L14 Aspirin

Question 1

What is the target action of Aspirin

Answer 1

Irreversibly acetylates (inhibits)
COX1 >> COX2: 

This prevents Arachidonic acid being made into

• Prostaglandins: gastric mucus
• Prostacyclins: vasodilator
• Thromboxane: platelet activator, aggregator, vasoconstrictor

Question 2

What are the two enzymes that aspirin works on , compare their site and presence

(also acetylates random tf, enzymes, genes, cytokines, ROS, gf

Answer 2

COX1 is in most tissues: platelets (activator/aggregator), stomach (mucus), kidney (blood flow)

It is constitutive

COX2 in certain organs, increased by WBC

It is inducible

Question 3

What are the 4 effects of Aspirin and how does it come about

Answer 3

1. Antiplatelet:
   - inhibits TxA2 synthesis in platelets for the life of the platelet as they are anuclear

• inhibits endothelial cells too but are nuclear so make new COX1 –> vasodilation from prostacyclins.
  2. Analgesia/anti-inflammatory: needs higher doses to inhibit COX2 in inflam cells
  3. Anti-pyrexia: reduce PGE (pyretic agent)
  4. Anti tumour: Reduce PGE2 and TxA2 which help angiogenesis, proliferation, metastasis, immune escape.

Question 4

What is the absorption, metabolism, excretion and dose (for antiplatelet effect) of Aspirin

Answer 4

1. Readily absorbed - loading dose is tablet 300mg- rapid inhib of all circulating platelets
2. Metabolised to two components by cholinesterases in liver and RBC
3. Salicylate excreted by kidneys
4. Dose is 50-100 mg daily: COX-1 inhib saturable so greater doses have no greater effect - only more SE.

Question 5

What conditions does Aspirin treat.

What factors can lead to aspirin resistance (recurrent thrombotic vascular events despite aspirin)

Answer 5

Secondary prevention of arterial diseases –> improves mortality

• Acute MI + long term
• Acute stroke/TIA + long term
• Peripheral disease

(not 1’ treatment)

Resistance causes?

• individual variation in absorption/metabolism
• TXA2 biosynthesis independent of aspirin
• other platelet activators
• Adherence

Question 6

What are the adverse effects for Aspirin

Answer 6

1. Intracranial/extracranial Bleeding
2. Hypersensitivity/bronchospasm (AA shunted leukotriene pathway)
3. Upper GI effects: dyspepsia/ulcer/haemorrhage
   due to COX1 inhib in gastric mucosa + antiplatelet.

Question 7

Compare the mech of action, time to action, metabolism of Clopidogrel and Ticagrelor

(both oral)

Answer 7

1.Mech of action: Both inhibit P2Y12 - stopping ADP platelet activation
C: Irreversible
T: Reversible, non competitive

2. time to action
   T faster than C
3. Metabolism
   C: prodrug: needing liver metabolism by CYP450-2C19. In theory this is blocked by omeprazole

T: not a prodrug; liver metabolised CYP450 with minimal renal clearance

Question 8

Compare the adverse effects of Clopidegrel and Ticagrelor

Answer 8

1.AE
Both:
-GI and intracranial bleeding

C:
-Dyspepsia

T: prevents re-uptake of ADP into RBC so circulating conc increases

• Self limiting Dyspnoea (ADP=bronchoconstrictor)
• Pauses/bradycardic events (ADP on SA, AV node slows conduction)

Question 9

Compare the uses of Clopidogrel and Ticagrelor in single and combo therapy (synergistic with aspirin)

Answer 9

Uses
C: 
-Coronary artery disease
-Cerebrovascular disease
-Aspirin alternative for resistant
- Combo w Aspirin for 3-6 month post Elective stent 
- 3wks for minor stroke/high risk TIA

T:
-Combo w Aspirin for Post acute coronary syndrome (more effective than C) 12 months

Question 10

What determines the duration of combo therapy

-Aspirin is kept for a long time

Answer 10

Care has to be taken in conjunction with anticoagulants/long term

Its the trade off between increased bleeding risk vs vascular efficacy

Time post stent put in allows endothelial migration to cover prothrombotic metallic surface