L27. Drugs Affecting Coagulation

Question 1

What are the three major steps of normal clot formation?

Answer 1

1. Coagulation (fibrin formatin)
2. Platelets (adhesion and activation)
3. Fibrinolysis (dissolving the clots)

Question 2

What is a major inherent difficulty in coagulation medications?

Answer 2

Getting the right amount of medication right

Clot vs. Bleeding

Question 3

What are the three major types of drugs that affect fibrin formation?

Answer 3

1. Procoagulant drugs
2. Injectable anticoagulant: Heparin and LMW Heparins
3. Oral anticoagulants: Warfarin

Question 4

What is Vitamin K important for (in terms of the coagulation cascade)?

Answer 4

The formation of clotting factors: II, VII, IX and X

- require gamma carboxylation after synthesis which is done by a reduced vitamin K

Question 5

What is the mechanism of action of Heparin?

Draw the pathway

Answer 5

It binds to and activates anti-thrombin III which is a natural inhibitor of factor Xa and Thrombin thus preventing the formation of thrombin (less coagulation cascade, less fibrin formation and less platelet activation)

It also has the power to inhibit the action of all the other major factors in the cascade XII, XI and IX

Question 6

What is the structure of Heparin? What does this mean for the drug?

Answer 6

It is a very large compound (60-100kD), negatively charged

- thus it is not orally available (must be given by IV)

Question 7

What are the low molecular weight Heparins?

Answer 7

The are much smaller (2-9kD)
Still not orally available
Have the same effects on Xa (not on thrombin) and has a longer elimination half life.

Question 8

Why must patients taking Heparin be monitored closely? How is this done?

Answer 8

The very serious side effects of the drug and the ‘swinging’ effect of thrombosis vs. bleeding.
Done by monitoring the Activated Partial Thromboplastin Time (APTT) that measures the time for clot formation in plasma after addition of calcium.

Question 9

What are the side effects of Heparin?

Answer 9

Haemorrhage
Thrombocytopaenia (platelet deficiency)
Osteroporosis (not a well known mechanism)

Question 10

In what settings is Heparin used?

Answer 10

Usually only in the ICU in dire and heavily monitored situations due to the serious side effects.
Only used Acutely and once out of the dire situation, the patients are switched to oral warfarin.

Question 11

What are the oral anticoagulants?

Answer 11

Derivatives of Coumarin which all inhibit the reduction of Vitamin K and thus inhibit the gamma carboxylation of factors II, XII, IX and X

Question 12

What is the mechanism of action of Warfarin?

Answer 12

It competes with vitamin K and thus inhibits its action to gamma carboxylation (Activation) of Factors in the coagulation cascade.

Question 13

Does the drug act on already active factors?

What is the impact of this?

Answer 13

No. It acts on the next ‘generation’ of factors by affecting their development/activation and has no affecting already activated ones.
This means there is a DELAYED onset of action of the drug and so the dosages must be titrated accordingly

Question 14

What is the administration and distribution of the drug warfarin?

Answer 14

It is orally available

Rapidly absorbed drug

Question 15

What are the adverse effects of warfarin?

Answer 15

Haemorrhage
Abdominal pains
Burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings
Confusion
Chest pain or discomfort

Question 16

How is warfarin overdose combated?

Answer 16

Vitamin K (oral), phytomedadione natural vitamin K (by IV) or fresh frozen plasma

Question 17

Why is warfarin called a ‘moody drug’?

Answer 17

It is difficult to control
99% Strongly bound to plasma and only 1% unbound (active portion)
= Any changes in plasma proteins have an effect on warfarin activity
EG. dietary changes in Vitamin K, Hepatic disease, hypermetabolic states, drug interactions

Question 18

What drug interactions occur with Warfarin?

Answer 18

Aspirin impairs platelet aggregation and leads to increased warfarin activity
NSAIDS compete with the same plasma binding protein as warfarin
Competition for the cytochrome p450 pathway with cimetidine (anti-H2) or alcohol, decreases warfarin clearance

Question 19

What states affect warfarin activity?

Answer 19

Pregnancy and Drug interactions

Question 20

How and why is careful monitoring of patients on warfarin required?

Answer 20

Because the drug is highly labile
PT and INR monitoring
Because side effects are important and because the dosages constantly change (difficult to have compliance)

Question 21

What kind of drugs (give examples) are commonly used adjunctly with anti-coagulants or used in other less severe states and why?

Answer 21

Drugs that affect platelet activation and adhesion eg. Aspirin as prevention for clots
For long term anticoagulation
For patients with not a high enough risk to use warfarin

Question 22

What are the three main types of anti-platelet drugs?

Answer 22

1. ADP receptor antagonists: eg. Clopidegrel
2. Thromboxane synthesis inhibitors eg. aspirin
3. Glycoprotein IIb/IIIa receptor antagonists eg. abciximab
4. Increased production of prostacyclin eg. Dypiradamoles

Question 23

How do the ADP receptor antagonists work?

Answer 23

Prevent adenosine diphosphate binding (ADP) to the platelet receptor. This inhibits formation of the Glycoprotein IIb/IIIa complex and thus prevents binding to fibrinogen and platelet AGGREGATION

Question 24

How to the thromboxane inhibitors work

Answer 24

Thromboxanes normally activate platelets and aspirin acts on COX which inhibits the ability of the platelet to produce thromboxane

Question 25

How does an increase in prostacycline lead to anti-platelet activity?

Answer 25

Dipyridamoles increase the levels of prostacyclin from endothelial cells) which have anti-platelet activity.
They also inhibit phosphodiesterases PDE, which also leads to a decrease in the GP IIa/IIIb formation.

Question 26

How to the glycoprotein IIb/IIIa receptor angatonigs work?

Answer 26

They are monoclonal antibodies raised against the complex (very expensive) - IV use and only used when other drugs are not working

Question 27

What are some methods of controlling fibrinolysis? How are they administered?

Answer 27

Streptokinase by activation of plasminogen (to plasmin which is a potent activator of fibrinolysis
- IV only once (highly antigenic)

Alteplase: a human recombinant tissue plasminogen activator (tPA)
- IV with short half life