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CDL301 Cardiovascular Pharmacology > Lecture 17 Platelet Pharmacology > Flashcards

Lecture 17 Platelet Pharmacology Flashcards

1
Q

What is the main target of platelet drugs

A

Arterial thrombosis

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2
Q

What is the problem with targeting thrombosis

A

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

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3
Q

Describe the shape and structure of a platelet

A

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

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4
Q

What is different about the shape of an activated platelet

A

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

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5
Q

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

A

Glycoprotein IIb/IIIa

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6
Q

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

A

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

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7
Q

What is the other name for gp IIb/IIIa

A

Integrin αiibβ3

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8
Q

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

A

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

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9
Q

Give some examples of gp IIb/IIIa antagonists

A

Abciximab Tirofiban Eptifibatide

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10
Q

What are the downsides of gp IIb/IIIa antagonists

A

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

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11
Q

How are gp IIb/IIIa antagonists administered

A

Intravenous

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12
Q

Aspirin is an effective and strong antiplatelet drug T of F

A

F – it is a weak APT

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13
Q

Which two isoforms of its enzyme target does aspirin inhibit

A

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

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14
Q

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

A

COX1 is expressed in platelets and is involved in aggregation

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15
Q

At low doses aspirin selectively inhibits which COX isoform

A

COX1 – higher concentrations inhibit COX2 as well

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16
Q

What is the main role of COX2

A

Inflammation

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17
Q

What is the role of COX

A

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

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18
Q

What is the other name for COX enzymes

A

Prostaglandin H synthases

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19
Q

Describe the subunit composition of COX

A

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

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20
Q

What is the molecular mechanism of action of aspirin

A

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

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21
Q

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

A

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

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22
Q

How long does aspirins effect on platelets last

A

7 to 10 days

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23
Q

What is the specific effect of inhibiting COX1 on platelet function

A

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

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24
Q

What does this data show about the efficacy of aspirin

A

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

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25
Q

What is meant by aspirin resistance

A

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

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26
Q

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

A

F

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27
Q

True aspirin resistance is rate T or F

A

T

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28
Q

Explain the interaction of aspirin with ibuprofen

A

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

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29
Q

Why is aspirin only a weak antiplatelet drug

A

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

30
Q

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

A

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

31
Q

There are three classes of purinergic receptors activated by nucleotides such as ADP and ATP what are they

A

P2Y1 P2Y12 and P2X1

32
Q

Describe the role of P2Y1

A

P2Y1 is a GαQ linked GPCR whose activation leads to the activation of PLC-β. This receptor is responsible for the initiation of platelet aggregation and the subsequent shape change

33
Q

Describe the role of P2Y12

A

P2Y12 is a GαI linked GPCR whose activation leads to the activation of PI3K+ and an inhibition of adenylate cyclase. This receptor is responsible for the amplification/sustenance of platelet aggregation. It is also involved in the amplification of granule release and procoagulant activity

34
Q

Describe the role of P2X1

A

P2X1 is a Ca2+ channel and a weak activator of platelets. It has a minor role in the shape change of the activated platelet as well as an amplification of activation

35
Q

Which nucleotide is the main activator of platelets and which receptor(s) does it act on

A

ADP is the main activator of platelets acting on the P2Y1 and P2Y12 receptors

36
Q

Explain what happens as a result of ADP binding to receptors on the platelet

A

ADP binds to the P2Y1 receptor to activate the platelet. It also binds to the P2Y12 receptor which serves as an amplification step to increase the activation by P2Y1 receptor activation. Activation of these purinergic receptors leads to the upregulation of integrin αIIbβ3. Activation of integrin αIIbβ3 leads to its binding to fibrinogen and cross linking of platelets hence platelet aggregation

37
Q

What is the origin of the ADP responsible for activating platelets

A

ADP comes from the platelet itself where it is stored in dense granules in the cytosol. Hence upon activation of the platelet it degranulates releasing its stored ADP

38
Q

Outline the positive feedback loop that exists in platelet activation

A

ADP released from the activated platelet feeds back to further activate more P2Y1 receptors hence amplifying the activation

39
Q

Explain how the coagulation cascade can interact with platelets to cause activation

A

Thrombin can also activate platelets by binding to the platelet receptors PAR-1 and PAR-4. In addition activated platelets also catalyse the generation of thrombin which feeds back to activate the platelet receptors and cause aggregation

40
Q

Other than ADP what factors can activate platelets

A

Thromboxane A2 binding to the TPα receptor collagen binding to CPVI and 5HT binding to 5HT2A

41
Q

What evidence from knockout mice supports the role of P2Y12 in the activation of platelets

A

P2Y12 knockout mice have a drastically weakened thrombus formation

42
Q

What type of drug is clopidogrel

A

A thienopyridine prodrug

43
Q

Clopidogrel has to be converted to its active metabolite before it can exert its effects on P2Y12. Which enzymes are responsible for this metabolism

A

CYP2C19 and CYP34A

44
Q

How does the active metabolite of clopidogrel interact with the P2Y12 receptor

A

R-130964 binds to and inhibits the P2Y12 receptor via its thiol group (-SH) to prevent activation of platelets

45
Q

Why is clopidogrel in ineffective prodrug

A

Approximately 85% of absorbed clopidogrel is hydrolysed by hepatic carboxylesterase (CES1) to an inactive metabolite

46
Q

The CURE study investigated the effects of clopidogrel plus aspirin compared to aspirin alone in patients with ACS. What were the results of this study

A

Clopidogrel plus aspirin was effective in reducing the incidence of CV death/MI/stroke

47
Q

What does the data below show about the key issue with clopidogrel

A

This data shows that there is massive variation between individuals in their response to clopidogrel. Some patients had a complete inhibition of platelet aggregation whilst in others it had almost no effect

48
Q

Give an example of a drug interaction that changes the response of a patient to clopidogrel

A

CYP2C19 metabolises many other drugs such as proton-pump inhibitors. Omeprazole is often given with aspirin and clopidogrel to counteract the increased risk of gastrointestinal bleeding that is likely with these drugs. However omeprazole has a negative impact on the effect of clopidogrel by impairing its conversion to its active metabolite which in turn decreases the inhibitory effect of clopidogrel on platelet activation

49
Q

Give an example of a drug interaction that increases the responsiveness of a patient to clopidogrel

A

Rifampicin is a drug used for treating tuberculosis that ramps up the response of the liver to clopidogrel. Pretreatment of patients with rifampicin increases clopidogrel active metabolite production (4-fold increase). This leads to a much more effective blockade of P2Y12 receptors which leads to a greater inhibition of platelet aggregation

50
Q

What is the genetic basis for some patients decreased ability to respond to clopidogrel

A

Around a quarter of people have a loss of function allele for the gene CYP2C19 that is involved in the formation of the active metabolite of clopidogrel. The patients often have one of two single nucleotide polymorphisms in the CYP2C19 gene. Homozygotes for the *2/*2 and *3/*3 variant are poor metabolisers of clopidogrel and are unlikely to respond to treatment

51
Q

What is the relationship between CYP2C19 loss of function genotype patients and the risk of complications following PCI

A

Patients with loss of function alleles in CYP2C19 carry a greater risk of thrombosis following stenting

52
Q

How can we measure a patients’ response to clopidogrel

A

The VerifyNow test measures platelet reactivity in response to anti-platelet therapy. This test measures the transmission of light through a blood sample taken from a patient on clopidogrel in order to determine the ability of the blood to coagulate. This can be used to determine whether or not the patient is responding to P2Y12 antagonism

53
Q

Other than genetics and drug interactions what factors influence a patients’ response to clopidogrel

A

Dose age weight disease states including diabetes mellitus and chronic kidney disease

54
Q

Why is clopidogrel less often used now in the clinic

A

The complexity of factors influencing the response to clopidogrel makes the response of each patient impossible to predict accurately

55
Q

Why is prasugrel as more effective thienopyridine drug than clopidogrel

A

The thiol group of prasugrel require for its action on P2Y12 is effectively more protected due to its location in the structure of the molecule. This means that it is less susceptible to degradation by esterases. In fact esterases convert prasugrel to its intermediate prior to conversion to the active metabolite by CYP enzymes.

56
Q

What does the data below show about the response of patients to prasugrel compared to clopidogrel

A

Patients treated with 60mg of prasugrel had a much more consistent inhibition of platelet aggregation than patients treated with clopidogrel

57
Q

Outline the results of the TRITON-TIMI trial that compared the incidence of CV death MI and stroke in patients receiving prasugrel compared to clopidogrel

A

There was a decreased incidence of CV death MI and stroke in patients with prasugrel compared to clopidogrel

58
Q

What is the downside of using prasugrel compared to clopidogrel

A

TRITON-TIMI found that prasugrel did result in an increased incidence of major bleeds life-threatening bleeds and fatal bleeds. Hence due to the significantly increased chance of bleeding prasugrel is often limited to the most high-risk patients of MI stroke etc.

59
Q

What is different about ticagrelor compared to other P2Y12 antagonists

A

Ticagrelor is the first oral reversibly binding platelet P2Y12 antagonist. It is from a different class of drug to clopidogrel and prasugrel and not a prodrug so doesn’t require conversion to an active metabolite. Ticagrelor reversibly binds to a different site on the P2Y12 receptor than the thienopyridines

60
Q

To what class of drugs does ticagrelor belong

A

Ticagrelor is a cyclo-pentyl-triazolo-pyrimidine (CPTP) drug

61
Q

What evidence from mice models supports the efficacy of ticagrelor in prevents platelet aggregation

A

Ticagrelor effectively inhibits platelet aggregation in wild type mice to the levels seen in P2Y12 knockout mice models whose platelets can’t aggregate

62
Q

What is the benefit of ticagrelor over clopidogrel in terms of onset and offset

A

Ticagrelor has a faster onset of effects compared to clopidogrel. In addition the effects of ticagrelor wear off much quicker than clopidogrel. Clopidogrel takes 7-10days for the inhibition to wear off whereas ticagrelor inhibition is alleviated over 72hours.

63
Q

What is the main benefit of ticagrelors faster offset of effects

A

This is advantageous in MI patients who may need to go to surgery for bypass operations as it allows for the increased chance of bleeding associated with the drug to wear off before surgery is conducted

64
Q

The PLATO trial compared aspirin and clopidogrel to aspirin and ticagrelor. What did the results of this trial show on the incidence of CV death/MI/stroke

A

Aspirin + ticagrelor group has decreased incidence of CV death/MI/stroke

65
Q

The PLATO trial compared aspirin and clopidogrel to aspirin and ticagrelor. What did the results of this trial show on the risk of bleeding associated to surgery

A

Bleeding related to bypass surgery was decreased with ticagrelor compared to clopidogrel reflecting the rapid offset of action

66
Q

Ticagrelor is cost effective compared to clopidogrel T or F

A

T – NICE verified its cost-effectiveness

67
Q

What is the first line treatment for STEMI and NSTEMI patients in South Yorkshire

A

DAPT – aspirin + ticagrelor

68
Q

Currently how long are patients on anti-platelet drugs following MI

A

Anti-platelet drugs tend to be used for the first year after a heart attack before the drug is stopped

69
Q

What evidence is there for the long-term use of ticagrelor in preventing thrombotic events

A

Ticagrelor at two different doses on a background of aspirin reduced thrombotic events (CV death/MI/stroke) when given for several years. This was significantly better than placebo for all endpoints

70
Q

What are the current ESC guidelines on the management of ACS

A

Dual antiplatelet therapy (DAPT) is the first line treatment for patients with acute coronary syndromes. This consists of aspirin + ticagrelor or aspirin + prasugrel

CDL301 Cardiovascular Pharmacology (17 decks)

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