NSAIDS

Question 1

What are the 3 major clinical uses of NSAIDS?

Answer 1

Analgesics
Antipyretics
Anti-inflammatories

Question 2

From what are prostanoids derived, and where does this originate?

Answer 2

Arachdionic acid

Plasma membrane

Question 3

Recall 2 key prostanoids

Answer 3

TXA2 (thromboxane A2)

PGI2 (prostacyclin)

Question 4

What is the rate-limiting step in prostaglandin synthesis?

Answer 4

COX-driven conversion of arachdionic acid to endoperoxidases such as PGH2 and PGG2

Question 5

Recall the 10 types of prostanoid receptor

Answer 5

DP1 DP2
EP1 EP2 EP3 EP4
FP
IP1 IP2
TP

Question 6

What is PGE2?

Answer 6

Type of prostanoid

Question 7

What receptors does PGE2 have affinity for?

Answer 7

EP1234

Question 8

Recall a desirable action of PGE2

Answer 8

Neuroplasticity, bronchodilation, osmotic homeostasis, gastroprotection, vasoregulation

Question 9

Summarise 4 unwanted effects of PGE2

Answer 9

1. Enhanced pain perception
2. Pyrogenic
3. Acute inflammation
4. Cancer risk increased

Question 10

How does PGE2 lower the pain threshold?

Answer 10

Sensitises nocioreceptors

Question 11

Why is PGE2 pyrogenic?

Answer 11

It stimulates hypothalamic neurons that initiate a rise in body temp

Question 12

Recall the mechanism by which PGE2 regulates inflammation?

Answer 12

Moderated by:

• EP3
• Calcium
• Multiple GPCRs

Question 13

How does PGE2 increase risk of malignancy?

Answer 13

Inhibits apoptosis

Question 14

Why is aspirin unique among the NSAIDS?

Answer 14

Selective for COX1

Binds IRreversible

Question 15

Describe how aspirin reduces platelet aggregation

Answer 15

Platelets:
- produce TXA2 which increases aggregation
- cannot replenish COX1 as have no nucleus
Endothelium:
- Produces PGI2 which decreases aggregation
- are nucleated so can replenish COX1+2
Aspirin inhibits TXA2 production and it cannot be replaced, PGI2 synthesis is affected to a lesser extent

Question 16

What is the main consequence of paracetamol overdose?

Answer 16

Irreversible liver failure

Question 17

Recall the metabolism of paracetamol

Answer 17

CYP450
Metabolite = NAPQI: toxic as oxidises thiol groups on key enzymes for cell survial
NAPQI usually mopped up by glutathione, but if this is depleted NAPQI accumulates

Question 18

What is the antidote to paracetamol overdose?

Answer 18

Acetylcysteine - it has thiol (SH) groups

Question 19

Recall the 4 main side effects of NSAID use

Answer 19

Loss of benefits of PGE2:

1. Bronchoconstriction
2. Renal toxicity
3. Loss of PGE2 gastroprotectivity
4. Vasoconstriction

Question 20

How do NSAIDS lead to bronchoconstriction?

Answer 20

Inhibit COX
COX inhibits leukotriene production
Leukotrienes are bronchoconstictors

Question 21

What is the effect of PGE2 on the kidney?

Answer 21

Increases renal blood flow

Question 22

How do NSAIDS cause renal toxicity?

Answer 22

Constrict afferent arteriole to reduce GFR

Question 23

What is the effect of PGE2 on the stomach?

Answer 23

Downregulates HCl
Stimulates mucous production
Stimulates HCO3- production

Question 24

What is the danger of NSAIDS to the stomach?

Answer 24

Increase risk of ulcers by inhibiting PGE2

Question 25

Give an example of a drug that inhibits both COX1 and COX2

Answer 25

Ibuprofen

Question 26

Give an example of a COX2 inhibitor

Answer 26

Celecoxib

Question 27

What is the benefit of having a drug that specifically inhibits COX2?

Answer 27

Avoids gastric ulcer risk

Question 28

What is the risk of having a drug that specifically inhibits COX2 as compared to aspirin?

Answer 28

CVD risk higher

Question 29

What is the main drawback of drugs that inhibit COX2 as well as COX2?

Answer 29

Significant side effect profile

Question 30

What can be coadministered with NSAIDS to offer gastroprotection?

Answer 30

PPI such as omeprazole

Question 31

Recall 2 contraindictions for NSAID use

Answer 31

Steroid use

Alcohol dependency