NSAIDs Flashcards
What are the major uses of NSAIDs?
Relief of mild to moderate pain (analgesic)
Reduction of fever (antipyretic)
Reduction of inflammation (anti-inflammatory)
What is the mechanism of action of NSAIDs?
They inhibit the production of Prostanoids by COX enzymes
They inhibit Cyclo-oxygenases (COX 1 & 2)
Prevent production of Prostaglandin H2 from Arachidonic acid
How do prostanoids exert their effects?
All receptor-mediated (G-protein coupled)
Action can be physiological or pro-inflammatory
The receptors may act through different pathways (e.g. EP2 receptor acts through 5 pathways - leading to beneficial and detrimental effects)
(We have 5 prostaglandins, but at least 10 different receptors)
What are the main actions of PGE2?
Increased Pain perception
Thermoregulation
Acute Inflammatory response
Immune responses
Tumorigenesis
Inhibition of Apoptosis - leading to necrosis
How does PGE2 lower the pain threshold?
Stimulation of PG receptors sensitises the nociceptors, meaning pain sensitivity increases
How do COX inhibitors raise the pain threshold?
We’re not really sure…
EP4 receptors (in spine and periphery) Endocannabinoid involvement (Neuromodulation)
Both sensitise Nociception
COX inhibitors reduce levels of PGE2 which stimulate these - raising the threshold
How does PGE2 act as a Pyrogenic?
How do COX inhibitors reduce this effect?
PGE2 stimulates Hypothalamic neurones to initiate a rise in body temperature - hyperpyrexia
Reducing levels of PGE2 reduces this effect, and has been shown to have anti-pyretic effects in influenza
What is the role of PGE2 in acute inflammation?
PGE2 binds to EP3 receptors (Mast cells)
Has multiple pathways that lead to the secretion of Ca2+, Histamine degranulation and Interleukin release (Leukocyte recruitment)
Why are NSAIDs useful in treating Contact dematitis, MS and rheumatoid arthritis?
EP4 mediated PGE2 effects activated many complicated immune pathways that cause the maturation of Naive T-cells
This sustains chronic inflammation
Therefore COX inhibition and reduced levels of PGE2 reduce this effect
Apart from direct acute and chronic inflammatory effects, how else may PGE2 contribute to inflammation?
They have anti-apoptotic effects
If you don’t have managed and programmed cell death, you are more likely to get Necrosis which will contribute to inflammation
What are the main Desirable effects of Prostanoids?
Gastroprotection
Regulation of renal blood flow
Bronchodilation
Vasoregulation
What is the role of PGE2 in Gastric Cytoprotection?
What is the significance of this?
PGE2 downregulates HCL production
It also stimulates the production of mucus and bicarbonate - boots the physical barrier between the acidic lumen and the cell surface
Therefore reducing PGE2 levels increases the risk of ulceration due
How do NSAIDs cause renal toxicity?
Reducing PGE2 causes:
Constriction of the afferent arterioles
Reduction in renal artery flow
Reduced glomerular filtration rate
This not that good really…
Why should Asthmatics probably not take NSAIDs?
Prostanoids cause bronchodilation
Inhibition of COX favours the production of leukotrienes which are bronchoconstrictors
What are the unwanted effects of NSAIDs on the CVS?
What has this been shown to increase the incidence of?
NSAIDs cause:
Small rise in BP
Sodium retention
Vasoconstriction
May reduce the effects fo anti-hypertensives
Significant rise in incidence of MI and Strokes in chronic NSAID users
Why are Ibuprofen and Indomethacin simmilar?
They are both non-selective, reversible COX inhibitors
Why did we try to make COX-2 selective inhibitors?
What was the problem with them?
It was believed they would lessen the GI side-effects - they did
They proved to produce a higher risk of Cardiovascular disease than conventional NSAIDs
(they could also be tolerated by asthmatic patients)
What strategies for limiting GI side-effects of NSAIDs other than COX-2 selection are there?
Topical application
Minimise use in patients with risk factors:
History of ulceration
High alcohol consumption
Anticoag or Glucocorticoid steroid use
Coadminister PPIs in use is essential
Why is Aspirin special and unique??
It is selective for COX-1
It Irreversibly binds to COX-1
How does Aspirin reduce platelet aggregation?
It reduces the production of Thromboxane A2 made by COX-1 in platelets
Reduces production of PGI2 (Prostacyclin) by COX-1&2 in endothelial cells
This leads to reduced Platelet aggregation
What is the difference between the effects of Aspirin on Platelets and endothelial cells in terms of levels of TXA2 and PGI2?
Once (high dose) aspirin is given existing Platelets will irreversible be unable to produce TXA2 as they won’t be able to replenish supply of COX-1 as they don’t have a nucleus
Endothelial cells will replenish their COX-1 and therefore begin to produce PGI2 again
What are the major side effects seen with Therapeutic doses of Aspirin?
Gastric irritation and ulceration
Bronchospasm in sensitive asthmatics
Prolonged bleeding times
Nephrotoxicity
Side effects are more likely with aspirin than other NSAIDs because it inhibits
COX covalently, rather than just because it is selective for COX-1
Why is Paracetamol not an NSAID?
It does not have any anti-inflammatory effect
How does Paracetamol work?
Not understood. Probably central
COX-3 and Cannabinoid receptors?
What happens in a Paracetamol overdose?
Normal Paracetamol metabolism produces a toxic intermediary metabolite which is reduced by Glutathione
In an overdose, the Glutathione may be depleted
The toxic metabolite will indiscriminately bind to any -SH (thiol) group it can find
These groups are often attached to key hepatic enzymes which will lead to apoptosis of hepatocytes and Liver Failure
What is the antidote for Paracetamol poisoning?
Compounds with -SH groups
Usually IV Acetylcysteine
(Occasionally Oral methionine)
