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32 terms

Pharm 30: Agents used in anemias

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Define anemia
reduction in red cell mass -> objective sign of a disease, can be caused by chronic blood loss, bone marrow abnormalities, increased hemolysis, renal failure, drugs, nutritional deficiencies of substances needed for normal erythropoiesis -> evaluate with CBC and look at morphological appearance
B12 deficiency
Macrocytic anemia with GI symptoms and neurologic abnormalities
Folate deficiency
macrocytic anemia without neurologic abnormalities
Hypochromic Microcytic anemia
iron deficiency
Oral Ferrous Salts (ferrous iron is best absorbed) -> Ferrous sulfate, ferrous gluconate, ferrous fumarate
used to treat iron deficiency anemia -> given orally and should be continued for 3-6 months after correction of the cause of the iron loss, AE: nausea, epigastric discomfort, abdominal cramps, constipation, diarrhea, may develop black stools (may obscure diagnosis of GI blood loss)
Parenteral iron therapy
reserved for patients with iron deficiency anemia who are unable to tolerate or absorb oral iron or patients with extensive chronic anemia who cannot be maintained by oral iron alone
Iron dextran
parenteral iron therapy -> may cause hypersensitivity reactions (give small test dose), risk of anaphylaxis associated with high molecular weight formulations; may also cause headache, arthralgias, fever, nausea and vomiting, flushing and pruritis
Sodium ferric gluconate complex, Iron sucrose complex
parenteral iron therapy less likely to cause hypersensitivity reactions
Acute iron toxicity
seen in young children who accidentally ingest iron tablets -> leads to necrotizing gastroenteritis with vomiting, abdominal pain, bloody diarrhea which may be followed by shock, metabolic acidosis, coma, and death
Deferoxamine
treatment for acute iron toxicity -> iron chelator binds iron that has already been absorbed and promotes its excretion in urine and feces
Chelation therapy with parenteral Deferoxamine or Deferasirox
used in patients with thalassemia major to retard the accumulation of iron in patients who have developed chronic iron toxicity
Vitamin B12
active forms found in humans are deoxyadenosylcobalamin and methylcobalamine -> cyanocobalamin and hydroxocobalamin can be found in food and converted to active forms -> best source is from microorganisms (not synthesized by animals or plants) in meat, eggs and dairy products -> stored in the liver, need 2 micrograms/day (takes 5 years for storage to be depleted if absorption was stopped) -> uses intrinsic factor (secreted by parietal cells) to be absorbed in the distal ileum by a receptor mediated transport system
Malabsorption of B12
can be due to lack of intrinsic factor or to loss or malfunction of the transporter
Methylcobalamine
serves as an intermediate in the transfer of a methyl group from N5-MTHF to homocysteine (forms methionine) -> N5-MTHF is converted to THF which is the precursor of folate cofactors (deficiency of B12 causes deficiency of folate cofactors -> prevents synthesis of dTMP and purines required for DNA synthesis -> macrocytic anemia)
Methyl-folate trap
accumulation of folate as N5-MTHF and associated depletion of THF cofactors in vitamin B deficiency
Folic acid
can correct anemia in B12 deficiency but does not correct neurological problems because of disruption of the methionine synthesis pathway -> neurologic problems will worsen -> do blood sample to determine type of deficiency, give both until test results are known
Deoxyadenosylcobalamine
used to convert methylmalonyl CoA to succinyl-CoA using methylmalonyl-CoA mutase -> vitamin B12 deficiency causes accumulation of methylmalonyl CoA and methylmalonate
B12 deficiency
most common causes are pernicious anemia, gastrectomy, malabsorption syndromes, IBS, small bowel resection -> give parenteral injections
Pernicious anemia
defective secretion of intrinsic factor -> B12 therapy must be continued for remainder of the life of a patient with this disease
Cyanocobalamine or hydroxycobalamine
parenteral injections to treat B12 deficiency
Folic acid deficiency
common and easily corrected -> causes congenital malformations in newborns and may play a role in vascular disease -> can take 1-6 months after intake stops -> causes megaloblastic anemia but no neurological problems, can be caused by drugs or inadequate dietary intake
N5-MTHF
used in the reaction to convert homocysteine to methionine
THF cofactors
donate one carbon units during the de-novo synthesis of purines and is involved in the reactions that produce the dTMP needed for DNA synthesis
Methotrexate (and to a lesser extent trimethoprim and pyrimethamine)
inhibit dihydrofolate reductase and may cause deficiency of folate cofactors causing megaloblastic anemia
Erythropoietin
stimulates erythroid proliferation and differentiation by interacting with JAK/STAT receptors on red cell progenitors -> also induces the release of reticulocytes from the bone marrow -> endogenously produced in the kidney in response to hypoxia (increased rate of transcription) -> inverse relationship with Hb
Chronic renal failure
patients Epo levels are low and cannot produce the growth factor -> these patients are the most likely to respond to treatment with exogenous Epo
Epo
used to help treat anemia due to cancer, primary bone marrow disorders, cancer chemo, HIV treatment, bone marrow transplantation, AIDS
Darbepoetin
long acting version of Epo (two additional carbohydrate chains, half life is 3x longer)
Epo AE
HTN and thrombotic complications, patients with chronic renal failure or cancer whose serum Hb is raised to more than 12 are at risk of thrombotic event or, in patients with advanced head and neck cancers, faster tumor growth
Filgrastim and sargramostin
myeloid growth factors used to stimulate proliferation and differentiation of myeloid progenitor cells by acting on a JAK/STAT receptor -> used to accelerate recovery of neutrophils after chemo and to treat other forms of secondary and primary neutropenia -> toxicity of G-CSF is minimal (may cause bone pain), GM-CSF can cause fever, arthralgias and capillary damage -> rarely allergic reactions
IL-11
megakaryocytic growth factor stimulates growth of megakaryocytic progenitors and increases the number of peripheral platelets -> used to treat patients who had prior episode of thrombocytopenia after a cycle of cancer chemo -> reduces need for platelet infusions
Hydroxyurea
used to treat pain in sickle-cell disease by increasing HbF (diluting HbS) -> may take several months; AE: bone marrow suppression and cutaneous vasculitis