Aspirin

Question 1

Aspirin

Answer 1

• good antithrombotic
• effective
• doesn’t stop clotting (safe)
• appropriate half-life (approx 1 day)
• good oral bioavailability
• easily reversible if side effects occur
• not affected by polymorphisms
• cheap
• no interactions with other drugs

Question 2

Structure of aspirin

Answer 2

• salicyclic acid = found in white willow
  -aspirin = acetylsalicyclic acid

Question 3

Aspirin for anti-fever

Answer 3

• originally marketed for anti-fever
• and as not affecting the heart!
• aspergum for pain relief resulted in excessive bleeding at the site of a tonsilectomy
• aspirin shown to decrease the risk of heart attacks - better for people who at risk or who have already had one
• 1/4 of dose for anti-fever is used

Question 4

History of aspirin

Answer 4

• multiple trials with little significant results
• thought aspirin may mask pain so more likely to die of a heart attack - wrong
• meta-analysis revealed statistically significant results
• ISIS-2 large scale study

Question 5

ISIS-2 large scale study

Answer 5

• aspirin vs aspirin + streptokinase
• greater benefit when used together
• aspirin especially beneficial when used in first month after a myocardial infarction
• relative risk decrease but absolute decrease only by a couple of percentage (not a life-saver!)

Question 6

Mechanism of action

Answer 6

• inhibits COX1 and likely COX2
• prevents thromboxane A2 synthesis

Question 7

Is aspirin platelet-specific?

Answer 7

• permanently inhibits COX
• platelets cannot create more COX
• but endothelial cells can
• so makes it platelet specific
• but do endothelial cells make more COX?
• how do they know to?

other methods of platelet specificity:
- irreversible acetylation
- metabolism
- different enzymes - platelets through portal circulation so more contact with aspirin

Question 8

Aspirin response variation

Answer 8

• loss of 1st pass metabolism due to plasma esterases
• patient compliance
• PK genetic variation
• competition with other NSAIDs for COX active site
• other activators of platelet aggregation

Question 9

Safety of aspirin

Answer 9

• COX2 inhibitors are prothrombotic
• rofecoxib withdrawn in 2004
• celecoxib has a black box warning as can increase the risk in already at-risk patients

all reversible NSAIDs increase risk
- when used more consistantly
- major increase in CV risk
- may be the irreversible effects of aspirin mean that the antithrombotic effects outweigh the prothrombotic effects?