Session 3 Topics. Argatroban. Argatroban. Drug Use and Adverse Effects. Laboratory Monitoring of Anticoagulant Therapy

Transcription

1 ~~Marshfield Labs Presents~~ Laboratory Monitoring of Anticoagulant Therapy Session 3 of 4 Michael J. Sanfelippo, M.S. Technical Director, Coagulation Services Session 3 Topics Direct Thrombin Inhibitors: o Argatroban o Refludan o Dabigatran o Rivaroxaban Argatroban Argatroban A small molecule: molecular weight of 526 Derived from arginine Inhibits by reversibly binding to thrombin independent of antithrombin Half life of minutes Therapeutic Levels and Monitoring Given by continuous infusion Monitor with activated partial thromboplastin time (APTT) At 2 hour of infusion, target APTT range is times baseline Argatroban will prolong prothrombin time (PT) Use chromogenic assay of factor X to monitor warfarin during transition from argatroban to warfarin Drug Use and Adverse Effects Primary use to treat patients with heparin induced thrombocytopenia (HIT) Hemorrhage is the only major adverse effect No known antidote 1

2 Refludan Lepirudin Nature and Action of Lepirudin Recombinant hirudin Direct thrombin inhibitor not dependent on antithrombin Half life: 50 min intravenous; 2 3 hours subcutaneous Therapeutic Levels and Monitoring Monitored by APTT General target range: times baseline APTT Adverse Effects of Lepirudin Hemorrhage No known antidote Dabigatran (Pradaxa ) Dabigatran Pradaxa Oral direct thrombin inhibitor Pro-drug is dabigatran etexilate Metabolized to active drug by blood and liver esterases Excreted by kidneys 2

3 Dabigatran Dosing Twice per day dosing, half life hours Reduced dosing in patients with renal insufficiency Monitoring not required Approved for treatment of atrial fibrillation at this time Lab Testing for Dabigatran May be necessary for patients requiring surgery or to check for compliance Will prolong the APTT Ecarin clotting time or Ecarin chromogenic assay recommended Hemoclot Thrombin Inhibitor (modified thrombin time) Ecarin Clotting Time Ecarin venom from saw-scaled viper Ecarin activates prothrombin directly to thrombin Clotting time indirectly related to Dabigatran level Ecarin Chromogenic Assay Prothrombin activated by Ecarin to thrombin Thrombin measured by reaction with a chromogenic substrate Color generated is indirectly related to Dabigatran concentration Problems with Dabigatran Twice per day dosing Cost over $200/month Calibration of Ecarin clotting time or chromogenic assay Excreted by kidneys -- cannot be used in patients with renal impairment Interaction with drugs used to treat atrial fibrillation Problems with Dabigatran (cont.) Higher incidence of GI bleeding than warfarin Requires acid environment for absorption Proton pump inhibitors reduce dabigatran concentration by 20-30% Higher incidence of major bleed in patients over 75 years 3

4 Chemistry of Rivaroxaban Rivaroxaban Xarelto A synthesized chemical Molecular weight of Mechanism of action Selectively blocks active site of factor Xa Not antithrombin dependent Orally bioavailable Pharmacokinetics Bioavailability % Rapid absorbed peak 2-4 hours after intake Unaffected by food intake or gastric ph Drug released in GI tract (small intestine) Excretion Excreted in the urine and feces Half life of 5-9 hour in healthy subjects Reduced clearance in elderly subjects half life hours Hemorrhage No antidote Adverse Reactions 4

5 Laboratory Monitoring Not required; standard dose 10 mg orally Will prolong prothrombin time and activated partial thromboplastin time in dose dependent fashion Will inhibit Xa as in heparin, low molecular weight heparin, and fondaparinux assays Clinical Application Prophylaxis of deep vein thrombosis following knee surgery, 12 days Prophylaxis of deep vein thrombosis following hip surgery, 35 days 10 mg once per day With or without food Dosage Questions? Contact: Michael J. Sanfelippo, M.S. Technical Director, Coagulation Services Marshfield Labs Direct Ph: