DIRECT THROMBIN INHIBITORS
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THROMBIN
Exosite 2
Binds with heparin Binds with fibrinogen
Active Site
Exosite 1
major docking site interaction with fibrinogen and other receptors fibrinogen recognition site
DIRECT THROMBIN INHIBITORS
Bivalent DTIs
Lepirudin Desirudin Bivalirudin
Univalent DTIs (small molecule)
Argatroban Dabigatran
HIRUDIN
Medicinal leeches
secrete a substance that prevents blood from clotting
65 AAs long
Natural compound
Recombinant hirudin made in yeast cells
Lepirudin Desirudin Bivalirudin
Hirudo medicinalis
Recombinant 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
LEPIRUDIN (Refludan)
MOA
Irreversible inhibitor of thrombin IV infusion up to 0.1 mg/kg/hr t1/2 = 0.8 to 2 hrs Renal: (CrCl below 60 mL/min) dose reduction HIT Acute coronary syndrome Surgery Active bleeding Hemorrhage Fever Monitored with aPTT daily, measure 4 hr after dose Target aPTT ratio: 1.5 - 2.5 Can monitor with ECT Antihirudin antibodies develop in 40-70% of patients
Pharmacokinetics
Indications
CI
Side Effects
Clinical Pearls
DESIRUDIN (Iprivask)
MOA
Irreversible inhibitor of thrombin 15 mg SC 5-15 min before surgery every 12 hr for up to 12 days t1/2 = 2 to 3 hrs Renal adj: 31 CrCl 60 mL/min: 5 mg SC q12h CrCl 30 mL/min 1.7 mg SC q12h Prophylaxis: DVT, hip replacement surgery Active bleeding Hemorrhage Long-term or permanent paralysis may occur with neuraxial anesthesia or spinal puncture Monitored with aPTT daily, measure 4 hr after dose If aPTT > 2x control aPTT, stop therapy until aPTT < 2x control aPTT
Pharmacokinetics
Indications
CI
Side Effects Black Box Warning Clinical Pearls
BIVALIRUDIN (Angiomax)
MOA
Reversible inhibitor of thrombin 0.75 mg/kg IV bolus, then 1.75 mg/kg/hr IV infusion for the duration of procedure t1/2 = 25 min Renal adj: CrCl 30 mL/min: reduce infusion rate to 1 mg/kg/hr
HIT with thrombosis
Dosing
Pharmacokinetics
Indications
Prophylaxis for thrombosis: Percutaneous coronary interventions Acute MI: adjunct for thrombolytic therapy Active bleeding Hemorrhage Hypotension Nausea, Pain, Backache, Headache Less immunogenic (is only 20 AAs long) Monitored with aPTT or ACT
CI
Side Effects
Clinical Pearls
ARGATROBAN (Novastan)
Binds at active site reversibly Does not bind at exosites First introduced in Japan in 1990 for treatment of peripheral vascular disorders
ARGATROBAN (Novastan)
MOA
Reversible inhibitor of thrombin t1/2 = 30 to 51 min Renal adj: None HIT treatment and prophylaxis 2 mcg/kg/min continuous IV infusion, adjust until steady-state aPTT is 1.5 to 3 times the initial baseline value (not to exceed 100 seconds); MAX 10 mcg/kg/min Prophylaxis: percutaneous coronary intervention (PCI) Active bleeding Hemorrhage GI effects HIT: Monitor aPTT at baseline, 2 hours after therapy initiation, and any dose change Target aPTT: 1.5 3x initial baseline value PCI: Monitor ACT (therapeutic range, 300 to 450 seconds) Elevates INR; INR may be elevated (up to 5) and still be therapeutic.
Pharmacokinetics
Indications
CI
Side Effects
Clinical Pearls
DABIGATRAN (PRADAXA)
MOA
Reversible inhibitor of thrombin 150 mg PO BID t1/2 = 12-17 hrs Renal adj: 15 CrCl 30 mL/min: 75 mg PO BID Prophylaxis: venous thromboembolism (VTE) Acute MI: adjunct for thrombolytic therapy Before D/C dabigatran, bridge with another anticoagulant Active bleeding Prosthetic heart valve, mechanical Hemorrhage Monitor with ECT or aPTT Hold 1-2d prior to surgery. Hold 3-5d prior to surgery (CrCl < 50 mL/min) Decreased absorption when taken with proton pump inhibitor (e.g. omeprazole)
Pharmacokinetics
Indications
Black Box Warning
CI
Side Effects
Clinical Pearls
XIMELAGATRAN (Exanta) - Withdrawn
Discontinued in 2006
hepatotoxicity in clinical trials
preventing stroke and thrombo-embolic events in atrial fibrillation
Failed to prove non-inferiority to warfarin
First oral DTI
AZD0837 (In development)
new and improved ximelagatran Phase II trials Oral form
MONITORING
No required anticoagulation monitoring Why not use PT/INR?
Little to no sensitivity to some Rx and less than optimal to others INR can be markedly different depending on reagent used One recent study of lepirudin, argatroban, & bivalirudin observed a dose dependent effect on the INR
PT/INR most affected by argatroban at therapeutic concentrations Lepirudin had the least overall effect on PT/INR
DTIs: Close to IDEAL ANTICOAGULANT
Effective Minimal complications/side effects Convenient administration (only dabigatran PO) Rapid absorption Fast on and offset action Predictable pharmacokinetics No interactions with food or drugs No HIT (DTI used to treat HIT!) No coagulation monitoring (None yet)
Drawback: No antidote (unlike vit K for warfarin)