Oral Anticoagulant Therapy Benedict R. Lucchesi, M.D., Ph.D. Department of Pharmacology University of Michigan Medical School

O O ONa CH CH 2 CO CH 3 WARFARIN SODIUM O O OH CH 2 O O 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, KH 2 ) –Reduced vitamin K is necessary for carboxylation of glutamate residues –Decrease in KH 2 limits the gamma-carboxylation of vitamin K dependent coagulant proteins - –Prothrombin (Factor II) –Factors VII, IX, X – Protein C and Protein S

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 - Pharmacokinetics - Pharmacodynamics Two optical isomers have different pathways of metabolic disposition. R-Warfarin - metabolized primarily by reduction of the acetonyl side chain into Warfarin alcohols, excreted in urine. S-Warfarin - metabolized by oxidation to 7- hydroxy-S-Warfarin; eliminated in bile. In a given subject, good relationship between dose and effect. Marked variation among subjects.

Warfarin - Pharmacokinetics - Pharmacodynamics Two optical isomers have different potencies with respect to inhibiting formation of vitamin K dependent clotting proteins S - Warfarin is 5 times more active than the R isomer

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 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

International Normalized Ratio (INR) System Thromboplastin used in the test is calibrated with the reference preparation Convert the prothrombin time ratio measured with the locally prepared thromboplastin into an INR according to the formula: INR = (observed prothrombin/Control PT ) ISI ISI = International Sensitivity Index - a measure of the responsiveness of a thromboplastin preparation to reduction in the vitamin K-dependent coagulation factors. Most rabbit brain thromboplastins in the US have an ISI of

Warfarin results in altered hepatic synthesis of several vitamin K-dependent factors Factor Coagulant Anticoagulant T1/2 Factor IIyes no50hrs Factor VIIyes no 6 hrs Factor IXyes no24hrs Factor Xyes no36hrs _________________________________ Protein Cno 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 hours - longer t1/2 of Factors II, IX, X.

Warfarin - Dosing Considerations Protein C has a short t 1/2 as does Factor VII In the early phase of treatment ( 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 Racemic warfarin is more than 95% absorbed through the GI tract. Food decreases rate of absorption, but not the extent % protein bound to albumin. Albumin bound warfarin is inactive and cannot be metabolized. Excretion occurs only after warfarin is metabolized. No intact drug is found in the urine or stool.

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 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 (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 stopping the drug administering large doses of vitamin K 1 (5 to 10 mg; may need to repeat dose) administering fresh-frozen plasma (10-20 ml/kg) combined with vitamin K 1 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:

Management of Warfarin Overdose Reversal of the anticoagulant effect by vitamin K 1 requires synthesis of FULLY CARBOXYLATED coagulation proteins Improvement in hemostasis does not occur for several hours Maximal effect may require 24 hours The use of vitamin K 1 can make the subsequent response to warfarin erratic for several days

Dosing Regimens for Anticoagulation Warfarin (Oral Administration) – Day mg – Day mg – Day 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.

Monitoring Warfarin Therapy Quick One-Stage Prothrombin Time (PT) – Results are estimates of the combined activities of the complex: prothrombin, factor V, VII, X and to a minor extent fibrinogen – Prothrombin, factors VII and X are functionally depressed with oral anticoagulants – Factor IX is Vitamin K dependent, but is not measured by the PT test.

Monitoring Warfarin Therapy Depression of the vitamin K dependent clotting factors is not additive and each has a markedly different half-life. The factor depressed most quickly and profoundly (usually Factor VII) acts as a determinant of a routine PT test during the first few days of therapy. With prolonged therapy, Factor X ultimately shows the lowest activity in the steady state.

Monitoring Warfarin Therapy To adjust dose of warfarin – PT determined: » three times during first week » twice during the second week » weekly thereafter until maintenance dose is established » then monthly – Caution - drug interactions, dietary changes, diarrhea, liver dysfunction, CHF.

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 mg of warfarin to achieve a therapeutic prothrombin time. Warfarin Anticoagulation Failure