Vitamin K Antagonist Pharmacology, Pharmacotherapy and Pharmacogenomics

Faculty & Faculty Disclosure

Mary Jane E. Mattern, PharmD Pharmacist

William W., Backus Hospital

There are no actual or potential conflicts of interest associated with this presentation.

Learning Objectives

  • Discuss the basic physiology of coagulation
  • Discuss the pharmacology of the vitamin K antagonist
  • Discuss the indications and contraindications for the vitamin K antagonist
  • Discuss the roles genetics plays in the dosing of warfarin
  • Discuss the utility of how genetic testing will affect initial dosing of warfarin

Course Materials & Handouts

Downloadable Files

All Documentation

Virchow’s Triad

Coagulation Physiology

The process of coagulation is mediated by the presence of tissue factor, negatively charged phospholipid surfaces, and collagen

Under normal conditions, these compounds are not in contact with blood

Endothelial damage, exposure to toxins, and inflammation expose these components to intravascular blood flow

The extrinsic and early intrinsic coagulation pathways begin upon this exposure

Tissue Factor

Injury occurs

Tissue factor (TF) is expressed by damaged endothelium

TF complexes with circulating activated factor VII (VIIa)

The extrinsic pathway of the coagulation cascade is catalyzed

Phospholipid Surfaces

Injury occurs

Endothelial cells expose negatively charged phospholipid surfaces to blood

Activated platelet surfaces also expose negatively charged phospholipid surfaces

Vitamin K dependent clotting factors bind to these surfaces

Collagen

Injury occurs Collagen is exposed

Collagen binds von Willebrand factor (VWF) Platelets bind VWF via glycoprotein Ia

Platelets are activated, secrete adenosine diphosphate (ADP) and thromboxane A2 (TXA2), and aggregate

The Clotting Cascade

Which of the following is NOT a catalyst for the coagulation cascade?

a) Tissue Factor

b) Plasminogen

c) Collagen

d) Negatively charged phospholipid surfaces

Vitamin K Dependent Clotting Factor Physiology

Clotting factors II, VII, IX, and X and endogenous anticoagulants Protein C and Protein S are synthesized in the liver

Vitamin K Epoxide Reductase (VKOR) enzyme reduces vitamin K in quinone form (vitamin K1) to active vitamin KH2

Vitamin KH2 serves as cofactor for carboxylation of clotting factor precursors-carboxylation of glutamic acid (glu) residues at N-terminal region of clotting factor precursors yield -carboxyglutamic acid (gla) residues

Clotting factors can now complex with negatively charged phospholipid membranes in the presence of calcium

Vitamin K Dependent Clotting Factor Physiology

Clotting factors II, VII, IX, and X and endogenous anticoagulants Protein C and Protein S are synthesized in the liver

Vitamin K Epoxide Reductase (VKOR) enzyme reduces vitamin K in quinone form (vitamin K1) to active vitamin KH2

Vitamin KH2 serves as cofactor for carboxylation of clotting factor precursors-carboxylation of glutamic acid (glu) residues at N-terminal region of clotting factor precursors yield -carboxyglutamic acid (gla) residues

Clotting factors can now complex with negatively charged phospholipid membranes in the presence of calcium

Vitamin K Epoxide Reductase (VKOR)

Vitamin K1 occurs naturally in quinone oxidated state Vitamin K1 must be reduced to hydroquinone form (vitamin KH2) to serve as cofactor for carboxylase

Vitamin K epoxide reductase (VKOR) is the enzyme responsible for conversion from the inactive vitamin K1 quinone to the active vitamin KH2

VKOR also “recycles” vitamin K epoxide (a byproduct of gamma carboxylation) back to active vitamin KH2

Warfarin’s mechanism of action targets VKOR

DT-diaphorase

An NAD(P)H dehydrogenase

Reduces quinone form of vitamin K1 to vitamin KH2 Has no effect on vitamin K epoxide

Likely has little role in vitamin K recycling process May have a role in vitamin K reversal of warfarin overdose

The following is true regarding VKOR, except:

a) It converts vitamin K1 to active vitamin KH2

b) It is the target of warfarin’s mechanism of action

c) It binds to negatively charged phospholipids in the presence of calcium

d) It recycles vitamin K epoxide to active vitamin KH2

Warfarin Structure

Molecular Formula C19H16O4

4-hydroxycoumarin nucleus

Commercially available as a racemic mixture of optical isomers

R and S enantiomers have similar mechanisms but different kinetic and dynamic properties

Mechanism of Action

Warfarin shares a common ring structure with vitamin K

Warfarin inhibits VKOR = lower yield of hydroquinone

With less active cofactor, carboxylation of vitamin K dependent proteins in hindered

Glu residues on vitamin K dependent proteins are not as easily carboxylated to gla residues

Vitamin K dependent proteins cannot function normally

Pharmacokinetics – Absorption

Rapid absorption from GI tract with high bioavailability

Highly water soluble

Food has no effect on absorption

Absorption likely occurs in proximal small bowel

Pharmacokinetics – Distribution

99% protein bound (mainly albumin)

Volume of distribution = 0.11 to 0.2 L/kg

Specific disease states (i.e.: cancer, uremia) and use of other highly albumin bound medications (i.e.: phenytoin, ibuprofen) may affect warfarin binding to proteins and alter free fraction of circulating warfarin

Pharmacokinetics – Metabolism

Metabolism

R and S isomers are metabolized by the liver

S-warfarin is principally metabolized by CYP2C9 enzyme R-warfarin is principally metabolized by CYP3A4 and CYP1A2

enzyme enzymes

Genetic variability in CYP2C9 enzyme may pose additional risk to patients

S-warfarin has 2-5 times the anticoagulant activity of its optical isomer, R-warfarin

Pharmacokinetics – Excretion

Elimination t1/2 = 20-60 hours

S-warfarin =18-43 hours

R-warfarin = 20-89 hours

Excreted as inactive metabolites in bile, then urine

Excreted as inactive metabolites in breast milk (considered compatible with breast feeding with appropriate monitoring)

Lifespan of Vitamin K Dependent Proteins

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References

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