AntiCoag/Platelets - Chen

Each stage of the Intrinsic Pathway needs

Protease, protein Cofactor, Ca2+, Phospholipid surface

Extrinsic pathway is activated by ____ and is _____ than the intrinsic pathway

trauma; faster

Common pathway in the Coag Cascade

Factor X is activated, which converts prothrombin (Factor II) to thrombin (Factor IIa), thrombin Converts Fibrinogen into a fibrin clot

Vit K in the Coag Cascade

Vit k dependent carboxylase adds Carb acid which eventually gets a gammacarboxyglutamic acid that chelates Ca2+

Warfarin MOA

Inhibits Vit K 2,3-epoxide Reductase which prevents activation of Factor II, VII, IX, X

antidote: More VIt K

UFH & LMWH MOA

Inhibit Xa & Thrombin through antithrombin 

Antidote: Protamine 

Factor Xa inhibitor MOA

Directly or indirectly (via antithrombin) inhibit Xa

Antidote: Andexanet alfa approved for rivaroxaban and apixaban

Direct Thrombin Inhib MOA

Inhibit thrombin :/

Antidote: Idarucizumab for dabigatran.

What Pharmacophore is this?

Coumarin

Warfarin Structure 

3 and/or 4-substituted, has lactone motif, weak
acidic (formulated as Na salt), one chiral center with S-isomer 4X more potent/d 

T/F Heparin is NOT Orally Bioavailable

True

Unfractionated Heparin

Ionically binds to Antithrombin III & helps inactivate Xa & thrombin

Pentasaccharide

LMWH

Slective against Factor Xa than thrombin

Safer against AEs than UF 

Fondaparinux

Synthetic Factor Xa inhibitor

pentasaccharide with a methyl Cap

long half life, renal insufficiency means longer half life

Protamine

Antidote to Heparins - Incomplete nuetralization of LMWH

NO effect on fondaparinux

Arganine Rich = very BASIC

Factor Xa inhibitors / DOAC Structure 

L shape with two hydrophobic binding pockets and one H-bond interaction

Direct Thrombin Inhibitors

Directly inhibits thrombin- free and bound thrombin inactivation

Can be Bivalent or Univalent

Dabigatran is the only prodrug

Aspirin Works by:

Irreversibly inactivating COX-1; causing long and short term-antiplatelet effects

Low dose aspirin causes antiplatelet effects without anti-inflammatory effects

Dipyridamol w/ aspirin  

Enhances effects of warfarin and aspirin in thrombolytic events 

P2Y12 inhibitors

Inhibit activation of glycoprotein IIb/IIIa complex, block platelet activation and aggregation

Most Irreversibly Bind to active site

Ticagrelor

reversible allosteric P2Y12 inhibitor

Cangrelor

Reversible Competitive P2Y12 inhibitor

GP IIb/IIIa antagonist drugs

abciximab, eptifibastide, tirofban

GP IIb/IIIa antagonists

Block final step of Activation - Cross-linking 

Abciximab: monoclonal antibody, irreversible inhibitor

Eptifibatide and tirofiban: small molecules, reversible inhibitors