Lecture 17 Platelet Pharmacology Flashcards Preview

CDL301 Cardiovascular Pharmacology > Lecture 17 Platelet Pharmacology > Flashcards

Flashcards in Lecture 17 Platelet Pharmacology Deck (70)
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What is the main target of platelet drugs

Arterial thrombosis


What is the problem with targeting thrombosis

Blood clots that stop bleeding are essential for life yet thrombus formation is a problem


Describe the shape and structure of a platelet

Platelets are much smaller than red and white blood cells. They are flat but with channels that increase their surface area


What is different about the shape of an activated platelet

Upon activation there is a change in the shape of the platelet which transitions from smooth and discoid to spiculated and with pseudopodia. This increases the surface area of the platelet and also increases the efficiency with which they interact


Which receptor on the surface of the platelets binds to fibrinogen to trigger aggregation

Glycoprotein IIb/IIIa


What can be said about the number of receptors that trigger aggregation in response to platelet activation. What is the effect of this on the platelet

At rest there are 50000 to 100000 copies of the receptor on each resting platelet however following platelet activation there is an upregulation of glycoprotein IIb/IIIa receptors. This results in an increased affinity of the receptor for fibrinogen which acts to link the receptors on several platelets together causing aggregation


What is the other name for gp IIb/IIIa

Integrin αiibβ3


How can the gp IIb/IIIa receptor be used as a therapeutic target

Antagonists of gp IIb/IIIa can be used therapeutically to stop clot formation


Give some examples of gp IIb/IIIa antagonists

Abciximab Tirofiban Eptifibatide


What are the downsides of gp IIb/IIIa antagonists

They have a narrow therapeutic window as they aren’t effective at low doses and high doses cause to greater risk of bleeding. The increased risk of major bleeding actually offsets their benefit in reducing ischaemic events


How are gp IIb/IIIa antagonists administered



Aspirin is an effective and strong antiplatelet drug T of F

F – it is a weak APT


Which two isoforms of its enzyme target does aspirin inhibit

Constitutive COX1 (housekeeping gene) and inducible COX2 (inflammatory gene)


Which COX isoform is important for aspirins action as an antiplatelet drug

COX1 is expressed in platelets and is involved in aggregation


At low doses aspirin selectively inhibits which COX isoform

COX1 – higher concentrations inhibit COX2 as well


What is the main role of COX2



What is the role of COX

Phospholipids are metabolised by phospholipase A2 to arachidonic acid. Arachidonic acid is then metabolised by COX to produce prostaglandins H


What is the other name for COX enzymes

Prostaglandin H synthases


Describe the subunit composition of COX

COX is made up of two identical subunits each with two catalytic sites; a peroxidase site and a cyclooxygenase site


What is the molecular mechanism of action of aspirin

The acetyl group from aspirin forms a covalent bond with a serine residue in the COX enzyme. This prevents the arachidonic acid that was made at the plasma membrane from entering the COX channel and reaching the cyclooxygenase site


What is meant when aspirin is referred to as a suicide inhibitor

Because it forms a covalent bond aspirin binds permanently to the enzyme and hence the duration of aspirin’s effects depends on ability of the body to synthesise new COX enzymes. In the case of platelets which have no nucleus this isn’t possible and hence aspirin lasts for the lifetime of the platelet itself


How long does aspirins effect on platelets last

7 to 10 days


What is the specific effect of inhibiting COX1 on platelet function

By preventing the conversion of arachidonic acid to prostaglandin H aspirin blocks the pathway that leads to platelet thromboxane A2 release. Thromboxane A2 activates platelets via binding to the TPα surface receptor


What does this data show about the efficacy of aspirin

This data shows that aspirin reduced the number of vascular deaths compared to placebo. This reduction in vascular mortality was comparable to the clotbuster drug streptokinase


What is meant by aspirin resistance

The continued secretion of thromboxane A2 by platelets in response to appropriate agonist stimulation (such as arachidonic acid and collagen) despite therapy with aspirin at a standard dose


High platelet reactivity despite aspirin therapy signifies aspirin resistance T or F



True aspirin resistance is rate T or F



Explain the interaction of aspirin with ibuprofen

Unlike aspirin ibuprofen reversibly binds to the COX1 enzyme. Therefore if ibuprofen is taken before an aspirin the inhibition of COX1 activity (TxB2 levels) is lessened. This is because aspirin is metabolised within hours so by the time its able to exert its effect and displace ibuprofen its begun to be metabolised. Hence this is a negative interaction that decreases the efficacy of aspirin


Why is aspirin only a weak antiplatelet drug

Overall aspirin has excellent efficacy in inhibiting platelet thromboxane A2 release but this process plays a limited role in platelet reactivity


What is the most effective target in the treatment of arterial thrombosis

Most effective treatment is targeting the P2Y purinergic receptor on the platelet