NSAIDs

Question 1

What are eicasanoids?

Answer 1

Phospholipid derivatives used as signalling molecules eg. Prostaglandins
They’re all derived from arachinoid acid

Question 2

What enzymes are used to synthesise prostaglandins?

Answer 2

Cycloxygenase enzymes

Question 3

How do COX enzymes synthesise prostaglandins?

Answer 3

Phospholipase A2 from cell membrane phospholipids makes arachindonic acid
COX 1 and 2 synthesise prostaglandins from this

Question 4

Which prostaglandin is most important in mediating an inflammatory response?

Answer 4

E

Does vasodilation, hyperalgesia, fever, immunomodulation

Question 5

What are some of the other roles of prostaglandins produced by COX-1?

Answer 5

Protection of

• gastric mucosa
• myocardium
• renal parenchyma

Question 6

What is COX-2 expression induced by?

Answer 6

Inflammatory mediators like bradykinin

Question 7

What COX in particular do NSAIDs work on?

Answer 7

2

Question 8

Discuss the structures of COX 1 and 2?

Answer 8

1 is very narrow mouthed so it fits small, sharp drugs like aspirin
2 is big and blunt

Aspirin fits in both

Question 9

When are autacoids and prostaglandins released?

Answer 9

Released from local tissues and blood vessels post-injury

Prostaglandins act as potent vasodilators

Question 10

What receptors of prostaglandins do what?

Answer 10

EP1 receptors (Gq) increase peripheral nociception 
EP2 receptors (Gs) increases vasodilation

Question 11

How does EP1 work?

Answer 11

Painful stimuli is carried by afferent C fibres
Following trauma, surrounding tissue and neurones synthesise PG
PG binds with GPCR on EP1 and activates it
GPCR activation leads to
- increased neuronal sensitivity
- decreased potassium channels
- increased sodium channel sensitivity

All of this increase C fibre activity by increasing intracellular ca2+

Question 12

How does EP2 work?

Answer 12

Increased sustained nociceptive signalling peripherally result in increased cytokines levels in the dorsal horn cell body
Causes increased COX2 and prostaglandin synthesis
Acts on the GPCR on EP2: increasing cAMP and pKa
This decreases glycine receptor binding affinity
Which increases pain perception

Question 13

What does EP3 bring about?

Answer 13

Pyrexia

Question 14

How does EP3 work?

Answer 14

In infected sites, bacterial endotoxins stimulate macrophage release of IL-1
IL-1 within the hypothalamus stimulates PG synthesis
When this activates the GPCR on EP3
Results in increased heat production and decreased heat loss

Question 15

How do NSAIDs work?

Answer 15

COX-2 inhibition is the main thing
Work on COX 1 too
Nearly all have therapeutic efficacy as analgesics, anti-inflammatories and anti-pyretics

Question 16

How are NSAIDs given?

Answer 16

Orally

Can be given topically for soft tissue injury

Question 17

What is the anti-inflammatory effect of NSAIDs?

Answer 17

MSK Disorders: rheumatoid and osteoarthritis

Question 18

What are the analgesic effects of NSAIDs?

Answer 18

Work on mild to moderate pain

Question 19

What are the ADRs of NSAIDs?

Answer 19

Peptic ulcers 
Renal failure
 - prostaglandins important for maintaining renal blood flow 
 - NSAIDs can reduce GFR therefore
Increased risk of bleeding, bruising and haemorrhage
Hypersensitivity
 - skin rashes
 - bronchial asthma 
Steven Johnson's Syndrome

Question 20

Discuss the drug interactions of NSAIDs

Answer 20

Extends therapeutic range with low dose opiates
In combination with other NSAIDs, increase risk of ADRs
Affects other drugs that are highly protein bound like
- sulphonylureas
- warfarin
- methotrexate

Question 21

What are autacoids?

Answer 21

A range of molecular mediators and signalling agents such as

Bradykinin, histamine, cytokines, leukotrienes, nitric oxides

Question 22

What is the mechanism of action of Paracetamol?

Answer 22

Mainly use phase 2 but some uses phase 1 - producing a little NAPQI
NAPQI is usually detoxified by phase 2 using glutathione

Question 23

What happens when you overdose on paracetamol?

Answer 23

Phase 2 becomes saturated 
So glutathione is rapidly depleted 
So there is an increase in NAPQI 
Unconjugated NAPQI binds with mitochondria and causes
 - necrotic hepatic cell death
 - renal failure

Question 24

How do you treat paracetamol overdose?

Answer 24

0-4 hours: oral activated charcoal

0-36 hours: N-acetyl cysteine