NSAIDs

Question 1

Give 5 examples of NSAIDs

Answer 1

Ibuprofen
Aspirin
Naproxen
Diclofenac
Celecoxib

Question 2

What are the 3 major therapeutic effects of NSAIDs?

Answer 2

Analgesia
Anti-inflammatory
Antipyretic

Question 3

What is the mechanism of action of NSAIDs in broad terms?

Answer 3

Competitively inhibit COX1 and COX2, meaning arachadonic acid cannot bind

Question 4

How do NSAIDs exert their analgesic effect?

Answer 4

Inhibition of COX2 which prevents arachadonic acid conversion to prostaglandin H2.
Hence reduce synthesis of PGs which prevents sensitisation of nociceptors to inflammatory mediators

Question 5

How do NSAIDs exert their anti-inflammatory effect?

Answer 5

Reduce PGs

Question 6

How do NSAIDs exert their antipyretic effects?

Answer 6

Reduce thalamic PGE2 synthesis triggered by IL-1 release from macrophages, hence prevent their action at EP3 receptors, in turn preventing heat production

Question 7

What is the important thing about NSAIDS’ PK?

Answer 7

Heavily plasma protein bound

Question 8

Are the ADRs mainly due to COX1 or COX2 inhibition?

Answer 8

COX1

Therapeutic effects = COX2

Question 9

List 4 ADRs of NSAIDs

Answer 9

• GI irritation - ulceration/bleeding/pain
• Risk of bleeding
• Hypersensitivity
• Renal

Question 10

Why do NSAIDs cause GI irritation?

Answer 10

Decreased PGE2 production means that mucus production is decreased, acid production is increased and there is decreased mucosal blood flow.

Question 11

How could you overcome the problem of GI irritation with NSAID use?

Answer 11

Co-prescribe a PPI

Question 12

Give 3 DDIs associated with NSAIDs (and explain why)

Answer 12

• NSAID + NSAID - increased risk of ADRs
• NSAIDs + warfarin/methotrexate/sulphonylureas - protein binding - displace other drugs
• NSAIDs + ACEi - risk of AKI due to decreased perfusion pressure

Question 13

What is unique about aspirin?

2 things

Answer 13

1) Irreversibly inhibits COX1 via acetylation

2) Very short half-life and zero order kinetics at high dose

Question 14

Why might paracetamol not be counted as an NSAID?

Answer 14

No anti-inflammatory properties

Question 15

Outline the basis of paracetamol toxicity

Answer 15

• At high dose, PK becomes zero order - phase II pathway saturation
• More phase I oxidation - hence build up of NAPQI
• To get rid of NAPQI, needs glutathione - becomes saturated
• Hence leads to both build up of toxic NAPQI and depletion of glutathione - more free radical threat to liver

Question 16

Outline the treatment of paracetamol overdose

Answer 16

• 0 - 4 hours - activated charcoal
• 0 - 36 hours - IV N-acetylcysteine - depending on plasma conc of paracetamol
  Or possibly oral methionine