Review 2 Flashcards
(76 cards)
what are 3 types of iron and vitamin deficiency anemias?
– Hypochromic, microcytic anemia (small red cells with low hemoglobin; caused by chronic blood loss giving rise to iron deficiency)
– Megaloblastic anemia (large red cells, few in number); caused by a deficiency of Vit B12 or folic acid
– Pernicious anemia (fewer normal-sized red cells, each with a normal hemoglobin content); caused by a deficiency of Vit B12 due to defect in intrinsic factor
causes of anemia
which nutrients necessary for haemopoiesis might be deficient?
– iron
– folic acid and vitamin B 12
– pyridoxine (vit B6) and vitamin C (important for iron abs)
what are 2 categories for treating anemia?
hematinic agents
hematopoietic growth factors
name 2 hematinic agents
- Iron
- Folic acid and Vit B12
name 4 Hematopoietic Growth Factors
- Erythropoietin
- Granulocyte Colony-Stimulating Factor (G-CSF)
- Granulocyte-Monocyte Colony-Stimulating Factor (GM-CSF)
- Megakaryocyte (Thrombopoietic) Growth Factors
Hematinic agents: Iron
which form of iron is absorbed?
where is it absorbed?
what is a transport protein for iron?
• Ferric iron (Fe3+) must be converted to ferrous iron (Fe2+, reduced form) for absorption (by ferric reductase enzyme) in the GI tract.
• Absorption involves active transport into mucosal cells in the duodenum and jejunum (the upper ileum), from where it can be transported into the plasma and/or stored intracellularly as ferritin.
• Total body iron is controlled exclusively by absorption; in iron deficiency, more is transported into plasma than is stored as ferritin in jejunal mucosa.
• Iron that is released is transported by transferrin (the
transport protein).
• Transferrin delivers the iron to either the liver for storage or to bone marrow for further hemoglobin and RBC production
Hematinic agents: Iron
name oral and IV common drugs
Iron formulations are used for treatment of iron deficiency
Oral: ferrous sulfate, ferrous fumarate, ferrous gluconate, polysaccharide-iron complex
IV: iron dextran, sodium ferric gluconate, iron sucrose
Hematinic agents: Iron
side effects
• Gastrointestinal disturbances.
• Severe toxic effects occur if large doses are ingested;
such acute poisoning can be treated with desferrioxamine, an iron chelator as can chronic iron overload in diseases such as thalassemia.
when does iron overload occur? (2)
Iron overload occurs in chronic hemolytic anaemias
requiring frequent blood transfusions, such as;
- Thalassaemias (a large group of genetic disorders of globin chain synthesis)
- Hemochromatosis (a genetic iron storage disease with increased iron absorption, resulting in damage to liver, islets of Langerhans, joints and skin).
how to treat iron overload?
3
- Desferrioxamine: form a complex with ferric iron which, unlike unbound iron, is excreted in the urine.
- Desferrioxamine is not absorbed from the gut. Therefore, it must be given by slow SC infusion. For acute iron overdose, it is given IM or IV
- Deferiprone is an orally absorbed iron chelator, used as an alternative treatment for iron overload in patients who are unable to take desferrioxamine.
- Deferasirox is similar, but can cause GI bleeding
Hematinic agents: Folic Acid and Vitamin B12
what is the role of folic acid and Vit B12
Prototype: B9: Folic acid; B12: Cyanocobalamin,
hydroxocobalamin
• Vitamin B12 and folic acid play key roles in DNA synthesis. Active forms of folic acid serve as enzyme cofactors that play key roles in the synthesis of purines and pyrimidines, as well as amino acids, in the body.
• A deficiency of folic acid or B12 affect cells that are actively dividing, such as the cells of the bone marrow, which are involved in erythropoiesis. Therefore, the deficiencies of these vitamins is anemia.
• Specifically, B12 deficiency results in abnormal DNA replication, which prevents cells from maturing properly, leading to production of large, dysfunctional RBC precursors (megaloblasts) that do not leave the marrow, or abnormal cells that do leave the marrow.
• B12 deficiency can also affect the nervous system, causing inflammation, demyelination, and neuronal cell death
Hematinic agents: Folic Acid and Vitamin B12
MOA?
- Folic acid: Reduction of folic acid, catalyzed by dihydrofolate reductase in two stages yields dihydrofolate (FH 2 ) and tetrahydrofolate (FH 4 ), co-factors which transfer methyl groups (1- carbon transfers) in several important metabolic pathways.
- FH 4 is essential for DNA synthesis.
- B12: involves conversion of both methyl-FH 4 to FH 4 and homocysteine to methionine
see diagram:
- Convert homocysteine to methionine important for DNA synthesis B12 important for conversion of methyl tetrahydrofolate to and tetrahydrofolate (methyl FH4 tp FH4)
- Thymidylate synthase convert methylene dUMP to dTMP or DNA synthesis
- Reduction of folic acid yields dihydrofolate and tetrahydrofolate
Hematinic agents: Folic Acid and Vitamin B12
indications for Vitamin B12
- Pernicious anemia
* Megaloblastic and macrocytic anemias caused by poor B12 absorption
Hematinic agents: Folic Acid and Vitamin B12
Folic Acid
- Megaloblastic and macrocytic anemias
- Prevention of neural tube defects in neonates (give to pregant women)
- Adjunct to methotrexate to prevent methotrexate toxicity (can be used for alopecia)
- Pernicious anemia (combined with B12)
Hematopoietic Growth Factors: Erythropoietins
MOA continued
where does EPO bind a receptor and what types of effects will happen
- Patients with a deficiency of erythropoietin will be anemic. This occurs commonly in patients with renal failure.
- Once released, erythropoietin binds to a receptor on the surface of committed erythroid progenitor cells in the bone marrow.
- Binding to this receptor mediates a variety of intracellular effects through tyrosine kinases, including the inhibition of apoptosis.
- Inhibiting apoptosis prevents RBCs from dying at an early stage of development. Erythropoietin also promotes proliferation through Janus protein kinase-2 (JAK2) pathways
More cell proliferation, no death of RBCs
Hematopoietic Growth Factors: Erythropoietins
Indications
- Anemia
- In advanced renal failure (can’t make it)
- Associated with chemotherapy and acquired immunodeficiency syndrome (AIDS)
Hematopoietic Growth Factors: Erythropoietins
AE (4)
• Iron deficiency: If iron stores cannot keep up with
erythropoiesis, patients may develop a functional iron
deficiency. Patients need an iron supplement.
When you make RBC it has hemoglobin which needs iron - will take plasma iron
• Thrombosis: particularly in patients on dialysis. It is
recommended that these patients receive anticoagulant therapy as a prophylactic measure.
• Hypertension: Although increased hematocrit can lead to increased blood pressure, the mechanism is believed to be more likely a result of the interaction between erythropoietin and vasoactive factors such as angiotensin II.
• Seizures: Seizures have been reported in dialysis patients receiving epoetin alfa
Hematopoietic Growth Factors: Colony Stimulating Factors
function?
2 prototypes
Colony-stimulating factors (CSFs) are agents that stimulate the production of neutrophils and monocytes
• Granulocyte Colony-Stimulating Factor (G-CSF):
filgrastim, lenograstim, pegfilgrastim
- astim
• Granulocyte-Monocyte Colony-Stimulating Factor (GMCSF): sargramostim
- ostim
Hematopoietic Growth Factors: Colony Stimulating Factors
MOA?
• The CSFs work by binding to receptors on myeloid
progenitor cells. These are cells in the bone marrow that make RBCs, platelets, granulocytes, and monocytes. The actions of these receptors are mediated through the Janus protein kinase/signal transducers and activators of transcription (JAK/STAT) pathway.
• G-CSFs stimulate proliferation and differentiation only of progenitors commited to becoming neutrophils.
• GM-CSFs stimulate the production of neutrophils and
monocytes, as well as the actions (phagocytosis,
superoxide production, and cell-mediated toxicity) of
neutrophils, monocytes, and eosinophils
Hematopoietic Growth Factors: Colony Stimulating Factors
Indications
• Adjunct to myelosuppressive chemotherapy
• Severe chronic neutropenia
• Prevention and treatment of neutropenia in human
immunodeficiency virus (HIV) infection
Hematopoietic Growth Factors: Colony Stimulating Factors
AE? (6)
- Bone loss: G-CSF increases osteoclast activity, leading to bone resorption.
- Joint pain: G-CSF appears to stimulate cytokine release, leading to joint pain.
- Renal dysfunction: G-CSF causes a transient and reversible renal impairment, believed to be caused by leukostasis (clumping of leukocytes) in the kidneys.
- Acute respiratory distress: G-CSF can lead to lung injury because of accumulation and activation of neutrophils in the lungs.
- Splenomegaly or splenic rupture: Cases of splenic rupture have been reported with G-CSF. balloon like
- Sickle cell crises: Sometimes fatal in patients with sickle cell disorders
Hematopoietic Growth Factors: Megakaryocyte
(Thrombopoietic) Growth Factors
• Megakaryocyte (Thrombopoietic) Growth Factors
- Oprelvekin (IL-11)
- Thrombopoietin
• Oprelvekin (IL-11) and Thrombopoietin stimulate the growth of megakaryocytic progenitors and increase the number of peripheral platelets. They are used to treat thrombocytopenia following cancer chemotherapy.
- Eltrombopag (oral) and romiplostim (injectable) are recently approved thrombopoietin agonists.
- IL-11 treatment is associated with dizziness, headache and fatigue. Recombinant human trombopoietin is supposed to be better tolerated.
what are 2 types of agents that can treat osteoporosis?
- antiresorptive drugs
2. anabolic agents
how do antiresorptive drugs work?
decrease bone loss, e.g. bisphosphonates, calcitonin, selective estrogen receptor modulators (SERMs), denusomab , calcium
