NSAIDs Flashcards
What are the main uses of NSAIDs?
Relief of mild-moderate pain
Reduce fever
Reduce inflammation
How do NSAIDs work?
Inhbit synthesis of protanoids (inhbits COX)-
(prostaglandin and thromboxane)- (made from arachnidonic acid with COX)
Never stored and very widely distributed
but act on receptors
What are prostanoids receptors?
10 known receptors -names are shit (named afyer agonist potency
Have G protein dependent and independent effect
and can have both physiological and inflammatory effecy-so inhbitions isnt always good
PGE2 is one of the main ones-ring leader in the body
What receptors can PGE2 bind?
Can bind 4 receptors-EP1/2/3/4
EP1/3-Ca2+ mobilisation
EP2/4-cAMP dependent
what are the unwanted actions of PGE2?
Increased pain perception-lowers the pain threshold (need less to activate) - seems to be EP4/1 mediated (in inflam condition, seem to have higher cAMP to activate nociceptors + more nociceptors) –but other pathways seem to exist
Increase body temperature - pyrogenic-stimulates hypothalamic neurons to initiate a rise in body temp (with inflam, PGE2 increased, temp increases too)-and if block PGE2, reduce pyrexia
Acute inflammatory response-plays role in many pathways
=> main 3
Immune response
Tumorigenesis
Inhbition of apoptosis
What are the desirable physiological actions of PGE2?
Can cause bronchodilation, Gastroprotective effects
Renal salt and water homeostasis
And role in vasoregulation -(dilation/constriction)
How does PGE2 affect patients with ashtma?
COX produces provide help with bronchodilation
10% of ashmatics get worse with NSAIDs
COX inhbition causes accumulation of Arachidoinic acid-and that causes leukotrienes production (highly potent bronchoconstriction)–cant be given to ashtmatic
What role does PGE2 has in Gastric protection
Downregulates the HCl secretion and upregulated the production of mucus+bicarbonate secretion in partietal cells (Ep1/3 receptors)
So powerful cytoprotective effects on the stomach
Blocking COX causes large increase of Ulcers in stomach-cause over 50% of death NSAID associated (aspirin main one)
Is a COX2 selective NSAID useful? Why?
Try to spare stomach by creating COX2 only inhbitor
Created Coxib family -> and it worked
Celecoxib and stuff- much lower GI ulcers
But higher CVD causes (cause of vasoregulation effect of PGE2-unclear)
what is the role of PGE2 in kidney function?
PGE2 increases Kidney blood flow and help regulate water and salt homeostasis
COX1 mainly found in ascending tubule
COX2 in Collecting tubule
Both found in glomerulus
So unsure if “good” or “bad”
So what are the main bad effects of NSAIDs?
COX1 inhbitors seem to increase GI risks
COX2 inhbitors seem to increase MI risk
All are on a spectrum-and the more then bind to one isoform, the more they will cause one or the other side effect
Ibuprofen is kinda bang in the middle
So is there a point is taking NSAIDs with the side effects?
Yes because if not taken regularly-occasionally-relatively low risks of side effects (usually as analgesic)
If taken chronically-anti inflammatory-chronic problems, higher doses, older patients- much higher risks
What are the other options to minimise NSAIDS side effects?
Topical applications
Minimise NSAIDs in patients with GI issues
Give combined with omeprazole/proton pump inhib
Reduce other risk factors (where you can)
newer NSAIDS-maybe COX and LOX inhbit (LOX-leukotriene)-
NO releasing NSAIDs
What is different about aspirin? Why does it have that extra effect? what about its side effect? why cant it be given to youth?
COX irreversible inhbiors -selective for COX1
Anti-inflam, analgesic, anti-pyrexic + ANTI-PLATELET
Platelets make TxA2, and endothelium makes prostacyclin (both COX produce)–so at LOW dose-inhbit the COX1 (irreversible)-endothelial cells can still make PGI2 with COX2, and also can remake the COX enzyme
Platelet doesnt have a nucleus-cannot remake COX1-cant make TXA2 used to activate
still has GO side effects, Bronchospasm, Nephrotoxicity, side effect more likely because irreversible
In younger people, aspirin+ viral infection can cause permanant mitochondria damage leading to astrocyte damage-oedema in brain
What is the use of paracetamol? How does it work? what are the side effects?
Analgesic and anti-pyerexic-but not anti-inflammatory (not an NSAID)
Overall no clue how it works
Maybe through COX3, maybe Cannabinoid receptors, maybe endogenous opiods, maybe with 5HT/adenosine receptors -lol we have no clue
but overdose can cause irreversible liver failure-mainly used in suicide (NAPQI-damage liver-slow process and irreversible)
Can treat if early enough with acetylcysteine-mop up extra metabolite
this was reduced by making less tablet per pack-and max pack per transaction
