Block 3 - Anticoagulants Med Chem Flashcards
What are the types of anticoagulants?
- Heparins
- Direct thrombin inhibitors
- Direct factor Xa inhibitors
- Warfarin
What drugs facilitate clotting?
- Replacement factors
- Vitamin K
- Antiplasmin drugs
What is the difference between intrinsic and extrinsic?
Intrinsic: internal damage
Extrinsic: Trauma
What factors are inhibited by heparin?
XIIa, XIa, IXa, Xa, IIa, XIIIa
What factors are inhibited by warfarin?
IX, X, VII, II
At what point do the intrinsic and extrinsic pathway converge?
Xa
Describe the process of fibrin crosslinking?
Glutamine and lysine comes together by factor XIIIa → cross linked fibrin
Describe the structure of heparin based anticoags.? How does it affect its dosage form?
Polymeric in nature → require IV administration to by pass first pass
What is the brand name for UFH?
Calcilean
What is the MOA of heparin?
Binds to antithrombin III (endogenous) using a pentasaccharide sequence
Heparin increased the binding rate between antithrombin and coagulation factor → inactivating it
What is the difference between unfractioned and LMW heparin binding?
What is the MOA of UFH?
Binds to many proteins including platelet factor 4 → HIT
High affinity fro antithrombin III → inhibition of thrombin and factor Xa
How is UFH dosed? Monitored?
Dose: Standard is 120USP/mg
Monitoring: aPTT (activated partial thromboplastin time) for intrinsic; INR for extrinsic
What is 1 USP?
Quantity required to prevent 1 mL of sheep blood from clotting for 1 hr
What is the MOA of LMWH?
Same as UFH however is more selective for Xa and has less HIT
More reliable
How is LMWH monitored?
Does not require it → reliable dosing and metabolism
How does fondaparinux differ from the other heparin drugs?
More specific for Xa than LMWH (no thrombin inhibition)
100% bioavailability, no metabolism, no plasma protein binding due to its synthetic nature
Very hydrophilic
What are the reversal agents of heparin? What is the fastest?
- Recombinant factor VIIa
- Protamine sulfate
- Platelet transfusion the fastest in emergency situations
- Fondaparinux
How does recombinant factor VIIa reverse heparin?
More VIIa means more Factor X converted to Xa → Increasing crosslinking fibrin and coagulation
How does protamine sulfate reverse heparin? What are the disadvantages?
Protamine is a basic (arginine) protein that binds to carboxylate on heparin → ionic binding that forms a stable and inactive complex
Lots of ADRs
What is another name for direct thrombin inhibitors?
Factor IIa inhibitors because thrombin is factor IIa
All thrombin inhibitors from heparin are classified as ____? How do direct differ?
Indirect inhibitors; Direct binds to antithrombin → inhibiting thrombin
What are the binding sites of direct thrombin inhibitors?
Active site (catalytic) and exosite 1 (responsible for binding fibrin)
What are the direct thrombin inhibitors?
- Lepirudin (Refludan)
- Desiruden (Iprivask)
- Bivalirudin (Angiomax)
- Argatroban (Novastan)
- Hirudin
What is hirudin?
Care from medical leeches
What are the analogues of hirudin?
Lepirudin and desirudin
What the mechanism of bivalrudin?
Binds to both the active and execute of thrombin, action is reversible from metabolism
Short DOA and quick onset
Doesn’t elicit antibody formation
What are some of the Argotroban properties?
- 1st small molecule DTI
- IV or SC (too hydrophilic → non-oral)
- Produces 3 metabolites
How does Dabigatran differ from other DTI?
1st PO active DTI
Prodrug of one ester, one carbamate
Bis-hydrolysis must happen in order to produce active drug
What is the dabigatran reversal agents?
Praxbind (Idarucizumab)
What is the MOA of idarucizumab?
Binds to dabigatran with much higher affinity that dabigatran binds to thrombin
Homanized monoclonal antibody
What are the Factor Xa inhibitors?
- Rivaroxaban (Xarelto)
- Apixiban (Eliquis)
- Endoxaban (Savaysa)
What is the MOA of rivaroxaban?
Binds to both free and bound Factor Xa creating a prothrombinase complex
Highly selective factor Xa inhibitor
What is the MOA of apixaban?
Eliquis is highly selective factor Xa inhibitor creating a prothrombinase complex
What are the reversal agents for Factor Xa inhibitors?
- Andexanet alfa (Andexxa): Recombinant factor Xa (rFXa)
What is the MOA of Andexxa?
Rivaroxaban/apixiban bind to rFXa with same affinity as endogenous FXa
What the Vitamin K antagonists?
- Warfarin (Coumadin)
Describe Warfarin binding?
Looks like vitamin K and inhibits Vitamin K 2,3- quinone/epoxide reductase
What are the biggest barriers of warfarin?
- Narrow therapeutic index
- Overdose → inhibition of coagulation → Internal bleeding
- Must be monitored by a clinical facility → expensive
- High plasma protein bound can increase or decrease concentration
What are the reversal agents of warfarin?
- Mephyton (phytonadione/Vitamin K1)
- Centra (Prothrombin Complex concentrate)
What is the purpose for mephyton?
Replenishes vitamin K in order to overcome effects providing competition
How does Kcentra provide warfarin reversal?
Replacement of the coagulation cascade factors deactivating warfarin
What are the components of KCentra?
- Mix of Factors II, VII, IX, X
- Contains Protein C and S (prothrombics)
- Albumin
What are high vitamin K sources?
Spinach, cheddar cheese, cabbage
What enzymes metabolize Warfarin?
CYP2C9, Cyp2C19, CYP1A2
