Antiplatelets and Fibrinolytics

Question 1

Compare arterial and venous thrombi in terms of fibrin and platelet count

Answer 1

Arterial (at site of atherosclerotic plaque);

• Low fibrin content
• High platelet content

Venous (stasis of blood);

• High fibrin content (and RBC)
• Low platelet content

Question 2

Describe what happens at a healthy endothelium with regards to platelet aggregation

Answer 2

• PGI2/ Prostacyclin produced by endothelial cells
• PGI2 binds to platelet receptors causing an increase in cAMP
• cAMP inhibits the release of sequestered Ca into platelet’s cytosol, thus reducing platelet aggregation

Question 3

How does PGI2 affect GP IIb/ IIIa receptors?

Answer 3

Stabilises them

Question 4

Platelet adhesion-> platelet activation-> platelet aggregation-> platelet plug

What causes platelet adhesion

Answer 4

Exposure of blood to sub-endothelial factors (Collagen, VWF)

Question 5

Describe platelet activation and aggregation

Answer 5

• Platelets adhere to each other, activate and change shape causing the release of granules (ADP, Thromboxane A2, Thrombin, Platelet Activation factor)
• These act via their respective receptors to increase cytosolic Ca and promote further granule release
• Granules also activate GPIIb/IIIa receptors using fibrinogen, forming bonds between platelets

Question 6

What drugs are used to treat;

• Platelet rich arterial thrombi
• Low platelet venous thrombi

Answer 6

Arterial- Antiplatelet and Fibrinolytic drugs
Venous- Anticoagulants (parental and oral)

(Can use a combination e.g in secondary prevention)

Question 7

What colour are arterial and venous thrombi?

Answer 7

Arterial- White

Venous- Red

Question 8

What is the most potent platelet aggregator factor?

Answer 8

Thromboxane A2 (TXA2)

Question 9

List 4 antiplatelet drug classes

Answer 9

• Cyclo-oxygenase inhibitors
• ADP receptor antagonists
• Phosphodiesterase inhibitors
• GPIIb/IIIa inhibitors

Question 12

Is aspirin reversible?

Do we use low or high doses for antiplatelet effects?

Answer 12

No

Low doses (High for analgesic effects)

Question 13

Higher doses of Aspirin inhibit endothelial PGI2

Describe its absorption and metabolism

Answer 13

Absorbed by passive diffusion, metabolised in liver into Salicylic acid

Question 14

List 4 ADRs of Aspirin

Answer 14

• GI Irritation
• GI Bleeding (peptic ulcer)
• Haemorrhage (stroke)
• Hypersensitivity

Question 15

List 3 contraindications of Aspirin

Answer 15

• Reye’s Syndrome (can cause liver and brain damage)
• Hypersensitivity
• Trimester 3 pregnancy (premature DA closure)

Question 16

List important DDIs of aspirin

Answer 16

Caution with other antiplatelets and anticoagulants

Question 17

Why may aspirin have a lack of efficacy in some patients?

Answer 17

Due to COX1 polymorphism in individuals

Question 18

Why does Aspirin not completely inhibit platelet aggregation?

Why does aspirin’s antiplatelet effects last for the entire lifespan of the platelet? (7-10 days)

Answer 18

• Half life of only 20 min, rapidly metabolised-> Salicylic acid (no effect on COX)
• Platelets cannot generate new COX

Question 19

What aspirin course would you give to patients;

• With a STEMI/ NSTEMI
• With acute ischaemic stroke

Answer 19

NSTEMI/ STEMI: One loading dose of 300mg

Acute ischaemic stroke: 300mg daily for 2 weeks

Question 20

Why can Aspirin irritate the stomach?

How is this covered against when prescribing long term use of aspirin?

Answer 20

• Inhibit COX1 in gastric mucosa-> Reduced prostaglandin production
• Provide gastric protection (e.g a Proton pump inhibitor)

Question 21

Clopidogrel, Prasugrel and Ticagrelor are all a member of what class of drugs?

How do these work?

Answer 21

• ADP receptor antagonists

- Inhibit ADP binding to P2Y12 receptor-> Inhibit activation of GPIIb/IIIa receptors-> Inhibit platelet aggregation

Question 22

List 2 common features of Clopidogrel and Prasugrel

Answer 22

• Are both Prodrugs

- Are both irreversible P2Y12 inhibitors

Question 23

Compare Clopidogrel, Prasugrel and Ticagrelor with regards to onset of action

Answer 23

Clopidogrel- Slow onset of action, unless initial loading dose given

Prasugrel & Ticagelor- Rapid onset of action

Question 24

List 2 features of Ticagrelor that are distinguish it from Clopidogrel and Prasugrel

Answer 24

• Is active itself AND has active metabolites

- Reversible action (at a different site to Clopidogrel)

Question 25

List 3 ADRs of ADP Receptor Antagonists

State 3 contraindications of these drugs

Answer 25

• GI bleeding
• GI Upset (Dyspepsia + diarrhoea)
• Rarely, thrombocytopenia

Caution in patients;

• at high risk of bleeding
• with renal and hepatic impairment
• using other antiplatelets/ anticoagulants

Question 26

List important DDIs of ADP receptor antagonists

Answer 26

Clopidogrel;
- Avoid drugs that inhibit the CYP enzymes needed to activate (Erythromycin, some SSRIs, Omeprazole, Ciprofloxacilin)

Ticagrelor;
- Interacts with CYP inducers & inhibitors

Question 27

How many days prior to surgery should Aspirin, Clopidogrel and Prasugrel be stopped? Why?

Answer 27

7-10 days Due to their effects being irreversible, can lead to bleeding during surgery

Question 28

Clopidogrel can be used as a monotherapy, where aspirin is contraindicated. Suggest courses for NSTEMI and STEMI patients

Answer 28

NSTEMI: up to 3 months STEMI: up to 4 weeks

Question 29

Suggest 2 drugs that can be taken with Aspirin in a patient who had an MI, for upto 12 months

Answer 29

Prasugrel and Ticagrelor

Question 30

What class of drug is Dipyridamole? In what 2 ways does this drug work?

Answer 30

- Phosphodiesterase inhibitors - Inhibits cellular reuptake of Adenosine, so increased [plasma adenosine]-> Platelet aggregation inhibited via adenosine A2 receptors - Inhibits phosphodiesterase, leading to reduced cAMP degradation. Thus inhibits activation of GPIIb/IIIa receptors

Question 31

List 2 ADRs and DDIs of Dipyridamole

Answer 31

- Vomiting + diarrhoea - Dizziness - Use of other antiplatelets/ anticoagulants - Adenosine

Question 32

Suggest 2 uses of Dipyridamole

Answer 32

- Secondary prevention of ischaemic stroke/ TIAs | - Adjunct for prophylaxis of thromboembolism following valve replacement

Question 33

What class of drug is Abciximab? How does it work?

Answer 33

- GPIIb/IIIa inhibitor | - Blocks binding of Fibrinogen and VWF (more complete as it targets final part of aggregation pathway)

Question 34

Describe the administration and use of abciximab

Answer 34

- Administered IV | - Used only in very specific circumstances (Percutaneous Transluminal Coronary Angioplasty)

Question 35

What class of drugs are Streptokinase and Alteplase? How do they work?

Answer 35

- Fibrinolytic agents/ ‘Clot busters’ | - Promote activation of Plasminogen to Plasmin, which breaks down Fibrin

Question 36

Describe the use of Alteplase and Steptokinase

Answer 36

Steptokinase- Can only be used once as antibodies develop Alteplase; - In acute ischaemic stroke <4.5 hours from when symptoms start - Acutely following a STEMI diagnosis (vs a Primary PCI)

Question 37

List an ADR and DDI of Fibrinolytic agents

Answer 37

- Bleeding | - Caution with use of other antiplatelets/ anticoagulants

Question 38

How does Tranexamic acid work? Suggest 2 uses

Answer 38

- Inhibits Fibrinolysis, thus stopping bleeding - Nosebleeds - Heavy, persistent period bleeding

Question 39

What is Primary PCI (Percutaneous Coronary Intervention)?

Answer 39

Insertion of a Catheter via Femoral artery, though Aorta to reach occluded coronary vessel, where a stent can be placed to leave it patent

Question 40

When should Primary PCI be used instead of a Fibrinolytic? | Primary PCI saves more muscle tissue

Answer 40

If; - Presentation is within 2 hours of symptom onset AND - Primary PCI can be done within 120 mins of the time where a Fibrinolytic could’ve been given

Question 41

What do you offer to all patients post MI once haemodynamically stable?

Answer 41

ACE inhibitors

Question 42

List an ADR and a DDI for abciximab

Answer 42

- Bleeding (dose adjusted for body weight) | - Caution with use of other antiplatelets/ anticoagulants

Question 43

Name a Cyclo-oxygenase inhibitor How do these work as antiplatelets?

Answer 43

- Aspirin | - Inhibit COX1, which produces TXA2 from Arachidonic acid (thus reduced platelet aggregation)