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

Mechanism of blood coagulation

Mechanism of blood coagulation

Fibrinolysis

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)

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

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

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)

Mechanism of blood coagulation

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

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

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

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

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

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

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

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

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

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

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)

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

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

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

Mechanism of Action Conversion of plasminogen to plasmin

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

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

ANTIPLATELET DRUGS

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

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

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

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)

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)