NSAIDs Flashcards
What are the three major uses of NSAIDs?
Anti-pyretic
Anti-inflammatory
Analgesic
What are most deaths due to NSAIDs caused by?
GI ulceration
Broadly speaking, how do NSAIDs act?
They inhibit the production of prostanoids by COX enzymes
What are the main prostanoids?
Prostaglandins (D2, E2 and F2) Prostacyclin (PGI2) Thromboxane A2
What does COX convert arachidonic acid to?
Prostaglandin H2
Which is then converted by specific synthases to: Thromboxane A2
Prostacyclin (PGI2)
Prostaglandin D2, E2, F2
How are prostanoid receptors named?
Prostanoid receptors aren’t very specific - they are named based on which prostanoid they have the highest affinity for (e.g. DP1 has the highest affinity for PGD2)
List all the prostanoid receptors.
DP1, DP2 EP1, EP2, EP3, EP4 FP IP1, IP2 TP
What type of receptor are all the prostanoid receptors?
G protein coupled receptors (though not all their actions are G protein mediated)
Explain why the EP receptor system is complex.
There are four different EP receptors and EP2 has two mechanisms of action and five pathways
State some unwanted actions of PGE2.
Increased pain perception Thermoregulation Acute inflammatory response Tumorigenesis Inhibition of apoptosis
How does PGE2 increase pain perception?
There is involvement of EP1/ EP4 receptors and endocannabinoids
NSAIDs also increase beta-endorphins, so PGE2 may reduce them
The mechanisms are unclear
How does PGE2 affect body temperature?
It’s pyrogenic
PGE2 stimulates hypothalamic neurones initiating a rise in body temperature
NOTE: there is a bit of a lag between PGE2 rising and temperature rising
Which diseases are treated with NSAIDs due to its effects on the immune system?
Multiple Sclerosis and Rheumatoid Arthritis (Th17 involvement)
Contact Dermatitis (Th1 cells involved)
What is the problem with PGE2 inhibiting apoptosis?
Inhibition of apoptosis increases the likelihood of necrosis
NOTE: there are 3 prostanoids, 7 prostanoid receptors and 2 downstream signalling pathways involved
State some desirable actions of PGE2 and other prostanoids.
GASTROPROTECTION
Regulation of renal blood flow
Bronchodilation
Vasoregulation
Describe the gastroprotective action of PGE2.
PGE2 downregulates stomach acid production
PGE2 stimulates mucus production
PGE2 stimulates bicarbonate production
What main effects does PGE2 have on the kidneys?
Increase renal blood flow
What effect do NSAIDs have on the kidneys?
Constriction of the afferent arteriole
Reduction in renal artery flow
Reduced GFR
Why should NSAIDs not be given to asthma patients?
Most prostaglandins are bronchodilators, so a reduction in prostaglandin production due to COX inhibition could exacerbate asthma
Furthermore, inhibition of COX favours the production of leukotrienes, which are bronchoconstrictors
Prostanoids are vasoregulators, so what are the consequences of NSAIDs on the cardiovascular system?
Increased risk of MI and stroke because chronic use of NSAIDs cause:
Small rise in blood pressure
Sodium retention
Vasoconstriction
Can reduce the effectiveness of anti-hypertensives
What is the difference in terms of risk of side effects when using NSAIDs for analgesic use compared to anti-inflammatory use?
Analgesic use – usually occasionally used so low risk of side effects
Anti-inflammatory use – often sustained use with higher doses = higher risk of side effects
Name two non-selective COX inhibitors.
Ibuprofen
Indomethacin
Name a COX-2 selective inhibitor.
Celecoxib
What is the major problem with COX-2 selective NSAIDs?
They have a significantly increased risk of cardiovascular disease than conventional NSAIDs
Describe the relative GI and CVS risks of COX-1 selective and COX-2 selective NSAIDs when compared to non-selective NSAIDs.
COX-1 selective: Same CVS risk as non-selective NSAIDs, Increased GI risk
COX-2 selective: Decreased GI risk, Increased CVS risk
What effect does ibuprofen have on the action of anti-hypertensive drugs?
It reduces the effectiveness of anti-hypertensive drugs
It will reduce the drop in blood pressure that has been seen when the anti-hypertensives are used without ibuprofen
What are the potential reasons for increased risk of cardiovascular disease with non-selective and COX-2 selective NSAIDs?
Non-selective NSAIDs and COX-2 selective NSAIDs both increase cardiac work
Also, all NSAIDs produce oxygen free radicals, which can contribute to cardiovascular disease
State some strategies for avoiding/limiting the GI side effects of NSAIDs.
Use topical application
Minimise NSAID use in patients with a history of GI ulceration
Treat H. pylori if present
If NSAID is essential, administer omeprazole or another proton pump inhibitor
Minimise NSAID use in patients with other risk factors and reduce risk factors where possible e.g. alcohol consumption, anticoagulant use
Producing new drugs currently - not yet in use
Describe the action of aspirin.
It irreversibly binds to cox enzymes (binds covalently) It is selective for COX-1
(IT’S THE ONLY IRREVERSABLE ONE - SO IT’S ACTION ON PLATELETS IS UNIQUE)
Explain how aspirin reduces platelet aggregation.
Aspirin irreversibly inhibits COX-1 in platelets meaning that they can’t produce thromboxane A2, which enhances platelet activation and aggregation
Furthermore, aspirin preserves the production of prostacyclin, which decreases platelet action
Why is it important to use a low dose of aspirin?
A low dose will allow the endothelial cells to resynthesise COX-1, which can then continue to produce prostacyclin
A high dose would mean that the COX-1 in the endothelial cells would be inhibited as it is being produced, thus decreasing prostacyclin production as well as thromboxane production
Why don’t you want to inhibit COX-2 too much?
Inhibition of prostacyclin synthesis is proportional to inhibition of COX-2
We don’t want to inhibit prostacyclin production too much so we’d like to keep COX-2 inhibition low
What are the major side effects of therapeutic doses of aspirin?
Gastric irritation and ulceration
Bronchospasm in sensitive asthmatics
Prolonged bleeding times
Nephrotoxicity
Why is paracetamol NOT an NSAID?
It does not have anti-inflammatory action
Explain how paracetamol overdose can cause liver failure.
Paracetamol is metabolised to produce a toxic metabolite (N-acetyl-p-benzochinon imine (NAPQI)) This is normally mopped up rapidly by glutathione In overdose, the glutathione stores are depleted and the free toxic metabolite binds indiscriminately to any –SH groups The –SH groups tend to be on key hepatic enzymes and this interference leads to cell death
What is the antidote for paracetamol poisoning?
IV Acetyl cysteine This has a lot of –SH groups
If this is given too late, the liver damage could be permanent
What legislation was brought in to try and reduce paracetamol related deaths?
No more than 2 packs per transaction Illegal to sell more than 100 paracetamol in 1 transaction
