Drugs used in Thromboembolic Disease. Munir Gharaibeh, MD, PhD, MHPE Department of Pharmacology Faculty of Medicine October 2014
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1 Drugs used in Thromboembolic Disease Munir Gharaibeh, MD, PhD, MHPE Department of Pharmacology Faculty of Medicine October 2014
2 Drugs used in Thromboembolic Disease Anticoagulants: Heparin. Oral anticoagulants. Fbrinolytic Drugs: Streptokinase. ASPAC Rt-PA. Urokinase. Scu-PA. Antiplatelet Drugs: Aspirin. Dipyridamole. Sulphinpyrazone. 2
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9 December 14 Munir Gharaibeh,MD, PhD, MHPE 9
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12 Risk Factors for Thromboembolism Abnormalities of Blood Flow: Atrial fibrillation. Left ventricular dysfunction. Bed rest/immobilization/paralysis. Venous obstruction. 12
13 Risk Factors for Thromboembolism Abnormalities of Surface Contact with blood: Vascular injury/trauma. Heart valve disease and replacement. Atherosclerosis. Acute myocardial infarction. Indwelling catheters. Previous DVT/PE. Fractures. Chemical irritation (K+, hypertonic solutions, chemotherapy). Tumor invasion. 13
14 Risk Factors for Thromboembolism Abnormalities of Clotting Components: Protein C, Protein S, Antithrombin deficiency. Prothrombin G20210A mutation. Antiphospholipd antibody syndrome. Estrogen therapy. Pregnancy, malignancy. Homocystenemia, dysfibrinogenemia, Polycythemia, thrombocytosis. Myeloproliferative disorders. 14
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16 Non Thrombogenic Mechanisms in Blood Vessels Transmural negative electrical charges. Plasminogen activation. Protein C activation. Production of heparin-like proteoglyans. Release of PGI 2. 16
17 Inhibitors of Clotting Mechanisms Inhibitor Target Antithrombin Protein C Protein S Tissue factor pathway inhibitor (TFPI) Inhibits factor IIa, IXa and Xa. Inactivates factor Va and VIIIa Cofactor for activation of factor C Inhibits activity of factor VIIa. Plasmin Lyses fibrin into fibrin degradation products. 17
18 Indirect Thrombin Inhibitors HEPARIN: Unfractionated heparin (UFH). Low Molecular Weight Heparins (LMWHs): Enoxaparin. Dalteparin. Tinzaparin( Innohep). Danaparoid. FONDAPARINUX 18
19 HEPARIN(1922) Heterogenous mixture of sulfated mucopolysacharides. Composed of sulfated glucosamine and D- glucoronic acid connected by sulfaminic bridges. It is a normal physiological anticoagulant. Normally found in mast cells in an inactive form but has an obscure function. Released with anaphylaxis. Found in heart, liver, intestine and lungs. Obtained from cow lung and pig intestinal 19 mucosa.
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21 HEPARIN Molecular weight varies: Commercial Unfractionated(UFH):5,000-30,000. High Molecular Weight Heparin (HMWH):2/3rds of UFH Low Molecular Weight Heparin (LMWH) T 1/2 = 1 hr. Distribution limited to the intravascular compartment. Does not cross the placenta and not excreted in breast milk. Eliminated by rapid metabolism by heparinase enzyme in the liver, renal excretion and uptake 21 by the RES.
22 HEPARIN Acts directly in peripheral blood. Does not affect the biosynthesis or plasma levels of any coagulation factor. Taken up by the endothelium where it increases the electronegative potential of the vessel wall. Binds to a variety of plasma proteins, mainly antithrombin. Causes the release of Tissue Factor Pathway Inhibitor (TFPI), which works on Xa, platelets and endothelium. UFH inhibits platelets aggregation. Activates Lipoprotein Lipase which reduces platelets December 14 adhesiveness. Munir Gharaibeh,MD, PhD, MHPE 22
23 HEPARIN Antithrombin inhibits clotting factor proteases, especially thrombin (IIa), IXa and Xa. Heparin binds tightly to antithrombin and causes a conformational change to expose its active site for more rapid interaction with the proteases. Heparin accelerates this comlexing by 1000 folds. Heparin functions as a cofactor, it is not consumed. 23
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25 HEPARIN HMWHs have high affinity for antithrombin and inhibit coagulation by inhibiting all three factors, especially thrombin and factor Xa. 25
26 LMWHs 15 Polysaccharide units. LMWHs inhibit factor Xa but have less effect on thrombin or endothelial cell-heparin receptors and plasma protein binding sites. LMWHs have: Equal efficacy. More predictable effects. More bioavailability from s.c site of injection. Less frequent dosing requirements. Doses specified in milligrams rather than in units. Treatment is not generally monitored (except in renal failure, pregnancy and obesity). 26
27 MONITORING: HEPARIN Activated Partial Thromboplastin Time (aptt) Also, Protamine Titration and Anti-Xa units. Monitoring the response is needed only in patients receiving UFH, but not needed with LMWH. 27
28 TOXICITY: Bleeding. HEPARIN Allergic reactions: fever, anaphylaxis. Loss of hair, alopecia. Osteoporosis and ostealgia. Mineralocorticoid deficiency. Thrombocytopenia: Occurs in 1-4% of patients taking UFH for 7 days. More with UFH from bovine sources. Lower with LMWH. 28
29 HEPARIN Contraindications: Thrombocytopenia (<75,000). Hypersensitivity. Active bleeding. Severe hypertension. Hemophilia, purpura. Infective endocarditis, active TB. Ulcerative lesions of GIT. Threatened abortion. Visceral carcinoma. December Advanced 14 liver or Munir Gharaibeh,MD, renal PhD, disease. MHPE 29
30 HEPARIN Administration of UFH: Initial bolus injection:80-100units/kg. Continuous infusion through a pump: unit/kg/hr. This usually maintains aptt at times control. Not by intramuscular injection. Low dose prophylaxis: Subcutaneously 5000 units every 8-12 hrs. Antidote: Protamine sulfate: is a highly basic low mol.wt compound. 30
31 HEPARIN Administration of LMWHs: Almost completely absorbed after s.c. injection. Usually once or twice daily by subcutaneous injection. Monitoring is by Xa inhibition assay which is not routinely carried. Antidote: Protamine binds poorly and ineffective. No antidote is available nor needed. 31
32 Fondaparinux Synthetic pentasaccharide. Binds antithrombin with high specific activity, resulting in inactivation of factor Xa. Has a long half-life of 15 hours. 32
33 Direct Thrombin Inhibitors Hirudine ( from leeches, Hirudo medicinalis) Lepirudin, recombinant form. Bivalirudin. Are bivalent compounds, i.e. they bind at both the catalytic site and the substrate recognition site of thrombin. Eliminated by the kidneys. Can cause allergy and anaphylaxis. 33
34 Direct Thrombin Inhibitors Argatroban. Ximelagatran. Melagatran. Are small molecules that bind only at the active site of thrombin. Eliminated by the liver. 34
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