Anticoagulation/AntiThrombotic Therapy Flashcards
Effects of thrombin
- Forms and ____ the ___ clot.
- Stimulates TAFI: what is this?
Effects of thrombin
- stabilizes; fibrin
- Thrombin Activated Fibrinolysis Inhibitor
Fibrolytic Pathway
- Activators converting plasminogen to plasmin?
- Inhibitors of plasminogen to plasmin conversion?
Fibrinolytic pathway
- Urokinase type plasminogen activator and tissue type
- Plasmin activator inhibitiors (PAI-I or PAI-II)
Fibrinolytic pathway
Inhibitors of plasmin itself?
Fibrinolytic pathway
a. Alpha1-antitrypsin
b. alpha2-antiplasmin
c. Thrombin-activatable fibrinolysis inhibitor
Anti-Platelet therapy:
Drugs?
Anti-Platelet therapy:
a. Aspirin
b. Thienopyridines
c. G IIb/IIIa receptor antagonists
d. PAR-1 inhibitor
Anti-Platelet therapy:
Aspirin:
- Mechanism of action?
- How can effects be reversed?
- Clinical implications?
Anti-Platelet therapy:
Aspirin:
- Irreversibly inhibits COX activity of PG synthesis
- Can only be reversed by new platelet generation
- Once daily dosing (and prolonged dissipation of anti-platelet effect)
Anti-Platelet therapy:
Thienopyridines:
Drugs?
Anti-Platelet therapy:
a. Ticlopidine
b. Clopidogrel
c. Prasugrel
d. Ticagrelor
Anti-Platelet therapy:
Thienopyridines (ticlopidine/clopidogrel/prasugrel/ticagrelor)
What do they inhibit? What is the result?
Anti-Platelet therapy:
Thienopyridines:
These are ADP receptor inhibitors and thus inhibit platelet aggregation
Anti-Platelet therapy:
Clopidogrel:
Mechanism of action?
How is it inactivated? What is this a problem with?
Peak level? Half life is longer than?
Anti-Platelet therapy:
Clopidogrel:
Irreversibly inhibits ADP binding to platelet P2Y12 receptor
Can only generate new platelets; issue with surgery
Peaks within an hour of ingestion; longer T1/2 than aspirin
Anti-Platelet therapy:
ADP receptor inhibitors:
- Intake of what is restricted when taking Ticagrelor?
- Who should not take Prasugrel?
Anti-Platelet therapy:
ADP receptor inhibitors:
- Aspirin intake, must be less than 100mg
- Patients over 76 or who weigh under 60kg shouldnt take prasugrel
Anti-Platelet therapy:
What drug had bad marketing on reduction in CVA patients?
Anti-Platelet therapy:
Vorapaxor
Anti-Platelet therapy:
Glycoprotein IIb/IIIa inhibitors:
- What does it bind to?
- What stage is it important for in platelet aggregation?
- What are the 3 in use? Route of administration?
Anti-Platelet therapy:
Glycoprotein IIb/IIIa inhibitors:
- vWF and fibrinogen
- Final common pathway
- Abciximab, Eptifibatide, Tirofiban; given IV only
Anti-Platelet therapy:
Abciximab:
- What is this? Function?
- Size? Duration of action?
- Binding?
Anti-Platelet therapy:
Abciximab:
- Fab fragment of ab against IIb/IIIa
- Large; Long duration of action
- nonspecific
Anti-Platelet therapy:
Eptifibatide and Tirofiban:
- Highly ___ and ___ inhibitors of what receptor?
- Half life? Speed of recovery of platelet function?
- ___% inhibition of platelet aggregation
Anti-Platelet therapy:
Eptifibatide and Tirofiban:
- Highly selective and reversible inhibitors of IIb/IIIa
- short half life; fast recovery of platelet function
- 80% inhibition of platelet aggregation
Anticoagulant classes:
- Inhibitors of clot initiation are blocking what pathway?
- Inhibitors of clot propagation are blocking what factor?
- Inhibitors of the fibrin formation are inhibiting?
Anticoagulant classes:
- VIIa/TF pathway (clot initiation)
- Factor Xa inhibitors (clot propagation)
- Direct thrombin inhibitors (fibrin formation)
Anti-Thrombosis:
Antithrombin agents (name 3)
Anti-Thrombosis:
Antithrombin agents:
a. Heparin
b. Low molecular weight heparin
c. Direct Thrombin inhibitors
Anti-Thrombosis:
Unfractionated Heparin:
- These are nonselective inhibitors of?
- Binds to?
- Elimination not dependent on?
Anti-Thrombosis:
Unfractionated heparin:
- Factor Xa inhibitors (inhibit clot propagation)
- Binds to endothelial cells and plasma proteins
- Elimination is not dependent on renal function
Anti-Thrombosis:
Unfractionated heparin:
- What does it stimulate? (that it doesnt want)
- What does it release? (that is good)
- What is its cofactor?
Anti-Thrombosis:
Unfractionated heparin:
- Simulates platelets and releases platelet factor 4
- Tissue factor pathway inhibitor
- Requires Anti-thrombin III as a cofactor
Anti-Thrombosis:
Antihemostatic effects of Heparin:
- What factors does it inactivate?
- Role in platelet function?
Anti-Thrombosis:
Antihemostatic effects of heparin:
- Inactivates factors IIa, IXa, Xa, and XIIa
- Inhibits platelet function and contributes to the hemorrhagic effects of heparin
Anti-Thrombosis:
Limitations of Unfractionated Heparin:
- Unpredictable what?
- Narrow ____ window
- Reduced activity in the vicinity of ___ ____ ___
- It can also ___ clotting.
Anti-Thrombosis:
Limitations of UFH:
- Unpredictable anticoagulant response
- Narrow therapeutic window
- Reduced activity in the vicinity of platelet-rich thrombi
- It can also ACTIVATE clotting
Anti-Thrombosis:
Advantages of LMWH vs. UFH:
- Administration?
- More ___ anticoagulant response.
- Half life?
- Lower incidence of _____.
Anti-Thrombosis:
Advantages of LMWH vs. UFH
- LMWH is easier to administer (subcutaneous not IV)
- More predictable anticoagulant response
- LMWH has a half life that is 2-4x longer
- Lowers the incidence of thrombocytopenia
Anti-Thrombosis:
UFH:
This must be monitored: monitoring the therapeutic range with?
Anti-Thrombosis:
UFH:
PTT - Partial thromboplastin time
Vitamin K Antagonists:
Name 6 drugs.
Vitamin K Antagonists:
a. Warfarin
b. Dicoumarol
c. Phenprocoumon
d. Indandione
e. Acenocoumarol
f. Anisindione
Vitamin K Antagonists:
Warfarin:
- What factors and protiens are vitamin K dependent?
- These coagulation factors are biologically inactive unless ____ and this is dependend on ___ vitamin K
- What enzyme does warfarin inhibit?
Vitamin K Antagonists:
Warfarin:
- Factors II, VII, IX, and X as well as protein C and S are K depenent
- They are inactive unless decarboxylated which depends on reduction of vitamin K
- Vitamin K Oxide Reductase
Vitamin K Antagonists:
Warfarin:
- Effect on already carboxylated molecules?
- Anticoagulant effect depends on depletion of ___ ___ in circulation.
Vitamin K Antagonists:
Warfarin:
- No effect on already carboxylated molecules
- Depends on depletion of carboxylated proteins in circulation (this depends on half lives)
Vitamin K Antagonists:
Pharmacokinetics of Warfarin:
- Inter-individual sensitivity to warfarin is EXTREMELY ___.
- Intra-individual sensitivity is _____ affected by multiple factors: nutrition and ___ __ intake, gut ____, and ___.
Vitamin K Antagonists:
Pharmacokinetics of Warfarin:
- Interindividual sensitivity is EXTREMELY variable
- Intraindividual sensitivity is MARKEDLY affected by multiple factors: nutrition and vitamin K intake, gut flora, and medications
Vitamin K Antagonists:
Problems with Warfarin:
- ______ dose response.
- ____ therapeutic range
- Bleeding?
- Monitoring?
- Reversibility?
Vitamin K Antagonists:
Problems with Warfarin:
- Unpredictable dose response
- Narrow therapeutic range
- High bleeding rate
- Difficult to monitor
- Slow reversibility
Stroke in Atrial Fibrillation
In comparison to stroke without AF, how is stroke with AF?
Stroke in Atrial fibrillation
Strokes are more severe and disabling in patients with AF
Risk factors for stroke in Non-valvular AF:
- Use _____ score.
- What is worth 1 point?
- What is worth 2 points?
Risk factors for stroke in Non-valvular AF:
- CHADS2 score
- CHF, hypertension, Age (75+), Diabetes
- Stroke or TIA in the past
Antithrombic therapy in AF based on CHADS score:
What do you give for a patient with a score of:
- 0?
- 1?
- 2+?
Antithrombic therapy in AF based on CHADS score:
- Score of 0 = aspirin
- Score of 1 = Aspirin or Warfarin
- Score of 2+ = Warfarin
Warfarin Dosing: monitored by?
Warfarin dosing is monitored by PT (prothrombin time) extrensic pathway
Pentasaccharide:
Mechanism of action:
Produces an irriversible ____ change in ____, which binds to and inhibits factor ____. It thus inhibits clot ______.
Pentasaccharide:
Produces an irreversible conformational change in antithrombin which binds to and inhibits factor Xa. It thus inhibits clot propagation
Fondaparinux:
- Indirect inhibition of Factor ___. This is via ____.
- ____ selective.
- ____ inhibit thrombin activity
- ____ inhibit thrombin generation
- FDA approved for?
Fondaparinux:
- Indirect inhibition of Factor Xa. This is via AT-III
- Highly selective
- DOESNT inhibit thrombin activity
- DOES inhibit thrombin generation
- FDA approved for DVT prophylaxis in hip fracture, TKA/THA (Total hip/knee arthroplasty)
Direct Thrombin Inhibitors:
What ones are bivalent?
What ones are Univalent?
Direct Thrombin Inhibitors:
Bivalent - Hirudin and Bivalirudin
Univalent - Argatroban, dabigatran, ximelagatran
Potential advantages of direct inhibitors:
- Affect only one factor: ___
- Independent of ____
- Inhibition of thrombin-mediated activation of?
- Active against what types of thrombin?
Potential advantages of direct inhibitors
- Thrombin
- Independent of AT-III
- Inhibition of activation of clotting factors (V, VIII, and XIII) and platelets
- *****Active agains free and clot-bound thrombin
Which direct thrombin inhibitors are given IV?
Which are given orally?
Bivalirudin and Argatroban are IV
Ximelagatran and Dabigatran are oral
Bilavirudin:
- Partially ____ binding
- No inhibition of thrombin ____
- FDA approved for?
- Direct ____ thrombin binding.
Bilaviruden:
- reversible
- NO inhibition of thrombin generation
- FDA approved for anticoagulation during PCI (Percutaneous coronary intervention)
- Direct bivalent binding
Argatroban
- Type of binding?
- Excretion?
- FDA approval for treatment of?
Argatroban
- Reversible competitive binding
- Hepatic excretion
- FDA approval to treat HIT and for PCI in patients with a history of HIT (Heparin Induced Thrombocytopenia)
New oral Anticoagulants:
What two new drugs are Direct Xa inhibitors used for DVT and nonvalvular Afib?
What is Pradaxa? For?
New oral anticoagulants:
Xarelto and Eliquis (Direct Xa inhibitors)
Pradaxa - direct thrombin inhibitor for nonvalvular Afib and DVT
Fibrinolytic Therapy:
- TPA is released from endothelial cells but rapidly cleared by?
- What is protected from inhibition?
Fibrinolytic Therapy:
- Cleared by PAI-1 and PAI-II
- Fibrin-bound plasmin is protected from inhibition
Fibrinolytic Therapy:
Agents? (4)
Fibrinolytic Therapy:
a. Streptokinase
b. Reteplase
c. Tenecteplase (TNK)
d. Wild-type TPA
Fibrinolytic Therapy:
Wild-type t-PA:
- Activates what kind of plasminogen?
- Route of administration?
- Half life?
Fibrinolytic Therapy:
Wild-type t-PA:
- Activates bound plasminogen several hundred-fold more rapidly than circulating plasminogen
- IV (continuous infusion)
- Very short
Fibrinolytic Therapy:
All fibrinolytic agents have the ptoential to cause?
Fibrinolytic Therapy:
All can cause very serious bleeding including a very small incidence of intracranial hemorrhage
Clinical role for lytics?
Acute MI, stroke, pulmonary emboli, declot IV catheters/dialysis accesses, and DVT
