Pharmacology of Oral Anticoagulants: WARFARIN

Warfarin inhibits the activation of which Vitamin K dependent clotting factors?

VII, IX, X, II

Seven (shortest half life)

Nine

1O

Two (longest half life)

What’s the basic MOA of Warfarin?

• Interferes with the conversion of vitamin K epoxide

• Inhibits activation of vitamin K dependent clotting factors (7, 9, 10, and 2)

• Inhibits Protein C and S

What are contraindications to Warfarin use?

• Pregnancy (except in mechanical heart valve - MHV)

• Active major bleeding

• Inadequate lab facilities

• Unsupervised pts with senility, alcoholism, or psychosis or other lack of patient cooperation

• Spinal puncture or procedures with potential for uncontrolled bleeding

• Major regional, lumbar block anesthesia

• Malignant hypertension

• Known hypersensitivity (warfarin allergy is rare and often related to the dyes or excipients rather than active ingredient)

What are some PK factors of Warfarin?

• Peak effect takes 3-5 days

• 99% bound to plasma proteins (mainly albumin)

• Metabolized by CYP450 system

What are some genetic components that can affect Warfarin?

• Point mutations in the gene coding for CYP2C9 have been associated with an impaired ability to metabolize S-warfarin, leading to increased S-warfarin elimination half-life

• Genetic mutations in the gene for VKORC1 = greater resistance to warfarin therapy

What is the starting dose of Warfarin (in most cases)?

Initial dose: 5-10mg PO daily

What are proteins C and S? What are their half-lives?

Protein C and S = Natural anticoagulants

• Protein C = 8 hours

• Protein S = 60 hours

What is the initial dose of warfarin for patients with increased sensitivity?

Use smaller dose (< 5mg) in patients with increased sensitivity to warfarin

Which patients might have increased sensitivity to Warfarin?

• Older adults

• History of HF

• Hypoalbuminemia (albumin < 3)

• Diarrhea

• S/P (post) surgery

• Taking meds known to increase INR

• Low BW

• Malnourished or NPO status

• Liver disease

• Known CYP2C9 or VKORC1 variant

• ESRD

Is Warfarin alone an acceptable therapy for acute VTE treatment?

NO! Unacceptable as monotherapy because of slow onset → slow onset associated with high incidence of recurrent VTE

• Warfarin should be started within the same day of heparin/LMWH therapy, continue for 5 days and/or until INR is therapeutic

What lab should we use to monitor therapy and adjust dosing?

INR

• Goal INR is ~2-3

How do you adjust the dose of Warfarin depending on INR?

If INR is too low (<1.5)

• Give extra daily dose and increase weekly dose by 10-20%

If INR is 2-3 → Maintain current dose

If INR is too high (>3)

• Hold up to 1 daily dose & decrease weekly dose by 5-20% percent

What is the relationship between Warfarin and pregnancy?

Warfarin is teratogenic; avoid exposure during pregnancy

What is the relationship between Warfarin and advanced age?

Higher age = high sensitivity

• Increased sensitivity to warfarin due to reduced vit. K stores and/or lower plasma concentrations

What is the relationship between Warfarin and alcoholism?

• Acute alcohol ingestion: inhibits warfarin metabolism with acute elevation in INR

• Chronic ingestion: induces warfarin metabolism with higher dose requirements

What is the relationship between Warfarin and liver disease?

Possible coagulopathy induced by decreased production of clotting factors

Possible reduced clearance of warfarin

What is the relationship between Warfarin and fever?

Increased catabolism of clotting factors, causing an acute increase in INR

What is the relationship between Warfarin and diarrhea?

Reduction in secretion of vitamin K by gut flora, causing increase in INR

Which drugs INCREASES the effect of warfarin? What are the outcomes of these drugs?

FAB-4 + Quinolones

• Fluconazole (-azoles in general)

• Amiodarone

• Bactrim

• 4 - Flagyl (4 for F)

These drugs INCREASE INR, thus increasing the risk of bleeding

Which drugs DECREASE the effect of Warfarin? What is the possible outcome of these drugs?

CC-ARB

• Carbemazepine

• Cholestyramine

• Azathioprine

• Rifampin

• Barbiturates (anticonvulsants)

These drugs can DECREASE INR, therefore, Warfarin dose must be increased due to possible decrease in anticoagulant effectiveness

Is it ok if warfarin patients are eating food like spinach that contains lots of vitamin K?

Yes, just ask them to be consistent!

Do not ask patients to avoid healthy foods

What do we monitor for Warfarin?

• Check baseline INR, CBC, risk of bleeding, BMP (renal function)

• LFTs at baseline, then q12 months after

Warfarin can lead to increased risk of bleeding (increased INR): what are signs of bleeding to look out for?

• Epistaxis

• Cutaneous bleeding (bruising, hematomas)

• Hematuria

• GI bleeding

• Oral cavity bleeding

• Bleeding after tooth extraction or after surgery/major trauma

• Menorrhagia

• CNS bleeding

• HEMORR₂HAGES

• HAS-BLED

What does ISTH defined as major bleeding in non-surgical patients?

• Fatal bleeding and/or

• Bleeding in a critical area or organ and/or

• Bleeding causing a fall in hemoglobin level of 2g/dL or more, leading to a transfusion of 2 or more units of whole blood or RBCs

What are some side effects of Warfarin?

• Fetal hemorrhage and teratogenesis

• Warfarin-induced skin necrosis (rare)

  • If this happens → discontinue warfarin!

• Purple toe syndrome

  • Non-hemorrhagic, cutaneous complication due to cholesterol emboli

If a patients INR is 4.5 -10 but no signs of bleeding, what should we do?

Monitor INR, CBC, and bleeding, no vitamin K given

If a patients INR is >10 but no signs of bleeding, what should we do?

Give oral vitamin K (2.5mg PO)

For any INR, if there are signs of bleeding, how should you manage?

• Rapid reversal of anticoagulation with 4-factor PCC and

• Additional use of vitamin K 5-10 mg IV injection rather than reversal with coagulation factors alone