3. ORAL ANTI-COAGULANTS
WARFARIN:
-Mechanism of Action:
-antagonists of Vitamin K
-coagulation factors affected: II, VII, IX, X
-anticoagulants affected: protein C and S
-decreased the total amount of each Vitamin
K-dependent coagulation factor by 30-50%
4. ORAL ANTI-COAGULANTS
WARFARIN:
-Mechanism of Action:
-the time required for the activity of each factor
in the plasma to reach a new steady state after
therapy is based on its individual rate of
clearance. The approximate half-lives are:
FACTORS Half-life (t1/2)
II 50 hours
VII 6 hours
IX 24 hours
X 36 hours
Protein C 8 hours
Protein S 30 hours
5. ORAL ANTI-COAGULANTS
WARFARIN:
-Mechanism of Action:
-the full antithrombotic effect of warfarin is
not achieved for several days, even though the
PT may be prolonged soon after
administration due to more rapid reduction of
factors with shorter t1/2 (VII)
6. ORAL ANTI-COAGULANTS
WARFARIN:
-Dosage:
-warfarin (Coumadin) is 5mg/day for 2-4 days
-followed by 2-10mg/day as indicated by
measurements of the INR
-lower dose for elderly, pts at risk for bleeding
-can be given IV BUT NOT IM due to risk of
hematoma formation
7. ORAL ANTI-COAGULANTS
WARFARIN:
-Absorption:
-bioavailability nearly complete when drug is
administered PO, IV or rectally
-FOOD DECREASES the rate of absorption
-detected in plasma within 1 hour and peak
concentrations in 2-8 hours
8. ORAL ANTI-COAGULANTS
WARFARIN:
-Distribution:
-almost completely bound to plasma proteins,
principally albumin
-concentration in fetal plasma approach
maternal values
-active warfarin is not found in milk compared
to other coumarins and indandiones
9. ORAL ANTI-COAGULANTS
WARFARIN:
-Biotransformation and Elimination:
-transformed into inactive metabolites: -
weak warfarin (R) – by CYP1A2, CYP2C19,
CYP3A4
potent warfarin (S) – by CYP2C9
-inactive metabolites are excreted in urine and
stool
-t1/2: 25-60 hours (mean: 40 hours)
-duration of action: 2-5 days
10. ORAL ANTI-COAGULANTS
WARFARIN:
-Drug and other Interactions:
-patients must be educated to report the addition
or deletion of any medication
-any substance or condition is potentially
dangerous if it alters:
1. the uptake or metabolism of the oral
anticoagulant or vitamin K
2. the synthesis, function, or clearance of any
factor or cell involved in hemostasis or fibrinolysis
3. the integrity of any epithelial surface
11. ORAL ANTI-COAGULANTS
WARFARIN:
-Drug and other Interactions:
-factors that DECREASE the effects of oral anticoagulants:
1. reduced absorption of drug caused by binding to
CHOLESTYRAMINE in the GI tract
2. increased volume of distribution and a short t1/2
secondary to HYPOPROTEINEMIA
3. increased metabolic clearance of the drug secondary
to induction of hepatic enzymes, especially CYP2C9
4. ingestion of large amounts of Vitamin K rich foods or
supplements
5. increased levels of coagulation factors during
pregnancy
12. ORAL ANTI-COAGULANTS
WARFARIN:
-Drug and other Interactions:
-factors that INCREASE the effects of oral
anticoagulants (risk for hemorrhage):
1. decreased metabolism due to CYP2C9
inhibition (e.g. amiodarone, cotrimoxazole,
clopidogrel, isoniazin, metronidazole)
2. displacement from protein binding sites
caused by loop diuretics or valproate
3. relative deficiency of vitamin K
4. low concentration of coagulation factors
14. ORAL ANTI-COAGULANTS
WARFARIN:
-Toxicities:
1. Bleeding
-MAJOR TOXICITY OF ORAL ANTICOAGULANTS
-risk increases with:
a. intensity & duration of therapy
b. use of other meds that interfere with
hemostasis
c. presence of potential anatomic source
of bleeding
-INR >4 = risk for intracranial hemorrhage
-INR 5-9 = 1-2.5 mg vitamin K is given
-INR >9 = 3-5 mg vitamin K is given
- INR >20 = consider FFP transfusion w/ 10 mg vitamin K
15. ORAL ANTI-COAGULANTS
WARFARIN:
-Toxicities:
2. Birth Defects
-if administered during pregnancy, warfarin can
cause birth defects and abortion
-CNS abnormalities if given in 2nd/3rd trimester
3. Toxicities
-PURPLE TOE SYNDROME – REVERSIBLE bluish
discoloration of the plantar surfaces and sides of toes
that blanches with pressure and fades with elevation
d/t release of cholesterol emboli
-alopecia, urticaria, dermatitis, fever, nausea,
diarrhea, abdominal cramps, anorexia
16. ORAL ANTI-COAGULANTS
WARFARIN:
-Clinical Use:
-prevent the progression or recurrence of DVT
-prevent venous thromboembolism
-given concurrently with heparin; heparin is halted
4-5 days after initiation
- systemic embolization
-INR is calculated from the patient’s PT is used to
monitor efficacy and compliance (TARGET INR: 2-3 but
higher for pts with mechanical prosthetic hearts valves
2.5-3.5)
-Daily INR at onset of Rx, then lengthened gradually to
weekly then monthly for pts on long-term Rx
