Why aspirin acts as antithrombotic at low dose and analgesic at high dose?

Aspirin, a non-sterodal anti-inflammatory drug (NSAID), is used in the treatment of mild to moderate pain, inflammation, and fever.

It is also used as an antiplatelet agent to prevent myocardial infarction, stroke and transient ischemic episodes.

The reason behind why it acts as antithrombotic at small dose and analgesic at high dose is due to its pharmacokinetic profile.

The mechanism behind its analgesic, anti-inflammatory and antipyretic action is inhibition of Prostaglandin (PG) synthesis via inhibiting Cyclooxygenase (COX) enzyme. 

 

Aspirin inhibits COX irreversibly by acetylating one of its serine residues; return of COX activity depends on synthesis of fresh enzyme.

Aspirin also inhibits synthesis of both proaggregatory (TXA2) and antiaggregatory (PGI2) prostanoids, but effect on platelet TXA2 (COX-1 generated) predominates.

Aspirin is highly active; acetylates platelet COX irreversibly in the portal circulation before it is deacetylated by first pass metabolism in liver.

Hence when aspirin is given orally, it will remain unionized in stomach at acidic pH, and absorbed.

The absorbed aspirin will bind to platelet COX enzyme and inhibit the synthesis of Thromboxane A2 before reaching to liver for first-pass metabolism.

The analgesic action is produced after its first-pass metabolism in liver (Due to first-pass metabolism some amount of drug is metabolized hence less amount of drug is available in circulation).

Small doses are therefore able to exert antithrombotic effect for several days.