Prostanoids and NSAIDs

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  • Created by: LBCW0502
  • Created on: 26-01-19 12:46
Outline the metabolism of arachidonic acid (1)
Starts from phospholipid bilayer. Phospholipase A2 enzymes break down phospholipids to form arachidonic acid (20 C, poly-unsaturated omega 6 fatty acid). Can be modified by COX 1/2 enzymes.
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Outline the metabolism of arachidonic acid (2)
COX enzyme adds two oxygen groups to produce PGG2. This is reduced by peroxidase to PGH2 (direct precursor for e.g. prostaglandins)
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Outline the metabolism of arachidonic acid (3)
Prostaglandin synthase produces PGD2, PGE2 and PGF alpha (number 2 in structures - number of double bonds in prostaglandin molecule). Also produce PGI2 (opposite activation of platelet activation/thromboxane)
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Outline the metabolism of arachidonic acid (4)
Arachidonic acid can also be metabolised by lipoxygenase to form leukotrienes
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PGE2 is formed by which cells?
Formed from inflammatory/endothelial cells (important for inflammation)
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State features of PGI2
Released from endothelial cells, inhibits platelet activation
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Which chemicals stimulate platelet activation?
Thromboxanes
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State features of PGD2
Has inflammatory modulatory effects (also by mast cells)
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Describe features of acute and chronic inflammation increasing production of prostaglandins
Microvascular effects are triggered from a variety of cells and plasma in and around these vessels. Inflammatory mediators such as COX products are quickly released and are able to stimulate pain-sensitive sensory nerves
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Describe the role of PGs at inflammatory sites
PGs increase blood flow (vasodilate). PGs potentiate oedema formation (swelling). PGs sensitise nerves (hyperalgesic). PGs released from endothelial cells and inflammatory cells. E.g. stimuli - experience pain
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Outline a typical experiment in human skin with pain producing agent bradykinin
When PG is applied, no pain is experienced. When bradykinin is applied, some pain is experienced. When PG and bradykinin is applied, severe pain is experienced (sensitise sensory nerves)
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What are the pharmacological uses of prostaglandins? (1)
Abortion (PGE 1, geneprost, pessaries), induce labour (PGE2, dinoprostone/naturally occuring prostanoid, IV/vaginal tablet). Postpartum haemorrhage (PGF 2α, carboprost tromethamine)
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What are the pharmacological uses of prostaglandins? (2)
Male impotence (PGE1, alprostadil/naturally occuring prostanoid, calverjet). Anti-ulcer treatment (PGE 1, misoprostol). Platelet aggregation/primary pulmonary hypertension, Raynaud's disease (prostacyclin, epoprostenol/naturally occurring prostanoid)
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What are the pharmacological uses of prostaglandins? (3)
Glaucoma - increases uveoscleral outflow (promotes drainage of aqueous humour). Promotes eyelash to grow/thicken, browning of iris e.g. latanoprost, tafluporost (anaglogues of PGF2a)
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State features of NSAIDs
Most widely described. Most work by inhibiting COX, which inhibits prostaglandin production. Analgesic, anti-inflammatory, anti-pyretic
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Describe the inhibition of prostaglandin generation (NSAIDs)
Analgesic, anti-inflammatory, reduces fever, (anti-thrombotic), but can enhance bleeding
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Give examples of NSAIDs
Salicylates (aspirin), acetic acids (indomethacin, diclofenac), proprionic acids (ibuprofen, naproxen), oxicoms (piroxicam, phenylbutazone), fenamates (meclofenamate)
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Describe features of paracetamol
Not anti-inflammatory but often mentioned as NSAID. Paracetamol (acetaminophen)
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What were the issues with NSAIDs?
Toxicity led to GI complications and arthritic deaths (graph/diagram)
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Describe features of the COX-1 enzyme (1)
Constitutive, responds to physiological stimuli, physiological and cytoprotective roles, (prostaglandins, thromboxane, prostacyclins)
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Describe features of the COX-1 enzyme (2)
GIT (cytoprotective, decrease HCl secretion, increase mucus production), kidney - cytoprotective vasodilation, platelet (TXA2) - enhance platelet aggregation
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Describe features of COX-2 enzyme (1)
Inducible, responds to inflammatory stimuli, production of inflammatory mediators, (prostaglandins, prostacyclins)
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Describe features of COX-2 enzyme (2)
Macrophages - inflammatory mediators, kidney - cytoprotective vasodilation, increase Na/fluid excretion
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What are the advantages of NSAIDs?
Reversibly inhibit COX 1 enzyme/thromboxane production (aspirin irreversibly inhibits COX-1)
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What are the disadvantages of NSAIDs? (1)
Suppress gastro-protective prostaglandins (increase gastric acid secretion/suppress gastric mucosa), increase risk of peptic ulcer/haemorrrhage - main side effect - need to use PPI or prostaglandin agonist to reduce side effect of NSAIDs on GIT
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What are the disadvantages of NSAIDs? (2)
Inhibit cytoprotective prostaglandins induces renal vasoconstriction. Increase fluid/Na retention. Increase BP. Increase risk of CV complications
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Give examples of COX-2 selective inhibitors
Celecoxib, rofecoxib, valdecoxib
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What are the advantages of COX-2 selective inhibitors?
Main clinical indication - anti-inflammatory effect, less inhibitory effects on gastro-protective prostaglandins (better choice for patients with history of peptic ulcer disease)
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What are the disadvantages of COX-2 selective inhibitors?
Cardiovascular complications are the most serious. Inhibition of vasodilatory effect of PGI2 and unopposed activity of TXA2, increase risk of ischaemic heart diseases. (Study - COX-2 inhibitors tested for safety)
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Outline the study based on COX-2 inhibitor safety in CV conditions (1)
400,000 people in UK withdrawn from sale after evidence of medicines doubling the risk of MI/sudden death
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Outline the study based on COX-2 inhibitor safety in CV conditions (2)
Patients given ibuprofen, naprozen, esomeprazole and placebo. Results showed low rates of adverse effects
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What is the suggested use of COX-inhibitors in patients with a CV risk?
Associated use of PPIs to inhibit GI reflux or use prostaglandin analogues (e.g. misoprostol). Gradual increase in NSAID use via topical application e.g. diclofenac (Voltaren gel, Novartis) - still issues with prescribing NSAIDs/COX-inhibitors
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Card 2

Front

Outline the metabolism of arachidonic acid (2)

Back

COX enzyme adds two oxygen groups to produce PGG2. This is reduced by peroxidase to PGH2 (direct precursor for e.g. prostaglandins)

Card 3

Front

Outline the metabolism of arachidonic acid (3)

Back

Preview of the front of card 3

Card 4

Front

Outline the metabolism of arachidonic acid (4)

Back

Preview of the front of card 4

Card 5

Front

PGE2 is formed by which cells?

Back

Preview of the front of card 5
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