Lecture 14: Aspirin

Question 1

What are the effects of aspirin?

Answer 1

• Antiplatelet effect
• Analgesic/anti-inflam
• Anti-pyrexia
• Pleiotropic

Question 2

Whats the MoA of Aspirin?

Answer 2

Acetylates COX in cells.

COX1 (prefered) and COX2 inhibitor

COX1 (prevents thromboxane production (platelet activation inhibitor and prevents vasoconstriciton)

COX2 inducible in inflammation

Question 3

How does Aspirin effect platelets and endothelial cells different?

Answer 3

Platelets are anuclear therefore COX inhibition is permanent

Endothelial cells
- Continued prostacyclin production because aspiring inhibits cytoplasmic COX meanwhile nucleus produces prostacyclins & can synthesise new COX1

Question 4

How does Aspirin achieve its pleiotropic effects?

Answer 4

Pleiotropic
- Anti-inflma
- Anti-proliferative
- Anti-tumor

Via PGE/TXA inhibition

Acetylation of proteins
- Transcription factors
- Enzymes
- Genes
- Dec. cytokines, O2 radicles/growth factors

Question 5

What is the pharmacokinetics of aspirin?

Answer 5

Absorption:
- Gastric mucosa
- 70% reaches circulation.
- T1/2 13-19mins

Metabolism (Cholinesterases)
- Intracellular and liver

Excretion
- Renal (Salicylate)

Question 6

Whats the dosing regime for antiplatelet effect?

Answer 6

Oral loading dose (300mg)

Maintained 1dx 100mg

Relatively low doses because COX1 inhibition is saturable

Question 7

What are the anti-platelet indications for aspirin?

Answer 7

• Anti-platelet effect
• Secondary prevention of arterial disease
  -> Acute MI (Stemi vs non-stemi)
  -> TIA or stroke acutely
  -> Peripheral vascular disease

No good evidence for primary prevention.

Question 8

What are the non-platelet indications for aspirin?

Answer 8

Higher doses required

Anti-pyrexia (Cox inib = Dec. PGE)

Anti-inflam
- COX2 inhibition in inflam cells. need much higher doses since its COX1 preference.

Question 9

What are the adverse effects of aspirin?

Answer 9

Bleeding

Hypersensitivity / bronchospasm (COX1 can lead to enhanced leukotriene production and bronchoconstriction)

Upper GI effects; Dyspepsia, ulcer, heamorrhage

Question 10

What can lead to aspirin resistance?

Answer 10

• Recurrent thrombotic vascular events despite aspirin

Multifactorial
- Dec. absoprtion/ increased metabolism
- TXA2 biosynthesis indep. of aspirin
- Other platelet activators
- Adherance

Question 11

What are some other anti-platelet agents to be aware of?

Answer 11

Clopidogrel
Ticagrelor

Question 12

How does clopidogrel work?

Answer 12

P2Y12 inhibitor (Inhibits ADP platelet activation)
- Irreversible inhibitor

Question 13

What did the cure study find?

Answer 13

Clop and asp. combo best for reducing events BUT increased risk of heamorrhage

Question 14

What are the clopidogrel PK?

Answer 14

• Oral drug
• Loading dose (steady state 4-24hrs)
• Prodrug therefore requires liver activation, CYP450.

Question 15

What is clopidogrel used for?

Answer 15

CAD
Cerebrovascular disease
Aspirin ‘alternative’ / aspirin ‘resistant’

Question 16

What are the adverse effects of clopidogrel?

Answer 16

Bleeding
- GI
- Intracranial

Dyspepsia
- Less so than aspirin

Question 17

How does ticagrelor act?

Answer 17

• P2Y12 inhibitor also but reversible, non competitive

Question 18

What did the plato study find?

Answer 18

Asp+Clopidogrel is better in stable disease

Asp+Ticagrelor better in acute coronary syndromes

Question 19

Whats the PK of ticagrelor?

Answer 19

Oral
- Loading dose and twice daily maintainence
- Rapid absorption
- Not a prodrug
- Metabolized in liver and minimal renal excretion

Question 20

What are the adverse effects of ticagrelor?

Answer 20

• Bleeding
• Dyspnoea (self limiting but can persist)
• Pauses/bradycardic events (delayed adenosine metabolism, issues at AV node)

Question 21

Whats the recommendation for anti-platelet combination therapy?

Answer 21

Guidelines vary

Elective surgery: Aspirin + Clopdiogrel (3-6 months)

ACS: Aspirin + Ticagrelor (12 months)