8.2.2 NSAIDs II Flashcards
Give examples of Selective COX-2 inhibitors
Celecoxib
Etoricoxib
-coxib suffix
What is the intention of COX2 inhibitors?
Avoid inhibition of homeostatic actions mediated by COX1
What are the benefits of selective COX2 inhibitors?
Less GI and renal ADRs
What is the issue with COX-2 selective inhibitors?
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
What can COX2 selective inhibitors also be used for?
Severe osteoarthritis and rheumatoid arthritis
When should you not use COX2 selective inhibitors?
ALL NSAIDs increase risk of MI including low risk people
What happens in protein binding with NSAIDs?
NSAIDs displace other bound drugs increasing free drug concentration- competitive displacement
Therefore more plasma concentration of the drug thus exerts more effects
What drugs can be affected by NSAIDs?
High protein bound drugs e.g. sulfonylurea-hypoglycaemia
Methotrexate- accumulation and hepatotoxicity
Warfarin- increased risk of bleeding
When should you be careful using NSAIDs?
CVD
Renal function is low
GI disease
Third trimester of pregnancy, delayed labour and early closure of ductus arteriosus
What are some important drug to drug interactions with NSAIDs?
ACEi
ARBs
Steroids
Diuretics
Methotrexate
Warfarin
What are NSAIDs used for?
Inflammatory conditions
Osteoarthritis
Low dose aspirin for platelet aggregation inhibition
Opioid sparing when used in combination
What is paracetamol?
Not an NSAID, non-opiate analgesic with antipyretic action
Used for mild to moderate analgesia and fever
At therapeutic doses what ADRs does paracetamol have?
Well tolerated with few ADRs
No effects on platelets
Limited effect on GI
What is the mechanism of paracetamol?
COX2 selective inhibition in CNS, fewer pain signals transmitter to higher centres
Why does paracetamol not have anti-inflammatory effects?
Peroxides in peripheral inflammation
Paracetamol has no effect on peroxides
Therefore very little anti-inflammatory action
How is paracetamol metabolised and absorbed?
Inactivated by conjugation in the liver
Well absorbed from GI
How long is the half life of paracetamol?
2.5 hours
What should you be particularly aware about with paracetamol?
OTC preparations often contain paracetamol
Patients can easily overdose
Outline paracetamol metabolism
Phase 1 metabolism
Paracetamol metabolised by CYP450 to NAPQI (toxic metabolite)
Phase 2 metabolism
NAPQI conjugated with glutathione
What makes NAPQI toxic?
Highly nucleophilic
Oxidises key metabolic enzymes
Causes cell death- necrosis and apoptosis
How much paracetamol is needed to cause irreversible damage?
150mg/kg
Hepatic glutathione is limited, NAPQI accumulates and causes toxicity
How does paracetamol present?
Asymptomatic for many hours
Nausea, vomiting, abdominal pain
When does maximal liver damage occur?
3-4 days after overdose
How do we treat paracetamol overdose?
IV n-acetylcysteine replenishes glutathione concentration, allows more conjugation of NAPQI
Activated charcoal if overdose was very recent, not really used
