NSAIDs Flashcards by Georgia Leggett

What are the three major uses of NSAIDs?

Anti-pyretic
Anti-inflammatory
Analgesic

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What are most deaths due to NSAIDs caused by?

GI ulceration

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Broadly speaking, how do NSAIDs act?

Inhibit production of prostanoids by COX enzymes

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What are the main prostanoids?

Prostaglandins (D2, E2 + F2)
Prostacyclin (PGI2)
Thromboxane A2

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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

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How are prostanoid receptors named?

Based on which prostanoid they have the highest affinity for (e.g. DP1 has the highest affinity for PGD2)

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List all the prostanoid receptors.

DP 1 + 2 
EP 1 - 4
FP
IP 1 + 2  
TP

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What type of receptor are all the prostanoid receptors?

GPCRs (though not all their actions are G protein mediated)

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Explain why the EP receptor system is complex.

There are 4 different EP receptors + EP2 has 2 mechanisms of action + 5 pathways

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State 6 unwanted actions of PGE2.

Increased pain perception  
Increased body temperature 
Acute inflammatory response  
Immune responses
Tumorigenesis  
Inhibition of apoptosis

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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

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How does PGE2 affect body temperature?

PGE2 stimulates hypothalamic neurones initiating a rise in body temperature
Theres a lag between PGE2 rising + temperature rising

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State 4 desirable actions of PGE2 and other prostanoids.

Gastroprotection
Renal salt + water homeostasis
Bronchodilation
Vasoregulation

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Describe the gastroprotective action of PGE2.

PGE2 downregulates HCl secretion

PGE2 stimulates mucus + bicarbonate secretion

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What effect do NSAIDs have on the GI tract?

Increased risk of GI ulceration

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What main effects does PGE2 have on the kidneys?

Increase renal blood flow

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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