Saturday, April 2, 2011

Oral anticoagulants

Warfarin is a vitamin K antagonist. It antagonizes the cofactor functions of vitamin K.

Firstly, it was used as rodenticide.

Mechanism of action:

Factors like II, VII, IX, and X and certain natural anticoagulants such as protein C require vitamin K as cofactor for their synthesis.

These factors undergo vitamin K dependent posttranslational modification resulting in the carboxylation of glutamic acid residue which is converted into γ-carboxyglutamic acid residue by vitamin K dependent carboxylase. This residue gets bind to calcium ions, which is important for interaction between coagulation factors and platelet membranes.

The reduced form of vitamin K cofactor (active hydroquinone form) is changed into vitamin K epoxide during reaction. Vitamin K cofactor is regenerated by vitamin K epoxide reductase.

Warfarin inhibits this enzyme leading to inactive coagulation factors due to lack of γ-carboxyglutamyl chain.
Therapeutic Uses:

It is used for prophylaxis therapy of pulmonary embolism and venous thrombosis.

Pharmacokinetics:
It is readily absorbed by oral ingestion. 99% bind to plasma albumin leading to stoppage of its movement to CSF, breast milk and urine. Its onset of action is 8-12 hours.

It can cross placenta.

It is metabolized by cytochrome P450 system and its half life is variable ranging from 40-60 hours. Elimination is done through urine and feces after conjugation with glucuronic acid.

Dosage:
It is given in the dose of 2-5 mg for one week daily.

Adverse effects:
It may cause hemorrhage. In this case, dose must be adjusted. It can be controlled by intravenous administration of vitamin K. Plasma concentrates of the blood factors may be employed in severe cases. It may also cause rashes, diarrhea and alopecia.

Drug Interactions:
Food may delay its absorption.

Drugs having higher attraction for albumin binding sites such as sulfonamides can displace warfarin leading to short duration of increased activity.

Contraindications:
It is contraindicated in pregnancy as it is teratogenic and can lead to abortion.

Antidote:
Vitamin-K
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