NSAIDs Flashcards
what are the clinical uses of NSAIDs?
- analgesic (headache)
- anti-pyretic (influenza)
- anti-inflammatory (gout, rheumatoid arthritis)
what is the MoA of NSAIDs?
inhibit prostanoid synthesis by blocking COX
what are prostanoids?
- derived from arachidonic acid
- e.g. TXA2, prostacyclin, prostaglandins
- not stored, preformed
- receptor mediated
what are the 2 forms of COX? what do NSAIDs do?
- COX1, COX2
- NSAIDs inhibit both to varying drugs
what does the Coxib family do?
selectively reversibly inhibits COX2 e.g. celecoxib
what are the 5 prostanoids? how many receptors do they bind to?
- TXA2
- PGF2alpha
- PGE2
- PGI2
- PGD2
- bind to 10 receptors (G-protein coupled)
What 4 receptors does PGE2 bind to? what effect?
- activated EP1,2,3,4
- cAMP-dependant (EP2/4)
- Ca2+ mobilisation (EP1/3)
- or both (EP3)
what are the unwanted actions of PGE2?
- inc. pain perception
- thermoregulation
- acute inflammatory response
- inhibition of apoptosis
- tumorigenesis
how does PGE2 cause pain sensitisation?
- stimulation of PG receptors sensitises nociceptors
how do NSAIDs work to combat this pain sensitization?
co-injection of COX2 inhibitors reduces duration of prolonged pain
via activation of EP1 and EP4 receptors in spine and periphery
how does PGE2 interfere with thermoregulation?
PGE2 is pyrogenic
it stimulates hypothalamic neurones to initiate a rise in body temp
= hyperpyrexia
NSAIDs reduce this
how do PGE2 prostanoids cause an acute inflammatory reaction?
acute inflammatory response
- PGE2 –> EP3 signalling
- EP3 receptor then signals downstream using 2 mechanisms (cAMP and Ca mobilisation)
what are the desirable actions of PGE2 prostanoid?
- gastro-protection
- renal salt and water homeostasis
- bronchodilation
- vaso-regulation
How does PGE2 prostanoid cause gastro-protection?
- PGE2 stimulated mucus and bicarbonate secretion into gut
so what effect does NSAIDs have on gastro-protection?
- inc. risk of ulceration
- due to blocking of COX1
- fewer deaths when using Celecoxib (COX-2 selective inhibitor) than normal NSAIDs
what effect does PGE2 have on renal salt and water homeostasis? so what about NSAIDs?
- PGE2 inc. renal blood flow
- NSAIDs can cause renal toxicity
- not for renal failure patients
in what ways do NSAIDs cause renal toxicity?
- constriction of afferent renal arteriole
- reduction in renal artery flow
- reduction GFR
how do NSAIDs cause bronchodilation?
- COX inhibition favours production of leucotrienes (as other pathway for arachidonic acid is inhibited)
- leucotrienes are potent broncho-constrictors
due to this, who shouldn’t take NSAIDs?
asthmatics
how do NSAIDs interfere with vaso-regulation?
- dilation or constriction depending on receptors activated
- they cause vasoconstriction, salt/water retention and reduced effects of anti-hypertensives
what do NSAIDs then inc. risk of?
- hypertension, MI, stroke
- inc. risk of CVS events
what does COX1 inhibition lead to an inc. risk of? what about COX2 do?
- COX1 inhibition –> inc. GI risk
- COX2 inhbition –> inc. CVS risk
what is the risk/benefits of NSAID use?
- analgesic use: occasionally used so low risk of side effects
- anti-inflammatory: used chronically in higher doses so high side effect risk
how do you limit GI side effects? (other than using COX2 selective NSAIDs)
- topical application (less systemic access)
- limit use in pt with a GI-ulceration history or with other risk factors
- treat H. pylori
- co-administer omeprazole (or another PPI)
