Download Blood Coagulation Pathway

ORAL DIRECT THROMBIN INHIBITORS
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Girish C & M Jayanthi
Dept of Pharmacology
JIPMER
Coagulation Pathway
Intrinsic pathway
(Contact)
X
Prothrombin
Fibrinogen
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Extrinsic pathway
(Tissue factor)
Xa
Xa
Thrombin
Thrombin
Fibrin
Intrinsic Pathway
Contact (Eg: with glass)
XII
XIIa
XIa
XI
IXa
IX
VIIIa
PL
Ca++
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X
Xa
Extrinsic Pathway
Tissue factor (TF)
VIIa- TF
VII
XIa
IX
IXa
VIIIa
X
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Xa
Site of Action of Drugs
Tissue factor (TF)
VII
VIIa- TF
-
IXa
VIIIa
IX
-
Warfarin
-
-
Heparin
Xa
X
-
Va
Thrombin
Prothrombin
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TFPI,NAPc2
Fibrinogen
Fibrin
Why new oral anticoagulants ?
 Warfarin- sole oral anticoagulant for 60 years.
 Limitations-
Narrow therapeutic index
Delayed onset & offset of action
Mandatory lab monitoring
Drug interactions
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Warfarin Therapy
Clotting
Bleeding
Features of an ideal anticoagulant
 High efficacy to safety index
 Predictable dose response
 Administration by parenteral and oral routes
 Rapid onset of action
 Availability of a safe antidote
 Freedom from side effects
 Minimal interactions
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Why thrombin is an excellent target?
 Forms & stabilizes the clot
 Further generation of thrombin
 Stimulates thrombus- activated fibrinolysis
inhibitor (TAFI) resulting in inhibition of
fibrinolysis
 Activates platelets
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Direct Thrombin Inhibitors (DTIs)
 Directly binds and inhibit thrombin
 Action not mediated through antithrombin
 Hirudin from Hirudo medicinalis
 Lepirudin – Approved for thrombosis related to
Heparin Induced Thrombocytopenia (HIT)
 Bivalirudin – For percutaneous coronary
angioplasty
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Parenteral DTIs:
Bivalent:
Monovalent:
 Hirudin
 Argatroban
 Bivalirudin
 Melagatran
 Lepirudin
Oral DTIs:
 Ximelagatran
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Ximelagatran
 Competitive and reversible direct thrombin
inhibitor.
 Inhibits thrombin activity, thrombin generation
and platelet activation.
 Prolongs aPTT, Prothrombin time.
 No action on other serine proteases
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Pharmacokinetics
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Ximelagatran- Metabolites
(Active)
Kinetics…
 Prodrug of melagatran
 About 20% of oral dose is absorbed.
 Tmax - 2-3 hrs,
t1/2 – 4-5 hrs
 Eliminated via kidney (80%)
 Kinetics not influenced by sex, body weight and
ethnicity
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Pharmacodynamics
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Prothrombin
Thrombin
-
Fibrinogen
Amplification
Ximelagatran
Fibrin
Clot bound Thrombin
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Exosite 2
Thrombin
Active site
Melagatran
Exosite 1
Fibrinogen recognition site
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Thrombin
Hirudin
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Thrombin
Bivalirudin
Thrombin
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Thrombin
Argatroban
Thrombin
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Heparin
Thrombin
AT III
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LMWH
Factor X a
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A T III
Non- hemorrhagic adverse effects:
 Elevation in alanine transferase values in 6-10%
patients
 Developed with in 6 wks to 6 months
 Normalized after discontinuation
 Purpura, dizziness, edema, diarrhea, fatigue
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Drug Interactions
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Interactions…
 Metabolism independent of CYP 450
 No binding to plasma proteins or platelets
 No drug- food interaction
 Less propensity for drug interactions.
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Advantages
 Administered orally at Fixed doses
 Coagulation monitoring not required
 Immediate action
 More predictable anticoagulant response
 Wider safety margin
 Less inter subject variability
 Minimal drug interactions
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Disadvantages:
 Hepatotoxicity
 No antidote available (but dialysis can hasten
elimination)
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Indications & Dose
 Long term secondary prevention of VTE after
standard therapy for an episode of acute VTE
(24mg bid)
 Post operatively for the prevention of VTE after
TKR surgery ( 36 mg bid)
 Prevention of stroke in atrial fibrillation
(36mg bid)
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Clinical trials
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SPORTIF III& IV:
 Ximelagatran not inferior to warfarin for
preventing stroke with no difference in bleeding
rates.
METHRO III & EXPRESS:
 Ximelagatran is as effective as standard therapy
for VTE after major orthopaedic surgery.
THRIVE II& V:
 Ximelagatran is as efficacious as standard
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therapy for treating DVT with similar bleeding
incidents
Current Status
 NDA submitted on Dec 23, 2003
 US FDA approval pending
 In Europe, approved for short term
orthopaedic prophylaxis.
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Conclusion
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Conclusion…
 Favorable pharmacokinetic & dynamic
profile
 Efficacy similar to warfarin
 No data in pregnancy, lactation and children
 Hepatotoxicity
 Benefit- risk considerations
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Will ximelagatran replace warfarin ?
 Has many features of an ideal anticoagulant
 Hepatotoxicity is of concern
 Newer oral DTIs are being developed (Dabigatran
etexilate)
 If these are devoid of hepatotoxicity, it can replace
warfarin
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Reviews:
1. Hirsh J, O’Donnell M, Weitz JI. New anticoagulants.
Blood,2005;105:453-63.
2. Boos CJ, More RS. Anticoagulation for non-valvular atrial aibrillation –
towards a new beginning with ximelagatran. Curr Control Trials
Cardiovasc Med. 2004;5:3-10.
3. BrightonTA. The direct thrombin inhibitor melagatran/ximelagatran,
Med J Aust 2004; 181: 432–37.
4. Kokolis S, Cavusoglu E, Clark LT, Marmur JD. Anticoagulation
strategies for patients undergoing percutaneous coronary intervention:
Unfractioned heparin, low- molecular- weight heparins, and direct
thrombin inhibitors. Prog Cardvasc disease 2004;46: 506-23.
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Original Papers:
1. Clement B, Lopian K. Chacterization of in vitro biotransformation of
new, orally active, direct thrombin inhibitor ximelagatran, an
amidoxime and ester prodrug, Drug Metab Dispos 2003;31:645–51.
2. Eriksson UG, Johansson S, Attman PO, Mulec H, Frison L, Fager G,
Samuelsson O. Influence of severe renal impairment on the
pharmacokinetics and pharmacodynamics of oral ximelagatran and
subcutaneous melagatran. Clin Pharmacokinet. 2003;42:743-53.
3. Schulman S, Wahlander K, Lundstrom T, Clason AB, Eriksson H.
Secondary prevention of venous thromboembolism with the oral
direct thrombin inhibitor ximelagatran. N Engl J Med
2003;349:1713-21.
4. Bredberg E, Andersson TB, Frison L, Thuresson A, Johansson S,
Eriksson-Lepkowska M, Larsson M, Eriksson UG. Ximelagatran, an
oral direct thrombin inhibitor, has a low potential for cytochrome
P450-mediated drug-drug interactions. Clin Pharmacokinet.
2003;42:765-77.
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5. Albers GW, Diener HC, Frison L, Grind M, Nevinson M,
partridge S, et al. SPORTIF Executive Steering Committee for
the SPORTIF V Investigators. Ximelagatran vs warfarin for
stroke prevention in patients with nonvalvular atrial fibrillation: a
randomized trial. JAMA. 2005 ;293:690-8.
6. Fiessinger JN, Huisman MV, Davidson BL, Bounameaux H,
Francis CW, Eriksson H, et al. THRIVE Treatment Study
Investigators. Ximelagatran vs low-molecular-weight heparin
and warfarin for the treatment of deep vein thrombosis: a
randomized trial, JAMA.2005 ;293(6):681-9.
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Editorials:
1. Gurewich V. Ximelagatran—Promises and Concerns, JAMA 2005;
293:736-9.
2. Shapiro S S. Treating thrombosis in the 21st century. N Engl J Med
2003;18: 1762-4.
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Thank You
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