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.
