1. Drugs Used in Coagulation Disorders
Presented by
Dr. Sasan Zaeri
PharmD, PhD

2. Mechanism of blood coagulation

3. Mechanism of blood coagulation

4. Fibrinolysis

6. ANTICOAGULANTS Classification
Three major types of anticoagulants:
Heparin and related products
must be used parenterally
Direct thrombin inhibitors
used parenterally
Orally active coumarin derivatives (e.g. warfarin)

7. ANTICOAGULANTS Heparin
A large sulfated polysaccharide polymer obtained from animal sources
Highly acidic and can be neutralized by basic molecules
Protamine sulfate (heparin antidote)
Given IV or SC to avoid the risk of hematoma associated with IM injection

8. ANTICOAGULANTS Heparin
Low-molecular-weight (LMW) heparin
Enoxaparin, Dalteparin, Tinzaparin
Greater bioavailability (SC)
Longer durations of action
Administered once or twice a day
Fondaparinux
A small synthetic drug that contains the biologically active pentasaccharide
Administered SC once daily

9. Heparin Mechanism and effects
Heparin binds to antithrombin III (ATIII):
irreversible inactivation of thrombin and factor Xa
1000-fold faster than ATIII alone
Heparin provides anticoagulation immediately after administration
Heparin monitoring
Activated partial thromboplastin time (aPTT)

10. Mechanism of blood coagulation

11. Mechanism and effects LMW heparins and fondaparinux bind ATIII
same inhibitory effect on factor Xa as heparin–ATIII
they fail to affect thrombin
a more selective action
aPTT not required
potential problem in renal failure due to decreased clearance

12. Clinical uses
When anticoagulation is needed immediately e.g. when starting therapy
Common uses:
DVT
Pulmonary embolism
acute myocardial infarction
in combination with thrombolytics for revascularization
in combination with glycoprotein IIb/IIIa inhibitors during angioplasty and placement of coronary stents
The drug of choice in pregnancy

13. Toxicity Increased bleeding (most common)
may result in hemorrhagic stroke
Protamine as antidote
Not effective for LMW heparins and fondaparinux
Heparin-induced thrombocytopenia (HIT)
Due to antibody against complex of heparin and platelet factor 4
May yield venous thrombosis
less likely with LMW heparins and fondaparinux
Osteoporosis
Due to prolonged use of unfractionated heparin

14. Direct Thrombin Inhibitors
Lepirudin
Recombinant form hirudin (Hirudo medicinalis)
Desirudin and Bivalirudin
Modified forms of hirudin
Argatroban
A small molecule with a short half-life
Dabigatran
Orally active

15. Mechanism and effects
These drugs inhibit both soluble thrombin and the thrombin enmeshed within developing clots
Bivalirudin
also inhibits platelet activation

16. Clinical uses Alternatives to heparin Coronary angioplasty
primarily in patients with HIT
Coronary angioplasty
Bivalirudin in combination with aspirin
Monitoring using aPTT requiured

17. Toxicity Bleeding Anaphylactic reactions No reversal agents exist
Prolonged infusion of lepirudin induces antibodies that form a complex with lepirudin and prolong its action

18. Warfarin Small lipid-soluble molecule
readily absorbed after oral administration
Highly bound to plasma proteins (>99%)
Its elimination depends on metabolism by cytochrome P450 enzymes

19. Mechanism of action
Warfarin inhibits vitamin K epoxide reductase (VKOR) in liver
↓ reduced form of vitamin K → ↓ factors II, VII, IX, X, protein C and S

20. Anticoagulant effect is observed within 8-12 h
The action of warfarin can be reversed by:
Vitamin K1 (slowly within 6-24 h)
Transfusion with fresh or frozen plasma (more rapid reversal)
Warfarin monitoring:
Prothrombin time (PT) expressed by INR
INR: 2-3

21. Clinical uses
Chronic anticoagulation in all of the clinical situations described for heparin
Exception: anticoagulation in pregnant women
In DVT
Heparin + warfarin (5-7 days)
Warfarin (3-6 months)

22. Warfarin toxicity Bleeding (most common)
Hypercoagulability early in therapy → dermal vascular necrosis
due to deficiency of protein C
Bone defects and hemorrhage in fetus
Contraindicated in pregnancy

23. Warfarin toxicity Drug interactions Cytochrome P450 inducers
carbamazepine, phenytoin, rifampin, barbiturates
Cytochrome P450 inhibitors
amiodarone, selective serotonin reuptake inhibitors, cimetidine

25. THROMBOLYTIC AGENTS Streptokinase
synthesized by streptococci
Alteplase, Tenecteplase and Reteplase
Recombinant forms of t-PA

26. Mechanism of Action
Conversion of plasminogen to plasmin

27. Clinical Uses Alternative to coronary angioplasty Ischemic stroke
Best result in ST-elevated MI and bundle branch block
Prompt recanalization if used within 6 h
Ischemic stroke
Better clinical outcome if used within 3 h
Cerebral hemorrhage must be ruled out before such use
Severe pulmonary embolism

28. Toxicity Bleeding Allergic reactions (streptokinase)
Same frequency with all thrombolytics
Cerebral hemorrhage (most serious manifestation)
Allergic reactions (streptokinase)
Even at first dose (streptococcal infection history)
Loss of drug efficacy
Not observed with recombinant forms of t-PA
BUT, t-PA is more expensive and not much more effective

29. ANTIPLATELET DRUGS

30. Aspirin acts on COX irreversibly
ANTIPLATELET DRUGS
Aspirin acts on COX irreversibly
several-day effect
Other NSAIDs not used as antiplatelet drug
May interfere with aspirin antiplatelet effect
Abciximab (monoclonal antibody), eptifibatide and tirofiban
reversibly inhibit glycoprotein IIb/IIIa
Clopidogrel, ticlopidine
irreversibly inhibit the platelet ADP receptor

31. ANTIPLATELET DRUGS Dipyridamole and cilostazol
Inhibit phosphodiesterase enzymes → ↑ cAMP
Inhibit uptake of adenosine by endothelial cells and RBCs
Adenosine acts through platelet adenosine A2 receptors to increase platelet cAMP

32. Clinical Uses Aspirin To prevent first or further MI
To prevent transient ischemic attacks, ischemic stroke, and other thrombotic events

33. Clinical Uses Glycoprotein IIb/IIIa inhibitors
To prevent restenosis after coronary angioplasty
In acute coronary syndromes (unstable angina and non-Q-wave acute MI)
Clopidogrel and ticlopidine
To prevent transient ischemic attacks and ischemic strokes
especially in patients who cannot tolerate aspirin
To prevent thrombosis in patients with coronary artery stent (clopidogrel)

34. Clinical Use Dipyridamole
To prevent thrombosis in those with cardiac valve replacement (adjunct to warfarin)
To treat intermittent claudication (a manifestation of peripheral arterial disease)