Oral Anticoagulant
Therapy
Benedict R. Lucchesi, M.D., Ph.D.
Department of Pharmacology
University of Michigan Medical School
O
O
WARFARIN SODIUM
CH
ONa
CH2
CO
CH3
O
O O
O
DICUMAROL
CH2
OH
OH
Warfarin: Mechanism of Action
•Interferes with the cyclic interconversion of vitamin K
and its 2,3 epoxide (vitamin K epoxide)
•Vitamin K is an essential cofactor for post-translational
carboxylation of glutamate residues on the N-terminus
regions of vitamin K-dependent proteins to gammacarboxy-glutamates
•Descarboxyprothrombin is converted to prothrombin by
carboxylation of glutamate residues to gammacarboxyglutamate
Warfarin - Mechanism of Action
– By inhibiting vitamin K epoxide reductase and vitamin
K reductase, warfarin leads to the accumulation of
vitamin K epoxide in the liver and plasma and the
depletion of reduced vitamin K (active form, KH2)
– Reduced vitamin K is necessary for carboxylation of
glutamate residues
– Decrease in KH2 limits the gamma-carboxylation of
vitamin K dependent coagulant proteins – Prothrombin (Factor II)
– Factors VII, IX, X
– Protein C and Protein S
Factor II
(10 glutam ic
residues)
C arboxylated
Factor II
CO2
C H 2 -C H 2 C O O -
COOProtein
carb oxylase
CH2-CH
COO-
O2
O
OH
R
R
O
Reduced
V itam in K
(active)
CH3
CH3
OH
V itam in K
r e d u c t a se
W afarin
blocks
blocked by
W arfarin
V itam in K
epoxide
reductase
T hiol
Cofactor
O
E poxide form
V itam in K
(inactive)
How does gamma-carboxylation affect the vitamin
K dependent proteins ?
–gamma-carboxylation gives the proteins
the ability to bind CALCIUM IONS
–in the presence of calcium, the proteins
undergo a conformational change
–this allows them to bind to their
respective cofactors on phospholipid
surfaces
Warfarin - Pharmacokinetics Pharmacodynamics
•Racemic mixture of two optical isomers
•Absorbed rapidly from GI tract
•Maximal plasma concentration in 90 min
•Plasma t1/2 of 36 to 42 hours
•Circulates bound to plasma proteins
•Administered orally
Warfarin - drug-drug interactions
Prolong prothrombin time
• Stereoselective inhibition of clearance of the Sisomer • Phenylbutazone
• Metronidazole
• Sulfinpyrazone
• Trimethoprim-sulfamethoxazole
• Disulfuram
Warfarin - drug-drug interactions
Prolong prothrombin time
• Change Warfarin Plasma Concentration
– Stereoselective inhibition of clearance of the Risomer
• Cimetidine
• Omeprazole
– Nonstereoselective inhibition of R and S isomers
• Amiodarone
Warfarin - drug-drug interactions
Prolong Prothrombin Time
• Do Not Change Warfarin Plasma Concentration
• Inhibits cyclic interconversion of vitamin K
• 2nd and 3rd Generation of cephalosporins
• Other Mechanisms
• Clofibrate
• Inhibits Blood Coagulation
• Heparin
• Increases metabolism of coagulation factors
• Thyroxine
Warfarin - drug-drug interactions
Prolong Prothrombin Time
Effects on Warfarin Plasma Concentration are Unknown
Evidence is strong:
• Erythromycin
• Anabolic steroids
Evidence is lacking:
• Ketoconazole; Fluconazole; Isoniazid
• Piroxicam; Tamoxifen; Quinidine; Phenytoin
Warfarin - drug-drug interactions
Inhibit Platelet Function- Do Not Change Warfarin
Plasma Concentration
• Aspirin
• Ticlopidine
• Clopidogrel
• Moxalactam
• Carbenicillin and high doses of other penicillins
Warfarin - drug-drug interactions
Reduce Prothrombin Time
• Change Warfarin Plasma Concentration
• Cholestyramine (reduces absorption of
Warfarin)
• Increase metabolic clearance of warfarin
• Barbiturates
• Rifampin
• Griseofulvin
• Carbamazepine
Therapeutic Range for Oral Anticoagulant
Therapy
• Dose adjusted on the basis of laboratory tests
• Most often used is the one-stage prothrombin time
• PT is sensitive to: Factors II, VII, and X
• Makes use of Ca++ plus thromboplastin added to patient’s
citrated plasma - record time to clot
THROMBOPLASTINS DIFFER IN SENSITIVITY TO THE
REDUCTION OF VITAMIN K-DEPENDENT CLOTTING
FACTORS
Warfarin results in altered hepatic synthesis of
several vitamin K-dependent factors
Factor Coagulant Anticoagulant T1/2
Factor II
Factor VII
Factor IX
Factor X
yes
yes
yes
yes
no
no
no
no
50hrs
6 hrs
24hrs
36hrs
_________________________________
Protein C
no
yes
8hrs
Protein S
no
yes
30hrs
Both Factor VII and Protein C have short T1/2. The decrease in
Factor VII activity is countered by the thrombogenic effect of
decreased Protein C in the first 24 hours
Warfarin - Dosing Considerations
• Onset of anticoagulant effect is delayed as
existing clotting factors (II, VII, IX, X, Protein
C and Protein S) must be cleared from the
circulation.
• Effect occurs within 24 hours as Factor VII
(short t1/2 = 6-7 hrs) is reduced to a critical
value.
• Peak activity in about 72 - 96 hours - longer
t1/2 of Factors II, IX, X.
Warfarin - Dosing Considerations
• Protein C has a short t1/2 as does Factor VII
• In the early phase of treatment (24 - 48 hrs) the
relative reduction in the activity of protein C will
enhance the prothrombotic action of Factor VII
• Remember, Protein C exerts a negative feed-back
on thrombin via Factor VIII and Factor V.
Warfarin - Pharmacokinetics
• Only a small amount of the total circulating drug, 1-
2% causes the pharmacologic effect.
• Displacement of warfarin from albumin binding sites
augments the plasma concentration of active drug
and can increase the anticoagulant effect.
• Half life of racemic warfarin ranges from 20 - 60
hours, reflecting the contribution of its dextro- and
levo- isomers.
• d- isomer has longer half-life. l - isomer is 5.5 times
more active. Each isomer is metabolized by
different pathways. Levo metabolites appear in the
bile, dextro-metabolites appear in the urine.
Warfarin
- Clinical Uses
• Oral anticoagulants are effective in the primary
and secondary prevention of venous thromboembolism
• Prevention of systemic embolism in patients
with prosthetic heart valves or atrial fibrillation
• Prevention of stroke, recurrent infarction, and
death in patients with acute MI
• INR of 2.0 - 3.0 (moderate-intensity regimen) is
satisfactory for most situations
Warfarin - Adverse Effects
• Bleeding is the main concern, risk depends on:
–Intensity of the therapy
–Patient’s underlying disorder
–Concomitant use of aspirin or antiplatelet drugs.
–Patient’s age - risk > 65 yrs old, hx of stroke, hx of GI
bleeding
–Bleeding with an INR < 3, usually due to some occult
cause, GI or renal lesion
Warfarin - Adverse Effects
• Most important non-hemorrhagic effect is skin necrosis
• Occurs on 3rd to 8th day of dosing
• Due to excessive thrombosis of venules and capillaries in
subcutaneous fat
• May be associated with Protein C deficiency - initiation of
warfarin therapy can induce a rapid decline in protein C
because of its short half life (7 hours) resulting in a
parodoxical syndrome of transient hypercoagulation and
microthrombus formation beginning before effective
anticoagulation is achieved.
Warfarin in pregnancy
Crosses the placenta
Produces characteristic embryopathy,
CNS abnormalities, fetal bleeding
• Embryopathy consists of:
•nasal hypoplasia
•stippled epiphyses
•agenesis of corpus callosum
•ventral midline dysplasia - optic atrophy
Management of Warfarin Overdose
Excessive anticoagulant effect of warfarin can be
reversed by:
• stopping the drug
• administering large doses of vitamin K1
(5 to 10 mg; may need to repeat dose)
• administering fresh-frozen plasma (10-20 ml/kg)
•
•
combined with vitamin K1
administering factor IX concentrate
Improvement in hemostasis does not occur for several
hours - may require 24 hours.
Dosing Regimens for Anticoagulation
• Warfarin (Oral Administration)
–Day 1 - 15 mg
–Day 2 - 10 mg
–Day 3 - 10 mg
–Maintenance dose is 5 to 7.5 mg daily, but
there is marked variation among patients
–Prothrombin time changes little in first 24
hours with gradual prolongation by the third
day.
Warfarin Anticoagulation Failure
• Altered oral bioavailability
– drug/food interaction within the GI tract
• Variations in Vitamin K availabililty
– dietary
– altered GI flora
• Drug/Drug Interactions
– displacement from plasma albumin
– altered hepatic metabolism (cytochrome p450)
• Hereditary Resistance
– Rare disorder characterized by autosomal dominant inheritance.
– Individuals may require up to 75-80 mg of warfarin to achieve a
therapeutic prothrombin time.