Pharmacology of Anemia Flashcards
iron- oral preparations- drugs
- ferrous sulfate
- ferrous gluconate
- ferrous fumarate
iron- parenteral preparations- drugs
- iron dextran
- iron-sucrose complex
- sodium ferric gluconate complex
iron chelators- drugs
- deferoxamine
- deferasirox
vit B12 preparations- drugs
- Cyanocobalamin
- Hydroxocobalamin
Erythrocyte-stimulating agents- drugs
- Epoetin alpha
- Darbepoetin alpha
Myeloid GFs- drugs
- G-CSF (granulocyte colony-stimulating factor)- Filgrastim, pegfilgrastim
- GM-CSF- Sargramostim
- Plerixafor
Megakaryocyte GFs- drugs
- Oprelvekin, IL-11
- Romiplostim
iron def- causes what?
-microcytic hypochromic anemia
iron absorption- where?
-duodenum and jejunum
iron absorption- when iron stores are low- what happens?
- abs iron is transported from mucosal cells to bone marrow to support hemoglobin production
- transported by transferrin
clinical scenarios and iron transport
- increased erythropoiesis- inc in transferrin Rs on developing erythroid cells
- iron store depletion- inc conc of serum transferrin
iron storage
- stored as ferritin
- stored in intestinal mucosal cells, macrophages in liver, spleen, bone and in parenchymal liver cells
iron treatment- used for?
tx or prevention of iron def anemia
oral iron therapy- what is used?
- ferrous salts- b/c ferrous iron is most efficiently absorbed
- 25% or oral iron given as ferrous salts can be absorved
oral iron therapy- adverse effects
-nausea, epigastric discomfort, abd cramps, constipation, black stools, diarrhea
(reduced if taken with/after meals)
parenteral iron therapy- used for?
- pts with iron deficiency who cant tolerate or absorb oral iron
- pts with extensive chronic anemia who cant be maintained with oral iron alone
- can deliver more iron than can be safely be stored- bypasses iron storage regulatory mechanisms of the intestine
iron dextran- route, adverse effects
- IM injection or IV infusion (most common)
- HA, light-headedness, fever, arthralgias, N/V, back pain, flushing, urticaria, bronchospasm
- small test dose- check for hypersensitivity rxns!
Sodium ferric gluconate complex and iron-sucrose complex- route
- IV
- less likely to cause hypersensitivity rxns
Acute iron toxicity- in who? sx? tx?
- in young children who accidentally ingest iron tablets
- necrotizing gastroenteritis, vomiting, abd pain, bloody diarrhea- followed by shock, lethargy, dyspnea
- improvement may be noted followed by severe metabolic acidosis, coma, death!
- tx- whole bowel irrigation, parenteral deferoxamine (iron-chelating compound)
chronic iron toxicity (hemochromatosis)- causes what? in who? tx?
- iron deposits in heart, liver, pancreas, other organs- organ failure and death
- in pts with inherited hemochromatosis- disorder of excessive iron abs
- also in pts who have received many red cell transfusions over a long time
- tx- phlebotomy
- deferasirox- reduces liver iron conc
vit B12 def- causes what?
megaloblastic anemia, GI sx, neuro abnormalities
-B12 stored in liver; low daily requirement- if B12 abs stopped completely, it would take 5 yrs to develop anemia!!!
Vit B12- source from?
microbial synthesis
B12 absorption- occurs how? where? def due to?
- absorbed after complexing with intrinsic factor (secreted by parietal cells of gastric mucosa)
- absorption in ileum
- def due to lack of IF or loss/malfxn of absorption in the ileum
2 essential enzymatic rxns in humans require B12
- synthesis of methionine (aa)
- synthesis of succinyl-CoA
synthesis of methionine
- Homocysteine –> methionine
- requires cobalamin: N5-methyltetrahydrofolate–> tetrahydrofolate –> methylcobalamin: homocysteine–> methionine
- B12 def- causes accum of N5-methyltetrahydrofolate and depletion of tetrahydrofolate; accum of homocysteine
- inc serum levels of homocysteine- diagnostic of B12 def!!!
synthesis of succinyl-CoA- B12 def
- methylmalonic acid and methylmalonyl CoA accum
- diagnostic- serum and urine levels of methylmalonic acid!!
causes of B12 def?
- pernicious anemia
- partial or total gastrectomy
- conditions that affect distal ileum
- almost all due to malabsorption- need parenteral injections for tx!
B12 def- clinical manifestations
- megaloblastic, macrocytic anemia
- mild/moderate leukopenia or thrombocytopenia
- hypercellular bone marrow with accum of megaloblastic erythroid cells
- paresthesias in peripheral n’s and weakness
B12 def- tx?
(almost all due to malabsorption- need parenteral injections for tx!)
-cyanocobalamin and hydroxocobalamin
folic acid def- causes what?
- megaloblastic anemia! (same as B12)
- also congenital malformations in newborns
- doesnt cause the neuro syndrome seen in B12
folic acid- sources? def caused by?
diet- yeast, liver, kidney, green vegetables
-def caused by inadequate intake of folates (alcoholics, pregnant women
folic acid def- tx?
-PO folic acid
Erythropoietin- physiology
- in peritubular interstitial cells of kidney
- binds to a R on the surface of committed erythroid progenitors in the marrow after secretion- initiates JAK/STAT signal pathway
- anemia/hypoxia- synthesis inc by 100-fold or more- marrow progenitor cell survival, prolif, maturation stimulated!
- infl cytokines suppress erythropoietin secretion
Erythropoietin- moa
- induces erythropoiesis by stim the division and diff of committed erythroid progenitor cells
- induces the release of reticulocytes from bone marrow into bloodstream, where they mature to erythrocytes
- results in inc in reticulocyte counts (10 days), and a rise in hematocrit and hemoglobin levels (2-6 wks)
ESAs (erythropoiesis-stimulating agents)- used in who?
pts w/ anemia secondary to chronic kidney dz
- coupled with oral or parenteral iron supplementation in pts with chronic kidney dz
- also used to treat anemia due to primary bone marrow disorders and secondary anemias
ESAs- toxicity
- iron def- can be overcome with supplementation
- hypertension, thrombotic complications
Myeloid GFs- fxn?
- stim the prolif and diff of 1 or more myeloid cell lines
- enhance the fxn of mature granulocytes and monocytes
- bind to and activate members of the cytokine R superfamily
Myeloid GFs- available for clinical use
- G-CSF
- GM-CSF
Filgastrim
- recombinant human G-CSF
- half-life 2-3.5 hrs (IV)
Pegfilgrastim
- conjugation of filgrastim and polyethylene glycol
- longer half-life (15-80 hrs)
Sargramostim
- recombinant human GM-CSF
- half-life 1 hr (IV)
Plerixafor- moa
- reversibly inhibits binding of stromal cell-derived factor-1-alpha (SDF-1alpha), which is expressed on bone marrow stromal cells, to the CXCR4
- results in mobilization of hematopoietic stem and progenitor cells from bone marrow into peripheral blood
- used in combo with filgrastim- synergistic inc in CD34+ cell mobilization
- used in pts who respond suboptimally to G-CSF alone
G-CSF- moa
- stim the prolif and diff or progenitors already committed to the neutrophil lineage
- act the phagocytic activity of mature neutrophils and prolongs survival
- inc conc of hematopoietic stem cells in peripheral blood
GM-CSF- moa
broader biologic actions than G-CSF
- stimulates myelopoiesis
- stim prolif and diff of eraly and late granulocytic progenitor cells, as well as erythroid and megakaryocyte progenitors
- stim fxn of mature neutrophils
- stim T-cell prolif with IL-2
myeloid GFs- used for?
cancer chemotherapy-induced neutropenia
-G-CSF accelerates the rate of neutrophil recovery, reduces the duration of neutropenia
myeloid GFs- toxicity
- filgrastim and pegfilgrastim- used more than GM-CSF- better tolerated; both cause bone pain
- GM-CSF- fever, malaise, myalgias, capillary leak syndrome (peripheral edema, pleural or pericardial effusions)
megakaryocyte GFs- pts with thrombocytopenia have high risk of
hemorrhage
-thrombopoietin and IL-11- endogenous regulators of platelet production
IL-11- drug, moa
Oprelvekin
-act specific cell surface cytokine Rs to stim the growth of mult lymphoid and myeloid cells; inc the number of platelets and neutrophils
Romiplostim- moa
(recombinant thrombopoietin)
-act Mpl thrombopoietin R to cause a dose-dep inc in platelet count
IL-11- used for?
-secondary prevention of thrombocytopenia in pts receiving cytotoxic chemotherapy for nonmyeloid cancers
Romiplostim- used for?
-tx of thrombocytopenia in pts with chronic immune thrombocytopenia purpura
IL-11- toxicity
- fatigue, HA, dizziness, CV effects
- hypokalemia
Romiplostim- toxicity
mild headache on day of administration
