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)
what is the MoA of aspirin?
- selective for COX-1
- binds irreversibly to COX enzymes (odd for NSAIDs)
what are the actions of aspirin?
- anti-inflammatory
- analgesic
- anti-pyretic
- dec. platelet aggregation
how does aspirin cause the dec. platelet aggregation?
- platelets: reduces TXA2 production via COX1, no reproduction as platelet has no nucleus
- endothelial cells: reduces PGI2 synthesis by COX1/2. reproduction possible due to nucleus
- so less TXA2 and still PGI2
how does aspirin cause anti-platelet action?
- high degree of COX1 inhibition which supresses TXA2 synthesis in platelets
- covalent bonding which permanently inhibits platelets COX1
- relactively low capacity to inhibit COX2
- need low dose to enable endothelial re-synthesis of COX2
what are the side effects of aspirin?
- gastric ulceration
- bronchospasm
- prolonged bleeding time
- nephrotoxicity
why are the side effects more common in aspirin than other NSAIDs?
due to irreversible inhibition
is paracetamol an NSAID? what are its actions?
- has no anti-inflammatory action
- relieve mild/moderate pain
- no anti-pyretic actions
what is the MoA of paracetamol
- not understood but probably central
- COX3, cannabinoid receptors, interactions with endogenous-opiods
what happens in a paracetamol overdose?
if glutathione is depleted (saturated whilst metabolising other paracetamol molecules), the metabolites oxidise thiol groups of key hepatic enzymes and cause apoptosis
what is the antidote of a paracetamol overdose?
- add compound with an -SH group
- IV acetylcysteine (used in cases of attempted suicide)
- oral methionine
