Anticoagulant, Fibrinolytic and Antiplatelet Anticoagulant, Fibrinolytic and Antiplatelet.
Oral Anticoagulant Therapy Benedict R. Lucchesi, M.D., Ph.D. Department of Pharmacology University...
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Transcript of Oral Anticoagulant Therapy Benedict R. Lucchesi, M.D., Ph.D. Department of Pharmacology University...
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