Mechanism of Action of Warfarin (Vitamin K Antagonist)

Introduction

Warfarin is a widely used oral anticoagulant that inhibits the synthesis of vitamin K-dependent clotting factors. It is commonly prescribed for atrial fibrillation, deep vein thrombosis (DVT), pulmonary embolism, and prosthetic heart valves. Due to its narrow therapeutic window, multiple drug interactions, and the need for INR monitoring, warfarin is a high-yield topic for students preparing for USMLE, NCLEX, NAPLEX, GPAT, and NEET-PG.

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Mechanism of Action of Warfarin: Step-by-Step

1. Inhibition of Vitamin K epoxide reductase (VKORC1)
   Warfarin inhibits VKORC1, the enzyme responsible for regenerating reduced vitamin K.
2. Prevention of γ-carboxylation
   Without reduced vitamin K, the γ-carboxylation of glutamic acid residues in clotting factors is blocked.
3. Production of inactive clotting factors
   This leads to the synthesis of biologically inactive clotting factors II, VII, IX, and X, and proteins C and S.
4. Delayed onset of action
   Warfarin does not affect already circulating clotting factors, so the full anticoagulant effect is delayed until existing factors degrade.
5. Monitoring with INR
   The drug’s activity is monitored via the international normalized ratio (INR), with a typical therapeutic range of 2.0–3.0.

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Pharmacokinetic Parameters of Warfarin

Parameter	Value
Bioavailability	~100% (oral)
Half-life	~36–42 hours
Protein binding	~99% (albumin)
Metabolism	Hepatic (CYP2C9, CYP3A4)
Excretion	Renal (as metabolites)
Onset of action	24–72 hours
Duration of action	2–5 days (due to irreversible inhibition)

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Clinical Uses of Warfarin

• Prophylaxis and treatment of DVT and PE
• Prevention of stroke in atrial fibrillation
• Mechanical prosthetic heart valves
• Post-MI prophylaxis in selected patients
• Hypercoagulable states (e.g., protein C or S deficiency)

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Adverse Effects of Warfarin

• Bleeding (major risk)
• Skin necrosis (early, due to protein C depletion)
• Teratogenicity (fetal warfarin syndrome)
• Purple toe syndrome
• Drug interactions (CYP inhibitors/inducers)
• Requires regular INR monitoring

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Comparative Analysis: Warfarin vs DOACs (e.g., Apixaban)

Feature	Warfarin	DOACs (Apixaban, Rivaroxaban)
Target	Vitamin K epoxide reductase	Factor Xa or thrombin
Onset of action	Slow (24–72 hrs)	Rapid (2–4 hrs)
Monitoring	Required (INR)	Usually not required
Reversal agent	Vitamin K, FFP	Andexanet alfa (Xa); idarucizumab (IIa)
Diet interaction	Yes (vitamin K intake matters)	No
Use in pregnancy	Contraindicated	Contraindicated

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Practice MCQs

Q1. Warfarin inhibits which enzyme?
a. Cyclooxygenase
b. Thrombin
c. Vitamin K epoxide reductase ✅
d. Factor Xa

Q2. Which clotting factors are affected by warfarin?
a. II, VII, IX, X ✅
b. I, V, VIII, XIII
c. All clotting factors
d. Platelet factors

Q3. Warfarin requires monitoring of:
a. aPTT
b. Platelet count
c. INR ✅
d. Bleeding time

Q4. Warfarin is contraindicated in:
a. Diabetes
b. Pregnancy ✅
c. Asthma
d. Hypertension

Q5. Onset of action of warfarin is:
a. Immediate
b. 6 hours
c. 24–72 hours ✅
d. 1 week

Q6. Which protein is affected early by warfarin and causes skin necrosis?
a. Protein A
b. Protein B
c. Protein C ✅
d. Protein D

Q7. Warfarin is metabolized by:
a. Kidneys
b. CYP3A4 and CYP2C9 ✅
c. Plasma esterases
d. Acetylation

Q8. Which vitamin reverses warfarin effect?
a. B12
b. C
c. K ✅
d. D

Q9. Which food reduces warfarin’s effect?
a. Cheese
b. Yogurt
c. Leafy greens (high vitamin K) ✅
d. Eggs

Q10. Antidote for warfarin overdose includes:
a. Protamine
b. Vitamin K ✅
c. Naloxone
d. Glucagon

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FAQs

Q1: Is warfarin safe in pregnancy?
No. Warfarin is teratogenic and contraindicated during pregnancy.

Q2: Can I eat spinach while on warfarin?
Yes, but maintain consistent intake of vitamin K-rich foods.

Q3: Why is INR monitoring necessary?
To avoid bleeding or inadequate anticoagulation. Target INR: 2.0–3.0 (except in mechanical valves: 2.5–3.5).

Q4: What drugs interact with warfarin?
Many, including NSAIDs, antibiotics, antifungals, and antiepileptics.

Q5: Can warfarin and aspirin be used together?
Yes, but increases bleeding risk — only under strict medical supervision.

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References

• KD Tripathi – Essentials of Medical Pharmacology
• Goodman & Gilman – The Pharmacological Basis of Therapeutics
• Sparsh Gupta – Review of Pharmacology
• NCBI: https://www.ncbi.nlm.nih.gov/books/NBK470440/