Antiplatelets Flashcards
What are the dangers of blood clotting in CVD?
Atherosclerotic plaque rupture and thrombosis in coronary arteries - leading to NSTEMI and STEMI…
Atrial fibrillation can lead to thromboembolism - stasis of blood in atria forms blood clot.
= Ischaemic stroke/Transient Ischaemic attack…
= Deep Vein Thrombosis is a major risk for pulmonary embolism…
What is the general process of platelet activation?
Endothelial cell damage causes exposure of collagen + release of vWF.
vWF bridges subendothelial collagen and platelet glycoprotein GP1b receptors.
Activation:
Granular secretion - Dense granules = ADP, ATP, Ca2+, 5HT, Histamine.
Alpha granules - IGF-1, PDGF, coagulation factors.
Synthesis + release of Thromboxane A2 and Platelet-activating factor (PAF).
Shape changes and to spheres with protruding pseudopodia + AGGREGATION requires activation of BOTH P2Y1 and P2Y12 receptors by ADP (released by Dense granules of activated platelets)….
P2Y1 activated on their own causes shape changes…
What causes platelet aggregation?
Shape changes and to spheres with protruding pseudopodia + AGGREGATION requires activation of BOTH P2Y1 and P2Y12 receptors by ADP (released by Dense granules of activated platelets)….
P2Y1 activated on their own causes shape changes…
Activated platelets release Dense granules containing ADP, 5HT and actively secrete Thromboxane A2 and PAF.
= conformation change by ADP activating platelets into active GPIIb/IIIa receptor complex to bind FIBRINOGEN!!!
Fibrinogen aggregates activated platelets…
Acidic phospholipid exposure leads to adhesion of prothrombin and Factor Xa on platelet surface, with thrombin and fibrin formation.
What is the MoA of aspirin?
Aspirin irreversibly inhibits COX-1 in ENDOTHELIAL AND PLATELETS!!! through acetylation of serine residues.
Platelets have no nucleus - so cannot replace inhibited COX-1 = platelets turned over every 7-10 days..
BUT
Endothelial cells can re-synthesise COX-1 = overcome this effect.
This leads to decreased PGI2 synthesis in endothelial cells.
PGI2 is secreted and has negative feedback role on platelet expression of GPIIb/IIIa receptors, so reduces platelet aggregation = Aspirin reduces PGI2… so actually has this anti-thrombotic effect.
BUT main effect of aspirin is on PLATELETS since they cannot re-make COX-1….
= Reduced PGG2/PGH2 production leads to reduce Thromboxane A2 synthesis.
= Less TxA2 = reduces expression of GPIIb/IIIa on platelets required for binding fibrinogen…. and reduces platelet aggregation.
What are the roles of P2Y12 receptors in platelets?
Shape changes and to spheres with protruding pseudopodia + AGGREGATION requires activation of BOTH P2Y1 and P2Y12 receptors by ADP (released by Dense granules of activated platelets)….
P2Y1 activated on their own causes shape changes…
P2Y12 activation is essential to platelet aggregation - signal transduction leads to activation of fibrinogen receptors (GPIIb/IIIa).
P2Y12 receptors also stabilise activated receptors on platelets - TP (TxA2), PARs (thrombin) and P2Y1 (ADP, shape change).
AND Inhibit anti-thrombotic effects of Prostacyclin I2 - Prostacylcin I2 receptors inhibit platelet aggregation.
What are the P2Y12 receptor inhibitors?
Irreversible, pro drug antagonists to P2Y12 receptors:
Clopidogrel and Prasugrel = -grel = irreversible P2Y12 inhibitors.
Direct acting, Reversible antagonist to P2Y12 = Cangrelor and Ticagrelor
What are the pros and cons of the Irreversible, pro drug inhibitors of P2Y12?
MOA?
Irreversible, pro drug forms are Clopidogrel and Prasugrel.
= 1st gen = Clopidogrel - Has long onset of action + metabolised into active form by CYP…. so can have complications with other drugs and polymorphisms.
2nd gen = Prasugrel = less dependence on CYP metabolism = faster onset of action and less complications…
Forms disulphide bonds with cysteine residues in P2Y12. = Irreversible
What are the reversible, direct acting P2Y12 antagonists?
Ticragelor = reversible allosteric inhibitor.
Active metabolite, CYP metabolism = DONT USE WITH DILTIAZAM/VERAPAMIL/IVABRADINE
Cangrelor = ATP analogue = reversible, competitive .
= Rapid action short duration.
What are the Glycoprotein IIb/IIIa receptor inhibitors?
Inhibit platelet aggregation by blocking fibrinogen binding to GPIIb/IIIa receptors in activated platelets.
ABCIXIMAB - long-acting chimeric mAB = short plasma half life.
EPTIFIBATIDE - Shorter lasting effects - reversible inhibitor.
TIROFIBAN - Competitive reversible high affinity inhibitor, rapid on-off rate…
What is Dipyramidole?
PDE inhibitor.
PDE degrades cGMP and cAMP.
Increases cAMP in platelets and increases cGMP in vascular SM.
= cAMP stimulates PGI2 and inhibits TxA2 synthesis in platelets = prevent activation.
= cGMP stimulates vasodilation.
Dipyramidole also inhibits adenosine uptake by platelets, endothelial + vascular SM.
= Adenosine activates A2A and A2B receptors, which are Gs coupled…
= further inhibits aggregation.
= Vasodilation and platelet aggregation inhibition.
How can stable angina be treated and ACS prevented?
Low daily dose of aspirin or Clopidogrel (Irrversible P2Y12 antagonist)
How to treat NSTEMI and STEMI?
+ Secondary prevention?
high daily dose aspirin
Plus P2Y12 inhibitor + Tirofiban (GPIIb/IIIa inhibitor) + Heparin (anti-coagulant).
= Clopidrogrel/Prasugrel + Tirofiban + Heparin.
Low dose aspirin with clopidrogel/prasugrel…
How can these drugs be used for PCI surgery?
During angioplasty/removal of clot = Use aspirin and short term GPIIb/IIIa = Cangrelor.
Cangrelor + aspirin + Heparin….
What are the side effects of antiplatelets?
With aspirin:
GI bleeding, Bronchospasm, Hypersensitivity.
thrombocytopenia (from low platelets)…. ABCIXIMAB!
Clopidogrel = CYP metabolised = complications with Diltiazam and Verapamil…
Causes rashes and Dyspepsia/Diarrhoea…
TICLODIPINE = IRREVERSIBLE P2Y12 inhibitor = Obselete because causes neutropenia = neutrophil depletion.
What is TTP?
Thrombotic Thrombocytopenia Purpura:
Blood clots in vessel under the skin with lower platelets in the blood - causing subcutaenous bleeding + bruisiing…
Can be inheritetd by ADAMTS13 gene - ADAMTS13 enzyme degrades vWF.
OR Drug induced:
= TICLODIPINE, CLOPIDOGREL AND PRASUGREL!!!! = Irrerversible, pro drug P2Y12 inhibitors…
