Warfarin

Generic Name

Warfarin

Brand Names

Coumadin

Jantoven

Marevan

Warfilone

Aldocumar

Warin

Panwarfin

Drug Class

Oral anticoagulant

Vitamin K antagonist

Belongs to the coumarin derivative group

Mechanism of Action

Warfarin inhibits the enzyme vitamin K epoxide reductase complex 1 VKORC1

This inhibition reduces the regeneration of reduced vitamin K

Reduced vitamin K is essential for the gamma-carboxylation of clotting factors II VII IX and X and proteins C and S

Inhibiting this cycle decreases the synthesis of these clotting factors

Result is impaired coagulation leading to anticoagulant effect

Takes 24 to 72 hours to begin effect

Peak effect may take up to 5 to 7 days due to variable half-lives of clotting factors

Indications

Prophylaxis and treatment of venous thromboembolism

Deep vein thrombosis DVT

Pulmonary embolism PE

Prevention of stroke and systemic embolism in atrial fibrillation

Prevention of thromboembolic complications post-myocardial infarction

Mechanical and biological prosthetic heart valve thromboprophylaxis

Antiphospholipid syndrome-associated thrombosis

Long-term anticoagulation in patients at high risk for thrombosis

Dosage and Administration

Dosing is individualized based on INR

Initial dose typically 5 mg to 10 mg daily for 1 to 2 days

Maintenance dose generally 2 mg to 10 mg daily depending on INR response

Dose adjustments made based on INR values

Target INR

2 to 3 for DVT PE AF mechanical aortic valve

25 to 35 for mechanical mitral valve or recurrent thromboembolism

Administered orally once daily at the same time preferably in the evening to facilitate dose adjustments

Requires frequent INR monitoring especially in the first weeks

Parenteral anticoagulant bridging may be required initially until therapeutic INR is reached

Pharmacokinetics

Warfarin is a racemic mixture of R- and S-isomers

S-isomer is more potent and metabolized by CYP2C9

R-isomer metabolized by CYP1A2 and CYP3A4

Onset of action is delayed due to existing circulating clotting factors

Peak effect may take several days

Elimination half-life ranges from 20 to 60 hours

Highly protein bound over 97 percent

Excreted in urine mostly as metabolites

Crosses placenta but not into breast milk

Contraindications

Pregnancy Category X due to teratogenicity

Active bleeding or significant risk of bleeding

Uncontrolled hypertension

Recent surgery especially eye brain or spinal procedures

Hemorrhagic tendencies or blood dyscrasias

Peptic ulcer disease

Severe hepatic disease

Noncompliant patients or those unable to comply with regular INR monitoring

History of warfarin-induced skin necrosis

Warnings and Precautions

Narrow therapeutic index

Requires close INR monitoring

Bleeding risk increases with supratherapeutic INR

Vitamin K intake affects therapeutic response

Sudden changes in diet illness or medication may alter INR

Patients should maintain consistent vitamin K intake

Increased sensitivity in elderly and those with liver disease or CYP2C9 polymorphisms

Warfarin-induced skin necrosis and purple toe syndrome are rare but serious adverse effects

Bridging with heparin is essential in high thromboembolic risk situations when initiating or interrupting warfarin

Avoid intramuscular injections due to hematoma risk

Adverse Effects

Most common is bleeding including epistaxis gastrointestinal bleeding hematuria and intracranial hemorrhage

Minor bleeding such as bruising gum bleeding or prolonged bleeding from cuts

Rare adverse effects

Skin necrosis

Purple toe syndrome

Hair loss

Nausea

Abdominal cramps

Hepatic dysfunction

Allergic reactions

Reversal of Anticoagulation

Minor bleeding or elevated INR without bleeding

Hold warfarin and monitor

Oral vitamin K may be given if INR >5

Major bleeding

Administer intravenous vitamin K 5 to 10 mg slow infusion

Fresh frozen plasma FFP or prothrombin complex concentrate PCC for rapid reversal

Activated charcoal may be used if ingestion was recent

Drug Interactions

Warfarin has extensive drug interactions

CYP enzyme inhibitors increase warfarin levels and bleeding risk

Amiodarone

Azole antifungals

Macrolides

Fluoroquinolones

Cimetidine

SSRIs

Statins especially simvastatin and fluvastatin

CYP enzyme inducers reduce warfarin effect and increase thrombosis risk

Rifampin

Carbamazepine

Phenobarbital

Phenytoin

Oral contraceptives may antagonize warfarin

Antibiotics may reduce gut flora and vitamin K synthesis

NSAIDs aspirin and antiplatelets increase bleeding risk

Herbal supplements

St Johns wort reduces efficacy

Ginkgo biloba garlic ginger increase bleeding risk

Green leafy vegetables high in vitamin K may reduce anticoagulant effect

Food Interactions

Patients should maintain consistent intake of vitamin K-rich foods

These include spinach kale broccoli cabbage liver green tea

Alcohol increases bleeding risk and affects metabolism

Cranberry juice may enhance warfarin effects

Monitoring Parameters

INR should be monitored frequently initially then every 2 to 4 weeks

Target INR is 2 to 3 for most indications

Monitor for signs of bleeding or thrombosis

Liver function tests if hepatotoxicity suspected

Hemoglobin and hematocrit periodically

Assess compliance and dietary changes

Use in Special Populations

Pregnancy

Contraindicated in first trimester due to risk of fetal warfarin syndrome

May be used in second and third trimesters under specialist care but usually avoided

Switch to low molecular weight heparin LMWH during pregnancy is preferred

Lactation

Safe for breastfeeding

No significant excretion in breast milk

Elderly

Increased sensitivity due to altered metabolism

Start at lower doses

Hepatic Impairment

Requires lower doses and more frequent monitoring

Increased bleeding risk

Renal Impairment

No major adjustment required but caution with bleeding

Genetic Polymorphisms

VKORC1 and CYP2C9 gene variants affect response

Genotyping may assist in dosing in select patients

Patient Counseling Points

Importance of regular INR monitoring

Maintain consistent vitamin K intake

Report signs of bleeding immediately

Avoid OTC NSAIDs or aspirin unless prescribed

Use soft toothbrush and electric razors to minimize bleeding risk

Inform healthcare providers including dentists about warfarin therapy

Avoid major changes in diet without consulting healthcare provider

Carry anticoagulant alert card or wear medical ID

Comparative Considerations

Warfarin requires frequent monitoring unlike direct oral anticoagulants DOACs

DOACs like apixaban rivaroxaban dabigatran do not need INR monitoring

Warfarin remains preferred for mechanical heart valves antiphospholipid syndrome and severe renal dysfunction

Unlike DOACs warfarin has a specific reversal strategy using vitamin K and PCC

Warfarin is sensitive to food and drug interactions whereas DOACs are more predictable

Formulations Available

Tablets of various strengths 1 mg 2 mg 25 mg 3 mg 4 mg 5 mg 6 mg 75 mg 10 mg

Color-coded by strength to reduce dosing errors

Oral only no intravenous formulation

Regulatory and Legal Status

Prescription-only medicine

Approved globally since the 1950s

Listed on the WHO Model List of Essential Medicines

Not classified as controlled substance