytes and protecting the cells from TNFα insult.InflammationProteasesTherapeutic anti-inflammatory effects
8 COX-1 and COX-2 Comparison ParameterCOX-1COX-2Regulationusually constitutiveinducibleRange of gene induction2 to 4-fold10 to 80-foldRate of gene activation24 h0.5 to 4 hEffect of glucocorticosteroidsinhibits activity*Relative size of active sitesmallerlargerRate of arachidonic acid consumption34 nmol/min/mg39 nmol/min/mgEffect of aspirin on COX activityInhibitedAffected**Aspirin will inactivate COX-1. Its effects take longer to wear off because it takes 24 hours for new enzyme synthesis.Aspirin will acylate COX-2, but the larger active site can still bind arachidonic acid and will produce other mediators. **Aspirin modifies active site to produce lipoxins.Glucocorticosteroids have effects at both the gene and protein level. *Best to look at this as a reduction in arachidonic acid precursor (think lipocortin) for COX-1 or COX-2 to act on.There is recent work suggesting that inducible NO synthase activates COX-2 (no effect on COX-1). NO synthase and COX-2 enhances cPLA2 activity.Oxidized low-density lipoprotein (LDL) appear to increase gene expression of COX-2.Class I NSAIDs - simple, competitive COX inhibitors (ibuprofen, naproxen)Class II NSAIDs - competitive, time-dependent COX inhibitors (indomethacin)Class III NSAIDs - irreversible, competitive, time-dependent COX inhibitors (aspirin)
9 Tissue Comparison Brain/nerve Vascular beds Synovial cells Ar PGH2 PGF2aPGD2PGE2PGI2 (PC)PGE2PGI2 (PC)PGE2TXA2So what would happen if we gave a patient a large dose of aspirin or Coxib to reduce inflammation/pain in these tissues?Ar: arachidonic acid PG: prostaglandinPC: prostacyclin TX: thromboxane
11 Review QuestionsHow are prostaglandins, leukotrienes, lipoxins, and thromboxanes synthesized (substrates, enzymes, cofactors)?What is the nomenclature for prostaglandin, leukotriene, lipoxin, and thromboxane receptors?How do NSAIDs work?How do steroids work?What are important characteristics of COX-1 and COX-2?How do ω-3 fatty acids affect the inflammatory response?