BL Pharmacology of Anticoagulation Therapy

Question 1

Unfractionated Heparin

• what can it inactivate?
• what can it inhibit?
• what does it increase the rate of decay of?

Answer 1

binds to antithrombin III –> thrombin inactivation by 1000x.
–> ultimately preventing conversion of fibrinogen to fibrin.

• dont forget heparin can also inhibit Factor Xa

• Also increase rate of decay of IXa, Xa, and XIIa

Question 2

Is LMWH or unfractionated heparin the anticoag drug of choice in pregnancy?

Answer 2

Unfractionated

too large to cross the placenta
but does not inhibit thrombin

Question 3

complications associated with heparin therapy

Answer 3

Toxicity

• bleeding (if heparin effects doesnt go away after a few hours)
• Heparin-induced thrombocytopenia syndrome (HIT)

Allergic events

Question 4

How do you treat bleeding complications that resulted from heparin?

Answer 4

reverse it with IV protamine sulfate, a highly positively charged compound that neutralizes heparin.

Question 5

Heparin-induced thrombocytopenia syndrome (HIT)

Answer 5

Platelet count decrease by more than 50%
- Caused by development of AB to platelet factor 4/ heparin complexes. Ab bind to and activate platelets resulting in prothrombotic state
□ Too much platelets in thrombosis causes deficiency in available platelets

Question 6

Is HIT more common with unfractionated or LMWH? How do you treat HIT?

Answer 6

Thrombocytopenia is less common with LMWH

Treat with direct thrombin inhibitors:
Argatroban (small molecule inhibitor) and
Lepirudin (antocoagulant from leeches).

Question 7

Warfarin

Answer 7

vitamin K analogue; it inhibits epoxide reductase that reduces vitK. This prevents vit K from being used to gamma carboxylate factors in the coag cascade.

○ VII, IX, X, II, protein C, protein S

Question 8

vitamin K effect on coag

Answer 8

Factors VII, IX, X, II, and protein C
all have Glu residues that need reduced Vit K’s help to undergo gamma carboxylation (be modified to γ-carboxy glutamic acid residues), so that they can bind to calcium

-Vit K in its reduced form gets recycled back to oxidized Vit K after it carboxylases the factors

Question 9

Warfarin effects on Vit K

Answer 9

Warfarin inhibits Vit K reduction, thereby reducing the amount of Vit K that are very much needed for the gamma carboxylation reaction.

Remember:
-Vit K in its reduced form gets recycled back to oxidized Vit K after it carboxylates certain factors

Question 10

adverse effects and potential complications associated with use of warfarin.

Answer 10

1. Hemorrhage
2. Teratogenic
3. Drug and food interactions

Question 11

Drugs that increase action of warfarin:

Answer 11

Aspirin: inhibit platelet function

Antibiotics: decrease VitK synthesis by intestinal microbes

Clofibrate, phenytoin: displace warfarin from plasma protein; increase active free [warfarin]

Cimetidine, Amiodorone, phenylbutazone: reduce metabolism and elimination of warfarin in the liver.

Question 12

Drugs that decrease effect of warfarin:

Answer 12

Barbiturates and rifampin: increase metabolism by inducing metabolic enzymes in liver

Cholestyramine: decrease warfarin absorption from GI tract.

Question 13

New Oral anticoagulants

Answer 13

1. direct thrombin inhibitors (Dabigatran etexilate - Pradaxa)
2. Factor Xa inhibitor (Apixaban and Rivaroxaban):

Question 14

Disadvantages of using New oral anticoagulants

Answer 14

• contraindicated in kidney disease,
• greater GI bleeding than warfarin,
• short half life,
• $$$ (20x>warfarin),
• no antidote to reverse effects (compared to proamine sulfate in heparin bleeding).

Question 15

How does Tissue plasminogen activator (t-PA) make more plasmin?

Answer 15

□ Binds fibrin to increase cleavage of plasminogen to plasmin

• this is diff than Urokinase u-PA bc in renal cells, it does not bind to fibrin in order to activate plasmin

Question 16

When would you use the fibrinolytic agents t-PA or u-PA?

Answer 16

○ Acute myocardial infarction (combo w/ aspirin)
○ Ischemic stroke (effective if administered within 3 hours after stroke)
○ DVT (combo w/ heparin or warfarin Tx)
○ PE

Question 17

list 3 antiplatelet agents

Answer 17

1. Aspirin
2. ADP receptor blockers
3. Glycoprotein Iib/IIIa inhibitors

Question 18

Aspirin MOA

Answer 18

Irreversibly inactivates cyclooxygenase preventing thromboxane A2 formation by platelets. Reduces life of platelet.

Question 19

Aspirin uses

Answer 19

§ Thrombolytic therapy after MI (combo w/ aspirin)
§ thrombotic stroke
§ Used for prevention of AMI and stroke in high-risk patients with atherosclerosis.

Question 20

ADP Receptor Blockers MOA

Answer 20

○ Ticlopidine (Ticlid), 
Clopidogrel (Plavix), 
Prasugrel
Ticagrelor
       - MOA: bind irreversibly to ADP receptors to block alpha granule secretions and expression of adhesion proteins, GPIIb/IIIa

Question 21

ADP Receptor Blockers

uses

Answer 21

MI prevention and thrombotic stroke (used in combo w/ aspirin)

Question 22

Glycoprotein Iib/IIIa inhibitors

MOA

Answer 22

block binding of fibrinogen to adhesion protein GPIIb/IIIa

Question 23

Clofibrate, phenytoin: MOA

Answer 23

Clofibrate, phenytoin: displace warfarin from plasma protein; increase active free [warfarin]

Question 24

Cimetidine, Amiodorone, phenylbutazone:

Answer 24

reduce metabolism and elimination of warfarin in the liver.

Question 25

Is warfarin teratogenic?

Answer 25

Yes!!