New anticoagulants

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  • 1. New Anticoagulants:Beyond Warfarin and Heparin Rachel LaCount Resident in Pathology August 4, 2005
  • 2. Overview Older anticoagulants: Warfarin & Heparin, LMWH Why we need new drugs Newer drugs Direct Thrombin Inhibitors Xa inhibitors Heparinoids The future
  • 3. Brief Review: Warfarin MOA Blocks vitamin K- dependent glutamate carboxylation of precursor factors II, VII, IX, X Vit K = cofactor Warfarin blocks the reduction of Vit K Oral administration
  • 4. Review: Heparin MOA Indirect thrombin inhibitor: IV only Called UFH (unfractionated heparin) Complexes with AT (heparin co-factor I) AT by itself inactivates SLOWLY! Thrombin Factor Xa XIIa, XIa, IXa (lesser extent) AT + Heparin: conformational change in AT = 1000-4000 fold acceleration in inactivation At high concentrations: Also binds to platelets and heparin co-factor IIwhich inhibits thrombin
  • 5. Heparin made of polysaccharide chains of varying lengths Unique pentasaccharide sequence binds to AT Sequence is randomly distributed along heparin chains Inactivation of XaHeparin doesnt have to bind to it Inactivation of Thrombin--Requires heparin to bind to both AT and itself Heparin must be >18 monosaccharides long to do this Virtually all heparin molecules are > 18
  • 6. Limitations of Warfarin and Heparin: Both have narrow therapeutic windows Highly variable dose responses: requires laboratory monitoring (PT, APTT) Heparin can bind to other plasma proteins making bioavailability variable Warfarin has numerous food, drug interactions Limited ability to stop a clot from propagating: Heparin does not inactivate thrombin bound to fibrin or Xa bound to platelets very well
  • 7. LMWHs Molecular wt: Heparin: 15,000 vs LMWH: 4000-5000 LMWHs inactivate Xa but have less effect on thrombin (some molecules not long enough) ratio of anti-Xa to anti-thrombin activity of 3:1 Do not prolong PTT unless dose high Advantages over heparin: Easier to administer: sq, BID dosing Dosage and anticoagulant effect easier to predict; dose based on body weight Lab monitoring not necessary in all patients Less chance of inducing immune-mediated thrombocytopenia
  • 8. Names of LMWHs Enoxaparin (Lovenox) Dalteparin (Fragmin) Tinzaparin (Innohep) Differ chemically and pharmacokenetically but unsure if these differences are clinically significant Other products not yet approved here: Fraxiparin, reviparin, nadroparin, bemiparin, certoparin
  • 9. LMWH Rx monitoring Uncomplicated patients do not require monitoring Who may need to be? Newborns, children, pregnant women Conditions: obesity, renal insufficiency, malignancy, myeloproliferative disorders People with hemorrhagic complications or with initial therapy to confirm appropriate levels
  • 10. LMWH Rx monitoring Levels measured by chromogenic-based anti-factor Xa assays Clot based APTT only sensitive to very high levels of LMWHs Calibration is done with the same brand of LMWH that the patient is usingand not with Heparin!
  • 11. Anti Xa Assay Pt plasma + known amount of excess Factor Xa and antithrombin UFH/LMWH binds antithrombin & inhibits Factor Xa Residual Factor Xa is measured Factor Xa cleaves a chromogenic substrate similar to its natural substrate, releasing color detected by a spectrophotometer Residual Xa is inversely proportional to the amount of LMWH (or UFH)
  • 12. Why new drugs? UFH and LMWHs are inconvenient for the outpatient setting (IV or sq only) UFH and LMWHs can cause HIT: Risk 0.2% with LMWH vs. 2.6 % with UFH Pts with HIT still need to be anticoagulated
  • 13. Why new drugs? Warfarin is underused in pts who need it most: Only 47% of patients with afib are taking warfarin This is often due to hemorrhagic contraindications Convenience issues due to the need for frequent monitoring Difficulty in maintaining optimal anticoagulation
  • 14. The ideal anticoagulant Effective Minimal complications/side effects Convenient administration (ie: oral for outpatients) Rapid absorption Fast on and offset action Predictable pharmacokinetics No interactions with food or drugs No HIT No coagulation monitoring
  • 15. Categories of new drugs Direct Thrombin Inhibitors: hirudin, lepirudin, desirudin, bivalirudin, argatroban, ximelagatran Xa inhibitors: fondaparinux, idraparinux Heparinoids: Danaparoid (discontinued)
  • 16. Objectives for each drug Mechanism of Action Current uses Limitations Monitoring in the lab
  • 17. Direct Thrombin Inhibitors
  • 18. Direct Thrombin Inhibitors 3D structure of thrombin: 100s of thrombin inhibitors in last 15 yrs Most are peptidomimetic compounds Mimic the fibrinogen sequence which interacts with the thrombin active site Peptidomimetic: A compound that mimics binding and biological activity of the natural peptide
  • 19. Thrombin 3 important areas: Active site: fibrinogen binding Exosite I: major docking site--interaction with fibrinogen and other receptors; fibrinogen recognition site3. Exosite II: interacts with heparin
  • 20. Hirudin Medicinal leeches: Used since ancient times to relieve body of bad humors Egyptians, Greeks Reached peak Hirudo medicinalis popularity in mid-19th century
  • 21. 1884: John Haycraft in Birmingham demonstrated that medicinal leeches, Hirudo medicinalis, secrete a substance that prevents blood from clotting 1904: Substance named hirudin 1957: Markwardt isolated the active anticoagulant substance, determined it to be a polypeptide 65 AAs long which inhibited thrombin
  • 22. Estimated to require 50,000 leeches annually for diagnostics and treatment 1986: DNA isolated and cloned Today recombinant hirudin is made in yeast cells Lepirudin, desirudin, bivalirudin
  • 23. R-Hirudins All bind in active site and exosite I Irreversible: Lepirudin, Desirudin Reversible: Bivalirudin Minor differences in structure between them ie: Lepirudin has one extra oxygen molecule than desirudin and one AA difference
  • 24. Lepirudin (Refludan) Approved for use in HIT No binding to platelet factor IV 89% of patients with rapid increase in plt count Monitored with APTT daily Measure 4 hr after dose Target: Pts APTT to be 1.5-2.5 x the labs median APTT Caution in pts with renal insufficiency Dose dependent relationship Antihirudin antibodies develop in 40-70% Drug is made of non-human proteins Can cause irritation to skin Not neutralizing; may enhance drug potency by delaying clearance These patients need to be monitored with APTT
  • 25. Desirudin (Iprivask) Studied in DVT prophylaxis for total hip Lower rate of DVT than LMWH and no increase in bleeding complications Also used in HIT Also monitored with APTT Monitor especially in pts with renal insufficiency APTT twice upper limit of normal = stop and restart at reduced dose Dose dependent relationship Antihirudin antibodies can also develop
  • 26. Bivalirudin (Angiomax) Previously called hirulog Binds reversibly to thrombin Thrombin slowly cleaves the drug from its active site Short half-life 20-30 min Less immunogenic (is only 20 AAs long) FDA approved in 2002 for use in angioplasty for patients with unstable angina
  • 27. Bivalirudin, cont REPLACE-2 (2004) Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events Pts randomized to rec