Anticoagulation pharmacology

Question 1

What is haemostasis?

Answer 1

Arrest of blood loss from damaged blood vessels and via bleeding.

Question 2

What is thrombosis?

Answer 2

The formation of a clot in the vasculature in the absence of bleeding.

Question 3

At what stage does thrombi formation occur?

Answer 3

In terms of thrombi formation, it starts at the platelet activation step and initiates the coagulation cascade.

Question 4

What are the main drugs used to treat platelet-rich white thrombi?

Answer 4

Anti-platelet drugs - Aspirin

Question 5

What are the main drugs used to treat red thrombi?

Answer 5

• Injectable anticoagulants (heparin and newer thrombin inhibitors) - act immediately
• Oral anticoagulants (warfarin and related compounds) - take several days
• Patients with venous thrombosis given injectable anticoagulant until effects of warfarin established

Question 6

What parts of the clotting cascade does Warfarin affect?

Answer 6

It affects factor 9 and factor 10 and prothrombin (Intrinsic pathway). It affects factor 7 as well on the extrinsic pathway.

Question 7

What is an advantage of using Heparins?

Answer 7

Heparins are more focused/selective/controllable.

Question 8

What are heparins?

Answer 8

• They are extracted from the liver
• They are present in mast cells

Mechanism of action
- They activate antithrombin III
- Antithrombin III will inactivate thrombin and Xa (factor 10a) and other serine proteases
- The heparin binding leads to a change in the conformation of the antithrombin III.
- This change will accelerate the rate of action of antithrombin III

Question 9

What does inhibiting a single molecule of Xa (factor 10) do?

Answer 9

It helps prevent the formation of hundreds of downstream thrombin molecules. This is a very effective way of inhibiting the clot formation.

Question 10

What are the 2 different types of heparins that are used therapeutically?

Answer 10

1. Unfractionated heparins (UFH)
2. Low molecular weight heparins (LMWH)

Question 11

What are unfractionated heparins?

Answer 11

A combination of all the heparins including the low molecular weight heparins.

Unfractionated heparin inhibits both thrombin and Xa.

Used only in hospital due to the unpredictability.

Question 12

What are low molecular weight heparins?

Answer 12

They have been purified from the unfractionated heparins.

They inhibit mainly Xa, hence more specific and therefore its effect is more predictable.

Question 13

What are the pharmacokinetics of heparin?

Answer 13

1. Not absorbed orally
   - Large in size
   - Degraded relatively very quickly
2. Can be partially metabolised in the liver by enzymes (heparin’s to uroheparin)
3. Parenteral administration (due to lack of oral absorption)
   - IV or subcutaneous
   - Relatively short half life - t1/2 40-90mins
4. Heparin acts immediately
   - It will instantly start to function as an anticoagulant drug

Question 14

What are the advantages of low molecular weight heparin (LMWH) over unfractioned heparin?

Answer 14

1. LMWH binds less to endothelium and plasma proteins
   - Hence theres a greater bioavailability of LMWH and so its much more available to function because its not being absorbed or sticking to the endothelium or plasma protein.
2. Predictable dose response (only affect Xa)
   - Can be monitored in a lab very easily but is rarely required
3. Because of increased bioavailability, theres a reduced frequency of dosing
4. Less side effects - because your only targeting one of those factors
5. Can be used at home

Question 15

What is the pharmacology of warfarin?

Answer 15

• It inhibits vitamin K reductase
• It is a competitive inhibitor
• Vitamin K is essential for the coagulation cascade factors and the enzyme that warfarin targets is essential for the function of vitamin K so by inhibiting Vitamin K reductase, you reduce the synthesis of coagulation factors*

Question 16

What are the effects of vitamin K inhibition?

Answer 16

• Inhibits hepatic vitamin K dependent synthesis of factors II, VII, IX and X and of anticoagulation protein C and it cofactor protein S
• Since warfarin acts indirectly, it has no effect on existing clots, only affects clots that form after the reduction in these factors.
• Takes at least 48-72 hours to achieve an antithrombolytic effect and this is because you have to wait for the levels of the factors to decline, however dosing is important and may take weeks to get the dosing right for an individual patient.

Question 17

What is the pharmacokinetics of Warfarin?

Answer 17

1. Readily absorbed through the GIT - can be taken orally
   - Quite lipophilic
   - Can pass through the placenta to babies (hence pregnant women can’t have it)
   - Can pass into breast milk (hence can’t have it if your breast feeding because it can pass onto the child and potentially poison the child)
2. Extensively bound to plasma proteins (99%)
3. Long plasma half life ~37 hours (variable hence we need monitor the dosing to make sure in an individual we achieve the maximum effect)
4. Can be metabolised by cytochrome P450
5. Because of all these factors (plasma protein binding, variable half-life, metabolism etc) it is very difficult to control this drug hence why you need constant monitoring when on warfarin.