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Clinical Pharmacy in Haematology DRUGS USED IN DISORDERS OF COAGULATION AND HEMOPOIESIS Spectrum of haematological diseases Deficiency anaemias Disorders of haemoglobin structure Haemolytic structure Aplastic anaemia Haematological malignancies: leukaemias and lymphomas (all aspects of management, including bone marrow transplantation) Congenital and acquired bleeding disorders Thromboembolic disorders and anticoagulation Transfusion medicine Haematological problems associated with perinatal care; intensive care; renal medicine, organ transplantation, orthopaedic and vascular surgery (in adults). Thrombus formation at the site of the damaged vascular wall A model of blood coagulation ANTICOAGULANT DRUGS The ideal anticoagulant drug would prevent pathologic thrombosis and limit reperfusion injury, yet allow a normal response to vascular injury and limit bleeding. Theoretically this could be accomplished by preservation of the TF-VIIa initiation phase of the clotting mechanism with attenuation of the secondary intrinsic pathway propagation phase of clot development. At this time such a drug does not exist; all anticoagulants and fibrinolytic drugs have an increased bleeding risk as their principle toxicity INDIRECT THROMBIN INHIBITORS The indirect thrombin inhibitors are so-named because their antithrombotic effect is exerted by their interaction with a separate protein, antithrombin. Unfractionated heparin (UFH), low-molecularweight heparin (LMWH), and the synthetic pentasaccharide fondaparinux bind to antithrombin and enhance its inactivation of factor Xa. Unfractionated heparin and to a lesser extent LMWH also enhance antithrombin's inactivation of thrombin. Heparin Heparin is a heterogeneous mixture of sulfated mucopolysaccharides. It binds to endothelial cell surfaces and a variety of plasma proteins. Its biologic activity is dependent upon the endogenous anticoagulant antithrombin. Antithrombin inhibits clotting factor proteases, especially thrombin (IIa), IXa, and Xa, by forming equimolar stable complexes with them. In the absence of heparin, these reactions are slow; in the presence of heparin, they are accelerated 1000-fold. Only about a third of the molecules in commercial heparin preparations have an accelerating effect because the remainder lack the unique pentasaccharide sequence needed for high-affinity binding to antithrombin. The active heparin molecules bind tightly to antithrombin and cause a conformational change in this inhibitor. The conformational change of antithrombin exposes its active site for more rapid interaction with the proteases (the activated clotting factors). Heparin functions as a cofactor for the antithrombin-protease reaction without being consumed. Once the antithrombin-protease complex is formed, heparin is released intact for renewed binding to more antithrombin. The antithrombin binding region of commercial unfractionated heparin consists of repeating sulfated disaccharide units composed of D-glucosamine-L-iduronic acid and D-glucosamine-D-glucuronic acid. Highmolecular-weight fractions of heparin with high affinity for antithrombin markedly inhibit blood coagulation by inhibiting all three factors, especially thrombin and factor Xa. Unfractionated heparin has a molecular weight range of 5000-30,000. In contrast, the shorter-chain lowmolecular-weight (LMW) fractions of heparin inhibit activated factor X but have less effect on thrombin than the HMW species. Nevertheless, numerous studies have demonstrated that LMW heparins such as enoxaparin, dalteparin, and tinzaparin are effective in several thromboembolic conditions. In fact, these LMW heparins¾in comparison with UFH¾have equal efficacy, increased bioavailability from the subcutaneous site of injection, and less frequent dosing requirements (once or twice daily is sufficient). Monitoring of Heparin Effect Toxicity A. BLEEDING The major adverse effect of heparin is bleeding. This risk can be decreased by scrupulous patient selection, careful control of dosage, and close monitoring. Elderly women and patients with renal failure are more prone to hemorrhage. Heparin is of animal origin and should be used cautiously in patients with allergy. Increased loss of hair and reversible alopecia have been reported. Longterm heparin therapy is associated with osteoporosis and spontaneous fractures. Heparin accelerates the clearing of postprandial lipemia by causing the release of lipoprotein lipase from tissues, and long-term use is associated with mineralocorticoid deficiency. Monitoring of Heparin Effect Toxicity B. HEPARIN-INDUCED THROMBOCYTOPENIA Heparin-induced thrombocytopenia (HIT) is a systemic hypercoagulable state that occurs in 1-4% of individuals treated with UFH for a minimum of 7 days. Surgical patients are at greatest risk. The reported incidence of HIT is lower in pediatric populations outside the critical care setting and is relatively rare in pregnant women. The risk of HIT may be higher in individuals treated with UFH of bovine origin compared with porcine heparin and is lower in those treated exclusively with LMWH. HEPARIN Contraindications Heparin is contraindicated in patients with HIT, hypersensitivity to the drug, active bleeding, hemophilia, significant thrombocytopenia, purpura, severe hypertension, intracranial hemorrhage, infective endocarditis, active tuberculosis, ulcerative lesions of the gastrointestinal tract, threatened abortion, visceral carcinoma, or advanced hepatic or renal disease. Heparin should be avoided in patients who have recently had surgery of the brain, spinal cord, or eye, and in patients who are undergoing lumbar puncture or regional anesthetic block. Despite the apparent lack of placental transfer, heparin should be used in pregnant women only when clearly indicated. WARFARIN & THE COUMARIN ANTICOAGULANTS The clinical use of the coumarin anticoagulants began with the discovery of an anticoagulant substance formed in spoiled sweet clover silage which caused hemorrhagic disease in cattle. Warfarin is one of the most commonly prescribed drugs, used by approximately 1.5 million individuals, and several studies have indicated that the drug is significantly underused in clinical situations where it has proven benefit Warfarin is generally administered as the sodium salt and has 100% bioavailability. Coumarin anticoagulants Administration & Dosage Treatment with warfarin should be initiated with standard doses of 5-10 mg rather than the large loading doses formerly used. The initial adjustment of the prothrombin time takes about 1 week, which usually results in a maintenance dose of 5-7 mg/d. The prothrombin time (PT) should be increased to a level representing a reduction of prothrombin activity to 25% of normal and maintained there for long-term therapy. When the activity is less than 20%, the warfarin dosage should be reduced or omitted until the activity rises above 20%. Schematic representation of the fibrinolytic system FIBRINOLYTIC DRUGS Fibrinolytic drugs rapidly lyse thrombi by catalyzing the formation of the serine protease plasmin from its precursor zymogen, plasminogen. These drugs create a generalized lytic state when administered intravenously. Thus, both protective hemostatic thrombi and target thromboemboli are broken down. The Box: Thrombolytic Drugs for Acute Myocardial Infarction, describes the use of these drugs in one major application Fibrinolytic drugs Streptokinase Anistreplase alteplase Reteplase Tenecteplase ANTIPLATELET AGENTS several targets for platelet inhibitory drugs have been identified: Inhibition of prostaglandin synthesis ASPIRIN Inhibition of ADP-induced platelet aggregation CLOPIDOGREL & TICLOPIDINE BLOCKADE OF PLATELET GLYCOPROTEIN IIB/IIIA RECEPTORS (Abciximab, Eptifibatide, Tirofiban ) ADDITIONAL ANTIPLATELET-DIRECTED DRUGS (Dipyridamole, Cilostazol ) ASPIRIN Aspirin inhibits the synthesis of thromboxane A2 by irreversible acetylation of the enzyme cyclooxygenase. The FDA has approved the use of 325 mg/d for primary prophylaxis of myocardial infarction but urges caution in this use of aspirin by the general population except when prescribed as an adjunct to risk factor management by smoking cessation and lowering of blood cholesterol and blood pressure. Meta-analysis of many published trials of aspirin and other antiplatelet agents confirms the value of this intervention in the secondary prevention of vascular events among patients with a history of vascular events. FIBRINOLYTIC INHIBITORS: AMINOCAPROIC ACID Clinical uses of aminocaproic acid are as adjunctive therapy in hemophilia, as therapy for bleeding from fibrinolytic therapy, and as prophylaxis for rebleeding from intracranial aneurysms. FIBRINOLYTIC INHIBITORS: AMINOCAPROIC ACID Aminocaproic acid (EACA), which is chemically similar to the amino acid lysine, is a synthetic inhibitor of fibrinolysis. It competitively inhibits plasminogen activation. It is rapidly absorbed orally and is cleared from the body by the kidney. The usual oral dosage of EACA is 6 g four times a day. When the drug is administered intravenously, a 5 g loading dose should be infused over 30 minutes to avoid hypotension. Tranexamic acid is an analog of aminocaproic acid and has the same properties. It is administered orally with a 15 mg/kg loading dose followed by 30 mg/kg every 6 hours, but the drug is not currently available in the USA. Hematopoiesis Hematopoiesis, the production from undifferentiated stem cells of circulating erythrocytes, platelets, and leukocytes, is a remarkable process that produces over 200 billion new blood cells per day in the normal person and even greater numbers of cells in people with conditions that cause loss or destruction of blood cells. The hematopoietic machinery resides primarily in the bone marrow in adults and requires a constant supply of three essential nutrients¾iron, vitamin B12, and folic acid¾as well as the presence of hematopoietic growth factors, proteins that regulate the proliferation and differentiation of hematopoietic cells. Inadequate supplies of either the essential nutrients or the growth factors result in deficiency of functional blood cells. Absorption, transport, and storage of iron The average diet contains 10-15 mg of elemental iron daily. A normal individual absorbs 5-10% of this iron, or about 0.5-1 mg daily. Iron is normally absorbed in the duodenum and proximal jejunum, although the more distal small intestine can absorb iron if necessary. Iron absorption increases in response to low iron stores or increased iron requirements. Total iron absorption increases to 1-2 mg/d in normal menstruating women and may be as high as 3-4 mg/d in pregnant women. The only clinical indication for the use of iron preparations is the treatment or prevention of iron deficiency anemia 1. Oral iron therapy- a wide variety of oral iron preparations are available. Because ferrous iron is most efficiently absorbed, only ferrous salts should be used. Ferrous sulfate, ferrous gluconate, and ferrous fumarate are all effective and inexpensive and are recommended for the treatment of most patients. 2. Parenteral iron therapy- parenteral therapy should be reserved for patients with documented iron deficiency who are unable to tolerate or absorb oral iron and for patients with extensive chronic blood loss who cannot be maintained with oral iron alone. Enzymatic reactions that use vitamin B12, folates Vitamin B12 serves as a cofactor for several essential biochemical reactions in humans. Deficiency of vitamin B12 leads to anemia, gastrointestinal symptoms, and neurologic abnormalities. The most characteristic clinical manifestation of vitamin B12 deficiency is megaloblastic anemia. The typical clinical findings in megaloblastic anemia are macrocytic anemia, often with associated mild or moderate leukopenia or thrombocytopenia (or both), and a characteristic hypercellular bone marrow with an accumulation of megaloblastic erythroid and other precursor cells. The neurologic syndrome associated with vitamin B12 deficiency usually begins with paresthesias and weakness in peripheral nerves and progresses to spasticity, ataxia, and other central nervous system dysfunctions. Hematopoietic growth factors The hematopoietic growth factors are glycoprotein hormones that regulate the proliferation and differentiation of hematopoietic progenitor cells in the bone marrow. The first growth factors to be identified were called colony-stimulating factors because they could stimulate the growth of colonies of various bone marrow progenitor cells in vitro. Many of these growth factors have been purified and cloned, and their effects on hematopoiesis have been extensively studied. Erythropoietin (epoetin alfa), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and interleukin-11 (IL-11), thrombopoietin