Download Drugs Used in Coagulation Disorders

Drugs Used in
Coagulation Disorders
Presented by
Dr. Sasan Zaeri
PharmD, PhD
Mechanism of blood clotting
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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 and factor Xa inhibitors
• used parenterally or orally
– 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)
•
•
•
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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Direct Oral Factor Xa inhibitors
• Rivaroxaban and Apixaban
– Rapid onset of action
– Shorter half-lives than warfarin
– Given as fixed oral doses and do not require
monitoring
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Rivaroxaban and Apixaban
• Bind to both free factor Xa and factor Xa bound in the
clotting complex
• Rivaroxaban is approved for:
– Prevention of venous thromboembolism following hip or
knee surgery
– Prevention of stroke in patients with atrial fibrillation
• Toxicity
– Bleeding
• No reversal agents exist
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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
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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
• Cytochrome P450 2C9 and VKOR gene polymorphism
– Dose tailoring based on genetic profile (!)
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THROMBOLYTIC AGENTS
• Streptokinase
– synthesized by streptococci
• Urokinase
– Human enzyme produced by kidneys
• Anistreplase
– complex of purified human plasminogen and bacterial
streptokinase
• 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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t-PA
• Fibrin selectivity
– In theory, it should result in less danger of widespread
bleeding
– In fact, t-PA’s selectivity appears to be quite limited
• Reteplase
– slightly faster onset of action
– longer half-life
• Tenecteplase
– longer half-life
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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, prasugrel and ticlopidine (prodrugs)
– irreversibly inhibit the platelet ADP receptor
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ANTIPLATELET DRUGS
• Dipyridamole and cilostazol
– Inhibit phosphodiesterase enzymes → ↑ cAMP
– Inhibit reuptake 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)
– For secondary prevention of ischemic stroke (in
combination with aspirin)
• Cilostazol
– To treat intermittent claudication (a manifestation of
peripheral arterial disease)
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Toxicity
• Aspirin causes GI and CNS effects
• All antiplatelet drugs significantly enhance the
effects of other anticlotting agents
• Major toxicities of the glycoprotein IIb/IIIa
inhibitors:
– Bleeding
– Thrombocytopenia (in chronic use)
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Toxicity
• Ticlopidine
– Bleeding in up to 5% of patients
– Severe neutropenia in about 1%
– Thrombotic thrombocytopenic purpura (TTP)
• a syndrome characterized by the disseminated
formation of small thrombi, platelet consumption and
thrombocytopenia
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Toxicity
• Clopidogrel is less hematotoxic
• Dipyridamole and cilostazol
– headaches and palpitations (most common)
– Cilostazol; contraindicated in patients with CHF
(↓survival)
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DRUGS USED IN BLEEDING DISORDERS
• Causes of Inadequate blood clotting:
– Vitamin K deficiency
– Genetic defects in clotting factor synthesis
(hemophilia)
– A variety of drug-induced conditions
– Thrombocytopenia
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Vitamin K
• Deficiency of vitamin K in
– Older persons with abnormalities of fat absorption
(most common)
– Newborns
– Hospitalized patients
• Treatment
– Oral or parenteral phytonadione (vitamin K1)
• Caution: dyspnea in fast infusion
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Clotting Factors
• Treatment of hemophilia
– Fresh plasma
– Factor VIII (for hemophilia A) and factor IX (for
hemophilia B)
• Purified products
• Recombinant products
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Desmopressin
• Vasopressin V2 receptor agonist
– Increases activity of von Willebrand factor and
factor VIII
• Used to prepare patients with mild hemophilia A or
von Willebrand disease for surgery
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Antiplasmin Agents
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Antiplasmin Agents
• Aminocaproic acid and tranexamic acid
– To prevent or manage acute bleeding episodes in
patients with hemophilia and others bleeding
disorders
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