Terms in this set (110)
Indirect Thrombin Inhibitors
Low-Molecular Weight Heparin (LMWH)
Unfractional Heparin (UFH)/
High-Molecular Weight Heparin (HMWH)
***I L.U.H. indirect thrombin inhibitors <3
Direct Thrombin Inhibitors
Indirect Factor Xa Inhibitors
Direct Factor Xa Inhibitors
Vitamin K Antagonists
Indirect Thrombin Inhibitor (Unfractional Heparin and LMWH)
What does Heparin have an affinity for binding to?
How do UFH and HMWH inhibit clotting?
HIGH affinity for binding to antithrombin
inhibits thrombin (IIa) and factor Xa
How does LMWH inhibit clotting?
LOWER affintiy for binding to antithrombin
inhibits factor Xa
less effects on thrombin
Indirect Thrombin Inhibitor (Heparin) MoA
inhibits clotting factor proteases, especially thrombin (IIa) and Xa; binding of heparin to plasma antithrombin forms a complex that is more active than antithrombin alone in neutralizing thrombin and factor Xa
Indirect Thrombin Inhibitors (Heparin) Toxicity
allergy (natural substance of animal origin)
What is a full-dose IV regimen of Heparin used for?
What is a low dose SQ regimen of Heparin used for?
prophylaxis of bleeding after major surgery in high-risk pts
protamine sulfate (IV)
What is protamine sulfate?
mixture of LMW peptides rich in arginine residues; it inactivates heparin by forming stable inactive salt with acidic groups of heparin then excreted in urine
Which has a longer half life and requires fewer doses: LMWH or UFH?
Which has greater bioavailibility from SQ injections that leads to a more predictable anti-coag response: LMWH or UFH?
Which can be reversed/neutralized more completely/rapidly with protamine: LMWH or UFH?
Is UFH cleared via the kidneys?
no, so it's better in renal insufficiency
Which directly inhibits contact activation pathway which is important in genesis of thrombi in stents, catheter tips, and filters: LMWH or UFH?
Which is more likely to cause heparin-induced thrombocytopenia: LMWH or UFH?
Which has a more variable anticoag response so requires monitoring via INR: LMWH or UFH?
Why can HMWH/UFH block thrombin, but LMWH can't?
HMWH/UFH has a HMW chain that can wrap around the complex (LMWH does not)
Low Molecular Weight Heparins
Direct Thrombin Inhibitor (Dabigatran) Indication
prevention of thromboembolytic disorders (VTE, DVT, thromboembolitic stroke)
Direct Thrombin Inhibitor (Dabigatran) MoA
inhibits thrombin-mediated effects by binding competitively/reversibly to active site of thrombin through hydrophobic interactions
Direct Thrombin Inhibitor (Dabigatran) Toxicity
dyspepsia (remember from top 200)
gastritis (remember from top 200)
Why are Direct Thrombin Inhibitors (Dabigatrain) more effective than Indirect Thrombin Inhibitors (Heparin)?
DTIs inhibit BOTH clot-bound and free-circulating thrombin and decreases thrombin-stimulated platelet aggregation
Do DTIs bind to antithrombin or other plasma proteins?
no, IDTIs do
What is unique about dabigatran compared to warfarin?
1. no dietary restrictions :)
2. lower risk of intracranial bleeding :)
3. no established method/procedure for determining extent of anti-coagulation :(
4. higher incidence of major bleed/GI bleed :(
5. shorter-half life :(
idarucizumab (doesn't work with Direct Factor Xa Inhibitors)
Indirect Factor Xa Inhibitors (Fondaparinux) Indication
prophylaxis/treatment of VTE (just as effective/safe as UFH or LMWH)
Indirect Factor Xa Inhibitors (Fondaparinux) MoA
binds to antithrombin with high affinity and inhibits factor Xa INDIRECTLY through antithrombin without neutralizing thrombin
Indirect Factor Xa Inhibitors (Fondaparinux) Toxicity
much LESS likely to cause heparin-induced thrombocytopenia
Does fondaparinux inhibit clot-bound factor Xa?
no (like UFH and LMWH); it only inhibits free-circulating factor Xa
Direct Factor Xa Inhibitor (Rivaroxaban) Indication
1. prevention/treatment VTE
3. pulmonary embolism
4. stroke prevention (with afib)
Direct Factor Xa Inhibitor (Rivaroxaban) MoA
selective, competitive, reversible inhibitor of factor Xa which leads to inhibition of thrombin production via both intrinsic and extrinsic pathways in clotting cascade
Direct Factor Xa Inhibitor (Rivaroxaban) Toxicity
What is unique about rivaroxaban compared to warfarin?
1. shorter half-life :(
2. no effective antidote :(
3. no established method for determining extent of anti-coag
4. less intracranial bleeding :)
5. no dietary restrictions :)
Does rivaroxaban inhibit BOTH free-circulating and clot-bound factor Xa?
Yes! [unlike UFH, LMWH, and fondaparinux (indirect factor xa inhibitor)]
What is the antidote is under investigation for rivaroxaban?
What drugs can Andexanent Alfa reverse the effects of?
Direct Factor Xa Inhibitors (complete reversal)
Indirect Factor Xa Inhibitors (partial reversal)
Which causes more intracranial bleeding: 20mg QD rivaroxaban or 150 mg BID dabigatran?
used alone or in combo with heparin for prophylaxis/treatment of intravascular bleeding
Which enantiomer of warfarin is more potent?
S-warfarin is 3-5 more potent than R-warfarin
acting in liver, blocks gama-carboxylation of glutamate residues in vitamin-K-dependent clotting factors by inhibiting vitamin K epoxide reductase
What does vitamin K epoxide reductase do?
catalyzes the reductive metabolism of inactive vitamin K epoxide back to its active hydroquinone form
Does warfarin have immediate anti-coag effects?
no, there is an 8-12 hour delay
Does warfarin have effect on an already-formed emolus?
no, but it may prevent further clotting
Warfarin Drug Interactions
3rd gen cephalosporins
Warfarin Drug-Disease State Interactions
Warfarin and ASA interaction
aspirin increases warfarin's activity/prothrombin time by its effect on platelet function
Warfarin and Heparin interaction
heparin increases wafarin's activity by inhibiting activity of several clotting factors and prolongs prothrombin time
Warfarin and 3rd gen cephalosporins interaction
3rd gen cephalosporins increase warfarin's activity by eliminating bacterial microflora that produce vitamin K in intesine and directly inhibit vitamin K epoxide reductase
Warfarin and Hepatic Disease Interaction
hepatic disease increases warfarin's activity by inhibiting synthesis of clotting factors in the liver
Warfarin and Hyperthyroidism
Hyperthyroidism increases warfarin's activity by the degradation of clotting factors
Warfarin and Hypothydroidism
Hypothydroidism decreases warfarin's activity by decreasing the degradation of clotting factors
What metabolizes warfarin into its inactive metabolite?
Which clotting factors does warfarin affect?
plus protein C and protein S
Variations in which 2 genes affect variability in warfarin response?
How is warfarin activity reversed/regenerate normal clotting activity?
Phytonadione (Vitamin K)
Prothrombin Complex Concentrates
Recombinant Clotting Factor VIIa (rFVIIa)
Tissue Plasminogen Activator (t-PA)
Fibrinolytic Agent Indications
treatment of thrombotic diseases
multiple pulmonary emboli
peripheral vascular disease
management of acute MI
binds to proactivator plasminogen to form an enzymatic complex which catalyzes conversion of inactive plasminogen to active plasmin
directly converts plasminogen to plasmin
preferentially activates plasminogen that is bound to fibrin (targets formed thrombus and avoids systemic activation of plasminogen)
What is Alteplase?
recombinant human t-PA
What is Relteplase?
recombinant human t-PA that lacks the major fibrin-domain and is less fibrin-specific than t-PA
What is Tenecteplase?
mutant form of t-PA that has a longer half-life; sligtly more fibrin-specific that t-PA
How do Fibrinolytic drugs lyse thrombi?
by catalyzing formation of the serine protease plasmin from its precursor plasminogen
What is plasmin?
the active fibrinolytic enzyme that remodels the thrombus and limits the extention of thrombosis by protective digestion of fibrin
Why can't plasmin be used itself as a drug?
because naturally occurring inhibitors of plasma block its effects
inhibits activation of plasminogen to plasmin; inhibits process of fibronolysis so protects blood clots from lysis and reduces bleeding
GP IIb/IIIa Receptor Antagonists
GP IIb/IIIa Receptor Antagonists
***Who A.T.E. all the GP IIb/IIIa Receptor Antagonists?
GP IIb/IIIa Receptor Antagonist MoA
(Abiximab, Tirofiban, Eptifibatide)
blocks GP IIb/IIIa receptor complex
GP IIb/IIIa Receptor Antagonist Toxicity
PAR-1 Antagonists Indication
used PO with aspirin or clopidogrel to reduce risk of CV events in pts with peripheral arterial disease or history of MI
PAR-1 Antagonist MoA
blocks protease-activated receptor-1 (PAR-1), the major thrombin receptor on platelets, and inhibits thrombin-induced platelet aggregation
PAR-1 Antagonist Toxicity
PAR-1 Antagonist Contraindication
hx of stroke
hx of transient ischemic attack
hx of intracranial hemorrhage
active pathological bleeding
Which antiplatelet is a substrate for CYP3A4?
vorapaxar (PAR-1 Antagonist)
used in combo with ASA to prevent CV ischemia; also used in combo with warfarin for prophylaxis of thromboemboli
inhibits platelet aggregation by inhibiting platelet uptake by adenosine and blocking ATP-induced platelet aggregation
prophylaxis of MI; secondary prevention of vascular events in pts with history of vascular events
inhibits synthesis of TXA2 by irreverisble acetylation of COX-1 -> inhibits platelet activation and aggregation for the lifetime of platelets
asthma/other hypersensitivity symptoms*
(clopidogrel, prasugrel, ticlopidine)
prevention of thrombotic CV events in pts with acute transient ischemic attacks, completed strokes, and unstable angina pectoris
reduce platelet aggregation by inhibiting ADP pathway; bind and irreversibly block P2Y12 ADP receptor on platelet membranes
used in combo with low-dose ASA to reduce rate of thrombotic CV events in pts with acute coronary syndrome
inhibits platelet activation and aggregation by binding reversibly to P2Y12 ADP receptor on platelet membranes
increases uric acid and creatinine*
Nonthienopyridine ATP Analogs
Nonthienopyridine ATP Analogs Indication
an adjunct to percutaneous coronary intervention (PCI) in pts who have not been pretreated with P2Y12 blocker and are not being given a glycoprotein IIb/IIIa inhibitor
How is cangrelor given?
given as an IV bolus before PCI, followed immediately by a cangrelor IV infusion for the duration of the procedure or for 2 hours, whichever is longer. After stopping the cangrelor infusion, an oral P2Y12 blocker should be started to maintain platelet inhibition.
What is nice about cangrelor compared to clopidogrel and other P2Y12 blockers?
Unlike clopidogrel and the other oral P2Y12 blockers, the antiplatelet effect of cangrelor occurs rapidly and is quickly reversed.
Which is more effective: clopidogrel or cangrelor?
like ticagrelor, cangrelor appears to be more effective than clopidogrel
Nonthienopyridine ATP Analogs MoA
inhibits platelet activation/ aggregation by binding/reversibly blocking P2Y12 ADP receptor on platelet membranes
Nonthienopyridine ATP Analogs toxicity
Which antiplatelet a prodrug?
thienopyridines (clopidogrel, prasugrel, ticlopidine