Pharm of Anemia; Hematopoietic GFs Flashcards
Vitamin B12 deficiency
can lead to megaloblastic anemia, GI sxs, neuro abnorms
chief dietary source of VitB12
meat, eggs, dairy
Common signs of anemia
Pallor, fatigue, dizziness, extertional dyspnea, other generalized sx of tissue hypoxia, & CV adaptations such as tachycardia, increased CO and vasodilation
Absence of adequate iron leads to what type of anemia?
Microcytic hypochromic anemia - small erythrocytes with insufficient hemoglobin are formed
Iron absorption
Duodenum & prox jejuni my
When iron stores are high/iron requirements are low
Absorbed iron is diverted into ferritin in the intestinal epithelial mucosal cells for storage
Increased concentration of serum transferrin is associated with
Iron store depletion and iron deficiency anemia
Iron storage
As ferritin (complex of iron and apo-ferritin)
High levels of free iron stimulate production of apoferritin to reduce
Iron toxicity
Oral iron therapy
Only ferrous salts should be used bc ferrous iron is most efficiently absorbed
-ferrous sulfate, ferrous gluconate, ferrous karate
Ferrous salts adverse effects
Nausea, epigastric discomfort, abd cramps, constipation, black stools and diarrhea
Iron dextran
Par enteral iron therapy
-IV infusion -> can admin at higher dose
Adverse effects include: HA, light-headed mess, fever, athralgias, N/V, back pain, flushing, urticaria, bronchospasm, anaphylaxis and death
Sodium ferry gluconate complex and iron-sucrose complex
Parenteral iron therapy
Only IV
Less likely to cause hypersensitivity rxns
Acute iron toxicity
Young children who accidentally ingest iron tablets
-sx: necrotizing gastroenteritis, accompained by vomiting and abd pain and bloody diarrhea followed by shock, lethargy, dyspnea
-followed by severe metabolic acidosis, coma, death
Tx= parenteral deferoxamine
Chronic iron toxicity
Excess iron deposits in heart, liver, pancreas, & other organs
-most common in pts with inherited hemochromatosis & pts who receive many red cell transfusions over a long period of time
Chronic iron toxicity tx
Intermittent phlebotomy
-oral iron chelator deferasirox reduces liver iron concentrations
Vitamin B12 (Cobalamin) deficiency
Leads to Megaloblastic anemia (take 5 yrs to develop if absorption stopped completely), GI sx and neuro abnorms
-stored primarily in the liver
B12 absorption
Absorbed after complexing with intrinsic factor (secreted by parietal cells); absorbed in distal ileum
-after absorption, B12 transported by transcobalamin I,II, III
2 enzymatic rxns require B12
Synthesis of AA methionine & synthesis of succinyl-CoA
B12 deficiency causes
- Accumulation of N5-methylTHF and depletion of THF
- accumulation of homocysteine -> incr serum levels
- methylmalonic acid and methylmalonyl-CoA accumulate
Clinical manifestations of B12 deficiency
Megaloblastic, macrocytic anemia often with associated mild or mod leukopenia or thrombocytopenia and a characteristic hypercellular BM with an accumulation of Megaloblastic erythroid and other precursor cells
-neurologic syndrome associated with B12 def begins with paresthesias and peripheral nerves and weakness and progresses to spasticity, ataxia, & other CNS dysfxns
Folic acid
Required for synthesis of AAs, purines and DNA
Major consequence of folic acid deficiency
Anemia
-cause of congenital malformations in newborns and may play a role in vascular dz
Richest sources of folic acid
Yeast, liver, kidney, green veggies
Unaltered Folic acid is absorbed
In the prox jejunum
Once inside cells, N5-methylTHF is converted to THF by the demethylation rxn that requires
VitB12
Folic acid deficiency results in
Megaloblastic anemia
-does not cause neurologic syndrome seen with B12 def
Drugs that cause folic acid deficiency
Methotrexate, trimethoprim, and pyrimethamine (all inhib DHFR)
Erythropoietin
Peritubular interstitial cells of the kidney
-binds to receptor on the surface of committed erythroid progenitors in the marrow after secretion
Inflammatory CKs suppresses
Erythropoietin secretion, iron delivery, and progenitor proliferation
RHuEPO, Epoetin alpha
IV admin
T 1/2 4-8 hrs but effects on marrow progenitors lasts much longer
Darbepoetin alpha
Modified form of erythropoietin that is more glycosylated and has a half life of 24-26 hrs
Erythropoietin pharmacodynamics
Induces erythropoiesis, induces release of reticulocytes from the BM into the bloodstream where they mature into erythrocytes
-result in incr in reticulocytes counts (10 days) followed by a rise in hematocrit and Hb levels (2-6 wks)
Erythropoiesis-stimulating agents (ESAs)
Used in pts with anemia secondary to chronic kidney dz
- always coupled with oral or parenteral iron supplementation (& sometimes folate) in pts with chronic kidney dz
- may also be used for tx of anemia due to primary bone marrow disorders and secondary anemia so
Adverse effects of erythropoietin
HTN and thrombolytic complications
Myeloid GFs
Stimulate the proliferation and differentiation of one or more myeloid cells lines
-enhance the fxn of mature granulocytes and monocytes
Filgrastim
Recombinant human G-CSF
- nonglycosylated peptide
- IV -> serum half life 2-3.5 hrs
Pegfilgrastim
Covalent conjugation product of Filgrastim and polyethylene glycol (PEG)
Longer serum half life than Filgrastim
Sargramostim
Recombinant human GM-CSF
Plerixafor
Reversible inhibits binding of stromal cell-derived factor-1-alpha (SDF-1a) which is expressed on BM stromal cells, to the CXC chemokine receptor 4 (CXCR4)
- results in mobilization of hematopoietic stem and progenitor cells from BM into PB
- used in combo with Filgrastim results in synergistic incr in CD34+ cell mobilization prior to autologous transplantation
- used in pts who respond sub optimally to G-CSF alone
G-CSF
Stimulates prolif and diff of progenitors already committed to the neutrophil lineage
- activates the phagocytic activity of mature NTs and prolongs survival
- Increases conc of HSCs in the PB
GM-CSF
Stimulate myelopoiesis -> prolif and diff of early and late granulocytic progenitor cells as well as erythroid and megakaryocytes progenitors
- stimulates the fxn of mature NTs
- stimulates T-cell proliferation together with IL-2
Cancer chemotherapy-induced neutropenia
G-CSF accelerates the rate of NT recovery after myelosuppressive chemo & reduce duration of neutropenia
G-CSF reduces episodes of febrile neutropenia, Reqs for broad-spectrum antibiotics, infxs, & days of hospitalization
Pegfilgrastim vs Filgrastim
Pegfilgrastim may be admin less frequent and may shorten period of severe neutropenia
Filgrastim & Pegfilgrastim
Used more freq than GM-CSF -> better tolerated
Can cause bone pain
GM-CSF toxicity
Fever, malaise, athralgias, and a capillary leak syndrome characterized by peripheral edema and pleural or pericardial effusions
Megakaryocytes GFs
Pts with thrombocytopenia have a high risk of hemorrhage
Thrombopoietin and IL-11 are endogenous regulators of platelet production
IL-11: Oprelvekin
Recombinant form
Activates specific cell surface CK receptors to stimulate the growth of multiple lymphoid and myeloid cells, stimulate the growth of primitive megakaryocytic progenitors; increases # of peripheral platelets and NTs
Romiplostim (recombinant thrombopoietin)
Activates Mpl thrombopoietin receptor to cause a dose-dependent increase in platelet count
Increase in platelets begins 5 days after subQ injection, peaks 12-15 days
IL-11 is approved for
Secondary prevention of thrombocytopenia in pts receiving cytotoxic chemotherapy for no myeloid cancers
Romiplostim is approved for
Treatment of thrombocytopenia in pts with chronic immune (idiopathic) thrombocytopenia purpura (ITP)
IL-11 toxicity
Fatigue, headache, dizziness, CV effects (anemia, dyspnea, transient atrial arrhythmias
- hypokalemia
- all are reversible
Romiplostim toxicity
Well tolerated except for a mild HA on day of admin
