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Warfarin Coumadin® the most common anticoagulant

drug

By

Taher Haddad

King Faisal UniversityCollege of Clinical Pharmacy

Outlines

I. Background

II. What is Warfarin?

III. Mechanism of Action

IV. Pharmacokinetic

V. Indications

VI. Dosage and Administration

VII. Warfarin Monitoring

VIII.Adverse Effects

IX. Drug Interactions

X. Overdose Management

Background

In the early 20th century, bis-hydroxycoumarin (dicumarol) was discovered after cows livestock had eaten spoiled Sweet clover and died of a hemorrhagic disease.

Today, coumarin derivatives are used therapeutically as anticoagulants and commercially as rodenticides. Warfarin is the most common oral anticoagulant used today.

Approximately 2 million people in the U.S. start taking warfarin each year.

What is Warfarin?

Warfarin is an oral coumarin anticoagulant widely used to control and prevent thromboembolic disorders.

Warfarin is clinically available as a racemic mixture of R- and S-warfarin. The S-enantiomer has 3–5 times greater anticoagulation potency than its optical congener R-warfarin.

Mechanism of Action

Warfarin acts by antagonizing the antihemorrhagic effect of vitamin K.

It inhibits hepatic synthesis of vitamin K dependent coagulation factors II, VII, IX, and X by inhibiting vitamin K1 -2,3 epoxide reductase, preventing vitamin K from being reduced to its active form.

Pharmacokinetic

The oral bioavailability of warfarin is nearly 100%. It is highly bound (approximately 99%) to plasma

protein, mainly albumin. (The high degree of protein binding is

one of several mechanisms whereby other drugs interact with warfarin) Warfarin is distributed to the liver, lungs, spleen,

and kidneys. It does not appear to be distributed to breast milk in significant amounts. It crosses the placenta and is a known teratogen.

The duration of anticoagulant effect after a single dose of warfarin is usually 5-7 days.

Pharmacokinetic (cont’d)

Warfarin is metabolized by hepatic cytochrome P-450 (CYP) isoenzymes to inactive metabolites, which are excreted in the bile. (It also is metabolized by reductases to reduced metabolites “warfarin alcohols” , which are excreted in

the kidneys). Warfarin metabolism may be altered in the

presence of hepatic dysfunction or advanced age but is not affected by renal impairment.

Indications

1) prophylaxis and/or treatment of venous thrombosis and its extension, and pulmonary embolism.

2) prophylaxis and/or treatment of the thromboembolic complications associated with atrial fibrillation and/or cardiac valve replacement.

3) to reduce the risk of death, recurrent myocardial infarction, and thromboembolic events such as stroke or systemic embolization after myocardial infarction.

Dosage and Administration

Adults: PO 2-5 mg/day initially; adjust daily dose according to PT or INR determinations. Usual maintenance dose is 2-10 mg/day.

The IV dosages would be the same as those would be used orally. Administer as a slow bolus injection over 1 to 2 min in a peripheral vein.

Warfarin Monitoring

Prothrombin time (PT) — The most commonly used test to measure the effect of warfarin. It measures the time it takes for the clotting mechanism to progress. Normal range (12–15 seconds).

International Normalized Ratio (INR) — The INR is a way of expressing the PT in a standardized way; this ensures that results obtained by different laboratories can be reliably compared.

• The longer it takes the blood to clot, the higher the PT and INR. In most cases the target INR range will be 2 to 3, although other ranges may be chosen if there are special circumstances.

Adverse Effects

Hematologic: hemoptysis, bruising, epistaxis, bleeding gums, hematouria or blood in stool.

Cardiovascular: hypotension, syncope, vasculitis. CNS: dizziness, fatigue, headache, lethargy. Hepatic: elevated liver enzymes, hepatitis,

jaundice. Miscellaneous: hypersensitivity reactions,

osteoporosis, chest pain, fever, purple toe syndrome.

Drug Interactions

Divided into:

1. Pharmacokinetic mechanisms:

1) enzyme induction 2) enzyme inhibition 3) reduced plasma protein binding.

2. Pharmacodynamic mechanisms:

1) synergism 2) competitive antagonism (vit K) 3) an altered physiologic control for vitamin K (hereditary resistance to oral anticoagulants).

Overdose Management

Without bleeding: cessation of the drug may be enough.

With minor bleeding: by stopping the drug and administering vitamin K1 (Phytonadione) 5-20 mg PO or 10 mg IV.

In emergency situations of severe hemorrhage

1. activated charcoal 1 g/kg PO.

2. vitamin K1 5-20 mg PO or 10 mg IV.

3. administering 200-500 mL of fresh whole blood or 15 mL/kg fresh frozen plasma.

References Katzung PHARMACOLOGY, 9e > Drugs Used in

Disorders of Coagulation emedicine.medscape.com>Toxicity, Warfarin and

Superwarfarins, Warfarin Pharmacogenetics. drugs.com/pro/warfarin uptodate.com>Patient information: Warfarin

Questions?