CLOPIDOGREL

Mechanism of action

Here's a video (5m 9s) outlining how clopidogrel works as an antiplatelet and an explanation of why we give antiplatelet drugs in the first place.

Platelet plug formation and the role of ADP

1. When the vascular endothelium is damaged, collagen and von Willebrand factor (vWF) are exposed to the blood plasma.

2. Platelets circulating in blood plasma bind to collagen and vWF and the platelets become activated.

3. These activated platelets are ones which have changed shape (or conformation) and release dense granular bodies containing serotonin, thromboxane A2 and adenosine diphosphate (ADP).

4. The released ADP binds to ADP receptors on other platelets (which are circulating in the plasma and have yet to become activated).

5. This ADP receptor-binding causes platelets to become activated (thus releasing more dense bodies which further enhances platelet aggregation). When these platelets become activated, their conformation changes and that leads to the expression of receptors (GP IIb/IIIa) on their cell surface membrane which are structurally important in allowing platelets to bind together, using fibrinogen, in order to form the platelet plug.

In summary, adenosine diphosphate (ADP)...

is stored in platelets in dense bodies which are exocytosed following platelet activation.
binds to ADP receptors causing further release of dense bodies (containing ADP, TXA2 and serotonin) and expression of GP receptors - these are important in establishing fibrinogen-mediated cross-links between platelets (i.e. platelet aggregation).

ADP is released by activated platelets. It binds to ADP receptors on inactivated platelets causing their activation.

ADP receptor binding facilitates platelet activation and subsequent aggregation

Clopidogrel is a prodrug

Clopidogrel is a prodrug and is converted into its active form in the liver via CYP2C19 - part of the cytochrome P450 family of enzymes.
Their is variation in the level of antiplatelet response that patients have to clopidogrel and this may be due to polymorphic variations in their version of CYP2C19.
Omeprazole (a proton pump inhibitor) impairs CYP2C19 function, so the effects of clopidogrel may be reduced in patients taking omeprazole.

Clopidogrel is converted into its active form in the liver

Clopidogrel inhibits platelet activation and aggregation

After clopidogrel has been metabolised, the active metabolite then irreversibly binds to a part of the ADP receptor called P2Y12.
This inhibits the binding of ADP to the receptor and therefore clopidogrel reduces platelet aggregation.
Because it irreversibly binds to the receptor, the anti-platelet effects last ~7-10 days (the lifespan of platelet), until new platelets are regenerated.

The active metabolite of clopidogrel inhibits the ADP receptor on platelets

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