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

State some unwanted actions of PGE2.

Answer 9

Increased pain perception  
Thermoregulation  
Acute inflammatory response  
Tumorigenesis  
Inhibition of apoptosis

Question 10

How does PGE2 increase pain perception?

Answer 10

One possible mechanism:
cAMP mediated
Activates Epac pathway and PKA
Activate P2X3R noiciceptors that detect pain

Could also include:
EP1/EP4 receptors
Endocannabinoids
Beta-endorphin in the spine

Question 11

How does PGE2 affect body temperature?

Answer 11

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 12

State some desirable actions of PGE2 and other prostanoids.

Answer 12

GASTROPROTECTION
Regulation of renal blood flow
Bronchodilation
Vasoregulation

Question 13

Describe the gastroprotective action of PGE2.

Answer 13

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

Question 14

What effect do NSAIDs have on the GI tract?

Answer 14

Increased risk of GI ulceration

Question 15

What main effects does PGE2 have on the kidneys?

Answer 15

Increase renal blood flow

Question 16

What effect do NSAIDs have on the kidneys?

Answer 16

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

Question 17

Why should NSAIDs not be given to asthma patients?

Answer 17

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 18

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

Answer 18

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 19

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

Answer 19

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 20

Name a non-selective COX inhibitors.

Answer 20

Ibuprofen

Question 21

Name a COX-2 selective inhibitor.

Answer 21

Celecoxib

Question 22

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

Answer 22

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

Question 23

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

Answer 23

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

Question 24

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

Answer 24

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 25

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

Answer 25

COX-2 mediated effects increase workload of the heart

Unrestrianed platelet activation may cause increase in coronary atheroma

Also, all NSAIDs produce oxygen free radicals, which can contribute to cardiovascular disease

Question 26

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

Answer 26

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 27

Describe the action of aspirin.

Answer 27

It irreversibly binds to cox enzymes (binds covalently)

It is selective for COX-1

Question 28

Explain how aspirin reduces platelet aggregation.

Answer 28

Aspirin irreversibly inhibits COX-1 in platelets meaning that they can’t produce thromboxane A2, which normally enhances platelet activation and aggregation.

Furthermore, as prsotacyclin is produced via COX1 and COX2, aspirin preserves the production of prostacyclin, which decreases platelet action

Question 29

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

Answer 29

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 30

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

Answer 30

Inhibition of prostacyclin synthesis is proportional to inhibition of COX-2 as COX-2 produces prostacyclin
We don’t want to inhibit prostacyclin production too much so we’d like to keep COX-2 inhibition low

Question 31

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

Answer 31

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

Question 32

Why is paracetamol NOT an NSAID?

Answer 32

It does not have anti-inflammatory action

Question 33

Explain how paracetamol overdose can cause liver failure.

Answer 33

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 34

What is the antidote for paracetamol poisoning?

Answer 34

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

Question 35

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

Answer 35

Guideline - no more than 2 packs per transaction

Law - Illegal to sell more than 100 paracetamol in 1 transaction

Question 36

Explain why the EP receptor system is complex.

Answer 36

There are four different EP receptors and EP2 has two mechanisms of action (ca2+ mobilization and cAMP)