Anemia And Hematologic Drugs - Katzung

Pharmacology Agents Used in Anemias (katzung) 19 February 08 Agents Used in Anemias; Hematopoietic Growth Factors

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Hematopoiesis  The production from undifferentiated stem cells of circulating erythrocytes, platelets, and leukocytes.  Resides primarily in the bone marrow in adults  Requires a constant supply of three essential nutrients – iron, vitamin B12 and folic acid – as 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: Anemia, Thrombocytopenia and Neutropenia.

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AGENTS USED IN ANEMIAS IRON Iron deficiency is the most common cause of chronic anemia. Leads to pallor, fatigue, dizziness, exertional dyspnea, and other generalized symptoms of tissue hypoxia. The cardiovascular adaptations to chronic anemiatachycardia, increased cardiac output, vasodilation-can worsen the condition of patients with underlying cardiovascular disease. In the absence of adequate iron, small erythrocytes with insufficient hemoglobin are formed, giving rise to microcytic hypochromic anemia.

PHARMACOKINETICS A. Absorption  Duodenum and proximal jejunum  Heme iron in meat hemoglobin and myoglobin can be absorbed intact  Nonheme iron and iron in inorganic iron salts and complexes must be reduced to ferrous iron (Fe2+) before it can be absorbed  Excess iron can be stored in mucosal cell as ferritin, a water soluble complex consisting of a core of ferric hydroxide covered by a shell of a specialized storage protein called apoferritin. B. Transport  Iron is transported in the plasma bound to transferrin, a β-globulin that specifically binds two molecules of ferrous iron C. Storage  Iron is stored, primarily as ferritin, in intestinal mucosal cells, macrophages in the liver, spleen, and bone, and in parenchy mal liver cells D. Elimination  ≤1mg/day (feces, bile, sweat, urine) CLINICAL PHARMACOLOGY A. Indications for the Use of Iron  Treatment or prevention of iron deficiency anemia  Increased iron requirements: o Infants, especially premature infants; children during rapid growth periods; pregnant and lactating women; and patients with chronic kidney disease  Inadequate iron absorption o Post-gastrectomy; and severe small bowel disease

Elyu, Brim & Virns

Treatment  Oral Iron Therapy o Ferrous sulfate, ferrous gluconate, and ferrous fumarate o 200-400 mg of elemental iron daily and should be continued for 3-6 months after correction of iron loss o ADR: GI sx Parenteral Iron Therapy o 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. postgastrectomy conditions and previous small bowel resection, IBD involving the proximal small bowel, malabsorption syndromes, and advanced chronic renal disease including hemodialysis and treatment with erythropoietin. o Iron dextran A stable complex of ferric hydroxide and lowmolecular-weight dextran containing 50 mg of elemental iron per mL of solution. IM or IV. IV most common. ADR: hypersensitivity and anaphylaxis A small test dose of iron dextran should always be given before full IM or IV doses are given o Iron-sucrose complex and Iron sodium gluconate complex IV Less likely to cause hypersensitivity reactions o Periodically monitor iron storage levels to avoid the serious toxicity associated with iron overload. o Iron stores can be estimated on the basis of serum concentrations of ferritin and the transferrin saturation, which is the ratio of the total serum iron concentration to the total iron-binding capacity (TIBC).

CLINICAL TOXICITY A. Acute Iron Toxicity  Seen almost exclusively in young children who accidentally ingest iron tablets  Necrotizing gastroenteritis, with vomiting, abdominal pain, and bloody diarrhea followed by shock, lethargy, and dyspnea.  Tx: Whole bowel irrigation  Deferoxamine – a potent iron-chelating compound, can be given systemically to bind iron that has already been absorbed and to promote its excretion in urine and feces B.

Chronic Iron Toxicity  Also known as hemochromatosis  Results when excess iron is deposited in the heart, liver, pancreas, and other organs. It  Most commonly occurs in patients with inherited hemochromatosis, a disorder characterized by excessive iron absorption, and in patients who receive many red cell transfusions over a long period of time (eg, patients with thalassemia major).  Chronic iron overload in the absence of anemia is most efficiently treated by intermittent phlebotomy.

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Pharmacology – Agents Used in Anemias; Hematopoietic Growth Factors by Katzung 

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Deferasirox – an oral iron chelator approved for treatment of iron overload.

VITAMIN B12 A cofactor for several essential biochemical reactions in humans. Deficiency leads to anemia, gastrointestinal symptoms, and neurologic abnormalities. Consists of a porphyrin-like ring with a central cobalt atom attached to a nucleotide Deoxyadenosyl cobalamin and methylcobalamin are the active forms of the vitamin in humans. Cyanocobalamin and hydroxocobalamin and other cobalamins found in food sources are converted to the active forms. The ultimate source of vita min BI2 is from microbially derived vitamin B12 in meat (especially liver), eggs, and dairy products. Vitamin B12 is sometimes called extrinsic factor.

PHARMACOKINETICS  Stored primarily in the liver with a total storage pool of 30005000 mcg.  Only trace amounts are normally lost in urine and stool.  Normal daily requirements are only about 2 mcg

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Vitamin Bl2 in physiologic amounts is absorbed in the distal ileum only after it complexes with intrinsic factor

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Vitamin Bl2 deficiency in humans most often results from malabsorption of vitamin Bl2 due either to lack of intrinsic factor or to loss or malfunction of the specific absorptive mechanism in the distal ileum. Nutritional deficiency is rare but may be seen in strict vegetarians after many years without meat, eggs, or dairy products.

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Once absorbed, vit. BI2 is transported to the various cells of the body bound to a plasma glycoprotein, transcobalamin II.

PHARMACODYNAMICS

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Two essential enzymatic reactions in humans require vitamin Bl2 : 1. Methylcobalamin serves as an intermediate in the transfer of a methyl group from N5 -methyltetrahydrofolate to homocysteine, forming methionine. Without vitamin Bl2 conversion of the major dietary and storage folate, N5-methyltetrahydro folate, to tetrahydrofolate, the precursor of folate cofactors, cannot occur. The depletion of tetrahydrofolate prevents synthesis of adequate supplies of the deoxythymidylate (dTMP) and purines required for DNA synthesis in rapidly dividing cells. The accumulation of folate as N5-methyltetrahydro folate and the associated depletion of tetrahydrofolate cofactors in vitamin Bl2 deficiency have been referred to as the "methylfolate trap."

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Isomerization of methylmalonyl-CoA to succinyl CoA by the enzyme methylmalonyl-CoA mutase In vitamin BI2 deficiency, this conversion cannot take place, and the substrate, methylmalonyl. CoA, accumulates.

CLINICAL PHARMACOLOGY  Vitamin Bl2 is used to treat or prevent deficiency  Megaloblastic Anemia o The most characteristic clinical manifestation of vitamin Bl2 deficiency o Clinical findings: 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 o 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.  Schilling test, which measures absorption and urinary excretion of radioactively labeled vitamin B12 can be used to further define the mechanism of vitamin B12 malabsorption when this is found to be the cause of the megaloblastic anemia.  Most common causes of vitamin B12 deficiency: pernicious anemia, partial or total gastrectomy, and conditions that affect the distal ileum, such as malabsorption syndromes, inflammatory bowel disease, or small bowel resection.  Pernicious anemia results from defective secretion of intrinsic factor by the gastric mucosal cells. Patients with pernicious anemia have gastric atrophy and fail to secrete intrinsic factor (as well as hydrochloric acid).  Other rare causes of vitamin Bl2 deficiency include bacterial over growth of the small bowel, chronic pancreatitis, and thyroid disease.  Rare cases of vitamin Bl2 deficiency in children have been found to be secondary to congenital deficiency of intrinsic factor and congenital selective vitamin Bl2 malabsorption due to defects of the receptor sites in the distal ileum. TREATMENT  Parenteral injections of Vitamin B12  The underlying disease should be treated after initial treatment  Vitamin Bl2 for parenteral injection is available as cyanocobalamin or hydroxocobalamin. o Hydroxocobalamin is preferred because it is more highly protein-bound and therefore remains longer in the circulation.  Initial therapy should consist of 100-1000 mcg of vitamin B12 intramuscularly daily or every other day for 1-2 weeks to replenish body stores.  Maintenance therapy consists of 100-1000 mcg intramuscularly once a month for life.  If neurologic abnormalities are present, maintenance therapy injections should be given every 1-2 weeks for 6 months before switching to monthly injections.  Oral doses of 1000 mcg of vitamin B 12 daily are usually sufficient to treat patients with pernicious anemia who refuse or cannot tolerate the injections. o After pernicious anemia is in remission following parenteral vitamin B12 therapy, the vitamin can be administered intranasally as a spray or gel.

Pharmacology – Agents Used in Anemias; Hematopoietic Growth Factors by Katzung

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FOLIC ACID Reduced forms are required for essential biochemical reaction Provides precursor for the synthesis of amino acids, purines & DNA Folate deficiency is common

CHEMISTRY ● Heterocycle (pteridine) + p-aminobenzoic acid + glutamic acid = Folic acid (pteroylglutamic acid) ● It can undergo reduction through dihydrofolate reductase (“folate reductase”) PHARMACOKINETICS ● Average diet : 500 – 700 mcg ● Absorbed : 50 – 200 mcg ● Pregnant (absorption) : 300 – 400 mcg ● Folate stored in the liver and tissues : 5 – 20 mg ● Sources : yeast, liver, kidney, green veggies ● Excretion : Urine and stool ● Absorption : Proximal jejunum PHARMACODYNAMICS ● Tetrahydrofolate cofactors participate in one-carbon transfer reaction which produces the dTMP needed for DNA synthesis ● Other cofactors is required for the vitamin B12-dependent reaction that generates methionine from homocysteine ● Other cofactors donate 1-carbon units in de novo synthesis of essential purines CLINICAL PHARMACOLOGY ● Folate deficiency o Causes:  Inadequate dietary intake (most common)  Alcohol dependence  Liver disease  Pregnancy − Causes neural tube defects (e.g. spina bifida)  Pts w/ hemolytic anemia  Pts w/ malabsorption syndromes  Pts undergoing renal dialysis  Drug(methotrexate, trimethoprim, pyrimethamine, phenytoin) o Results in megaloblastic anemia o Does not cause neurologic syndrome (seen in vit B12 deficiency) o 1 mg oral dose daily is sufficient to treat effects of folate deficiency ● RBC folate level are of greater diagnostic value than serum levels

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HEMATOPOIETIC GROWTH FACTORS Glycoprotein hormones Regulates the proliferation and differentiation of hematopoietic progenitor cells in the bone marrow Colony-stimulating factors o 1st growth factors to be identified o Stimulates the growth of colonies of progenitor cells in vitro

CLINICALLY USED HEMATOPOIETIC GROWTH FACTORS ● Erythropoietin ● Myeloid Growth Factors o Granulocyte colony-stimulating factor

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o Granulocyte-macrophage colony stimulating factor Megakaryocyte Growth Factors o Iinterleukin-11

ERYTHROPOIETIN The first human hematopoietic growth factor Serum half life: 4 – 13 hrs in pts w/ chronic renal failure Not cleared by dialysis Darbepoietin alfa o Glycosylated form of erythropoietin o Twofold to threefold longer half-life

PHARMACODYNAMICS ● It stimulates erythroid proliferation and differentiation ● Erythropoietin receptor o Member of JAK/STAT superfamily ● It also induces release of reticulocytes from the bone marrow ● Kidney produces endogenous erythropoietin ● Erythropoietin production o Direct relationship w/ hypoxia o Inverse relationship w/ hematocrit level o Inverse relationship w/ hemoglobin level o Exception in inverse relationship: anemia of CRF CLINICAL PHARMACOLOGY ● Useful in the treatment of anemia due o Chronic renal failure o Primary bone marrow disorders  e.g. aplastic anemia o Secondary anemia o Zidovudine induced (in HIV) ● It is also useful to accelerate phlebotomies ● Effective for the treatment (hemochromatosis) ● One of the drugs banned by the committee

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MYELOID GROWTH FACTORS Recombinant human G-CSF (rHuG-CSF; filgrastim) o Produced in bacterial expression system Recombinant human GM-CSF (rHuGM-CSF; sargramostim) o Produced in yeast expression system Pegfilgrastim o A covalent conjugation product of filgrastim and a form of polyethylene glycol o Has a much longer half-life than recombinant G-CSF

PHARMACODYNAMICS ● Myeloid growthfactors stimulates proliferation and differentiation ● Receptors are members of JAK/STAT superfamily ● G-CSF o It also activates phagocytic activity of mature neutrophils and prolongs their survival o It also mobilizes stem cells ● GM-CSF o has a broader biologic actions than G-CSF o Stimulates proliferation and differentiation of early and late granulocytic progenitor cells o It also stimulates the function of mature neutrophils o Stimulates T-celll proliferation together with IL-2 o A local active factor at the site of inflammation o It mobilizes peripheral blood stem cells

Pharmacology – Agents Used in Anemias; Hematopoietic Growth Factors by Katzung

CLINICAL PHARMACOLOGY Cancer Chemotherapy-Induced Neutropenia ● G-CSF o Used as treatment of chemotherapy-induced neutropenia o Used for febrile neutropenia o Pegfilgrastim can used as an alternative treatment for G-CSF for the prevention of febrile neutropenia ● GM-CSF o Used as treatment of chemotherapy-induced neutropenia o Can not be used for febrile neutropenia because it can induce fever ● Both G-CSF and GM-CSF can be used for the treatment of pts with AML Other Applications ● Both are effective in treating neutropenia associated with congenital neutropenia, cyclic neuropenia, myelodysplasia, and aplastic anemia ● Both plays an important role in autologous stem cell transplantation ● The most important role of myeloid growth factors in transplantation is for the mobilization of peripheral blood stem cells (PBCs) TOXICITY ● G-CSF can cause bone pain ● GM-CSF can cause more severe side effects o Fever, malaise, arthralgias, myalgias, capillary leak sundrome (peripheral edema and pleural or pericardial effusion) ● Allergic rxnx may occur ● Splenic rupture is rare but can be a serious complication of G-CSF

MEGAKARYOCYTE GROWTH FACTORS CHEMISTRY AND PHARMACOKINETICS ● Il-11 o PRODUCED BY FIBROBLASTS AND STROMAL CELLS IN THE BONE MARROW ● Oprelvekin o Recombinant form of Il-11 ● Thrombopoietin o Hepatocytes are the major source of human thrombopoietin PHARMACOKINETICS ● Il-11 acts through specific cell surface cytokine receptor ● Stimulates the growth of multiple lymphoid and myeloid cells ● It increases the number of peripheral platelets and neutrophils ● Stimulates the growth of primitive megakaryocytic progenitors ● Stimulates mature megakaryocytes CLINICAL PHARMACOLOGY ● Used as treatment of thrombocytopenia TOXICITY ● Most common adverse effects: fatigue, headache, dizziness, cardiovascular effect (anemia due to hemodilution, dyspnea due to fluid accumulation in the lungs & transient atrial arrhythmias), and hypokalemia – all reversible

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