Drugs Affecting Coagulation Flashcards
Hemostasis is achieved in what three ways?
Vascular contraction (vasospasm)
Platelet adhesion, activation, aggregation
Fibrin formation and reinforcement of the platelet plug (coagulation)
What is the common point in the coagulation cascade, where the intrinsic and extrinsic pathways meet?
Factor Xa
Which factors are in the intrinsic pathway?
XII—>XIIa
XI —> XIa
IX —> IXa
X —> Xa (with VIIIa)
Which factors are in the extrinsic pathway?
III (TF) —> IIIa
VII —> VIIa-TF
X —> Xa
Heterogeneous mix of sulfates mucopolysaccharides (large negatively charged molecule)
Heparin
Action from a unique pentasaccharide
MOA for heparin
Activity is dependent on ANTITHROMBIN III
Mainly affects Xa and thrombin
Affects factors IXa, XIa and XIIa as well
Catalyst —> accelerates ATIII activity (x1000)
________ competes for binding to heparin and has immediate effect
Protamine sulfate
Works b/c it’s a large positive molecule (helps it bind to heparin’s large negative molecule)
What are the indications for Heparin use?
Anticoagulant for operations or IV catheters
Prophylaxis against thrombosis (DVT/PE)
***How is unfractionated heparin administered
Exclusively IV
Not IM —> hematoma
Onset of action is IMMEDIATE
Therapeutic target is PTT 2-2.5x normal
What are the adverse effects of Heparin?
HEMORRHAGE (true of all anticoagulants)
Allergic reactions
Mild decrease in platelets
HEPARIN-INDUCED THROMBOCYTOPENIA (HIT)
What is the reversal agent for Heparin
Protamine sulfate (think heParin)
Contraindications for heparin use
RENAL OR HEPATIC DYSFUNCTION
Don’t use in patients who are: • Actively bleeding • Hemophilia or other clotting disorders • Hypersensitve • During or after surgery of the brain, spinal cord, or eye
What are the names for the Low Molecular Weight Heparins?
Enoxaprin
Fondaparinux (a synthetic pentasaccharide)
***LMW Heparin is similar to UFH except…
Main inhibitory action is on factor Xa (not much effect on thrombin
Can be injected subcutaneously***
Lower incidence of HIT
Protamine sulfate does not completely reverse LMWH and has NO EFFECT on fondaparinux***
Bivalirudin is a recombinant form of hirudin, a natural anticoagulant from …
Leeches
Highly specific direct inhibitor of thrombin (no AT III)
What drug is given as an alternative anticoagulant in patients with HIT?
Bivalirudin (IV only)
Can cause hypersensitivity (40%)
Use caution in liver patients
Direct inhibitor of thrombin given as an alternative in patients with HIT
Argatroban (think “thro(M)Ban”)
Cleared by the liver and given by continuous IV infusion
Use caution in patients with poor liver function
***ORAL direct inhibitor of thrombin
Dabigatran (Pradaxa)***
Used to prevent stroke in patients with non-valvular a fib
***Direct thrombin inhibitor with predictable anticoagulant effects (so not monitored by PTT)
Dabigatran***
Why does Dabigatran (Pradaxa) have a black box warning?
Avoid abrupt d/c without adequate alternative anticoagulant —> increased risk of thrombotic events
What is the antidote for Dabigatran (Pradaxa)
Idarucizumab (Praxbind)
What are the “XaBans”?
Direct inhibitors of Factor Xa
Rivaroxaban, Apixaban, Edoxaban, Betrixaban
ORAL
Used for DVT, PE, and future clots (prophylaxis)
Rivaroxaban and Apixaban can be used in _______ patients, the other XaBans are for use in _______.
R/A —> any patients (been around longer, so more studies)
Other XaBans —> patients with non-valvular afib or critically ill
Avoid XaBans in patients with…
Liver Disease
Renal Failure
***What is the antidote for Direct Inhibitors of Factor Xa (XaBans)?
Factor Xa decoy (Andexxa)***
***What it’s the MOA for Warfarin
Inhibits reduction of vitamin K —> interferes with synthesis of factors II, VII, IX, X, and Proteins C & S***
Protein C&S have shorter 1/2 life so you start to see effect because of these factors first
***Why do you have to start Warfarin in combo with heparin?
Because it takes 4-5 days to take full effect because it works by inhibiting clotting factor synthesis***
Peak effect after 48 hours, monitored by INR (2-3)
Indications for Warfarin use
Prevent development of emboli —> DVT, thromboembolism
No effect on already formed thrombi
Given chronically*** (oral)
**ADVERSE EFFECTS OF WARFARIN****
Hemorrhage, esp into the bowel
***Reversal of action is with VITAMIN K (takes time to work) or FRESH FROZEN PLASMA
Quickly reduces levels of Protein C (short half-life) —> increased chance for warfarin-induced thrombosis —> CUTANEOUS NECROSIS AND INFARCTION
Must co-administer with heparin for first 5 days
Contraindications for Warfarin**
Pregnancy - Category X (crosses placenta, teratogenic)
Drug interactions (lots!)
What are the four steps in Fibrinolysis?
1) tPA released from healthy endothelium
2) Circulating tPA is inactivated by PAI
3) If not bound, tPA cleaves plasminogen into plasmin
4) Plasmin degrades the fibrin threads of the clot into soluble degradation products and removes the clot
What is the MOA for Fibrinolytic Agents?
Convert plasminogen to plasmin (lyses thrombus from within)
Given IV or intra-arterially for the lysis of clots, in MI, PE, DVT, or arterial thrombosis
Can cause serious bleeding (if so, give aminocaproic acid)
**What are the Thrombolytics drugs?
Alteplase (Tissue plasminogen activator or t-PA)
Tenecteplase
These guys are CLOT-SELECTIVE
How is Tenecteplase different from Alteplase?
Multiple point mutant of tPA (longer plasma half-life)
More fibrin specific and resistant to PAI-1 than standard tPA
Becoming the fibrinolytic agent of choice
________ drugs directly activate plasminogen but are not clot-fibrin specific (so they do generalized systemic fibrinolysis
Urokinase drugs
Streptokinase and Anistreplase
OFF-MARKET**
What drugs are useful in bleeding disorders AND reversal of fibrinolytic therapy?
Antifibrinolytics: Aminocaproic Acid, Tranexamic Acid
Completely inhibit plasminogen activation
DO NOT USE IN PATIENTS WITH DIC or GU BLEEDING
**What is the MOA for Aspirin
IRREVERSIBLE INHIBITION of COX enzyme —> reduced prostaglandin synthesis (TXA2) —> reduced platelet aggregation
Lasts the life of the platelet (7-10 days)
**Indications for Aspirin use
A single dose may prolong bleeding time for DAYS
May be useful in patients at risk for embolisms
SECONDARY PREVENTION OF CV EVENTS in patients with established CVD
**What is the MOA for Clopidigrel, Ticlopidine, and Prasugrel?
IRREVERSIBLY BLOCKS THE ADP RECEPTOR ON PLATELETS —> reduced platelet aggregation
How are Clopidigrel, Ticlopidine, and Prasugrel used?
***In patients who are allergic to aspirin (less GI bleeding)
To reduce thrombotic events following MI/stroke
**DOC for preventing thrombosis in patients undergoing placement of coronary stents
Clopidigrel is metabolized in its active form by CYP2C19, so use with caution when…
Using drugs that impair CYP2C19 function like OMEPRAZOLE
***What is the MOA for Abciximab, Eptifibatide, Tirofiban?
Inhibitors of GPIIb/IIIa receptor —> reduced platelet aggregation***
Abciximab is an antibody***
Eptifibatide and Tirofiban is an analog of carboxy end of fibrinogen
*****Indications for GPIIb/IIIa receptor inhibitors
Combined with heparin for percutaneous coronary intervention
Given IV in patients undergoing ANGIOPLASTY, ATHERECTOMY, AND STENT PLACEMENT
What is Vorapaxar?
Antagonist of the protease-activated receptor-1, the major thrombin receptor on human platelets
Potently inhibits thrombin-related platelet aggregation, used in prophylaxis in patients with previous MI or PAD
Given orally, long 1/2 life
Contraindicated in patients with Hx of stroke/TIA
