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?
Inhibit production of prostanoids by COX enzymes
What are the main prostanoids?
Prostaglandins (D2, E2 + 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?
Based on which prostanoid they have the highest affinity for (e.g. DP1 has the highest affinity for PGD2)
List all the prostanoid receptors.
DP 1 + 2 EP 1 - 4 FP IP 1 + 2 TP
What type of receptor are all the prostanoid receptors?
GPCRs (though not all their actions are G protein mediated)
Explain why the EP receptor system is complex.
There are 4 different EP receptors + EP2 has 2 mechanisms of action + 5 pathways
State 6 unwanted actions of PGE2.
Increased pain perception Increased body temperature Acute inflammatory response Immune responses Tumorigenesis Inhibition of apoptosis
How does PGE2 increase pain perception?
PGE2 activates its receptor increases cAMP, activates pKa, activates nociceptors
Inflammatory mediators recruit more PGE2 which produce more cAMP, activating more nociceptors
Through Epac pathway there is recruitment of more nociceptors
How does PGE2 affect body temperature?
PGE2 stimulates hypothalamic neurones initiating a rise in body temperature
Theres a lag between PGE2 rising + temperature rising
State 4 desirable actions of PGE2 and other prostanoids.
Gastroprotection
Renal salt + water homeostasis
Bronchodilation
Vasoregulation
Describe the gastroprotective action of PGE2.
PGE2 downregulates HCl secretion
PGE2 stimulates mucus + bicarbonate secretion
What effect do NSAIDs have on the GI tract?
Increased risk of GI ulceration
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 reduced production due to COX inhibition could exacerbate asthma
Furthermore, inhibition of COX favours production of leukotrienes, which are bronchoconstrictors
Prostanoids are vasoregulators, so what are 4 consequences of NSAIDs on the cardiovascular system?
Increased risk of MI + stroke because chronic use of NSAIDs:
Increases BP
Increases Water + Na+ retention
Increases Vasoconstriction
Can reduce 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 occasional use 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?
Increased risk of CVD 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?
Reduces effectiveness of anti-hypertensive drugs
Reduce the drop in BP 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 + COX-2 selective NSAIDs both increase cardiac work
Also, all NSAIDs produce oxygen free radicals, which can contribute to CVD
State 5 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 essential, administer omeprazole or other PPI
Minimise NSAID use in patients with other risk factors + reduce risk factors where possible e.g. alcohol consumption, anticoagulant use
Describe the action of aspirin.
Irreversibly binds to cox enzymes (binds covalently)
Selective for COX-1
Anti-inflammatory, Analgesic + Anti-pyretic actions
Reduces platelet aggregation
Explain how aspirin reduces platelet aggregation.
Irreversible inhibition of COX-1 in platelets means they can’t produce thromboxane A2, which enhances platelet activation + 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 endothelial cells to resynthesise COX-1, which can then continue to produce prostacyclin
A high dose would mean COX-1 in 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 keep COX-2 inhibition low
What are the major side effects of therapeutic doses of aspirin?
Gastric irritation + 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 (NAPQI) which is normally mopped up rapidly by glutathione
In OD, glutathione stores are depleted + NAPQI binds indiscriminately to any –SH groups
The –SH groups tend to be on key hepatic enzymes + this interference leads to cell death
What is the antidote for paracetamol poisoning?
IV Acetyl cysteine
Has a lot of –SH groups
If given too late, 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 > 100 paracetamol in 1 transaction
How else may PGE2 cause increased pain perception?
Involvement of EP 1 + 4 receptors
Involvement of endocannabinoids
Name a COX-1 selective drug and 1 unwanted effect it has
Aspirin
Causes bad GI ulcers
What is the action of the Coxib family?
Selectively reversibly inhibit COX-2
Why do side effects tend to be worse with Aspirin than other NSAIDs?
Because it irreversibly inhibits COX with strong covalent bonds
What syndrome does Aspirin increase likelihood of development of and who is this mostly seen in?
Reye’s syndrome
Under 20’s when a viral infection is being treated with aspirin
Permanent damage to mitochondria leads to ammonia production results in damage to astrocytes + oedema in brain
What are the actions of paracetamol?
Analgesic
Anti-pyretic
