Coag Drugs

Question 1

What does tPA do? What endogenous substance can inhibit it?

Answer 1

fibrinolysis via plasminogen –> plasmin
(plasmin will lyse the clot)

plasminogen activator inhibitor 1

Question 2

What is the last step in the coag pathway?

Answer 2

fibrinogen –> fibrin

Question 3

Clotting factors synth in liver?

Answer 3

II, V, VII, IX, X

Question 4

What clotting factors need vitamin K?

Answer 4

II, VII, IX, X

Question 5

Clotting factors targeted (most commonly) for pharm intervention?

Answer 5

II, X

Question 6

Heparin MOA:

Answer 6

bind antithrombin III, increasing its affinity for X

*makes thrombin inactivation more favorable

Question 7

Pathophys of HIT?

Answer 7

PF4 binds heparin (pt on hep for 5-10d)
Antibodies against hep/PF4 form, which:
–activate platelets to form arterial clots
–causes more PF4 release from platelets (destroys endothelial cells)

Question 8

MOA of warfarin (coumarin)

Answer 8

vitamin K antagonist; by binding to vit K sites, it blocks:

1. carboxylation of glutamic acid on II, VII, IX, X, C, S (*liver and some in circulation)
2. binding of vit K to epoxide reductase (this enzyme reduces the oxidized-VitK)

Question 9

Why is warfarin onset delayed?

Answer 9

1. long warfarin half life
2. pre-existing factors are slowly cleared from blood

*note: C/S are cleared more quickly, so you can actually be more coag in the first couple days; this is why you heparinize patients, then give them oral warfarin

Question 10

What is warfarin rx to treat?

Answer 10

DVT, PE, a-fib, rheumatic heart disease, mechanical/prosthetic heart valves

Question 11

What are some of the downsides to warfarin and other vitK antagonists?

Answer 11

slow onset
narrow therapeutic window
variability among patients
food/drug interactions (CYP2C9)
unpredictable
requires monitoring and dose-adjustment

*have to keep pts between INR of 2-3

Question 12

How does low-mol-wt heparin differ from unfractioned heparin?

Answer 12

low-mol-wt:
cannot stabilize thrombin (its smaller)
is more effective in binding Xa

*are there more??

Question 13

What are some uses/benefits of LMW heparin?

Answer 13

DVT prophylaxis (hip/abd srx)
no clotting test needed
longer duration/halflife
less binding to cellular proteins
more predictable

Question 14

Thrombin binding site exosite 1 functions in:

Answer 14

binding fibrinogen

interacts w thrombomodulin, protein C platelet activation

Question 15

Thrombin binding site exosite 2 functions in:

Answer 15

binding antithrombin

heparin binding site

Question 16

Direct thrombin inhibitors don’t require:

Answer 16

antithrombin III

FYI: most of these drugs are cleared by the kidneys. just an unrelated side note.

Question 17

What drugs can be used in patients with HIT?

Answer 17

Direct thrombin inhibitors

Question 18

What are some uses/benefits of Direct thrombin inhibitors?

Answer 18

no coag monitoring 
higher therapeutic index
no CYP effects
predictable
fixed dosing
rapid onset of action

downside:
no antidote
monitor hepatic enzymes

Question 19

How do dabigatran and hirudin differ?

Answer 19

dab binds reversibly to the thrombin active site

Question 20

Fibrin bound thrombin is resistant to:

Why is this notable?

Answer 20

inactivation by heparin-ATIII complex
(heparin binding site is no longer accessible)

even when bound, thrombin is enzymatically active and can be used to amplify the coag cascade

Question 21

Direct thrombin inhibitors prevent the activation of what clotting factors by thrombin?

Answer 21

V, VIII. XI, XIII

also, platelets

Question 22

What anti-coags can inhibit free and bound heparin?

Answer 22

direct thrombin inhibitors

direct factor Xa inhibitors

Question 23

What are some benefits of direct factor Xa inhibitors?

Answer 23

no interaction with food/drugs
reversible
predictable
no monitoring

Question 24

Why are direct factor Xa inhibitors so effective?

Answer 24

they can act on the intrinsic AND extrinsic pathways

act on a step in amplification (1X can activate 1,000 thrombin molecules)

Question 25

Blocking what receptor prevents fibrinogen cross-linking by activated platelets?

Answer 25

GpIIb/IIIa

Question 26

What is the ADP receptor on platelets?

Answer 26

P2Y1

Question 27

(Heparin/Warfarin) is used for acute therapy, whereas (Heparin/Warfarin) is used for chronic therapy.

Answer 27

1. heparin

2. warfarin

Question 28

What drugs require antithrombin III for function?

Answer 28

unfractioned heparin

LMW heparin

Question 29

Note: I skipped all the stuff that looks more like path, only covered the drugs

Answer 29

Week from hell.