Flashcards in Coag Drugs Deck (29):
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?
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:
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)
Why is warfarin onset delayed?
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
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?
narrow therapeutic window
variability among patients
food/drug interactions (CYP2C9)
requires monitoring and dose-adjustment
*have to keep pts between INR of 2-3
How does low-mol-wt heparin differ from unfractioned heparin?
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
less binding to cellular proteins
Thrombin binding site exosite 1 functions in:
interacts w thrombomodulin, protein C platelet activation
Thrombin binding site exosite 2 functions in:
heparin binding site
Direct thrombin inhibitors don't require:
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
rapid onset of action
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
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
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?
What is the ADP receptor on platelets?
(Heparin/Warfarin) is used for acute therapy, whereas (Heparin/Warfarin) is used for chronic therapy.
What drugs require antithrombin III for function?