NSAIDS Flashcards
What are the 3 major clinical uses of NSAIDS?
Analgesics
Antipyretics
Anti-inflammatories
From what are prostanoids derived, and where does this originate?
Arachdionic acid
Plasma membrane
Recall 2 key prostanoids
TXA2 (thromboxane A2)
PGI2 (prostacyclin)
What is the rate-limiting step in prostaglandin synthesis?
COX-driven conversion of arachdionic acid to endoperoxidases such as PGH2 and PGG2
Recall the 10 types of prostanoid receptor
DP1 DP2 EP1 EP2 EP3 EP4 FP IP1 IP2 TP
What is PGE2?
Type of prostanoid
What receptors does PGE2 have affinity for?
EP1234
Recall a desirable action of PGE2
Neuroplasticity, bronchodilation, osmotic homeostasis, gastroprotection, vasoregulation
Summarise 4 unwanted effects of PGE2
- Enhanced pain perception
- Pyrogenic
- Acute inflammation
- Cancer risk increased
How does PGE2 lower the pain threshold?
Sensitises nocioreceptors
Why is PGE2 pyrogenic?
It stimulates hypothalamic neurons that initiate a rise in body temp
Recall the mechanism by which PGE2 regulates inflammation?
Moderated by:
- EP3
- Calcium
- Multiple GPCRs
How does PGE2 increase risk of malignancy?
Inhibits apoptosis
Why is aspirin unique among the NSAIDS?
Selective for COX1
Binds IRreversible
Describe how aspirin reduces platelet aggregation
Platelets:
- produce TXA2 which increases aggregation
- cannot replenish COX1 as have no nucleus
Endothelium:
- Produces PGI2 which decreases aggregation
- are nucleated so can replenish COX1+2
Aspirin inhibits TXA2 production and it cannot be replaced, PGI2 synthesis is affected to a lesser extent
What is the main consequence of paracetamol overdose?
Irreversible liver failure
Recall the metabolism of paracetamol
CYP450
Metabolite = NAPQI: toxic as oxidises thiol groups on key enzymes for cell survial
NAPQI usually mopped up by glutathione, but if this is depleted NAPQI accumulates
What is the antidote to paracetamol overdose?
Acetylcysteine - it has thiol (SH) groups
Recall the 4 main side effects of NSAID use
Loss of benefits of PGE2:
- Bronchoconstriction
- Renal toxicity
- Loss of PGE2 gastroprotectivity
- Vasoconstriction
How do NSAIDS lead to bronchoconstriction?
Inhibit COX
COX inhibits leukotriene production
Leukotrienes are bronchoconstictors
What is the effect of PGE2 on the kidney?
Increases renal blood flow
How do NSAIDS cause renal toxicity?
Constrict afferent arteriole to reduce GFR
What is the effect of PGE2 on the stomach?
Downregulates HCl
Stimulates mucous production
Stimulates HCO3- production
What is the danger of NSAIDS to the stomach?
Increase risk of ulcers by inhibiting PGE2
Give an example of a drug that inhibits both COX1 and COX2
Ibuprofen
Give an example of a COX2 inhibitor
Celecoxib
What is the benefit of having a drug that specifically inhibits COX2?
Avoids gastric ulcer risk
What is the risk of having a drug that specifically inhibits COX2 as compared to aspirin?
CVD risk higher
What is the main drawback of drugs that inhibit COX2 as well as COX2?
Significant side effect profile
What can be coadministered with NSAIDS to offer gastroprotection?
PPI such as omeprazole
Recall 2 contraindictions for NSAID use
Steroid use
Alcohol dependency
