a set of biochemical reactions that produce deoxythymidylate (dTMP), an essential constituent of DNA synthesis

Cycle depends on convesion of dihyrdofolate to tetrahydrofolate by dihydrofolate reductase

deficiency in serum hemoglobin and erythrocytes in which the erythrocytes are abnormally small

often caused by iron deficiency

1) essential part of the heme molecule

2) an important fraction of iron boud to transferrin (transport protein) and ferritin (storage protein)

women - due to menstrual blood loss

vegetariansand malnourished persons = inadequate Fe intake

Children and pregnant women have increased iron demands

heme is in the form of the Ferrous ion (Fe²⁺) - taken up by specialized divalent metal transporter 1 (DMT1) in intestinal epithelial cells

cells store iron as either ferritin or transport the ferrous ion across basolateral by ferroportin

then it is oxizided to Ferric iron (Fe³⁺) by ferroxidase

ferric iron is transported in complex with transferrin

excess iron is stored in the protein bound form in:

• GI epithelial cells
• macrophages
• heptocytes
• parenchymal cells of skin, heart, and other organs (but that is in cases of great overload)

prevention or treatment of iron deficiency anemia is only indication for iron administration

iron supplementation with ferrous sulfate, ferrous gluconate, or ferrous fumarate

special case you treat with IV admin of a colloid containing a core of iron oxyhydroxide surrounded by a core of carbohydrate

IV preps include:

• iron dextran
• sodium ferric gluconate complex
• iron sucrose

acute iron intoxication is most common in children (by eating iron tablets)

• necrotizing gastroenteritis
• shock
• metabolic acidosis
• coma
• death

chronic iron overload (ie hemochromatosis) damages the organs that store excess iron (heart, liver, pancreas)

acute: immediate tx needed = removal of unabsorbed tablets from the gut; correct acid-base and enlectrolyte abnormalities; parentral admin of deferoxamine (chelates!!)

chronic: phlebotomy for genetic form; if due to infusions, chronically admin a chelator such as deferoxamine or deferasirox

deferoxamine (acute and chronic iron toxicity)

deferasirox (chronic iron toxicity)

it is a cobalt-containing molecule

along with folic acid, is a cofactor for transfer of 1-carbon units, a step necessary for the synthesis of DNA (which manifests first as anemia because RBCs are constantly being produced)

from GI tract in presence of intrinsic factor (product of parietal cells of stomach)

plasma transport = binding to transcobalamin II

stored in large amounts in liver (enough to last 5 yrs)

cyanocobalamin and hydroxocobalamin

have similar pharmacokinetics, but later has longer circulating half-life

B12 essential in 2 reactions:

1) conversion of methylmalonyl coenzyme A (CoA) to succinyl-CoA

2) conversion of homocysteine to methionine

rxn #2 related to folic acid metabolism and synthesis of deoxythymidylate (dTMP) --> precursor for DNA synthesis

2 forms available: hydroxocobalamin and cyanocobalamin

they have equivalent effects

tx of naturally occurring ernicious anemia and anemia caused by gastric resection

use parenteral therapy

no significant toxicity

role: required for normal DNA synthesis; defeciency = megaloblastic anemia; neural tube defects during pregnancy

pharmacokinetics: readily absorbed from GI tract; only modest amounts stored in body (so anemia is within months of depleted levels)

pharmacodynamics: converted to tetrahydrofolate by action of dihyrdofolate reductase; important for dTMP cycle = suplies dTMP required for DNA synthesis, so rapidly dividing cells, like RBCs are most often involved --> this is why antifolate drugs are useful in tx of various infections and cancers

Clinical use and tox: most often b/c dietary insufficiency or malabsorption - anemia is readily treated by folic acid supplementation

Remember folic acid BEFORE and during pregnancy (but doesn't correct NT defects)

erythropoietin and what is the name of the recombinant human EPO

toxicity of EPO

normally produced by kidney (so depletion of this = anemia of renal failure)

recombinant human erythropoietin = epoetin alfa

--> used for anemia associated with renal failure, but effective in other patients (HIV, cancer patients)

acute tox is minimal, but if increase Hct excessively = risk of thrombosis and cardiovacular events

Darbepoeitn alfa = glycosylated form of EPO = much longer half-life

Methoxy polyethylene glycol-epoetin beta = long-lasting form of erythropoietin that can be administered once or twice a month

filgrastim (granulocyte colony-stimulating factor; G-CSF)

sargramostim (granulocyte-macrophage colony-stimulating factor; GM-CSF)

used to acclerate recovery of neutrophils after cancer chemotherapy

production of neutrophils; also stimulates production of other myeloid and megakaryocytes progenitors

can mobilize hematopoietic stem cells (but to a lesser degree G-CSF)

more severe side effects: fever, arthralgias, and capillary damage with edema (allergic reactions are rare)

for neutrophils and can mobilitze hemopeotic stem cells

toxicity is minimal, but can cause bone pain

covalent conjugation product of filgrastim and a form of polyethylene glycol

much longer half-life

interleukin-11

stimulates growth of primitive megakaryocytic progenitors and increases the number of peripheral platelets

tx for thrombocytopenia after a cycle of cancer chemotherapy

tox/side effects: fatigue, headache, dizziness, fluid retention

novel megakaryocyte GF that depends on a peptide selected from a peptide library on the basis of thrombopoietin receptor activation

linked to polyglycine sequence to human Fc = stable half life (3-4 days)

approved for tx of patients with chronic idiopathic thrombocytopenia who have failed to respond to conventional tx

- absorption of B12 via intrinsic factor

- all formed elements of blood are affected

- if due to vit B12 deficiency, it does NOT develop readily

- high oral doses of B12 can be used in patients who refuse IM injections

- alcoholics may be at risk due to FOLIC ACID deficiency

- it's megaloblastic anemia is microscopically indistinguishable from that caused by B12 deficiency

- unlike B12 deficiency, in folic acid deficiency is caused by inadequate diet

- phenytoin and some other anticonvulsants can interfere with folic acid absorption

- neurologic syndrome produced by B12 deficiency can NOT be treated with folic acid

patients with anemia due to chronic renal failure do NOT have high serum EPO levels

- daropoetin alfa has longer half life than epoetin alfa

- adverse effects of epoetin alfa include htn and thrombotic complications

-failure to respond to EPO is commonly due to Fe deficiency

- Epoetin alpha can be used to offset the anemia produced by zidovudine tx in patients wiht HIV infection

- filgrastim is generally reserved for patients with a prior episode of febrile neutropenia after cytotoxic chemotherapy or those at high risk for febrile neutropenia

- advantage of pegfilgrastim compared to filgrastim = admin less frequently

sargramostim

both are NOT contraindicated in patients with AML