NSAIDs

Question 1

What are the major clinical uses of NSAIDs?

Answer 1

Relief of mild pain (analgesic):
- Toothache, headache and backache
-Post-op pain
-Dysmenorrhoea
Reduction of fever (antipyretic)
Reduction of inflammation (anti-inflammatory):
-Rheumatoid arthritis 
-Osteoarthritis
-Soft tissue injuries
-Gout

Question 2

How do NSAIDs work?

Answer 2

They inhibit the production of prostanoids by COX enzymes

Question 3

What are prostanoids derived from?

Answer 3

Arachidonic acid

Question 4

Name three main prostanoids?

Answer 4

Prostaglandins
Thromboxane
Prostacyclin

Question 5

What are prostanoid actions mediated by?

Answer 5

They are all receptor mediated: DP1 DP2 EP1 EP2 EP3 EP4 FP IP1 IP2 TP

Question 6

What are prostanoid receptors named based on?

Answer 6

Their potency/highest affinity- DP1 has the greatest affinity for prostaglandin D2

Question 7

What sort of receptors are all prostanoid receptors?

Answer 7

G protein coupled but not all their actions are G protein mediated

Question 8

How many prostaglandins do we have?

Answer 8

5

Question 9

Which receptors can PGE2 activate and how many pathways does it work through?

Answer 9

4 receptors: EP1, EP2, EP3 and EP4

5 pathways

Question 10

What is neuroplasticity?

Answer 10

A desirable feature- ability of one neurone to take over the job of another neurone if it were to become damaged

Question 11

What are the unwanted actions of PGE2?

Answer 11

Increased pain perception
Thermoregulation
Acute inflammatory response
Immune responses
Tumorigenesis
Inhibition of apoptosis- more likely to get necrosis

Question 12

What effect do PGE2 analogues have on pain threshold?

Answer 12

Lower the pain threshold and increases pain sensitivity

Question 13

What is believed to be involved in the mechanism by which COX inhibitors raise the pain threshold?

Answer 13

EP4 receptors (in periphery and spine)
Endocannabinoids (neuromodulators in thalamus, spine and periphery)- cross talk between the two so there is neuromodulation
They block the production of PGE2

Question 14

What effect does PGE2 have on body temperature?

Answer 14

It is pyrogenic- it stimulates hypothalamic neurones initiating a rise in body temperature

Question 15

What mediates the effect of PGE2 on the immune system?

Answer 15

EP4

Question 16

What inflammatory conditions are treated with NSAIDs?

Answer 16

Contact dermatitis
Multiple sclerosis
Rheumatoid arthritis
PGE2 is important in acute and chronic inflammation

Question 17

Why are the anti-apoptic effects of prostaglandins undesirable?

Answer 17

You are more likely to get necrosis- will contribute to inflammation

Question 18

What desirable actions do PGE2 and other prostanoids have?

Answer 18

Gastroprotection
Regulation of renal blood flow
Bronchodilation
Vasoregulation

Question 19

How does PGE2 have a role in gastroprotection?

Answer 19

Downregulates HCl secretion in the stomach

Stimulates production of mucus (physical barrier) and bicarbonate (neutralises stomach acid)

Question 20

What effect does NSAID use have on the gastric system?

Answer 20

Reduces PGE2 so causes increase in risk of ulceration

Question 21

What effect do NSAIDs have on renal blood flow?

Answer 21

Can cause renal toxicity:
Constriction of afferent arteriole
Reduction in renal artery flow
Reduced glomerular filtration rate

Question 22

In terms of the lungs what do most COX products cause?

Answer 22

Bronchodilation

Question 23

What do asthma patients experience with use of NSAIDs?

Answer 23

Exacerbation of symptoms- Inhibition of COX favours production of leukotrienes which are bronchoconstrictors

Question 24

What effect do NSAIDs have on cardiovascular system?

Answer 24

Serious unwanted effects- increase incidence in MI and stroke:
Small rise in blood pressure
Sodium retention
Vasoconstriction

Question 25

What is the risk vs benefit of NSAID use like for analgesic use and anti-inflammatory use?

Answer 25

``` Analgesic: Usually occasional Low risk of side effects Anti inflammatory: Often sustained Higher doses High risk of side effects ```

Question 26

Do NSAIDs vary in affinity for COX-1 and COX-2?

Answer 26

Yes

Question 27

What is the selectivity for ibuprofen and indomethacin like?

Answer 27

Typically non-selective NSAIDs and inhibit both COX1 and 2 - irreversibly

Question 28

What effects do ibuprofen and indomethacin have?

Answer 28

Analgesic Anti-pyretic Anti-inflammatory

Question 29

Why are selective COX-2 inhibitors used more to avoid side effects?

Answer 29

It's very difficult to make a selective COX-2 inhibitor because both COX enzymes are structurally very simiilar

Question 30

What does celecoxib do?

Answer 30

Selectively inhibits COX2- less effect on COX-1 mediated process than conventional NSAIDs such as ibuprofen- led to decrease in ulceration

Question 31

What do COX-2 selective inhibitors pose a greater risk of than conventional NSAIDs?

Answer 31

Cardiovascular disease even though mechanism is unclear

Question 32

What is the difference between COX-1 selective NSAIDs and conventional NSAIDs?

Answer 32

Cardiovascular risk is unchanged but GI risk is increased- PGE2 in stomach is generated through COx-1

Question 33

How are COX-2 inhibitors tolerated in asthmatics?

Answer 33

Well but not recommended

Question 34

What happens when a patient on antihypertensives takes ibuprofen?

Answer 34

Blood pressure will rise

Question 35

How do non-selective and COX 2 selective drugs increase cardiovascular disease?

Answer 35

They cause an increase in work COX2 selective probably exert effects via interfering with balance between prostacyclin and thromboxane- increase in thromboxane will cause increased risk of thrombosis All NSAIDs increase production of oxygen free radicals and they affect multiple different pathways that contribute to CVD

Question 36

What other strategies are there to limit GI side effects of NSAIDS apart from COX2 selective?

Answer 36

Topical application Minimise NSAID use in patients with history of GI ulceration Treat H pylori if present Administer with omeprazole or other proton pump inhibitor Minimise NSAID use in patients with other risk factors and reduce risk factors where possible

Question 37

What does aspirin do?

Answer 37

Selective for COX1 and binds irreversibly Has analgesic, anti-inflammatory and anti-pyretic actions It is unique among NSAIDs

Question 38

What is the effect of aspirin on platelets?

Answer 38

``` Inhibit thromboxane (which enhances platelet action) production by platelets In high doses, reduces prostacyclin (which decreases platelet action) production by endothelial cells ```

Question 39

Why are platelets not able to resynthesises COX after aspirin binds?

Answer 39

Platelets lack a nucleus so once aspirin irreversibly inhibits the COX enzymes in a platelet, it will not be able to resynthesise COX and hence will not regain its ability to produce thromboxane (Endothelial cells can replenish so maintain prostacyclin)

Question 40

What is responsible for anti platelet actions of aspirin?

Answer 40

Very high degree of COX-1 inhibition by covalent binding which irreversibly suppresses thromboxane A2 production

Question 41

Why do you need to give a low dose of aspirin?

Answer 41

To allow endothelial cells to resynthesises COX otherwise you will keep inhibiting endothelial COX as fast as it's being made so won't get beneficial effects- the inhibition of prostacyclin is proportional to the inhibition of thromboxane

Question 42

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

Answer 42

``` Gastric irritation and ulceration Bronchospasm in asthmatics Prolonged bleeding times Nephrotoxicity Side effects more likely with aspirin than other NSAIDs because it inhibits covalently ```

Question 43

What does paracetamol do?

Answer 43

It is a good analgesic for moderate pain and has anti-pyretic action

Question 44

Why is paracetamol not a NSAID?

Answer 44

It is not anti-inflammatory

Question 45

What is thought to be involved in the mechanism of paracetamol's action?

Answer 45

COX-3 Via cannabinoid receptors Interaction with endogenous opioids Interaction with 5HT and adenosine receptors

Question 46

What can overdose of paracetamol cause?

Answer 46

Liver failure

Question 47

What normally happens in paracetamol metabolism?

Answer 47

Toxic metabolite is formed (toxic= generates free radicals) and is normally mopped up by glutathione and is rendered safe

Question 48

How does paracetamol overdose cause liver failure?

Answer 48

Too much toxic metabolite is being generated leading to depletion of glutathione which means the toxic metabolite will indiscriminately bind to any -SH group that it can find- most of which are attached to key hepatic enzymes and you get inevitable cell death