Drugs Used in Coagulation Disorders Presented by Dr
Drugs Used in Coagulation Disorders Presented by Dr. Sasan Zaeri Pharm. D, Ph. D
Mechanism of blood coagulation 2
Mechanism of blood coagulation 3
Fibrinolysis 4
5
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) 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 (a. PTT) 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 – a. PTT 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 v. Monitoring using a. PTT 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
Warfarin • Small lipid-soluble molecule – readily absorbed after oral administration • Highly bound to plasma proteins (>99%) • Its elimination depends on metabolism by cytochrome P 450 enzymes 18
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 19
• Anticoagulant effect is observed within 8 -12 h • The action of warfarin can be reversed by: – Vitamin K 1 (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 20
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) 21
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 22
Warfarin toxicity • Drug interactions – Cytochrome P 450 inducers • carbamazepine, phenytoin, rifampin, barbiturates – Cytochrome P 450 inhibitors • amiodarone, selective serotonin reuptake inhibitors, cimetidine 23
24
THROMBOLYTIC AGENTS • Streptokinase – synthesized by streptococci • Alteplase, Tenecteplase and Reteplase – Recombinant forms of t-PA 25
Mechanism of Action • Conversion of plasminogen to plasmin 26
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 27
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 28
ANTIPLATELET DRUGS 29
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 30
ANTIPLATELET DRUGS • Dipyridamole and cilostazol – Inhibit phosphodiesterase enzymes → ↑ c. AMP and c. GMP – Inhibit uptake of adenosine by endothelial cells and RBCs • Adenosine acts through platelet adenosine A 2 receptors to increase platelet c. AMP 31
Clinical Uses • Aspirin – To prevent first or further MI – To prevent transient ischemic attacks, ischemic stroke, and other thrombotic events 32
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) 33
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) 34
- Slides: 34