eicosanoids and NSAIDs Flashcards
how are prostaglandins and thromboxanes synthesised
phospholipid is converted to arachidonic acid via phospholipase A2
arachidonic acid is converted into PGG2 via the cyclooxygenase enzyme
PGG2 is converted to PGH2 via cyclic endoperoxides
PGH2 is then converted to:
TXA2 via thromboxane synthase
PGD2 via PGD synthase
PGE2 via PGE synthase
to PGF2 via PGF synthase
PGI2 via prostacyclin synthase
what is action of phospholipaase A2
converts phospholipids into arachidonic acid
as well as lyse-glyceryl phosphorylcholine which is then converted into platelet activating factor by acetyl transferase
where is PGE2 synthesised
prostaglandin E synthase is produced by most cells
there is usually prostaglandin E synthase found in the cytosol, it can be induced in the membrane by inflammatory mediators
what are actions of prostaglandin E receptors
4 receptors EP1-4 with different actions;
EP1: contraction of bronchial and GIT smooth muscle, pain
EP2: bronchodilation, vasodilation, stimulation of intestinal fluid secretion, relaxation of GI smooth muscle
EP3: contraction of intestinal smooth muscle, inhibition of gastric acid secretion, increase gastric mucus secretion, inhibition of lipolysis
EP4: bronchoconstriction, vasodilation, leukocyte suppression
what other physiological actions does PGE2 have
causes fever via an increase in body temperature via the thalamus
causes pain (hyperalgesia) via both peripheral terminals of nociceptors and in the spine
cause oedema; since PGE2 is a powerful vasodilator, does not directly induce vascular permeability but potentiates the action of other inflammatory mediators
leukocytes: PGE2 inhibits actions of many leukocytes
where is prostaglandin D2 synthesised and what are its affects
prostaglandin D synthase found predominantly in mast cell but also brain
DP-receptors; vasodilation, inhibits platelet aggregation, relaxation of GI and uterine smooth muscle
TP-receptors: bronchoconstriction
CRTH2: chemoattractant for Th2 cells
what are actions of prostaglandin F2alpha
FP receptors: smooth muscle contraction, bronchoconstriction
where are prostaglandin I2 (prostacyclin) and thromboxane A2 synthesised and what are their effects
PGI2: prostaglandin I synthase found mainly in vascular endothelium
IP receptors; vasodilation, inhibition of platelet aggregation, renin release
TXA2: thromboxane A synthase found predominantly in platelets
TP receptors; vasoconstriction, platelet aggregation
how are prostaglandin analogues used therapeutically
misoprostol (PGE1 analogue); prevention of NSAID induced ulcer, to induce labour
PGF2alpha analogues are used to treat glaucoma e.g travoprost
iloprost (PGI2 analogue): pulmonary arterial hypertension, scleroderma, raynauds
how do classical NSAIDs act
they inhibit COX (cyclooxygenase) which converts arachidonic acid into PGG2 which is then converted to other prostaglandins and thromboxane
2 versions of COX enzyme; COX-1 and COX-2
COX-1 is involved in production of prostaglandins in gastric protection, renal blood flow and haemostasis
COX-2 is involved in production of PGE2 at inflammatory sites
classical NSAIDs inhibit both
selective COX-2 NSAIDs inhibit just COX-2
what are physiological and pathological effects of prostaglandins in general
physiological;
inhibition of gastric acid
contraction of uterus
increase renal blood flow
pathological;
pyretic
pro-inflammatory
hyperalgesic
how do prostaglandins effect gastric secretions
PGE1 and PGE2 via EP3 receptors and PGI2 reduce gastric secretion
PGE2 via EP3 receptors increase mucous and water secretions into gut
how do NSAIDs affect gastric secretions
increase gastric acid since less PGE1/2 and PGI2 and decrease water and mucous secretion since less PGE2
what affect do glucocorticoids have on prostaglandin synthesis
glucocorticoids such as lipocortin inhibit phospholipase A2 and so prevent synthesis of arachidonic acid
how is COX-1 and COX-2 different
COX 1 produces prostaglandins for gastric cytoprotection, renal blood flow and haemostasis, is also found constitutively (always found)
COX-2 is induced via cytokines, endotoxins and mitogens, produces PGE2 at inflammatory sites (target of NSAIDs)
what are risks of non aspirin NSAIDs
can cause heart attacks or strokes (since prostaglandins are anti platelet aggregation)
risk increases with higher doses and longer use
worsening of gastric ulcers, gastrointestinal damage (death rate due to NSAIDs comparable to HIV)
what are the effects of aspirin and what is its mechanism
irreversible inhibitor of COX (acetylation of COX)
elevated cAMP by aspirin reduces aggregation
analgesic, anti inflammatory (at high doses), anti-pyretic, lots of beneficial effects
how are prostaglandins involved in blood vessels and thrombosis
PGE2 is a vasodilator, increases venular permeability a small amount, also promotes increases in permeability by other agents
PGI2; powerful vasodilator, inhibits platelet aggregation, produced by vascular endothelial cells, not platelets
TXA2; vasoconstrictor, induces aggregation of platelets, promotes release of ADP from platelets, ADP aggregates platelets, TXA produced by platelets and outer layers of vessel walls
what causes platelet aggregation
ADP fromm damaged cells as well as ADP released due to PGG2 and TXA2 leading to formation of thrombus
cAMP reduces calcium concentration reducing aggregation
phospholipase C and so IP3 increase calcium concentratoins and so increase aggregation
how does aspirin help to reduce risk of thrombosis even though it reduces prostaglandins
inhibits TXA synthesis more than PGI2
how are leukotrienes synthesised
arachidonic acid is converted to 5-HPETE by 5-lipoxygenase
5-HPETE is converted to LTA4 by 5-lipoxygenase
LTA4 is then converted into other leukotrienes;
LTA is converted into LTB by LTA hydoxylase
LTA is converted into LTC by LTC synthase
LTC is converted into LTD by gamma-glutamyl transpeptidase
LTD is converted into LTE via dipeptidase
what are inhibitors of leukotriene synthesis and what is their mechanism
zileuton and FLAP inhibitors
inhibits 5-lipoxygenase
what are actions of leukotriene B
leukotriene B4:
produced by LTA4 hydroxylase in leukocytes
works on BLT receptor in leukocytes; action are leukocyte chemotaxis, leukotriene secretion, cytokine secretion, IgE synthesis
works on PPAR alpha: nuclear receptor which controls LTB4 metabolism
what are the actions of the cysteinyl leukotrienes
cys-LT1 receptor: leukotrienes D4 and E4; bronchospasm, plasma exudation, eosinophil recruitment
cysLT2 receptor: agonists: LTC4; causes smooth muscle contraction in pulmonary vessels
what factors contribute to thrombosis
endothelial injury (atherosclerosis)
abnormal blood flow
hypercoagulability
