W1 6 NSAIDs Flashcards
Give examples of NSAIDs
Ibuprofen, diclofenac, naproxen, piroxicam, aspirin, celecoxib
What is the general mechanism of NSAIDs?
NSAIDs inhibit production of certain eicosanoids = lipid derivatives
What are the 3 main categories of eicosanoids?
Prostaglandins (PGs) (prostanoids)
Thromboxanes (TX) (prostanoids)
Leukotrienes (LT)
(NSAIDs mainly affect PGs in their anti-inflammatory effect)
Describe the biosynthesis of prostanoids (PG52)
Enzyme PLA2 releases arachidonic acid from the cell membrane
COX converts arachidonic acid into intermediates = cyclic endoperoxides
Depending on the cell and enzymes present, you get a specific end-cell product:
- prostacyclin synthase is present in endothelial cells making prostacyclin
- thromboxane synthase is present in platelets producing TXA2
Do NSAIDs affect lipoxygenase or cyclooxygenase?
NSAIDs don’t directly affect lipoxygenase. Only affected if COX is inhibited and there is more arachidonic acid and thus potentially more production of leukotrienes from the lipoxygenase pathway.
(how do steroids affect the prostanoids pathway)
Increase expression of annexin1 which inhibits release of PLA2 so decreases free arachidonic acid
Decrease COX2 expression
What’s the difference between COX1 and COX2?
COX1 - constructive (most cells), produces prostanoids almost all the time
COX2 - inducible (inflammatory cells), produces prostanoids more when stimulated under inflammation
Where are the different end-products produced from?
PGI2 from endothelium
TXA2 from platelets
What are the primary actions of prostaglandins?
(All linked to inflammation)
Cause vasodilatation
Pyrexia - increased body temperature via action in hypothalamus
Pain
What are the non-inflammation related actions of PGs?
Prevent platelet aggregation, contraction of uterine smooth muscle, protects lining of stomach
What are the actions of thromboxanes?
Platelet aggregation, vasoconstriction
Which NSAIDs irreversibly inhibits COX1+2?
Aspirin
Which NSAID reversibly inhibits COX1+2?
Ibuprofen, diclofenac
Which NSAID is selective and inhibits COX2?
Celecoxib
What does paracetamol do?
Weakly inhibits COX in the presence of peroxides
(Peroxide levels high in inflammation and low in CNS)
Can have effect on canaboid receptors involved in pain pathways so beneficial for analgesia
What are the general effects of NSAIDs linked to the blockage of prostanoids?
Analgesia (esp musculoskeletal pain)
Reduced inflammation via less vasodilation
Reduced fever via reset of hypothalamus thermostat
When are NSAIDs used in dentistry?
Temperorary releif of mild/moderate dental pain/inflammation, I.e. 1-7 days until cause controlled
Ibuprofen, diclofenac, aspirin are effective
Is paracetamol an NSAID?
It is an analgesic and antipyretic, but has poor anti-inflammatory effect
What are the general side effects of NSAIDs?
- gastric irritation due to loss of protective PG in stomach lining (PGs decrease acid secretion and increase mucous)
- increased risk of cardiac arrest with ibuprofen and diclofenac
- hypersensitivity (asthma, rhinitis, urticaria, angioedema)
- decreased renal function
- renal necrosis following prolonged use
- prolonged gestation (due to loss of PG activity for labour - PG cause contraction)
When are NSAIDs contraindicated?
If hypersensitivity occurs, NSAIDs are contraindicated in future
(maybe more production of leukotrienes can cause constriction of airways)
Should you use NSAIDs in children and elderly?
OK in children (but not aspirin)
Caution in elderly (due to renal effects)
What does aspirin do?
Irreversibly inhibits COX1+2
What are the actions of aspirin?
Analgesic, antipyretic
Antiplatelet - important for ‘blood thinning’ to prevent clots
How does aspirin have an antiplatelet effect?
Platelets: produce TXA2 which aggregates platelets and causes vasoconstriction
Endothelium: produce PGI2 which inhibits aggregation of platelets and causes vasodilation
Why does aspirin only have blood thinning effect at low dose (about 150mg per day) and has analgesic effect at normal doses?
Aspirin blocks production of TXA2 so platelets and PGI2 so endothelial cells
Platelets have no nucleus so blocks COX permanently and is irreversible, so new platelets must be formed before TXA2 is produced again
Endothelial cells have a nucleus so between doses of aspirin, COX can resynthesis the PGI2, leading to a change in balance of PGI2 and TXA2, in favour of PGI2
So can only occur at low dose since at normal dose you are permanently blocking platelets and endothelial cells
Side effects of aspirin
GI effects
Tinnitus, dizziness, deafness
Acid-base disturbances
Who should avoid aspirin? (See BNF)
Children, elderly, peptic ulcer, haemophilia, cardiac failure, history of aspirin hypersensitivity, hepatic or renal impairment, pregnancy/breast feeding
Can you take aspirin if you’ve had a heart attack?
Usually patients who have had a heart attack will take 0.5-1 aspirins per day.
What is the benefit of just a COX2 inhibitor like celecoxib?
COX2 is the more important enzyme variant in inflammation that wants to be targeted
So fewer GI side effects since COX1 produces PG in stomach
What is the problem with using COX2 only inhibitors like Celecoxib?
Some people (genetic variation) have endothelial cells which use COX2 instead of in platelets to produce PGI2 (prostacyclin)
Thus drug decreases PGI2 but has no effect on TXA2 (since platelets use COX1), so clotting is promoted
So may cause heart attack
Why is paracetamol preferred to NSAIDs in elderly and children?
No adverse effects on GI tract, acid-base balance, bleeding time or uric acid excretion
What is the adverse effect of paracetamol and why?
Severe liver toxicity from ingestion of >=20 tablets
Overdosing means it gets metabolised by P450 pathway, producing a toxic metabolite killing hepatocytes
Compare paracetamol and ibuprofen for dental pain
Paracetamol is slightly less effective but:
- it does not affect bleeding time
- is less irritant to stomach
- does not interact with warfarin
- is suitable for children
