3. Parenteral Anticoagulants Flashcards
What is the major plasma protease inhibitor of thrombin?
antithrombin
Antithrombin inhibits what clotting factors?
Xa > IXa > XIIa
The rate of formation of inactivating complexes is increased several thousand fold in the presence of what?
heparin
Heparin is present as an endogenous component of vessel walls. (T/F)
True
Heparin is present in the fluid phase of plasma. (T/F)
False
Unfractionated heparin MW ranges from ______ - ______ .
3,000 - 30,000
What causes the anticoagulant effect produced by heparin?
interaction with antithrombin
What pharmacological compound neutralizes thrombin and other activated clotting factors?
heparin-bound antithrombin
Antithrombin is a ______ substrate.
suicide
Describe antithrombin’s “suicidal” mechanism
protease attacks a specific Arg-Ser peptide bond in antithrombin and becomes trapped as a 1:1 complex
______ serves as a catalytic template for inhibitor and protease to bind.
Heparin
Only heparin molecules that contain less than 18 monosaccharide units can catalyze inhibition of thrombin by antithrombin.
False: Heparin molecules of this size do not catalyze inhibition of thrombin by antithrombin
Heparin molecules of 18 monosaccharide units or more are required to bind thrombin and antithrombin _______.
simultaneously
Shorter heparin polysaccharides catalyze primarily inhibition of factor __ by antithrombin.
Xa
Heparin is ______ absorbed from the GI tract.
poorly
Heparin must be administered ________.
parenterally
IV infusion of heparin has a ________ effect.
immediate
Subcutaneous injection of heparin has a ________ effect.
delayed
SQ administration of heparin takes how long to take effect?
1-2 hours
What method of administration of heparin causes more bleeding complications?
intermittent IV injections
In addition to ACS, what other conditions are treated with heparin?
- venous thrombosis
- pulmonary embolism
Why is heparin used in ACS, DVT, and PE instead of warfarin, for example?
rapid onset of action
Unfractionated heparin has ________ PK and _______ therapeutic range.
- unpredictable
- narrow
What labs should be monitored when using unfractionated heparin?
activated partial thromboplastin time (aPTT)
What is the usual dose for unfractionated heparin in a UA/NSTEMI?
- IV bolus of 60u/kg (4000 u max)
- 12 u/kg/hr (1000 u/hr max)
- adjust to maintain aPTT at 1.5 - 2 times the control
What should aPTT value be after administration of heparin?
1.5 - 2 times the control value
When might very high doses of unfractionated heparin be given?
- PCI
- cardiac bypass surgery
In patients who require very high doses of unfractionated heparin, what lab values should be monitored?
- aPTT
- ACT
What are the 3 main limitations of heparin therapy?
- PK: binds to plasma proteins
- does not inactivate thrombin already bound to fibrin
- binds to platelets and inhibits function: could lead to uncontrolled bleeding
Why is the plasma protein binding of heparin an issue?
- Poor BA at low doses
- variability in dose response
- dose-dependent clearance
Why is it a problem that heparin does not bind thrombin that is already bound to fibrin?
It limits the effectiveness in preventing arterial thrombosis.
Why is it a problem that heparin binds to platelets and inhibits function?
heparin-induced bleeding
The half-life of heparin in plasma depends on ______.
dose
What is the half-life of 100 u/kg IV heparin?
1 hr
What is the half-life of 400 u/kg IV heparin?
2.5 hours
What is the half-life of 800 u/kg IV heparin?
5 hours
What are contraindications of heparin?
- surgery within 10 days
- serious GI bleed
- HTN
- active bleeding
- previous stroke
What are the ADRs of heparin?
- hemorrhage
- thrombocytopenia
- osteoporosis
What is the antidote to heparin?
protamine
How does protamine stop heparin action?
protamine binds mostly long heparin molecules, thereby preventing complex with antithrombin III
How is protamine administered?
IV infusion
What is the onset of action of protamine?
5 minutes
What is the low molecular weight heparin agent?
enoxaparin (Lovenox)
What is the average weight of LMWH?
4,500 daltons
How is the MOA of LMWH different than unfractionated heparin?
- ↑ inhibition of factor Xa
- ↓ inhibition of thrombin
- shorter molecules can’t bind antithrombin III and thrombin together
- anti-factor Xa/antithrombin activity is 4:1 vs 1:1 for unfractionated heparin
________ has easier administration. (UH/LMWH)
LMWH
________ has a shorter half life. (UH/LMWH)
UH
________ has a more predictable response. (UH/LMWH)
LMWH
_______ is administered by once or twice daily SQ injections. (UH/LMWH)
LMWH
_______ has a higher incidence of thrombocytopenia. (UH/LMWH)
UH
________ has a lower incidence of major bleeding complications. (UH/LMWH)
LMWH
Osteoporosis occurs more often with _______ long-term administration. (UH/LMWH)
UH
What is the factor Xa selective inhibitor agent?
fondaparinux (Arixtra)
What is the MOA of fondaparinux?
- binds antithrombin to selectively inhibit factor Xa
- does not inhibit thrombin
What are the approved indications of fondaparinux?
- DVT
- PE
In what condition is fondaparinux used off label in the US?
ACS
What are the advantages of using fondaparinux over heparin?
- easier administration
- more predictable response
- long half-life
- increased efficacy
- less variation between preparations
What is the disadvantage of using fondaparinux over heparin?
no antidote
Which parenteral anticoagulant is synthetic?
fondaparinux
Which parenteral anticoagulant has the highest bioavailability?
fondaparinux
Which parenteral anticoagulant has the longest half-life?
fondaparinux
Which parenteral anticoagulant is NOT eliminated renally?
unfractionated heparin
What are the hirudin analog agents?
- argatroban (Acova)
- lepirudin (Refludan)
- bivalirudin (Angiomax)
- desirudin ( Ipravask)
Where is hirudin naturally found?
produced by leeches
What is the route of administration of hirudin analogs?
injection
Which hirudin analogs are approved for heparin-induced thrombocytopenia?
- argatroban
- lepirudin
What is the MOA of hirudin analogs?
- direct inhibitor of thrombin (independent of antithrombin III)
- effectively inhibits thrombin bound to fibrin