8.2.2 NSAIDs II

Question 1

Give examples of Selective COX-2 inhibitors

Answer 1

Celecoxib
Etoricoxib

-coxib suffix

Question 2

What is the intention of COX2 inhibitors?

Answer 2

Avoid inhibition of homeostatic actions mediated by COX1

Question 3

What are the benefits of selective COX2 inhibitors?

Answer 3

Less GI and renal ADRs

Question 4

What is the issue with COX-2 selective inhibitors?

Answer 4

COX2 pathway controls production of PGI2

COX1 pathway controls production of TXA2

If COX2 is inhibited without COX1 being inhibited, you could end up with too much TXA2 production which could lead to unopposed platelet aggregation and vasoconstriction

Some evidence of less analgesic effect

Question 5

What can COX2 selective inhibitors also be used for?

Answer 5

Severe osteoarthritis and rheumatoid arthritis

Question 6

When should you not use COX2 selective inhibitors?

Answer 6

ALL NSAIDs increase risk of MI including low risk people

Question 7

What happens in protein binding with NSAIDs?

Answer 7

NSAIDs displace other bound drugs increasing free drug concentration- competitive displacement

Therefore more plasma concentration of the drug thus exerts more effects

Question 8

What drugs can be affected by NSAIDs?

Answer 8

High protein bound drugs e.g. sulfonylurea-hypoglycaemia

Methotrexate- accumulation and hepatotoxicity

Warfarin- increased risk of bleeding

Question 9

When should you be careful using NSAIDs?

Answer 9

CVD
Renal function is low
GI disease
Third trimester of pregnancy, delayed labour and early closure of ductus arteriosus

Question 10

What are some important drug to drug interactions with NSAIDs?

Answer 10

ACEi
ARBs
Steroids
Diuretics
Methotrexate
Warfarin

Question 11

What are NSAIDs used for?

Answer 11

Inflammatory conditions
Osteoarthritis
Low dose aspirin for platelet aggregation inhibition
Opioid sparing when used in combination

Question 12

What is paracetamol?

Answer 12

Not an NSAID, non-opiate analgesic with antipyretic action

Used for mild to moderate analgesia and fever

Question 13

At therapeutic doses what ADRs does paracetamol have?

Answer 13

Well tolerated with few ADRs
No effects on platelets
Limited effect on GI

Question 14

What is the mechanism of paracetamol?

Answer 14

COX2 selective inhibition in CNS, fewer pain signals transmitter to higher centres

Question 15

Why does paracetamol not have anti-inflammatory effects?

Answer 15

Peroxides in peripheral inflammation

Paracetamol has no effect on peroxides

Therefore very little anti-inflammatory action

Question 16

How is paracetamol metabolised and absorbed?

Answer 16

Inactivated by conjugation in the liver

Well absorbed from GI

Question 17

How long is the half life of paracetamol?

Answer 17

2.5 hours

Question 18

What should you be particularly aware about with paracetamol?

Answer 18

OTC preparations often contain paracetamol

Patients can easily overdose

Question 19

Outline paracetamol metabolism

Answer 19

Phase 1 metabolism
Paracetamol metabolised by CYP450 to NAPQI (toxic metabolite)

Phase 2 metabolism
NAPQI conjugated with glutathione

Question 20

What makes NAPQI toxic?

Answer 20

Highly nucleophilic

Oxidises key metabolic enzymes

Causes cell death- necrosis and apoptosis

Question 21

How much paracetamol is needed to cause irreversible damage?

Answer 21

150mg/kg

Hepatic glutathione is limited, NAPQI accumulates and causes toxicity

Question 22

How does paracetamol present?

Answer 22

Asymptomatic for many hours

Nausea, vomiting, abdominal pain

Question 23

When does maximal liver damage occur?

Answer 23

3-4 days after overdose

Question 24

How do we treat paracetamol overdose?

Answer 24

IV n-acetylcysteine replenishes glutathione concentration, allows more conjugation of NAPQI

Activated charcoal if overdose was very recent, not really used