eicosanoids and NSAIDs

Question 1

how are prostaglandins and thromboxanes synthesised

Answer 1

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

Question 2

what is action of phospholipaase A2

Answer 2

converts phospholipids into arachidonic acid

as well as lyse-glyceryl phosphorylcholine which is then converted into platelet activating factor by acetyl transferase

Question 3

where is PGE2 synthesised

Answer 3

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

Question 4

what are actions of prostaglandin E receptors

Answer 4

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

Question 5

what other physiological actions does PGE2 have

Answer 5

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

Question 6

where is prostaglandin D2 synthesised and what are its affects

Answer 6

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

Question 7

what are actions of prostaglandin F2alpha

Answer 7

FP receptors: smooth muscle contraction, bronchoconstriction

Question 8

where are prostaglandin I2 (prostacyclin) and thromboxane A2 synthesised and what are their effects

Answer 8

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

Question 9

how are prostaglandin analogues used therapeutically

Answer 9

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

Question 10

how do classical NSAIDs act

Answer 10

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

Question 11

what are physiological and pathological effects of prostaglandins in general

Answer 11

physiological;
inhibition of gastric acid
contraction of uterus
increase renal blood flow

pathological;
pyretic
pro-inflammatory
hyperalgesic

Question 12

how do prostaglandins effect gastric secretions

Answer 12

PGE1 and PGE2 via EP3 receptors and PGI2 reduce gastric secretion

PGE2 via EP3 receptors increase mucous and water secretions into gut

Question 13

how do NSAIDs affect gastric secretions

Answer 13

increase gastric acid since less PGE1/2 and PGI2 and decrease water and mucous secretion since less PGE2

Question 14

what affect do glucocorticoids have on prostaglandin synthesis

Answer 14

glucocorticoids such as lipocortin inhibit phospholipase A2 and so prevent synthesis of arachidonic acid

Question 15

how is COX-1 and COX-2 different

Answer 15

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)

Question 16

what are risks of non aspirin NSAIDs

Answer 16

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)

Question 17

what are the effects of aspirin and what is its mechanism

Answer 17

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

Question 18

how are prostaglandins involved in blood vessels and thrombosis

Answer 18

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

Question 19

what causes platelet aggregation

Answer 19

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

Question 20

how does aspirin help to reduce risk of thrombosis even though it reduces prostaglandins

Answer 20

inhibits TXA synthesis more than PGI2

Question 21

how are leukotrienes synthesised

Answer 21

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

Question 22

what are inhibitors of leukotriene synthesis and what is their mechanism

Answer 22

zileuton and FLAP inhibitors

inhibits 5-lipoxygenase

Question 23

what are actions of leukotriene B

Answer 23

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

Question 24

what are the actions of the cysteinyl leukotrienes

Answer 24

cys-LT1 receptor: leukotrienes D4 and E4; bronchospasm, plasma exudation, eosinophil recruitment

cysLT2 receptor: agonists: LTC4; causes smooth muscle contraction in pulmonary vessels

Question 25

what factors contribute to thrombosis

Answer 25

endothelial injury (atherosclerosis)

abnormal blood flow

hypercoagulability