NSAIDS

Question 1

Inflammation

Answer 1

Tissue response to injury/infection
o Bacteria, chemicals, trauma, heat
- Features of inflammation: hyperaemia; oedema; pain; leukocyte infiltration; loss of function

Question 2

Why treat inflammation?

Answer 2

Tissue response to injury/infection is protective for the host

• Anti-inflammatory treatment may delay repair or impair infection control
• If symptoms are disproportionate to injury/infection problem (e.g. fever/headache in viral infection)
• If immune response is maladaptive (e.g. rheumatoid arthritis) then treatment may be indicated

Question 3

Anti-inflammatory drug target eicosanoids

Answer 3

Glucocorticoids inhibit AA release and
metabolism (Lecture 7)
- NSAIDs inhibit cyclo-oxygenase (COX1 &
COX2) (Lecture 6)

Question 4

Cyclo-oxygenase 1

Answer 4

Expressed constitutively in most cells

Question 5

Cyclo-oxygenase 2

Answer 5

Expressed is inducible in inflammatory cells (e.g. macrophages, fibroblasts,
smooth muscle epithelium). Not present on platetes.

Question 6

The COX2 hypothesis

Answer 6

Inflammatory prostaglandins are primarily derived from COX-2, while prostaglandins formed by COX-1 have generally homeostatic roles, including the protection of the gastrointestinal mucosa

• Hence, aim for selective COX2 inhibition.
• As COX2 has a larger opening than COX1, the drug used to selectively target COX2 can be larger so it cannot fit into COX2

Question 7

Rofecoxib

Answer 7

COX-2 inhibition > COX-1
- Withdrawn from market due to increased risk of cardiovascular death.
o COX-2 present in endothelial cells not platelets- selective inhibition shifts balance towards procoagulation (TXA2 > PGI2)
o Avoid use of COX-2 inhibitors when patients have, or are at risk of having, cardiovascular disease

Question 8

Calecoxib

Answer 8

COX2 inhibition > COX1

• Less gastrointestinal adverse effects
• Less anti-platelet effect (platelets have COX1)

Question 9

PGI2

Answer 9

Anti-aggregatory: suppresses the binding of platelets to each other (anti-thrombotic)
- Vasodilator
- Anti-proliferative: suppresses smooth muscle proliferation events during atherosclerosis (plaque
build-up in arteries)

Question 10

TXA2

Answer 10

Aggregatory (pro-thrombotic)

• Vasoconstrictor
• Proliferative

Question 11

PGE2

Answer 11

Vasodilator (anti-thrombotic)
- Anti-proliferative
- Causes fever
Gastro-protective role of PGE2
- Reduces risk of ulceration
o Increases mucus secretion
o Reduces acid secretion
Promotes tissue repair
o Increased blood flow
o Stimulates angiogenesis

Question 12

Prostaglandins (PGs) induce acute hyperalgesia (pain)

Answer 12

PGE2 and bradykinin (BK) are hyperalgesic
o i.e. increase the sensitivity of receptors to painful stimuli
- Combination of PGE2 and BK induces the most painful sensation.
- Long term interaction: IL-1β induces…
o Increase in BK1 receptor number
o Increase in COX-2 and PLA2 expression – more PGE2

Question 13

Prostaglandin induced fever

Answer 13

Inflammation → Macrophage activation → Cytokines → induce PGE2 in hypothalamus → through cAMP,
increase temperature.

Question 14

NSAID actions

Answer 14

Anti-inflammatory
o Acute and chronic conditions e.g. rheumatoid arthritis, gout (not aspirin)
- Analgesia
o Headache, menstrual pain, musculo-skeletal pain etc,
- Anti-pyretic (reduces fever)
o Paracetamol often preferred

Question 15

Why not aspirin for gout?

Answer 15

Aspirin inhibits the uric acid excretion because they are competing
for the same weak organic acid transporter in the renal tubules. Thus, aspirin will treat the inflammation, but would not effectively treat this condition because it will increase the level of uric acid.

Question 16

NSAID adverse effects

Answer 16

Gastro-intestinal
o As PGE2 has a gastro-protective role
- Promotes tissue repair
o Increased blood flow
o Stimulates angiogenesis
18
- Bleeding time and Vascular
o Decrease TXA2 synthesis → impaired platelet aggregation → increased bleeding time
o Risk of haemorrhage (e.g. stroke)
o May increase blood pressure
- Renal
o NSAIDs compromise renal blood flow
o NSAIDs can lead to renal failure when patients are:
Hypovolaemic, have underlying renal disease, had heart failure
- Pulmonary
o Bronchoconstriction (10% of asthmatics)
o Thought to be caused by the redirection from prostanoid production to leukotrienes production
which has broncho-constrictive effects.

Question 17

Aspirin

Answer 17

Short half-life
- Differential effects on PGI2 and TXA2 production (↑PGI2:TXA2 ratio)
o Preservation of PGI2 production by the endothelial cells in the vessel wall that can remake more
COX. The irreversibly inhibited COX is degraded and can be replaced.
o TXA2 is produced by platelets that do not have a nucleus. COX cannot be replaced by newly synthesized COX.

Question 18

Aspirin acetylates COX

Answer 18

o Acetylated COX2 forms aspirin-triggered lipoxins (ATLs)
o Structurally analogous to NSAIDs
o Implicated in the resolution of inflammation
o Ligands for FPR2 (Formyl Peptide Receptor 2): a GPCR type receptor
FPR2 is a high affinity receptor for the arachidonic acid metabolite, lipoxin A4 (LXA4)
• LXA4 is an endogenous mediator for the resolution of inflammation.
o Aspirin increases the synthesis of FPR2 ligands thereby increasing the process to inflammation
resolution

Question 19

Aspirin adverse effects

Answer 19

Common of NSAIDs: gastric ulceration, renal damage

- Specific to aspirin: Reye’s Syndrome, Tinnitis, Uric acid retention (contra-indicated in gout; see above)

Question 20

Paracetamol

Answer 20

Analgesic
- Antipyretic
- Not anti-inflammatory (mechanism uncertain)
- Mechanism of action requires metabolism by peroxidase activity of COX (mechanism uncertain)
- Hepatotoxic in overdose
o Subject to CYP mediated metabolism (phase 1)