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1

Erythocyte factors

Iron
Vitamins B12 and folate
EPO

2

Granulocyte factors

Filgastim (g-CSF)
Sargramastim (GM-CSF)

3

Platelet factors

Oprelvekin (IL11)
Romiplostim
Eltrombopag

4

Most common causes of iron and vitamin diff.

• menstruation in females
• drug treatment w/ NSAIDS (blood loss)
• pathological conditions
• parasitic infestation.
• Pregnancy and child bearing

5

Iron uptake

Abs in duodenum/proximal jejunum
Give at 2 hrs before or 4 hours after food
Do not give with phosphates/phyates/tannates
Abs. better with Acids

6

1. Iron dextran– Low (InFeD®) and high (DexFerrum®) MW

IV/IM bolus or IV infusion (for large doses)

Because of allergic reactions a test dose infusion can be performed when giving this agent for the first time.

Indications
 Excessive continuing blood loss
 Inflammatory bowel disease
 Chronic kidney disease
 Use in cancer patients
 Use in heart failure

7

2. Ferric Gluconate Complex (Ferrlecit®)

Commonly used with EPO
1 hr IV infusion, lower incidence of hypersensitivity reactions than HMW dextran
The potential exists for fatal hypersensitivity reactions and test doses are recommended in patients with drug allergies including iron dextran.

8

3. Iron Sucrose (Venofer®)

 safe and effective for many conditions that require parental iron supplementation
 rountinely used in combination with erythropoietin during hemodialysis to prevent Fe deficiency anemia from loss of RBC during dialysis +  RBC production.
 Unlike other parental formulations iron sucrose is not used for total dose infusions and is limited to 300 mg every 2-3 weeks.
 total dose infusions – repeleting iron stores with a single treatment episode

9

Ferumoxytol (Feraheme®)

composed of superparamagnetic iron oxide nanoparticles coated with a low molecular weight semisynthetic carbohydrate.
It has been deemed safe and effective when given as a rapid intravenous infusion (> 1 min) in patients with chronic kidney disease (CKD) and those on dialysis.

10

. Ferric carboxymaltose (Ferinject®)

is a novel stable iron complex for intravenous use that can be given at single doses of up to 1000 mg of elemental iron per week over a recommended infusion time of 15 minutes.
Approved in July 2013 up to 1500 mg of iron can be administered over the course of two treatment sessions.

11


Side effects of IV iron

 Self-limiting fever, arthralgias, and myalgias, usually within 24 hours of infusions. These resolve without therapy but a small clinical benefit is obtained from the use of nonsteroidal anti-inflammatory agents.
 A flare of arthritis in patients with inflammatory arthritis, such as rheumatoid arthritis, commonly occurs. (steroids?)

12

Chelation therapy for iron toxicity

Treatment for acute toxicity: deferoxamine
Treatment of chronic toxicity: deferoxamine or deferasirox

13

Vitamin B12= Cyanocobalamin

• B12 is complexed w/ intrinsic factor and absorbed via a highly selective receptor-mediated transport system.
• Transcobalamin II – systemic transport

14

B12 is maintained as two important active coenzymes

a) Methylcobalamin: utilized for synthesis of methionine from homocysteine
b) Deoxyadenosylcobalamin: responsible for carbohydrate and lipid metabolism

15

B12 vs intrinsic factor anemias

B12- Megaloblastic (RBC first) and can have irrreversible neuro damage characterized by swelling of myelinated neurons, demyelination and cell death in spinal chord & cortex

Intrinsic- Pernicious

16

B12 drugs

Hydroxocobalamin (Generic) – IM Only
Cyanocobalamin (Generic) – IM /Deep SQ
Intranasal Gel (Nascobal)

Can also supplement folate to correct B12 problem but not resolve myelination problem

17

Folic acid

Used in myelination and in DNA synthesis
• DEFICIENCY  Megaloblastic Anemia indistinguishable from that caused by B12 deficiency.
• ANEMIA will appear more rapidly with folate deficiency than with B12 deficiency because there is a limited storage pool.
• Folic acid DOES NOT lead to neurological abnormalities
• Higher strengths + injectable require prescription

18

Erythropoietin - a.k.a. Epoetin Alfa or EPO (Epogen

 Erythropoietin binds to the erythropoietin receptor (EpoR) on red cell progenitors and precursors and promotes survival and proliferation.
 Titrate dose to prevent too rapid ↑ in Hct .
 Patients must have adequate Fe in circulation before therapy initiated
 Rapid expansion of red cell mass can ↑ blood volume & viscosity leading to↑ vascular resistance.
 Erythropoietins increase the risk of death, myocardial infarction, stroke, venous thromboembolism, thrombosis of vascular access and tumor progression or recurrence
Made in kidney

19

Three formulations all given by injection IV or SC

1. Erythropoietin - a.k.a. Epoetin Alfa or EPO (Epogen®) Recombinant form of erythopoietin 3x / week
2. Darbepoetin alfa - (Aranesp®) 1x/week
3. Methoxy polyethylene glycol-epoetin - (Mircera®) 1-2X/month
Uses:
 Anemias, particularly those associated with chronic renal failure (CRF).
 Adjunct to drugs therapies that cause bone marrow suppression & anemias.
(e.g. zidovudine to AIDS patients, granulocytopenia and anemia, cancer chemotherapy related bone marrow supression and anemias.
 During elective non-cardiac/non-vascular surgery to ↓ need for transfusions

20

Filgrastim
Two preparations: natural and PEG compound

granulocyte colony stimulating factor, G-CSF
 Stimulates proliferation of progenitor cells committed to the neutrophil lineage
 Activates neutrophil phagocytic activity
 Prolongs their lifetime
 Mobilize hematopoietic stem cells
Longer duration, injected once every few weeks
Filgrastim binds to the G-CSF receptor and stimulates the production of neutrophils in the bone marrow. It controls proliferation of committed progenitor cells and influences their maturation into mature neutrophils. Filgrastim also stimulates the release of neutrophils from bone marrow storage pools and reduces their maturation time.
Pegylation reduces clearance via glomerular filtration, cleared via NEUTROPHILS ONLY

21

Granulocyte Colony-stimulating Factor (G-CSF)

USES: To Treat severe neutropenia following:
1. Autologous marrow transplants  ↓ morbidity due to bacterial/fungal infections
2. Cancer chemotherapy.  ↓ hospitalization for febrile neutropenia.
3. Severe congenital neutropenia.
4. Neutropenia in AIDS patients on zidovudine
SIDE EFFECTS:
• Bone pain (mild-moderate)
• Local skin reactions if given S.C.
• Prolonged treatment can  marked GRANULOCYTOSIS that resolves with cessation of treatment.

22

Myeloid Growth Factors

Sargramostim - granulocyte-macrophage colony stimulating factor, GM-CSF
 Broader stimulatory activity
 Similar Neutrophil stimulatory activity

Sargramostim binds to the Granulocyte-macrophage colony stimulating factor receptor (GM-CSF-R-alpha or CSF2R) which stimulates a JAK2 STAT1/STAT3 signal transduction pathway. This leads to the production of hemopoietic cells and neutrophils.

Pegylation reduces clearance via glomerular filtration, cleared via NEUTROPHILS ONLY

23

SARGRAMOSTIM (Leukine

Acts similar to G-CSF but with broader spectrum.
USES:
1. Autologous marrow transplants to shorten duration of neutropenia  ↓ morbidity
2. Shorten neutropenia & ↓ morbidity in chemotherapy & AIDS-related neutropenia.
3. Effective in some patients with aplastic anemia or myelodysplasia.
SIDE EFFECTS
HIGHER DOSES Bone pain / malaise / fever / diarrhea / dyspnea / rash.

1ST Dose Acute Reaction: reaction to first infusion (may include face flushing, trouble breathing, dizziness)

24

Oprelvekin (Neumega®)

– recombinant form of endogenous cytokine IL-11.
• MOA: Stimulates the growth of primitive megakaryocytic progenitors, Increases peripheral platelets and neutrophils
• Clinical Use: Thrombocytopenia and reduces the need for platelets.
• Side Effects: fatigue, headache, dizziness, and cardiovascular effects.
• Major Complication – FLUID RETENTION (indicative of peripheral edema or dyspnea on exertion) CAUTION if CHF.

25

ROMIPLOSTIM (Nplate®)

new therapeutic class “peptibodies”. Genetically engineered protein in which Fc components of a human antibody are fused to multiple copies of a peptide that stimulates the thromboplastin receptors.

26

ELTROMBOPAG (Promacta

Orally active thromboplastin receptor agonist.
• SIDE EFFECT: ability to cause HEPATOTOXICITY and HEMORRHAGES

27

Nucleoside Reverse Transcriptase Inhibitors

1. NRTIs must first undergo intracellular phosphorylation to be active
2. NRTIs inhibit the viral reverse transcriptase enzyme (Enzyme responsible for transcribing viral RNA into double stranded DNA)
3. NRTIs mimic other nucleosides and are incorporated into the DNA strand
4. They prevent the addition of the natural nucleosides into the DNA strand
5. This halts the production of new virions

28

Some of the more common NRTI’s

Zidovudine (AZT)
Tenofovir (already phosphorylated)
Abacavir

Mainly undergo renal excretion EXCEPT
 Zidovudine (AZT) undergoes glucuronidation
 Abacavir (ABC) metabolized by alcohol dehydrogenase
 Do not have P-450 drug interactions

29

Highly active antiretroviral therapy (HAART) toxicity

NRTI-related mitochondrial toxicity, which manifests as serious side effects such as hepatic failure with steatosis and lactic acidosis

30

NRTI’s resistance

Can descriminate
Can remove