Anticoagulants Flashcards
What are the different classes of anticoagulants?
- Indirect thrombin inhibitors
- Direct thrombin inhibitors
- Indirect factor Xa inhibitors
- Direct factor Xa inhibitors
- Fibrinolytic agents
- Vitamin K antagonists
- Antiplatelets
What are the two indirect thrombin inhibitors?
Unfractionated heparin and low molecular weight heparin
What is the mechanism of action of the indirect thrombin inhibitors?
They bind to antithrombin causing a conformational change. This conformation change allows antithrombin to rapidly bind to factors IIa and Xa and inhibit their function.
What is the activity for UFH?
It has a high affinity for antithrombin and can inhibit both factor IIa and Xa
What is the activity for LMWH?
It is made up of fragments of UFH; therefore, it has a lower affinity for antithrombin and can inhibit factor Xa but has little inhibitory effect on IIa
What are the toxicities associated with indirect thrombin inhibitors?
- Bleeding
- Thrombocytopenia
- Caution w/ allergies
What is heparin made up of?
Sulfated mucopolysaccharides that are very acidic
What is heparin used to treat?
Full dose IV: venous thrombosis and pulmonary embolism
Lower dose SC: after surgery in high risk patients
What is the antidote for heparin?
Protamine sulfate
How does protamine sulfate work?
It binds to heparin forming an inactivated salt that is excreted by the kidneys
What are the advantages of LMWH?
- Greater bioavailability with SC; therefore, it has a more predictive anticoagulant response
- Longer half-life and less frequent dosing
- Three available preparations
What are the advantages of UFH?
- Rapid reversal of anticoagulant effect with protamine sulfate
- Doesn’t get clear by kidneys and may be safer in patients with renal insufficiencies
- Direct inhibitor of the contact activation pathway
What are the disadvantages of UFH?
- More likely to cause heparin induced thrombocytopenia
2. More variable anticoagulant response that requires monitoring
What drug is a direct thrombin inhibitor?
Dabigatran (Pradaxa)
What is the activity of Dabigitran?
It is used to prevent thromboembolic disorders such as venous thromboembolism, DVT, and thromboemobolic stroke
What types of thrombin does dabigatran inhibit?
fibrin bound and free thrombin
What is the mechanism of action of Dabigatran?
It is a potent, competitive, reversible inhibitor that binds to the active site of thrombin and inhibits its effects
What are the toxicities associated with Dabigatran?
- Dyspepsia
- Gastritis
- Bleeding (higher risk of general and GI bleeding than warfarin)
- Hemorrhagic stroke
Does Dabigatran require monitoring?
No, it’s effects are less variable than warfarin
Does dabigatran require a modified diet?
No
What is the half-life of dabigatran compared to warfarin?
It has a shorter half-life; therefore, missed doses could increase risk of thrombosis
What is the antidote for dabigatran?
Idarucizumab
Can dabigatran’s anticoagulant properties be measured during therapy?
No
What drug is an indirect factor Xa inhibitor?
Fondaparinux
What is the activity of fondaparinux?
It’s as safe and effective as UFH and LMWH in the prophylaxis and treatment of venous thromboembolism
What is the mechanism of action of fondaparinux?
It binds to antithrombin and indirectly inhibits factor Xa. This inhibits thrombin production in both pathways.
What are the toxicities associated with fondaparinux?
Much less likely to cause heparin-induced thrombocytopenia
What is fondaparinux (structural level)?
A synthetic analog of the pentasaccharide sequence of heparin
What type of factor can fondaparinux, UFH, and LMWH inhibit?
Only free circulating factor Xa
What drug is a direct factor Xa inhibitor?
Rivaroxaban
What is the activity of Rivaroxaban?
Used in the treatment of venous thromboembolism including DVT and pulmonary embolism. Also used in preventing strokes in patients with atrial fibrillation.
What is the mechanism of action for Rivaroxaban?
Highly selective, competitive, reversible inhibitor of free circulating and fibrin-bound factor Xa which inhibits the production of thrombin in both pathways
What are the toxicities associated with Rivaroxaban?
- Bleeding
2. Monitoring of renal function
Does Rivaroxaban require dietary modifications?
No
How does the half-life of Rivaroxaban compare to warfarin?
It has a shorter half-life; therefore, missed doses increase the risk of thrombosis
Can Rivaroxaban’s anticoagulant properties be measured during therapy?
No
What is the antidote for Rivaroxaban?
Andexanet Alfa
What does Andexanet Alfa do?
It is a factor Xa decoy that neutralizes direct factor Xa inhibitors
What are the fibrinolytic agents?
- Streptokinase
- Urokinase
- Tissue Plasminogen Activator (“teplase” ending)
What are the indications for the fibrinolytic agents?
Used for the treatment of thrombotic diseases and management of acute myocardial infarction
What is the mechanism of action of streptokinase?
Binds to pro-activator plasminogen to form a complex that catalyzes the conversion of inactive plasminogen to active plasmin.
What is the mechanism of action of Urokinase?
Directly converts plasminogen to active plasmin
What is the mechanism of action of Tissue Plasminogen Activator?
Preferentially activates plasminogen that is bound to fibrin
Where is urokinase synthesized?
The kidney
What is the difference between Alteplase, Reteplase, and Tenecteplase?
Alteplase: recombinant human t-PA
Reteplase: recombinant human t-PA that is less fibrin specific
Tenecteplase: mutant form of t-PA that has longer half-life and is slightly more fibrin-specific than t-PA
What drug is a Vitamin K antagonist?
Warfarin
What are the indications for warfarin?
It can be used along or in combination with heparin for prophylaxis and treatment of intravascular clotting
Which enantiomer of warfarin is stronger?
The S enantiomer is 3-5 times more potent
What is the mechanism of action of warfarin?
It inhibits the vitamin K epoxide reductase enzyme which prevents vitamin K from being produce. This blocks the carboxylation of clotting factors II, VII, IX, and X forming inactive molecules
How long is the delay in warfarin’s anticoagulant effect?
8-12 due to the time it takes to degrade clotting factors
Can warfarin effect an already formed embolism?
No, but it can prevent further clotting
What are the toxicities associated with warfarin?
- Bleeding
2. Can cross placenta causing hemorrhagic disorder
What are the 8 interactions that can alter the effects of warfarin?
- Aspirin
- Heparin
- 3rd generation cephalosporins
- Hepatic disease
- Hyperthyroidism
- Hypothyroidism
- Diuretics
- Vitamin K
What effect does aspirin have on warfarin?
increases anticoagulant effects by affecting platelet function
What effect does heparin have on warfarin?
increases anticoagulant effect by inhibiting several clotting factors
What effect do 3rd generation cephalosporins have on warfarin?
increase anticoagulant effect by eliminating bacterial microflora that produce vitamin K
What effect does hyperthyroidism have on warfarin?
increase anticoagulant effect by increasing the degradation of clotting factors
What effect does hypothyroidism have on warfarin?
decreases anticoagulant effect by decreasing the turnover rate of clotting factors
What effect does hepatic disease have on warfarin?
increases anticoagulant effect by inhibiting the synthesis of clotting factors in the liver
What effect does vitamin K have on warfarin?
decreases anticoagulant effect by increasing the production of clotting factors
What effect do diuretics have on warfarin?
decrease anticoagulant effect by increasing the concentration of clotting factors in circulation
What do genes have the most effect on warfarin response?
CYP2C9 and VKORC1
Variants of which gene are more prevalent?
VKORC1
Which gene has a greater effect on warfarin?
VKORC1
What should you do with the warfarin dose when dealing with variations in the CYP2C9 and VKORC1 genes?
Decrease the dose
What is the antidote for warfarin?
Phytonadione, fresh-frozen plasma, prothrombin complex concentrates, and recombinant clotting factor VIIa
How long does it take the antidote to fully restore vitamin K-dependent clotting factors?
24 hours
What is the negative aspect to FFP?
It requires blood group typing, thawing, and large volumes of fluid which can overload elderly patients and those with heart disease
What is included in 3-factor PCC?
Factors II, IX, and X
What is included in 4-factor PCC?
Factors II, VII, IX, and X
What can occur with the use of antidotes?
Fatal venous and arterial thromboembolic complications
What are the anti-platelet agents?
- Aspirin
- Thienopyridines
- Cyclopentyltriaxolopyrimidines
- Nonthienopyridine ATP analogs
- GP IIb/IIIa receptor antagonists
- PAR-1 antagonists
- Dipyridamole
What is the activity of aspirin?
- Prophylaxis
