NSAIDs Flashcards
NSAIDs mechanism of action: identify the underlying mechanism of action by which all NSAIDs have their therapeutic effects and the difference between the NSAIDs and paracetamol
3 uses of NSAIDs
analgesic (mild-to-moderate pain relief), antipyretic (reduces fever e.g. influenza), anti-inflammatory
examples of mild-to-moderate pain-causing conditions
toothache, headache, backache, postoperative pain (opiate sparing), dysmenorrohoea (menstrual pain)
examples of conditions causing inflammation
rheumatoid arthritis, osteoarthritis, musculo-skeletal inflammation, soft tissue injuries (strains and sprains), gout
what 2 things do NSAIDs inhibit the synthesis of
prostaglandin and thromboxane
what are prostaglandin and thromboxane (lipid mediators) derived from
arachidonic acid (AA), from phospholipid membrane
rate limiting steps of prostanoid production
cyclo-oxygenase enzymes
how are they stored and distributed
not stored pre-formed so never have to deplete stores, widely distributed
how are they mediated
receptor-mediated
what enzymes do NSAIDs inhibit
COX-1 and COX-2
what do COX enzymes convert AA into
prostaglandin H2
what do specific synthesases convert prostaglandin H2 into
other prostaglandins (I2, E2, D2, F2a), prostacyclin and thromboxane A2
what are the 10 known prostanoid receptors, and what are their names based on
DP1, DP2, EP1, EP2, EP3, EP4, FP, IP1,IP2, TP; named based on agonist potency
what receptor effects do prostanoids have
G protein-dependent and G protein-independent
prostanoid receptors use
normal physiological, but pro-inflammatory
what does inhibition of prostanoid production result in
multiple, complex consequences (e.g. PGE2 has many actions in many different parts of body)
what 4 receptors can PGE2 activate, and secondary messengers
EP1, EP3 (both cAMP-independent as Ca2+ mobilisation), EP2, EP4 (both cAMP-dependent)
6 unwanted actions of PGE2 (why NSAIDs are used to try to downregulate these effects)
increased pain perception, increased body temperature, acute inflammatory response, immune responses, tumorigenesis, inhibition of apoptosis
how do PGE2 analogues lower pain threshold, and what agonists used to increase pain threshold
stimulation of PG receptors in periphery sensitises nociceptors, which causes pain acutely and chronically; EP4-mediated so EP4 receptor antagonists therefore block effect of PGE2 analogue
possible main mechanism of action for sensitisation of nociceptors by stimulation of peripheral PG receptors by PGE2 analogues
cAMP mediated -> activates P2X3 nociceptors -> during inflammation, Epac pathway activated and more PGE2 produced -> greater activation of P2X3 receptors
other pathways of action for sensitisation of nociceptors by stimulation of peripheral PG receptors by PGE2 analogues
EP1 receptors and/or EP4 receptors (in periphery and spine), endocannabinoids (neuromodulators in thalamus, spine and periphery), NAIDs increase B-endorphin in spine
how is PGE2 pyrogenic (induces fever and raises temperature), and effects of NSAIDs
stimulates hypothalamic neurones, initiating a rise in body temperature; NSAIDs reduce raised temperature (max at -1 degree)
role of PGE2 in inflammation
extremely complex, but is pro-inflammatory
4 desirable physiological effects of PGE2 and other prostaglandins
bronchodilation (however may densitise B2-adrenoceptors), renal salt and water homeostasis, gastroprotection, vasoregulation (dilation and constriction depending on receptor activated)
why shouldn’t NSAIDs be taken by asthmatics
COX enzyme inhibition favours production of leukotrienes, which are bronchoconstrictiors (block bronchodilation of PGE2)
location of COX-1 and COX-2 in kidney nephron
COX-1 in glomerulus, distal tubule and collecting duct, COX-2 in glomerulus and ascending limb of loop of Henle
effect of PGE2 produced by COX enzymes in glomerulus
increased renal blood flow, so reduces salt and water retention
way in which NSAIDs can cause renal toxicity
constriction of afferent renal arteriole -> reduction in renal artery flow -> reduced GFR
role of PGE2 in gastric cytoprotection: effect on HCl secretion and mucus and bicarbonate secretions in parietal cells
in parietal cells, PGE2 stimulates mucus and bicarbonate secretions and downregulates HCl secretion
in the GI tract, what do NSAIDs increase the risk of
ulceration, as block gastroprotective effects of PGE2
possible solution to deaths caused by NSAID effetcs in GI tract
selective COX-2 inhibition (not used as raises CVD due to causing renal toxicity)
range of cardiovascular modulations by different prostanoids
vasodilation/constriction, increased/decreased platelet aggregation, inflammatory mediator, smooth muscle contraction
risk vs benefit of NSAID analgesic use
usually occasional, relatively low risk of side effects
risk vs benefit of NSAID anti-inflammatory use
often sustained, higher doses, relatively high risk of side effects
5 strategies (besides COX-2 selective NSAIDs) for limiting GI side effects
topical application, minimise use in patients with GI ulceration history, treat H pylori if present, administer NSAID with omeprazole (or other protein pump inhibitor to reduce HCl production in stomach), minimise use in patients with other risk factors/reduce risk factors
3 risk factors of GI ulceration besides NSAIDs
alcohol consumption, anticoagulant use, glucocorticoid use
what is aspirin (NSAID) selective for
COX-1
how does aspirin bind to COX enzymes
irreversibly
4 effects of aspirin
anti-inflammatory, analgesic, anti-pyretic (all 3 similar to other NSAIDs), reduces platelet aggregation
what prostanoid from platelets causes platelet aggregation
TXA2 (thromboxane A2)
what prostanoid from endothelial cells reduces platelet aggregation
prostacyclin (PGI2)
effect of aspirin on TXA2 and PGI2, and hence effect on platelet aggregation
as TXA2 is made by COX-1, and PGI2 is made by both COX-1 and COX-2, TXA2 synthesis completely stops but PGI2 synthesis reduced, meaning overall platelet aggregation is reduced
why can’t TXA2 be replaced upon aspirin use, but PGI2 can be, further reducing platelet aggregation
platelets (which produce TXA2 by COX-1) have no nucleus, so cannot resynthesise COX-1; endothelial cells have a nucleus, so can resynthesise COX-1 and COX-2 to create PGI2, reducing platelet aggregation
what does high degree of COX-1 inhibition cause
suppression of TXA2 production in platelets
what binding permanently inhibits platelet COX-1 by aspirin
covalent
capacity required to inhibit COX-2, and hence dose
relatively low capacity required, so low dose used to allow endothelial resynthesis of COX-2
4 major side effects of aspirin at therapeutic dose (due to irreversible binding, not selectivity to COX-1)
gastric irritation and ulceration, bronchospasm in sensitive asthmatics, prolonged bleeding times, nephrotoxicity (due to irreversible binding, not COX-1 selectivity)
actions of paracetamol, and reason why it is not an NSAID
analgesic for mild-to-moderate pain, anti-pyretic; minimal anti-inflammatory effect so not NSAID
mechanism of action of paracetamol
unknown, but probably central and peripheral (possibly cannabinoid receptors, interactions with endogenous opioids or through 5HT and adenosine receptors)
effect of overdose of paracetamol in liver and why
irreversible liver failure, as if glutathione depleted the metabolite (NAPQI) oxidises -SH groups of key hepatic enzymes, causing cell death
antidote for paracetamol poisoning
add compound with -SH group
2 examples of compounds with -SH groups (and administration route) which act as antidotes for paracetamol poisoning if administered before unpreventable liver failure (then liver transplant)
acetylcysteine (i.v.), methionine (oral)
how legislation has reduced paracetamol overdoses
restriced size of packs and no. of packs per transaction
