~Teachingcenter的醫學筆記~

用於貧血和促進造血的藥劑
Agents Used In Anemias and Hematopoietic Growth Factors

Iron

1. Agents
   • Ferrous sulfate
   • Ferrous gluconate and ferrous fumarate (oral iron preparation)
   • Iron dextran, iron sucrose complex, and sodium ferric gluconate complex (parenteral preparations, can cause pain, hypersensitivity reaction)
2. Mechanism of action
   • Required for biosynthesis of heme and heme-containing proteins, including hemoglobin and myoglobin.
3. Effects
   • Adequate supplies required for normal heme synthesis.
   • Deficiency results in inadequate heme production.
4. Clinical applications
   • Iron deficiency which manifests as microcytic anemia.
   • Oral preparation.
5. Pharmacokinetics, toxicities, interactions
   • Complicated endogenous system for absorbing, storing, and transporting iron.
   • Toxicity
     1. Acute overdose results in necrotizing gastroenteritis, abdominal pain, bloody diarrhea, shock, lethargy, and dyspnea.
     2. Chronic iron overload results in hemochromatosis, with damage to the heart, liver, pancreas, and other organs. Organ failure and death can ensue.

Iron chelators

1. Agents
   • Deferoxamine
2. Mechanism of action
   • Chelates excess iron.
3. Effects
   • Reduces toxicity associated with acute or chronic iron overload.
4. Clinical applications
   • Acute iron poisoning.
   • Inherited or acquired hemochromatosis.
5. Pharmacokinetics, toxicities, interactions
   • Preferred route of administration of IM or SC. (Deferasirox is and orally administrated chelator for treatment of hemochromatosis.)
   • Toxicity
     1. Rapid IV administration may cause hypotension.
     2. Neurotoxicity and increased susceptibility to certain infections have occurred with long-term use.

Vitamin B12

1. Agents
   • Cyanocobalamin
   • Hydroxocobalamin
2. Mechanism of action
   • Cofactor required for essential enzymatic reactions that form tetrahydrofolate.
   • Covert homocysteine to methionine.
   • Metabolize L-methylmalonyl-CoA.
3. Effects
   • Adequate supplies required for amino acid and fatty acid metabolism, and DNA synthesis.
4. Clinical applications
   • Vitamin B12 deficiency, which manifests as megaloblastic anemia and is the basis of pernicious anemia.
5. Pharmacokinetics, toxicities, interactions
   • Parenteral vitamin B12 is required for pernicious anemia and other malabsorption syndromes.
   • Toxicity: No toxicity associated with excess vitamin B12.

Folic acid

1. Agents
   • Folacin (pteroylglutamic acid)
2. Mechanism of action
   • Precursor of an essential donor of methyl groups used for synthesis of amino acids, purines and deoxynucleotide.
3. Effects
   • Adequate supplies required for essential biochemical reactions involving amino acid metabolism, and purine and DNA synthesis.
4. Clinical applications
   • Folic acid deficiency, which manifests as megaloblastic anemia, and prevention of congenital neural tube defects.
5. Pharmacokinetics, toxicities, interactions
   • Oral, well-absorbed.
   • Need for parenteral administration is rare.
   • Toxicity
     1. Folic acid is not toxic in overdose.
     2. However, large amounts can partially compensate for vitamin B12 deficiency and put people with unrecognized B12 deficiency at risk of neurologic consequences of vitamin B12 deficiency, which are not compensated by folic acid.

Erythrocyte-stimulating agents

1. Agents
   • Epoetin alfa (1~3 times per week)
   • Darbepoetin alfa is long-acting glycosylated form administrated weekly.
   • Methoxy polyethylene glycol-epoetin beta is long-acting form administrated 1~2 times per month.
2. Mechanism of action
   • Agonist of erythropoietin receptors expressed by red cell progenitors.
3. Effects
   • Stimulates erythroid proliferation and differentiation.
   • Induces the release of reticulocytes from the bone marrow.
4. Clinical applications
   • Anemia, especially anemia associated with chronic renal failure, HIV infection, cancer, and prematurity.
   • Prevention of the need for transfusion in patients undergoing certain types of elective surgery.
5. Pharmacokinetics, toxicities, interactions
   • IV or SC administration.
   • Toxicity: Hypertension, thrombotic complications, and very rarely, pure red cell aplasia.
   • To reduce the risk of serious CV events, hemoglobin levels should be maintained < 12 g/dL.

Myeloid growth factors

1. Agents
   • Granulocyte-macrophage colony-stimulating factor (GM-CSF)
   • Pegfilgrastim: long-acting form of filgrastim that is covalently linked to a type of polyethylene glycol.
   • GM-CSF (Sargramostim): myeloid growth factor that acts through a distinct GM-CSF receptor to stimulate proliferation and differentiation of early and late granulocytic progenitor cells, and erythroid and megakaryocyte progenitors; clinical uses are similar to those of G-CSF, but it is more likely than GM-CSF to cause fever, arthralgia, myalgia, and capillary leak syndrome.
   • Plerixafor: antagonist of CXCR4 used in combination with G-CSF for mobilization of peripheral blood cells prior to autologous transplantation in patients with multiple myeloma or non-Hodgkin’s lymphoma who responded suboptimally to G-CSF alone.
2. Mechanism of action
   • Stimulated G-CSF receptors expressed on mature neutrophils and their progenitors.
3. Effects
   • Stimulates neutrophil progenitor proliferation and differentiation.
   • Activates phagocytic activity of mature neutrophils and extends their survival.
   • Mobilizes hematopoietic stem cells.
4. Clinical applications
   • Neutropenia associated with congenital neutropenia, cyclic neutropenia, myelodysplasia, and aplastic anemia.
   • Secondary prevention of neutropenia in patients undergoing cytotoxic chemotherapy.
   • Mobilization of peripheral blood cells in preparation for autologous and allogeneic stem cell transplantation.
5. Pharmacokinetics, toxicities, interactions
   • Daily SC administration.
   • Toxicity: bone pain, (rarely) splenic rupture.

Megakaryocyte growth factors

1. Agents
   • Oprelvekin (interleukin-11, IL-11)
   • Romiplostim: genetically engineered protein in which fragment crystallizable (Fc) components of a human antibody are fused to multiple copies of a peptide that stimulates the thrombopoietin receptors; approved for treatment of idiopathic thrombocytopenic purpura.
   • Eltrombopag: orally active, restricted use.
2. Mechanism of action
   • Recombinant form of an endogenous cytokine.
   • Activates IL-11 receptors.
3. Effects
   • Stimulates growth of multiple lymphoid and myeloid cells, including megakaryocyte progenitors.
   • Increases the number of circulating platelets and neutrophils.
4. Clinical applications
   • Secondary prevention of thrombocytopenia in patients undergoing cytotoxic chemotherapy for non-myeloid cancers.
5. Pharmacokinetics, toxicities, interactions
   • Daily SC injection.
   • Toxicity: fatigue, headache, dizziness, anemia, fluid accumulation in the lungs, and transient atrial arrhythmias.