Post on 23-Dec-2015
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Oral AnticoagulantOral Anticoagulant
TherapyTherapy
Benedict R. Lucchesi, M.D., Ph.D.Department of Pharmacology
University of Michigan Medical School
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 gamma-carboxy-glutamates
•Descarboxyprothrombin is converted to prothrombin by carboxylation of glutamate residues to gamma-carboxyglutamate
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
Wafarinblocks
Vitamin Kepoxide
reductase
Vitamin Kreductase
blocked byWarfar in
Factor II(10 g lutamic
res idues)C H 2 -C H 2 C O O -
CarboxylatedFactor II
C H 2 - C H
C O O -
C O O -
CO2
OH
OH
CH3
R
O2
O
O
O
CH3
R
ReducedVitamin K
(act ive)
Epoxide formVitamin K( inact ive)
Pr o t e i nc a r b o x y l a se
T hi o lC o f a c t o r
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 S-isomer -
• Phenylbutazone
• Metronidazole
• Sulfinpyrazone
• Trimethoprim-sulfamethoxazole
• Disulfuram
Warfarin - drug-drug interactions
Prolong prothrombin time
• Change Warfarin Plasma Concentration– Stereoselective inhibition of clearance of the R-
isomer
• 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 UnknownEvidence 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 yes no 50hrs
Factor VII yes no 6 hrs
Factor IX yes no 24hrs
Factor X yes no 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 thrombo-embolism
•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 placentaProduces 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
• 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.
Excessive anticoagulant effect of warfarin can be reversed by:
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.
• 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.
Warfarin Anticoagulation Failure