What are Eicosanoids?
A precursor generated from phospholipids in the CNS
What are the 3 key groups of Eicosanoids?
- prostaglandins (PGs)
- thromboxanes (TXA)
Which enzyme produces Eicosanoids from the phospholipids in the plasma membrane?
What activates phospholipase A2 to produce Eicosanoids (5)?
- antigen-antibody binding on mast cells
- complement C5a
- cell damage
What is the precursor of Eicosanoids?
What other chemical mediator is produced from plasma membrane?
Platelet activating factor
Which two Eicosanoids can also be called prostanoids?
What is the nomenclature of prostaglandins?
PG = prostaglandin
Letter = basic structure it comes from
Number = the no of C=C
Most often (arachidonic acid is the precursor)
- how many C=C does PG have?
Which cells release prostaglandins?
ANY injured cell
Which process is Prostaglandin a key mediator in?
What are the effects of prostaglandin in blood vessels?
Vasodilation (PGE1&2, PGI1)
What are the effects of prostaglandin in healing?
Inhibit platelet aggregation (PGI2 & PGE)
n.b. TXA2 = increased platelet aggregation
What are the effects of prostaglandin in the respiratory system?
N.b. varies with prostaglandin
Bronchodilation = PGI2 & PGE2
Bronchoconstriction = PGF2 & TXA2
How do prostaglandins affect pain?
Sensitise nociceptive neurones to the action of mediators (bradykinin & serotonin) = activate pain fibres
How do prostaglandins affect fever?
Act on the hypothalamus = increase body temperatureInflammation = macrophages release IL-1 = AA-> PGE2 = acts on neurones in pre optic area (sets our internal core temp) = increase thermostatic set point = heat generation (shivering, skin vasoconstriction = destroy infection)
When PG production stops (immediately broken down) = decrease set point = heat dissipating (sweating and vasodilation)
Which enzyme converts arachidonic acid (AA) to PG H2 = prostanoid precursor?
How many active sites does COX have?
What are the actions of the two COX active sites?
- Cycloxegynase site = AA -> PGG2
- Heme with peroxidase activity = reduces PGG2 to PGH2
How many COX isoenzymes exist?
COX-3 (not really understood = splice variant of COX-1)
n.b. different tissues express varying levels of COX-1 & 2= SELECTIVE INHIBITION POSSIBLE
Where is COX-1 found?
Consitutive (always there) in most cells
What does COX-1 do?
Maintains tissue homeostasis
Housekeeping: gastric protection, blood clotting, renal blood regulation
n.b. inflammation is NOT the main role
What is the key difference between COX-1 & COX-2?
COX-1 binding pocket is NARROW
COX-2 binding picket is WIDE
What induces COX-2?
Inflammation (abundant in activated macrophages)
When is COX-2 unregulated?
In various carcinomas
What does COX-2 produce?
Prostanoids = mediate inflammation
What are the two main types of anti-inflammatory agents?
- non steroidal anti-inflammatory drugs (NSAIDs)
Which 3 other drugs act as anti- inflammatory agents?
- H1 receptor antagonists
- chondroprotective drugs
What does NSAIDs stand for?
Non steroidal anti-inflammatory drugs
How do NSAIDS target inflammation?
inhibit cyclo-oxygenase (COX) = reduced prostaglandin & thromboxane synthesis