NSAIDs

Question 1

What are the three major uses of NSAIDs?

Answer 1

Anti-pyretic
Anti-inflammatory
Analgesic

Question 2

What are most deaths due to NSAIDs caused by?

Answer 2

GI ulceration

Question 3

Broadly speaking, how do NSAIDs act?

Answer 3

They inhibit the production of prostanoids by COX enzymes

Question 4

What are the main prostanoids?

Answer 4

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

Question 5

What does COX convert arachidonic acid to?

Answer 5

Prostaglandin H2  
Which is then converted by specific synthases to: 
 Thromboxane A2
 Prostacyclin (PGI2)
 Prostaglandin D2, E2, F2

Question 6

How are prostanoid receptors named?

Answer 6

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)

Question 7

List all the prostanoid receptors.

Answer 7

DP1, DP2 
EP1, EP2, EP3, EP4 
FP
IP1, IP2 
TP

Question 8

What type of receptor are all the prostanoid receptors?

Answer 8

G protein coupled receptors (though not all their actions are G protein mediated)

Question 9

Explain why the EP receptor system is complex.

Answer 9

There are four different EP receptors and EP2 has two mechanisms of action and five pathways

Question 10

State some unwanted actions of PGE2.

Answer 10

Increased pain perception  
Thermoregulation  
Acute inflammatory response  
Tumorigenesis  
Inhibition of apoptosis

Question 11

How does PGE2 increase pain perception?

Answer 11

There is involvement of EP4 receptors and endocannabinoids

The mechanism is unclear

Question 12

How does PGE2 affect body temperature?

Answer 12

PGE2 stimulates hypothalamic neurones initiating a rise in body temperature
NOTE: there is a bit of a lag between PGE2 rising and temperature rising

Question 13

Which prostanoid receptor is responsible for signalling in acuteinflammation?

Answer 13

EP3 (on mast cells)

Question 14

Which prostanoid receptor is responsible for the effects of PGE2 on the immune system?

Answer 14

EP4

Question 15

Which diseases are treated with NSAIDs due to its effects on the immune system?

Answer 15

Multiple Sclerosis and Rheumatoid Arthritis (Th17 involvement)
Contact Dermatitis (Th1 cells involved)

Question 16

What is the problem with PGE2 inhibiting apoptosis?

Answer 16

Inhibition of apoptosis increases the likelihood of necrosis
NOTE: there are 3 prostanoids, 7 prostanoid receptors and 2 downstream signalling pathways involved

Question 17

State some desirable actions of PGE2 and other prostanoids.

Answer 17

GASTROPROTECTION
Regulation of renal blood flow
Bronchodilation
Vasoregulation

Question 18

Describe the gastroprotective action of PGE2.

Answer 18

PGE2 downregulates stomach acid production
PGE2 stimulates mucus production
PGE2 stimulates bicarbonate production

Question 19

What effect do NSAIDs have on the GI tract?

Answer 19

Increased risk of GI ulceration

Question 20

What main effects does PGE2 have on the kidneys?

Answer 20

Increase renal blood flow

Question 21

What effect do NSAIDs have on the kidneys?

Answer 21

Constriction of the afferent arteriole
Reduction in renal artery flow
Reduced GFR

Question 22

Why should NSAIDs not be given to asthma patients?

Answer 22

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

Question 23

Prostanoids are vasoregulators, so what are the consequences of NSAIDs on the cardiovascular system?

Answer 23

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

Question 24

What is the difference in terms of risk of side effects when using NSAIDs for analgesic use compared to anti-inflammatory use?

Answer 24

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

Question 25

Name two non-selective COX inhibitors.

Answer 25

Ibuprofen

Indomethacin

Question 26

Name a COX-2 selective inhibitor.

Answer 26

Celecoxib

Question 27

What is the major problem with COX-2 selective NSAIDs?

Answer 27

They have a significantly increased risk of cardiovascular disease than conventional NSAIDs

Question 28

Describe the relative GI and CVS risks of COX-1 selective and COX-2 selective NSAIDs when compared to non-selective NSAIDs.

Answer 28

COX-1 selective: 
 Same CVS risk as non-selective NSAIDs
 Increased GI risk 
COX-2 selective: 
 Decreased GI risk 
 Increased CVS risk

Question 29

What effect does ibuprofen have on the action of anti-hypertensive drugs?

Answer 29

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

Question 30

What are the potential reasons for increased risk of cardiovascular disease with non-selective and COX-2 selective NSAIDs?

Answer 30

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

Question 31

State some strategies for avoiding/limiting the GI side effects of NSAIDs.

Answer 31

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

Question 32

Describe the action of aspirin.

Answer 32

It irreversibly binds to cox enzymes (binds covalently)

It is selective for COX-1

Question 33

Explain how aspirin reduces platelet aggregation.

Answer 33

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

Question 34

Why is it important to use a low dose of aspirin?

Answer 34

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

Question 35

Why don’t you want to inhibit COX-2 too much?

Answer 35

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

Question 36

What are the major side effects of therapeutic doses of aspirin?

Answer 36

Gastric irritation and ulceration
Bronchospasm in sensitive asthmatics
Prolonged bleeding times
Nephrotoxicity

Question 37

Why is paracetamol NOT an NSAID?

Answer 37

It does not have anti-inflammatory action

Question 38

Explain how paracetamol overdose can cause liver failure.

Answer 38

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

Question 39

What is the antidote for paracetamol poisoning?

Answer 39

IV Acetyl cysteine
This has a lot of –SH groups
If this is given too late, the liver damage could be permanent

Question 40

What legislation was brought in to try and reduce paracetamol related deaths?

Answer 40

No more than 2 packs per transaction

Illegal to sell more than 100 paracetamol in 1 transaction