Download Drugs Used in Coagulation Disorders

Drugs Used in
Coagulation Disorders
Presented by
Dr. Sasan Zaeri
PharmD, PhD
Mechanism of blood coagulation
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Mechanism of blood coagulation
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Fibrinolysis
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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)
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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
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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
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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)
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Mechanism of blood coagulation
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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
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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
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Toxicity
• Increased bleeding (most common)
– may result in hemorrhagic stroke
– Protamine as antidote
• Not effective for LMW heparins and fondaparinux
• Heparin-induced thrombocytopenia (HIT)
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•
•
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
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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
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Mechanism and effects
• These drugs inhibit both soluble thrombin and
the thrombin enmeshed within developing
clots
• Bivalirudin
– also inhibits platelet activation
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Clinical uses
• Alternatives to heparin
– primarily in patients with HIT
• Coronary angioplasty
– Bivalirudin in combination with aspirin
Monitoring using aPTT requiured
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Toxicity
• Bleeding
– No reversal agents exist
• Anaphylactic reactions
– Prolonged infusion of lepirudin induces antibodies
that form a complex with lepirudin and prolong its
action
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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
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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
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• 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
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Clinical uses
• Chronic anticoagulation in all of the clinical
situations described for heparin
– Exception: anticoagulation in pregnant women
• In DVT
1. Heparin + warfarin (5-7 days)
2. Warfarin (3-6 months)
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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
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Warfarin toxicity
• Drug interactions
– Cytochrome P450 inducers
• carbamazepine, phenytoin, rifampin, barbiturates
– Cytochrome P450 inhibitors
• amiodarone, selective serotonin reuptake inhibitors,
cimetidine
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THROMBOLYTIC AGENTS
• Streptokinase
– synthesized by streptococci
• Alteplase, Tenecteplase and Reteplase
– Recombinant forms of t-PA
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Mechanism of Action
• Conversion of plasminogen to plasmin
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Clinical Uses
• Alternative to coronary angioplasty
– 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
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Toxicity
• Bleeding
– 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
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ANTIPLATELET DRUGS
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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
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ANTIPLATELET DRUGS
• Dipyridamole and cilostazol
– Inhibit phosphodiesterase enzymes → ↑ cAMP
and cGMP
– Inhibit uptake of adenosine by endothelial cells
and RBCs
• Adenosine acts through platelet adenosine A2
receptors to increase platelet cAMP
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Clinical Uses
• Aspirin
– To prevent first or further MI
– To prevent transient ischemic attacks, ischemic
stroke, and other thrombotic events
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Clinical Uses
• Glycoprotein IIb/IIIa inhibitors
– To prevent restenosis after coronary angioplasty
– In acute coronary syndromes (unstable angina and non-Qwave 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)
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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)
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