Lecture 7 - Clopidogrel

Question 1

What is the name for the process by which platelets are formed?
Describe this process

Answer 1

Thrombopoiesis
Polynucleate megakaryocytes explode into hundreds of platelets
Takes place in the bone marrow

Question 2

Describe the contents of platelets

Answer 2

No nucleus
Mitochondria
Dense granules
Alpha granules
Lots of cell surface receptors

Question 3

What is the contents of dense granules?

Answer 3

ATP
Phospholipids
Triglycerides
Cholesterol
ADP
Serotonin

Question 4

What is the function of platelets?

Answer 4

Adherence: to site of blood vessel damage
Activation: Change shape to plug the hole
Release granule contents to attract more platelets
Aggregation: with each other

Question 5

What is the contents of alpha granules?

Answer 5

Coagulation factors
Platelet derived growth factor
Vascular endothelial growth factor

Question 6

What is the term for high blood concentration of platelets?

Possible causes of this and consequences

Answer 6

Thrombocytosis
Caused by splenectomy, myloproliferative disorders such as CML
Leads to increase risk of thrombosis, stroke and myocardial infarction

Question 7

What is the term for low blood concentration of platelets?

Possible causes of this and consequences

Answer 7

Thrombocytopenia
Caused by bone marrow suppression, leukaemia, septicaemia
Leads to increased risk of bleeding

Question 8

What is the function of the spleen?

What is splenomegaly and a splenectomy?

Answer 8

Removal/recycling of blood cells, including platelets
Splenomegaly = abnormally enlarged spleen
Splenectomy = surgical removal of spleen

Question 9

What are the 3 most important platelet cell surface receptors for adherence/activation and aggregation?

Answer 9

GPIb
GPVI
Alpha-2-b-beta-3

Question 10

Describe the process of platelet adherence

Answer 10

Damage to blood vessel endothelium exposes collagen
Circulating von willebrand factor adheres to collagen
VW factor binds GPIb receptors on platelets, to induce transient tethering

Question 11

What is the role of GPVI?

Answer 11

Tethered platelets roll along the endothelium

GPVI stabilises binding of the platelet to the blood vessel

Question 12

What is the role of Alpha-2-b-beta-3?

Answer 12

Binds to fibrinogen

Allows fibrinogen to acts as a bridge between platelets, leading to aggregation

Question 13

Which two signalling molecules are key to recruiting more platelets for aggregation?

Answer 13

ADP

Thromboxane (TXA2)

Question 14

How does ADP initiate platelet aggregation?

Answer 14

Binds to P2Y1 and P2Y12 receptors on other platelets
P2Y1 initiates aggregation
P2Y12 allows for changes in the cytoskeleton that stabilises aggregation

Question 15

What type of receptors are P2Y1 and P2Y12? What are they coupled to?

Answer 15

Both GPCRs
P2Y1 = Gq
P2Y12 = Gi

Question 16

What is clopidogrel?

Answer 16

Oral antiplatelet
Used to treat vascular diseases
Inhibits the P2Y12 receptor

Question 17

Describe the metabolism of clopidogrel

Answer 17

Prodrug
Metabolised by CYP2C19 enzymes
15% active metabolites
85% inactive metabolites

Question 18

Name 4 limitations of clopidogrel

Answer 18

1. Since it requires hepatic metabolism, not effective in those with reduce liver function
2. Variability in CYP2C19 enzymes means different responses
3. Reliance of hepatic processing facilitates development of resistance
4. Therapeutic dose difficult to determine due to slow onset, interactions with other drugs

Question 19

Name another, new type of ADP receptor inhibitor and explain why it is better

Answer 19

Prasugrel
Simpler metabolism, less can go wrong
Faster action
Less resistance