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

Mechanism of blood clotting 2

Mechanism of blood coagulation 3

Fibrinolysis 4

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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) 6

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 7

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 8

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) 9

Mechanism of blood coagulation 10

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 11

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 12

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 13

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 14

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

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

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

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 18

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 19

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 20

Mechanism of action Warfarin inhibits vitamin K epoxide reductase (VKOR) in liver – ↓ reduced form of vitamin K → ↓ factors II, VII, IX, X, protein C 21

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:

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) 23

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 24

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 (!) 25

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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 27

Mechanism of Action Conversion of plasminogen to plasmin 28

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 29

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 30

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 31

ANTIPLATELET DRUGS 32

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 33 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 34

Clinical Uses Aspirin – To prevent first or further MI – To prevent transient ischemic attacks, ischemic stroke, and other thrombotic events 35

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) 36

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) 37

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) 38

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 39

Toxicity Clopidogrel is less hematotoxic Dipyridamole and cilostazol – headaches and palpitations (most common) – Cilostazol; contraindicated in patients with CHF (↓survival) 40

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 41

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 42

Clotting Factors Treatment of hemophilia – Fresh plasma – Factor VIII (for hemophilia A) and factor IX (for hemophilia B) Purified products Recombinant products 43

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 44

Antiplasmin Agents 45

Antiplasmin Agents Aminocaproic acid and tranexamic acid – To prevent or manage acute bleeding episodes in patients with hemophilia and others bleeding disorders 46