Coag Drugs Flashcards
What does tPA do? What endogenous substance can inhibit it?
fibrinolysis via plasminogen –> plasmin
(plasmin will lyse the clot)
plasminogen activator inhibitor 1
What is the last step in the coag pathway?
fibrinogen –> fibrin
Clotting factors synth in liver?
II, V, VII, IX, X
What clotting factors need vitamin K?
II, VII, IX, X
Clotting factors targeted (most commonly) for pharm intervention?
II, X
Heparin MOA:
bind antithrombin III, increasing its affinity for X
*makes thrombin inactivation more favorable
Pathophys of HIT?
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)
MOA of warfarin (coumarin)
vitamin K antagonist; by binding to vit K sites, it blocks:
- carboxylation of glutamic acid on II, VII, IX, X, C, S (*liver and some in circulation)
- binding of vit K to epoxide reductase (this enzyme reduces the oxidized-VitK)
Why is warfarin onset delayed?
- long warfarin half life
- 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
What is warfarin rx to treat?
DVT, PE, a-fib, rheumatic heart disease, mechanical/prosthetic heart valves
What are some of the downsides to warfarin and other vitK antagonists?
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
How does low-mol-wt heparin differ from unfractioned heparin?
low-mol-wt:
cannot stabilize thrombin (its smaller)
is more effective in binding Xa
*are there more??
What are some uses/benefits of LMW heparin?
DVT prophylaxis (hip/abd srx) no clotting test needed longer duration/halflife less binding to cellular proteins more predictable
Thrombin binding site exosite 1 functions in:
binding fibrinogen
interacts w thrombomodulin, protein C platelet activation
Thrombin binding site exosite 2 functions in:
binding antithrombin
heparin binding site
Direct thrombin inhibitors don’t require:
antithrombin III
FYI: most of these drugs are cleared by the kidneys. just an unrelated side note.
What drugs can be used in patients with HIT?
Direct thrombin inhibitors
What are some uses/benefits of Direct thrombin inhibitors?
no coag monitoring higher therapeutic index no CYP effects predictable fixed dosing rapid onset of action
downside:
no antidote
monitor hepatic enzymes
How do dabigatran and hirudin differ?
dab binds reversibly to the thrombin active site
Fibrin bound thrombin is resistant to:
Why is this notable?
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
Direct thrombin inhibitors prevent the activation of what clotting factors by thrombin?
V, VIII. XI, XIII
also, platelets
What anti-coags can inhibit free and bound heparin?
direct thrombin inhibitors
direct factor Xa inhibitors
What are some benefits of direct factor Xa inhibitors?
no interaction with food/drugs
reversible
predictable
no monitoring
Why are direct factor Xa inhibitors so effective?
they can act on the intrinsic AND extrinsic pathways
act on a step in amplification (1X can activate 1,000 thrombin molecules)
Blocking what receptor prevents fibrinogen cross-linking by activated platelets?
GpIIb/IIIa
What is the ADP receptor on platelets?
P2Y1
(Heparin/Warfarin) is used for acute therapy, whereas (Heparin/Warfarin) is used for chronic therapy.
- heparin
2. warfarin
What drugs require antithrombin III for function?
unfractioned heparin
LMW heparin
Note: I skipped all the stuff that looks more like path, only covered the drugs
Week from hell.
