7. Anticoagulants

Question 1

What are the 4 main classes of anticoagulants?

Answer 1

Heparin (and LMWH)
Warfarin
Factor X inhibitors
Direct thrombin inhibitors

Question 2

How does Heparin work?

Answer 2

• Family of sulphated mucopolysaccharides found in mast cell granules - naturally occurring, but treatment uses synthetic
• inhibits coagulation by activating antithrombin III
• ATIII is a naturally occurring inhibitor of thrombin + factors IX, X, XI and XII
• in the presence of heparin, ATIII becomes 1000x more active, and the clotting factor inhibition is instantaneous

Question 3

What is the difference between heparin and LMWH?

Answer 3

• LMWH is fragments, synthetic heparin with a more consistent activity
• Inactivates factor Xa (and thrombin) via ATIII

Question 4

What are the pharmacokinetics of heparin and LMWH?

Answer 4

• inactive given orally, not absorbed from GI -> give IV or SC
• Heparin has short half life, so has to be frequently given, or continuously infused
• LMWH has longer duration, so once daily
• Renal excretion
• side effects = bleeding and hypersensitivity

Question 5

What is the clinical use of heparin and LMWH?

Answer 5

• treatment of established VTE
• prevention of VTE
• Cardiac disease - reduces VTE risk following MI
• LMWH to reduce PE clot formation
• Heparin used to start long-term anticoagulation therapy, but stopped once oral takes over

Question 6

How does warfarin work?

Answer 6

• inhibits the activation of Vit K-dependent clotting factors - II, VII, IX, X
• Takes 48-72 hours for anticoagulant effect to develop

Question 7

What are some pharmacokinetics of warfarin?

Answer 7

• Rapidly absorbed from GI
• Low Vd, 99% plasma protein bound (mainly albumin) - limits it to plasma compartment
• Metabolism by CYP450 (2C9, 2C19, and 3A4)
• Excretion via glucuronidation and the urine and faeces

Question 8

What is the clinical use of warfarin?

Answer 8

• Prevent the progression or reoccurrence of VTE and PE
• Prevent arterial thromboembolism in patients with AF or cardiac disease
• At least 6 weeks anticoagulation recommended for calf vein thrombosis, and at least 3 months for DVT/PE

Question 9

What are the INR targets?

Answer 9

2. 5
   - DT/PE treatment
   - AF
   - Dilated cardiomyopathy
3. 5
   - Recurrent DVT or PE
   - Mechanical prosthetic heart valves

Question 10

What are the NOACs?

Answer 10

Dabigatran
Rivaroxaban
Edoxaban
Apixaban

Question 11

How does dabigatran work?

Answer 11

• Competitive reversible inhibitor of thrombin
• Used for prevention of stroke and embolism in AF patients, and prophylaxis of VTE after hip/knee surgery
• Has a rapid onset
• No monitoring required
• Rapid reversal agent = idarucizumab

Question 12

How do antiplatelets work?

Answer 12

• Inhibition of platelet plugs, useful in prophylaxis and therapeutic strategy against MI and stroke caused by thrombosis

Aspirin

• irreversibly inhibits COX-1 —> no TXA2 synthesis
• platelets cant make new COX-1, so have none for the rest of their lifespan (7-10 days)

Question 13

How do fibronolytics/thrombolytics work?

Answer 13

Eg streptokinase, alteplase

• increase fibrinolytic effects
• activate conversion of plasminogen to plasmin —> breaks down fibrin
• IV administration
• Short half life
• Main hazard is bleeding
• Used to restore catheter and shunt function by removing occluding clots, also dissolve clots that have resulted in strokes
• need to be careful not to cause haemorrhage though