Pharmacology of Warfarin

Name the types of anti-thrombotic drugs

Antiplatelet drugs- used to prevent ATE

Anticoagulants- Warfarin, DOACs, Heparins

Thrombolytic agents- used to lyse clots forms by activating fibrinolysis pathway

What is the role of calcium in coagulation

Ca++ ‘bridges’ the binding of the

negatively-charged coagulation factors to

negatively-charged Phospholipids that are

found on the surface of activated

platelets / damaged endothelium –

localises them at sites of vessel damage

• Negatively charged residues on

coagulation proteins are often formed

through Vitamin K-dependent

mechanisms

What is the role of Vitamin K in coagulation

Vitamin K is necessary for synthesis of Gal residues in vitamin K dependent proteases

Hepatic synthesis of coagulation factors II, VII,IX and X, require the presence of vitamin K

What is carboxylation and what does it involve

Process of converting Vita dependent proteases to their active forms is called carboxylation, which involves the addition of a y- carboxyl group to glutamic acid residues

What can Vitamin K deficiency cause

bleeding, bruising , nose bleeds

Hemorrhagic disease of the new born

Liver disease

How is Warfarin a Vitamin K antagonist

Competitively inhibits the vitamin K epoxide reductase complex

1 (VKORC1), an essential enzyme for activating the vitamin K

available in the body

• Inhibits synthesis of Vitamin K dependent clotting factors (II VII,

IX and X) by inhibiting carboxylation of glutamic acid residues

When s Warfarin prescribed

Prophylaxis and treatment of VTE and PE

Prophylaxis and treatment of thromboembolic complications from atrial fibrillation or cardiac valve replacement

How is Warfarin administered, what is it metabolized by and what’s the onset of action, how long does it take for effect, and what therapeutic index does it have and what’s the monitoring for it

Administered orally

Metabolized by Cytochrome P450 in liver

Slow onset and offset of action

Takes 24-48hrs to work

Has low therapeutic index

Needs careful monitoring

Monitored in the lab by the modified prothrombin time called INR

What are the challenges to Warfarin treatment involving genetics

Individuals have genetic variants(termed SNPs) in the gene encoding CYP2C9 enzyme needed to metabolize warfarin

Metabolites active 5-warfarin to its inactive form

Variants at this allele result in reduced warfarin clearance and increase bleeding risk

Variants in VKORC1 gene causes warfarin resistance

Challenges to warfarin in terms of drug interactions

Many drug interactions exist

Grapefruit juice

What is the adverse effects of warfarin

Bleeding risk

Skin necrosis- protein C deficiency

When is warfarin contraindicated

in pregnancy

What’s the target INR during warfarin use and range

Target INR: 2.5

Range: 2-3