NSAIDs Flashcards
What are autocoids
Autocoids are local inflammatory mediators in acute inflammation (acute response to noxious stimuli)
bradykinin, histamine, leukotriene, prostaglandins
They act locally with short T1/2 - can be finely controlled
Their signalling pathways overlap - robust inflammatory response
What are prostaglandins
Type of autocoids synthesised from Arachidonic acid
How are prostaglandins synthesised
From arachidonic acids by COX enzymes:
Cell membrane Phospholipid to Arachidonic acid by phospholipase A
Arachidonic acid to PG H by COX 1 or COX2
PG H to PG E/F/I/D by specific PG enzymes
PG E most important in Inflammation
What are COX enzymes
Enzymes involved in synthesis of prostaglandins from arachidonic acid
What are the differences in COX1 and COX2 enzymes
COX1: constitutively expressed
COX2: only active in inflammation, expression is induced by inflammatory mediators
Different binding site for NSAIDs
What is the role of COX1
Produce PGs constantly in normal state to allow vasodilation and perfusion of tissues in: GI mucosa, renal parenchyma, myocardium
What is the effect of COX1 inhibition
Side effects of NSAIDs
Prostaglandins are required in normal state but have short half life so need to be constantly produced by COX1
What is the role of COX2
Produce PGE in inflammation
What is the effect of COX2 inhibition
Therapeutic effect of NSAIDS
Anti inflammatory, antipyrexial, analgesia
What is the mechanism of action of PGs in inflammation
Pyrexia, inflammation and pain sensitisation by acting on GPCRs
What is the process of peripheral nociceptor sensitisation
PGE bind to EP1 GPCR receptor on C fibre neurones
Increase neuronal sensitivity to bradykinin
Activate Na channels, inhibit K channels
Increase excitability of C fibres
Cause hyperalgesia: increased sensitivity to pain
What is the process of central nociceptor sensitisation
Sustained peripheral pain signalling cause cytokine release in dorsal horn cell body
Cytokines increase COX2 activity and PGE
PGE bind to EP2 GPCR
Remove glycinergic inhibition by inhibitory interneurones
Increase sensitivity of secondary pain fibres
Allodynia: perceive pain to stimuli that normally doesn’t cause pain
What is the process of pyrexia
Macrophages release IL-1 in inflammation
IL-1 act on hypothalamus to produce PGE
PGE act on EP3 GPCR in hypothalamus
Increase heat production and decrease heat loss
What is mechanism of action of NSAIDs
Competitive inhibition of COX1/2 enzymes
What are PK properties of NSAIDs
Administration: oral, topical
T1/2: <6 hours or >10hours
Linear PK
Heavily bound to plasma proteins
What are the main effects of NSAIDs
Anti inflammatory
Analgesia
Antipyrexial
What are indications of NSAIDs
Inflammatory joint disease
Mild to moderate pain - isolation
Severe pain with opioids - acts as Opioid-sparing agent (better adr profile, extended therapeutic range than in isolation)
What are the main side effects of NSAIDs
GI Nephrotoxicity Vascular Hypersensitivity Reye’s syndrome
What are the GI side effects of NSAIDs
Peptic ulcer disease, UGI Bleeding, gastritis, nausea, heartburn, abdominal pain
How can you offset GI side effects
PPI
Misoprostol (PGE derivative - when Hx of PUD but NSAID cannot be stopped)
Why do GI side effects occur
Non-selective inhibition of COX1
Inhibit constitutive synthesis of PGE in GI mucosa
Loss of cytoprotective effects: bicarbonate and mucus production, vasodilation
What are renal side effects
Na retention
Renal failure
Why do renal side effects occur
Non-selective inhibition of COX1 enzymes
Inhibit constitutive production of PG in medulla + glomeruli
PG normally cause Na excretion, AA vasodilation
Which patients are more at risk of nephrotoxicity from NSAIDs
Hepatic cirrhosis (hepatorenal Syndrome) Renal disease (preexisting poor renal function) Heart failure (poor renal perfusion)
