Warfarin Pharmacology

Indications of Warfarin
Prophylaxis and treatment of:
-Venous thrombosis
-Pulmonary Embolism
-Thromboembolism disorders
-Atrial Fibrillation with risk of embolism
-Prophylaxis of systemic embolism post MI (LV thrombus)

Which form of Warfarin is more important to us
S-Warfarin is more important than R-Warfarin

S form is 5x more active than R

Which CYP enzymes metabolize R-Warfarin

Which CYP enzymes metabolize S-Warfarin

Metabolism is 3x faster than R

Warfarin MOA
Extrinsic Pathway

Warfarin blocks Vitamin K Epoxide Reductase.
Vitamin K is required to activate II, VII, IX, and X cofactors

How do Polymorphisms affect warfarin metabolism?
Polymorphisms of CYP2C9 DECREASE metabolism of warfarin

We see the polymorphisms at the promotor region which decreases the synthesis of Vitamin K Epoxide Reductase Complex 1 = decreased Vitamin K regeneration

Important SNPs


Displayed 8-13%
430 C > T
17% decrease in activity

Important SNPs


Displayed <0.5% 818A > del
0% activity

Important SNPs


Displayed 6-10%
1075A > C
37% decrease in activity

CYP2C9 dosing adjustments to remember
*1/*1: Rapid metabolism-↑ dose
*1/*2: Rapid Metabolism- same dose
*1/*3: Reduced Metabolism- ↓ dose
*2/*2: Poor Metabolism- ↓↓ dose
*2/*3: Very Poor Meta.- ↓↓↓ dose

VKORC1 (VK) dosing adjustments to remember
GG – More protein- ↑ dose
AG – Less Protein- Usual dose
AA – Even less protein- ↓ dose

Typical Warfarin sensitivity genotype found in African American Populations
CYP2C9*1*1 VK GA – 29%

Warfarin Adverse Effects
Bleeding (GI)
Contraindicated in pregnancy (would give LMWH)
Warfarin induced skin necrosis – increased in patients with protein C or S deficiency
“Purple toes syndrome”
Hepatic dysfunction

Important points of Warfarin
-Blocks the Vitamin K-dependent glutamate carboxylation of precursor clotting
-Also inhibits Proteins C & S
-7-15 day delay in action because of T1/2 of clotting factors in plamsa
-Recovery needs synthesis of new clotting factors
-Action reversed with vitamin K
-Highly plasma protein bound (95%)
-Warfarin for long-term, Heparin for short-term

Drugs that affect warfarin MOA
Food rich in Vitamin K

Drugs that are substrates of CYP2C9
NSAIDs, Ketoprofen, Ibuprofen, Diclofenac, Antidiabetics (Glipizide)

Drugs that are CYP2C9 inhibitors
Antifungals (Fluconazole, Miconazole)
Antibacterials (Sulphaphenazole)
Anticonvulsants (Valproic acid)

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