Antiplatelets Flashcards
When are haemostasis promotion drugs used?
If a patient has:
Haemophilia
Extensive anticoagulation therapy
Haemorrhage after surgery
Menorrhagia (v.heavy period)
What do platelets do?
Maintain integrity of circulation and make thrombois and thrombi
-Essential for haemostasis, healing of vessels and inflammation
What properties do platelets have?
-Adhesion following vascular damage
-Shape change
-Secretion of granule contents
-Biosynthesis of PAF and prostaglandins
-Aggregation**
-Exposure of acidic phospholipid on surface to promote aggregation
What are the mechanism’s of platelet adhesion, activation and secretion?
1) Only activated in blood when damage occurs.
2) The endothelial dies, matrix is then exposed, platelet binds to collagen receptors
3) Soluble Thromboxane A2, stimulates platelets
4) Aggregation activates fibrin,
5) Change of shape and the cytoskeleton changes the platelet
What causes bleeding to stop by blocking the blood vessel?
Platelet plug, when contracting this further blocks the blood vessel.
What can we inhibit to influence platelet aggregation?
INHIBITING - Thromboxane A2 and ADP, this stops the cells from aggregating, limiting NO + p.
-Removing ADP means less activation of platelets
What can we stimulate to influence platelet aggregation?
STIMULATING - Prostacyclin and Nitric oxide
-NO production is short lived, increasing prostacyclin formation inhibits platelets
What activates platelets?
ADP
TXA2
Collagen
Fibrinogen
What is the aim of antiplatelet drugs?
To decrease platelet aggregation and inhibit thrombus formation in arterial circulation.
What are some examples of antiplatelets?
Aspirin
Thienopyridines - Clopidogrel (prasugrel/ticlopidine)
Ticagrelor
Glycoprotein IIb/IIIa inhibitors - Eptifibatide/Tirofiban/Abciximab
Dipyridamole
What is Aspirin used for?
NSAID
Antiplatelet
Colonic and rectal cancer
Alzheimer’s disease
Radiation induced diarrhoea
What is the MOA of aspirin?
*Irreversibly inactivates COX 1 & 2
Where is COX 1 located?
In platelets
Where is COX 2 located?
Endothelial cells
What is the function of COX 2?
Make prostacyclin, inhibit platelet activation and aggregation
What is the function of COX 1?
Synthesises of A2 –> Platelet stimulation
What does aspirin do to COX 1?
Irreversibly inactivates cox 1 in platelets
-reducing thromboxane A2
-reducing platelet aggregation
What does aspirin do to cox 2?
Irreversible inactivates COX 2 in endothelium
-reduces prostacyclin formation
-Increases platelet aggregation
Although aspirin acts on both cox 1 and cox 2 in different ways, this has a net effect zero, so how does it work?
Because, endothelial cells can synthesise new COX-2, as fresh RNA/protein and more COX2/prostacyclin is made. Platelets cannot because they have no nuclei - meaning no thromboxane A2 is made and stores are low.
Meaning: Lower does just inhibit platelets and Higher doses inhibit both
What effect does a lower dose of antiplatelets have?
Inhibits platelets only
What effect do higher doses of antiplatelet have?
Inhibit platelets and synthesis of new COX 2 is promoted.
Can you take a Thienopyridine (clopidogrel/prasugrel) with aspirin?
Yes, they act on a different pathway.
What do Thienopyridines work on?
Pro-Drugs
-Inhibit ADP-induced aggregation (ADP receptor antagonists) - block ADP binding to receptors, inhibit platelet activation
-Also antagonise the platelet P2Y12 receptor (Purinergic receptor)
What is the role of ADP in platelet aggregation?
Platelet primary and secondary aggregation.
Induces platelet shape, secretion from storage granules, influx and intracellular mobilisation of calcium and inhibition of stimulated adenylyl cyclase activity.
What is the role of the P2Y12 receptor?
Plays a central role in platelet function, haemostasis and thrombosis.
What type of drug is Ticagrelor?
Nucleoside analogue - like adenosine
How does Ticagrelor work?
Blocks P2Y12 ADP receptors on platelets,
How is Ticagrelor a allosteric inhibitor?
It has a different binding site than ADP and the blockage is reversible and therefore acts faster and for a shorter period of time.
What drug has had a PLATO trial, showing less mortality from all CV causes than another drug?
Ticagrelor causes less mortality than clopidogrel
How do Glycoprotein IIB/IIIA receptor antagonists work?
They stop aggregation causing reduced platelets
-These inhibit ALL pathways of platelet activation because they bind to glycoproteins IIb/IIIA receptors, which blocks fibrinogen binding so inhibits aggregation.
What is an example of a glycoprotein IIB/IIIA receptor antagonist? - monoclonal antibody
Abciximab - monoclonal antibody
-Only used ONCE - this is £260!
-Used with heparin and aspirin for prevention of complications in pts undergoing percutaneous coronary intervention
What cyclic peptides are glycoprotein IIB/IIIA receptor antagonists?
Eptifibatide and Tirofiban
-Adjunct with heparin and aspirin to prevent early MI in pts with unstable angina or NSTEMI
