Oral AnticoagulantOral Anticoagulant

TherapyTherapy

Benedict R. Lucchesi, M.D., Ph.D.Department of Pharmacology

University of Michigan Medical School

O O

ONa

CH

CH2

CO

CH3

WARFARIN SODIUM

O O

OH

CH2

OO

OH

DICUMAROL

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