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What is anemia? What is caused by?
- *First of all: Anemia can be caused by many diseases and disorders:
- It is a disorder of hematopoiesis that can be treated with pharmacological agents
Caused by: low
number of erythrocytes, quantity
of hemoglobin (Hb) or volume
of packed RBCs in blood(Hct)
Pharmacological treatment of anemia includes what?
- Iron Preps
- Vitamin B12 Preps
- Folic Acid Preps
- Erythropoiesis-stimulation agents
Free inorganic iron exists in two oxidative (cationionic forms) what are they?
- Ferrous (Fe2+)Ferric (Fe3+)
Agents used pharmacologically for Iron:
- Ferrous fumarate
- Ferrous gluconate
- Ferrous sulfate (hydrated and dessicated)
- Iron dextran
- Iron sucrose
- Sodium ferric gluconate complex
The bioavailability of iron is highly restricted why?
Because of poor solubility @ physiological pH
Iron act as what in Hb? And this complex acts to do what?
- Metal iron of the heme cofactor in Hb!!!!!!
- It is responsible for O2 binding and transport.
- 60-70% of our IRON is found in Hb!!!
**There is no molecular mechanism for what?
IRON elimination. Noway for Iron to get out!!!
Absorption of Iron:
What is the recommended dietary allowance (RDA) for Fe
- Infants: 0.27 mg/day
- Children:: 7-10mg/day (depending on age)
- Adolescent females/males: 15/11 mg/day
- Adult females/males: 18/8 mg/day
- Pregnant women: 27 mg/day
- Lactating women: 9-10 mg/day
Normal USA diet contains 10-15 mg of elemental Fe with individual only absorbing 5-10% of it. What is Fe readily found in diet wise?
Why is Fe in meat protein efficently absorbed?
- Because heme Fe in meat Hb and myoglobin can be absorbed intact without having to be dissociated into elemental Fe.
- ***Note: Fe in other foods like grains/vegetables is often tightly bound to organic molecules and is much less available for absorption
Fe absorption increase in response to what?
Low Fe Stores OR Increased Fe requirements
- So for menstruating women:
absorption inccreases 1-2 mg/day
- Pregnant women: absorb. increase of 3-4 mg/day
Where is Fe absorbed?* Think of Grogan's Lecture with the Picture!
- Proximal jejunum
- Distal small intestin can absorb if needed.
Nonheme Fe in foods and Fe in inorganic Fe-salts/complexes must be reduced by what to the ferrous form?
Think, you want Fe to be in the reduced or Fe2+ form. So Ferroreductase is the enzyme to do this!
Fe crosses the luminal membrane of the intestinal mucosal cells by what 2 mechanisms?
- Active transport of ferrous (Fe2+) via the action of divalent metal transporter 1 DMT1
- Absorption of heme-complexed Fe via action of heme carrier protein 1 (HCP1)
When Fe stores are low what occurs in intestinal mucosal cells?
Rate of uptake is increased into the cell by DMT1
What are the two fates of Fe that is absorbed by intestinal epithelial cells?
- Active transport into blood across basolateral epithelial cell membrane via ferroportin (Fe)
- transported ferrous Fe is then oxidized by ferroxidase into the ferric (fe3+) form
is stored as FERRITIN--
water solublecomplex consisting of a core Fe(OH3) covered by a shell apoferritin, specialized storage protein!!!!
The fate of Fe absorbed by intestines is determined by what?
- Total body [Fe] &Requirements
- If [Fe] high, low need---Ferritin
- If [Fe] low, high need---Active tranport to BLOOD...Gotta Use that Fe!!!!
What is Fe transported by in the plasma?
- the protein Transferrin (Tf)
- B-globulin binds two ferric ions (Fe3+)
** don't forget this easy crap!
Maturning erythroid cells in bone marrow get their Iron how?
As a Tf-(Fe3+)2 complex which is transported into the bone marrow via transferrin receptor (TfR)
Fe storage occurs in what?
In macrophages in the liver, spleen, and bone and in parenchymal liver cells
Apoferritin (AF) is what?
A specialized Fe storage protein.
Apoferritin (an Fe storage protein) is regulated by what?
***Important, Know what AF is and what happens to it during varying levels of Fe.
- Free Fe Levels!
- If Fe is low, AF synthesis is inhibited (less storage) and you get a shift towards transferritin production
- If Fe is high, AF synthesis is stimulated to sequester more Fe in order to protect organs from toxic effects of excess free Fe.
What is detectible in the serum (related to Fe)?
- Serum ferritin is in equilibrium with storage ferritin in reticuloendothelial cells
******Serum ferritin can be used to estimate the total body Fe stores!!!
What can be used to estimate total body Fe stores?
Elimination of Fe?
- Tenaciously conserved: no mechanism for excretion of Fe
- Small amounts lost in feces (exfoliatio of intestinal mucosal cells) bile, urine and sweat (about 1 mg/day)
- This elimination necessitates Fe be balanced in body, and it must be tightly regulated.
How is Fe balance in the body tightly regulated?****
- Easily achieved by changing the intestinal absorption and storage of Fe in response to the body's needs
What is Fe's Function?
As a metal cofactor in heme (metalloprophyrin prosthetic group of Hb, myoglobin, cytochromes, and other enzymes)
Clinical uses of Fe?
- Iron deficency Anemia:treated with oral or parenteral Fe preps
- ***Oral prep correct probelm just as rapidly/completely as parenteral prep as long as GI absorption of Fe is not hindered
admin of Fe is PREFERRED.
What are the three oral Fe Therapy preps?
- Only as Ferrous salts (most efficently absorbed)
- Ferrous sulfate
- Ferrous gluconate
- Ferrous fumarate
KNOW: gluconate salts better tolerated than sulfate salts: g = "good"
In an Fe deficent patient how much Fe can be absorbed per day?
- 50-100 mg of Fe can be incorporated into Hb daily.
- 25% of oral Fe from ferrous salt can be absorbed
- Deficent patients hould be given 200-400 mg of elemental Fe (lower doses for intolerant people)
****Treatment of Fe deficent patients with Fe salts should continue how long?
Dr.B wasted a slide on this. Know it!
- Treatment should continue for at least 3-6 months after the correction of the cause of Fe loss.
- This will correct the ANEMIA and REPLENISHES Fe Stores. ***
Parenteral Fe therapy is preferred for who?
PTs with documented Fe deficency
, who can't absorb oral prpe, and people with chronic anemia.
- People on Hemodialysis (renal disease), EPO stimulating agents
- People with IBD (inflammatory bowel disease)
- People with malabsorption syndromes
**Parenteral admin of inorganic free ferric Fe produces serious dose dependent toxicity so?
Limit the dose administered idiot!
Three forms of parenteral Fe administration:
- Iron dextran
- Sodium ferric gluconate complex
- Iron sucrose
KNOW THESE THREE
- Parenteral prep of of Iron, stable ferric oxyhydroxide and dextran polymers with 50 mg/ml of elemental Fe
- Administered by deep IM injection or IVIV admin eliminates local pain and tissue staining that occurs with IM route
Sodium ferric gluconate complex and iron sucrose is administered by?
administered by IV
Only documented Fe deficency should be prescribed?
- Parenteral Fe prep.
- Oral is the desired route!
Adverse Effects and Toxicity of Fe therapy (ORAL prep)
- Oral Fe Therapy:
- -nausea, epigastric discomfort, abdominal cramps constipation, diarrhea usually dose-related can be overcome by lowering daily does or taking tabs with meals
- -black stools****not clinically significat but black stools that occur during oral Fe therapy can obscure any GI blood loss
**What are black stools during oral Fe therapy important to pay attention to?
Although the black stools are not clinically significant the black stool may obscure the diagnosis of continued GI blood loss
Parenteral Fe Therapy necessitates what?
Chronic treatment necessitates monitoring of Fe storage levels to avoid toxicity of iron overload.
Parenteral Fe Therapy adverse effects and toxicty?
- Iron Dextran: IM:local pain tissue staining
- IV: headache, lightheadness, fever, arthralgias, nausea/vomiting, back pain, flushing, urticaria (hives), brochospasm, anaphylaxis (rare)
Parenteral Fe Therapy adverse effects and toxicty?
- Acute Fe Toxicity:
- almost exclusive to children who accidently ingest Fe tablets. 10 tablets are lethal!
- Poisoned Children experience necrotizing gastroenteritis, vomiting, abdominal pain, bloody diarrhea, shock, lethargy, dyspnea, metabolic acidosis, coma, death.
- = URGENT treatment
- Whole bowel irrigation should be performed to flush out unabsorbed pills
- Systemic administration of iron antidote
Chronic Fe Toxicity:
- Also called Fe overload or hemochromatosis*****
- Most commonly occurs in patients with inherited hemochromatosis and in patients who recieve many RBC transfusions over a long period time (pts with thalassemia major)
- chronic Fe toxicity can occur when excess Fe is deposited in the heart, liver, pancream and other organs (can cause DEATH)
How do you treat Chronic Fe toxicity?
- Intermittent phlebotomy in the absence of anemia!!!!***
- Save your patients!
- One unit of blood can be removed per week until all the excess Fe is removed
- administer an Fe antitode
Contraindications of Fe therapy?
- Anemias NOT caused by Fe deficency!
- State of Fe overload (only people who are deficent!)
- Parkinson's disease: Fe supplements appear to increase the rate at which disease progressses!!!!!!--aggregates the protein responsible and makes the disease worseIncreases in gastric pH and phosphates (which decreases Fe absorption)
- Decreased absorption of certain drugs (tetracycline, quinolones, thyroid hormone)-->avoid this by spaces seperate doses of Fe from these drugs by 2hrs.
What are two IRON CHELATORs?
- Deferoxamine (used most often)
What is the pharmacology of Deferoxamine?
- First of all memorize, it's an Fe chelator.
- It binds metal irons (Fe3+ specific) and pulls them out of the blood
- It has low oral availabilityAdministered IM or IV
MOA of Deferoxamine?
- It's an Fe chelator (antidote) remember**most commonly used one!
- It has a very very very high affinity for Ferric (fe3+) iron
- It binds ferric Fe forming a pharmacologically inactive chelate complex
- It can remove Fe from hemosiderin (poorly organized form), ferritin (storage) and Tf (transferritin) but NOT from Hb or cytochromes.
Clinical Uses of Deferoxamine?
- Iron poisoning (too much Fe)
- Transfusional Fe overload (thalassemia, sickle cell disease)
Adverse Effects/Toxicity of Deferoxamine?
- Allergic rxn (rash, uticaria (hives))
- Neurotoxicity (after long time use)
- Acute respiratory distress syndrome (in high doses)
Pharmacology of Deferasirox?
- Know its an Tridentate iron chelator
- Pharmokinetics: good absorption, oral admin
Clinical Uses of Deferasirox?
Chronic Iron overload due to blood transfusions
Adverse effects of Deferasirox?
- Fever, Rash, Headache
- Abdominal pain, diarrhea, nausea/vomitting
- Increased [creatinine] in serum
*it's an Fe chelator
What two vitamin B12 agents used pharmacologically?
Vitamin B12 (cobalamin)
Consists of a porphyrin-like rink with a central cobalt atom attached to a nucleotide
Active forms of Vitamin B12 in humans: (due to various organic groups being covalently bound to the cobalt atom = different forms)
Chief Dietary source of B12?
microbially derived vitamin b12 in meat (liver especially) eggs, dairy products
Pharmokinetics of Vitamin B12?
- Avg US diet: 5-30 micrograms/day
- Daily Requirement 2 micrograms/day
Vitamin B12 stored where?
- Primarily in LIVER
- about 3000-5000 micrograms
- Would take 5 YEARS to deplete B12 in liver stores....
Vitamin B12 deficency results in ?
Megaloblastic Anemia if all absorption is lost
In physiological amounts B12 is absorbed how?
As a COMPLEX with Intrinsic Factor (IF) a glycoprotein secreted by parietal cellls of gastric mucosa
IF complexes with B12 liberated from dietary sources in stomach and duodenum.
Where is the IF/B12 complex absorbed?
IN the distal ILEUM! by highly selective receptor-mediated transport system
Vitamin B12 Deficency in human typically is due to what?
Malabsorption due to lack of INTRINSIC FACTOR
OR loss/malfunction of specific absorption mechanism in the distal ileum
Nutritional deficency of B12 can been seen in what populations?
Those freaking vegetarians!! or vegans! who have had many years without meat, eggs, or dairy products
How is B12 transported in the body?
to various cells of body by Transcobalamin I, II, III
Excess B12 is sent where?
to the Liver for storage!!!
B12 is required for what? ***Important Slide. Know this cold.
- three essential enzymatic reactions!!!!!**
- 1) Methyl Transfers to make Folate, Methionine (Synthesis of these) Methylcobalamin serves as an intermediate in the transfer of a methyl group from N5-methyltetrahydrofolate to homocystein converting it into methionine. B12 deficiency can cause accumulation of homocysteine and increase in homocysteine serum concentration***
- 2.) Cobalamin is an intermediate recieve the methyl group from N5-methtetrahydrofolate to become tetrahydrofolate (THF) THF is the precursor for all FOLATE cofactors: in B12 deficency, the loss of folate cofactors and accumulation of N5-methyltetrahydrofolate is called the methylfolate trap and this prevents the synthesis of purines and hence DNA!!!!
- 3.) Deoxyadensoylcobalamin is necessary for the conversion of L-methylmalonyl CoA to succinyl-CoA by the enzyme methylmalonyl-CoA mutase
- Deficency of B12, causes accumulation of methylmalonyl-CoA and methylmalonic acid.
- Increased [methylmalonic acid] serum/urine levels can be used to support a diagnosis of vitamin B12 deficency (as can homocysteine)
So a deficency of B12 (cobalamin) causes what?
- Accumulation of homocysteine and increase in its serum concentration
- B12 deficency causes loss of folate precursors, preventing synthesis of purines and DNA synthesis!!!! KNOW!
- ( correct with admin of folic acid)
- Increases methylmalonic acid concentration in urine and serum!
Clinical uses of B12?
Treat or prevent B12 Deficency
What is the most common clinical manifestation of deficency in B12?
- Megaloblastic, macrocytic anemiaAlso can cause neurologic syndrome associate with deficency is arrested but may not be fully revered if it has occured for several months.
- When Diagnosis of megaloblastic anemia is made, it must be determined if it is vitamin b12 or folic acid deficent --> CHECK serum levels of the vitamins
- Administration of radiolabeled vitamin B12 allows determination of the mechanisms of vitamin B12 deficency.
- Assayed by measuring amount of radiolabled B12 excreted in urine!
You have a PT with B12 in her Urine. What does this mean?
B12 was absorbed successfuly in the GI system! :)
You have a PT with B12 in her stool. What does this mean?
B12 NOT absorbed successfully.
Two causes of Vitamin B12 deficency?
Pernicious anemia (lack of IF), Damage to distal ileum, bacterial overgrowth, ALMOST ALL CASES caused by MALABSORPTION--> so parenteral injections of B12 would be required (lifelong)
Pernicious anemia shows what in the shilling test?
Shilling tests shows diminished absorption of radiolabeled Vitamin B12 which is corrected with concomitant admin of IF (intrinsic factor)
Damage to distal ileum? What does this do to B12 metabolism?
Schilling test shows non-absorption of radiolabeled vitamin B12 even in presence of Intrinsic factor***
You can administer a DUAL-LABELLED SHILLING TEST, and look at the urine levels
If it is not absorbed in a dual labelled shilling test, then there is a problem with ABSORPTION!
Used in Vit B12 deficency!
Used in Vit B12 deficency!
Administer radiolabelled B12. Look @ amount of B12 excreted in urine: Any B12 that is present in URINE means it was absorbed!!!
This man obviously has pernicous anemia
due to the fact that B12 with IF (Co-57) was excreted more in urine than just B12 (Co-58) (without IF). Without IF the B12 was not absorbed by GI system and went out via stool! (less than 0.82 total), man isn't making his own IF. he needs IF
- With IF/B12, you get uptake (on the left)
- If less than 1% in both? then it is a receptor problem!!!!
When you do a dual labelled shilling test and there are low values of B12 in the urnine in both of the radiolableled forms, what does this mean?
- This is a diagnostic test using B12 to determine the mechanism behind a person's B12 deficency.
- This means there is probably a receptor problem. Because if you're providing one radio-labelled form with IF/B12 and one that is just B12, and both are not being taken up, you know that the person probably has something wrong with the receptors involved with uptake of B12 and not neccissarily a lack of B12
What if a person shows a high amount of absorption of both forms (one with IF/B12) and one with just B12 in a dual-labelled Shilling test?
Then you would know that maybe that patient is just not getting enough B12 in their diet! (they took up both forms in high amounts!!)
Who forms of B12 that are administered phamacologically?
Cyanocobalamin and Hydroxocobalamin
Adverse effects/Toxicity of B12 administration?
- Extremely rare (almost always follows parenteral treatment)
- Hypersensitivity rxns (especially to cobalt)
- Hypokalemia and thrombocytosis (which is high platelet count) (occurs upon conversion of severe megaloblastic anemia to normal erythropoiesis--->due to the body switching from an anemia state to a normal state
Folic acid is called? What is the useful form of folate?
Pteroylglutamic acid (which is NOT
useful to the cell)
- it is composed of pteridine, p-aminobenzoic acid, glutamic acid (several numbers of glutamic acid moieties may be attached to the pteroyl potion of the molecule resulting in monoglutamates, tiglutamates or polyglutamates.
- Pteroyglutamic acid undergoes a reaction by dihydrofolate reductase to become dihydrofolic acid (which is the useful form that can feed into the folate cycle)
Fill in the blank
Unlike B12 our body doesn't have a _____store of folate.
does not have a HUGE store. We do not have a huge store of folate--about 1-6 months you would develop an anemia due to folate deficency.
Various forms of folic acid are present in ?
plant and animal tissues, richests sources are yeast, liver kidney and green veggies.
Avg. USA diet contains how much folates?
500-700 micrograms daily.
Pregnant women how much folic acid is absorbed daily?
Where is unaltered folic acid absorbed?
in the proximal jejunum!
Dietary folates consist of what form of folate?
- polyglutamate forms of N-methyltetrahydrofolate.
- In order to be absorbed, all but one glutamyl reside must be hydrolyzed by the alpha glutamyl transferase within the brush border of the intestinal mucosa.
- Monoglutamate N5-methyltetrahydrofolate is transported into the blood stream by both active a passive transport and is widely distributed throughout the bloodstream by both active and passive transport and is widely distributed throughout the body.
Inside cells N5
methyltetrahydrofolate is converted to THF
by vitamin B12 dependent demethylation reaction. What is THF?
THF is tetrahydrofolate, and it requires cobalamin in order to convert the dietary folates that were converted to N5 methyltetrahydrofolate to tetrahydrofolate, which is used to convert serine into glycine. This is 1 of 4 reactions that require THF cofactors to participate in one-carbon transfer reactions.
Dietary folates are converted to THF (tetrahydrofolate) by what?
They require B12 (cobalamin) to convert N5-methyltetrahydrofolate to THF which is then used in conversion of serine to glycine.
What are the four reactions that require
folate (THF cofactors for one-carbon metabolism)? **Recall: foalte must be first converted to a usable form, DHF by dihydrofolate reductase.
- Without folate you won't carry out these reactions!****
- Conversion of dUMP to dTMP (deoxy) via thymidylate synthatase to create nucleotides for DNA synthesis!!! need folic acid (#1)
- Conversion of AAs serine to glycine (catabolic rxn, going from more complex serine to glycine) via action of serine transhydroxymethylase (#2)
- Synthesis of purines required for nucleotide synthesis and then DNA synthesis-->we need purines for DNA synthesis for erythropoiesis!!! Cancer cells also depend on this part of the cycle (#3)
- Methylation of Vitamin B12 for the production of methionine. this is where B12 and Folate metabolism meet! B12 is required for the production of the AA methionine from methylcobalamin (#4)
****What step brings folic acid into this cycle? Basically folic acid ingested is worthless to our body. It must
be converted to what by what in order to utilized?
Folic acid is brought into the cycle when it is converted to dihydrofolate by folate reductase. This is essential to bring folate into a usable form.
****KNOW this. This is an essential step.
***Why do some anti-cancer drugs
work? (think of the 4 reactions that require folate to work!)
- *** Very Important!
- Methotexate is an anti-folate drug, which blocks dihydrofolate reductase so no folic acid can be converted into dihydrofolate. This reaction is neccessary in order for folic acid to be converted into a useable form and to make dTMP, which is required for DNA synthesis. So what do cancer cells do? They divide over and over and over again. To divide, they need DNA and methotrexate is targeting folic acid synthesis or the folatic cycle is a good way to target cancer. BOOM!
One clinical use of folate? EASY!!!
- Treatment and prevention of megaloblastic anemia caused by folic acid deficency (this is microscopically indistinguishable from the megaloblastic anemia caused by B12 deficency!!!)
One clinical use of folate?***Very important...think pregnant women!
Prevention of neural tube
defects! This is critical!
- *Parenteral administration of folate is rarely neccessary since folic acid is well absorbed even in patients with malabsorptive syndromes*Therapy with folate should be continues unti the underlying cause is removed or corrected. Patients with malabsorptive issues or dietary inadequacy may be treated indefinitely.
- *Folate typically doesn't have any adverse effects or toxicity
Why is it so special?
folic acid prep consisting of folinic acid or 5-formyltetrahydrofolate! It is a unique form of Folic acid
- It is completely abesent
- **Why is Leucovorin unique?
It bypasses the dihydrofolate reductase step in the synthesis of THF. from the small intestine and is converted into its active metabolites inside GI cells.
Why is Leucovorin
Leucovorin (5-formyltetrahydrofolate) can be used to rescue cells that have been exposed to folate antagonists (like cancer drugs methotrexate, trimethoprim, pyrimethamine) so what is does is provide THF to the folic acid cycle by bypassing the DHF reductase step--Folic acid doesn't have to be converted to dihydrofolate.. it comes in at the THF step it feeds in directly!!!!
What is the "Leucovorin
- It is referring to one of the clinical uses of lecovorin, the prophylaxis of methotrexate toxicity.
- Because methotrexate targets all cells and not just cancerous ones you need a way to still get DNA synthesis, methionine synthesis, purine synthesis and keep the folate cycle going! So leucovorin at standard clinical doeses will provide normal cells with THF to keep the cycle moving because Leucovorin bypasses the DHF step.
What is one of the uses of Leucovorin besides the leucovorin rescue?
- Potientiation of 5-fluorouracil therapy (a cancer drug)! basically makes 5-fluorouracil a better drug for cancer therapy!
- 5-FU inhibits thymidylate synthetase, binding depends on the presence of methylene-THF. Leucovorin is metabolized to methylene-THF and increases and stabilizes the binding of 5-FU and its cytotoxic effect.
- It can also be used for patients with a congential deficency in DHF reductase and can't get folate into the cycle!!!!
So megaloblastic anemia is caused by both folic acid and B12 deficency. How do you differentiate between the two clinically?
You would test B12 and folate levels in the serum.
What are the two uses of Leucovorin?
- TWO USES: ONE TO DECREASE TOXICITY (Methotrexate) ONE TO INCREASE TOXICITY (5-FU).
- 1) Prophylaxis of methotrexate toxicity (see above picture)= the "leucovorin rescue"
- 2.) Potentiation of 5-FU (5-fluorouracil therapy) making it more cytotoxic! 5-FU inhibits the enzyme thymydlate synthetase to convert dUMP to dTMP for formation of DNA.
Methotrexate is what?
a cytotoxic drug that targets all cells (normal and cancerous) that blocks the dihydrofolate reductase step----we can use leucovorin to "rescue" normal cells by feeding directly into the THF step --and provide the necessary folic acid!
Erythropoietin agents used pharmacologically?
- Darbepoetin alfa
- Epoetin alfa
- Epoetin beta (approved by FDA, not available in US due to legal issues)
- 34-39 kDa glycoprotein
- As a drug: recombinant human protein
- -recombinant human EPO
- -produced in a mammalian cell expression system
Pharmokinetics of Erythropoietin?
- Administration is partenteral because EPO is a large protein that is broken down in the GI system by proteases.
- Epoetin alfa (3x week), 1/2 life of 4-13 hours in patients with chronic renal protein (not cleared by dialysis)
- Darbepoetin alfa (1x dose a week): modified from that is more heavily glycosylated and has a 2-3 fold longer half life
- Epoetin beta (1-2 doses/month): isoform that is covalently attached to a long polyethylene glycol polymer--long lived!!
What is the MOA of Erythropoietin?****
Binds to erythropoietin receptors on the plasma membrane of red cell progenitors, which stimulates JAK/STAT signal transduction pathway.
Clinical uses of Erythropoietin?
- Erthyropoiesis-stimulating agents (ESAs) can be used successfully to impact different types of anemia
- What it does is increase: Hb and Hct
- Often it eliminates the need for blood transfusions
- Increases quality of life
- Used routinely for patients with anemia secondary to their chronic renal disease
- Most patients will require Fe and Folate supplementation to support the increased erythropoiesis.
- EPO also useful for treatment of anemia due to primary bone marrow disorders and secondary anemias
- Used for : aplastic anemia, other bone marrow failure states
- Multiple myeloma and other bone marrow malignancies
- Anemias associated with chronic inflammation, AIDS, and myelosuppresive cancer therapy
- Anemia produced by zidvudine treatment (AZT), a breakthrough aids drug
- Anemia of prematurity
- Used to reduce the need for transfusion in high-risk patients undergoing elective, non-cardiac, nonvascular surgery.
- Used to accelerate erythropoiesis after phlebotomies for autologous transfusion of elctive surgery
- Treatment of hemochromatosis (overload of Fe, deposited in RBCs instead of storage)
Pharmacological effects of Erythropoietin?
- Expression is upregulated by tissue hypoxia mediated stimulation of EPO transcription: this corrects the anemia (which is the cause of the tissue hypoxia) provided that the bone marrow response is not impaired by RBC nutritional deficency, primary bone disorders or bone marrow suppression from drugs or chronic diseases
- EPO stimulates erythroid proliferation and differentiationIt induces release of reticulocytes from the bone marrow (shift to the left)*****
What is the anti-therapeutic use of ESAs (Erythropoiesis-stimulating agents?)
- Treatment of hemochromatosis (the overload of Fe)
- So instead of depositing Fe for storage, you make more RBCs for the Fe to go into.
What is Epoetin alfa?
The recombinant version of EPO, the use of EPO as a drug is in this form.
Why is EPO given parenterally? (NOT ORALLY)
- typically 3x weekly (if given by epoetin alfa)
- Because it's a BIG protein. It can't cross the plasma membrane, and proteases break down in the GI system
- -This holds true for ALL recombinant proteins used as drugs. must be given parenterally
Adverse effects & toxicity and thrombotic complications & Contraindications and Percautions
- Renal Failure
- Increased rate of deep venous thromboses (epoetin alfa) patients should be on deep venous thrombosis prophylaxis
- Thrombotic complications have a greater incidence in patients whith chronic renal failure or cancer in who ESAs rais HB serum levels >12g/dL or faster tumor growth in patients with head/neck cancers
- Allergic reactions are infrequent
- Small number of cases of pure red cell aplasia (PRCA) accompanied by neutralizing antibodies.
- Most commonly seen in dialysis patient treated SC with Eprex (specfic form of Epoetin Alfa)
- Use of epoetin beta to treat anemia caused by cancer chemotherapy---increases chance of death.
You almost always have to give Fe/Folate supplements when you give a patient EPO why?
Because EPO stimulates erythropoiesis. If you are making new red blood cells you need more DNA, if you want more DNA you need folate to synthesize DNA. If you want to carry more oxygen in your RBCs you need more Fe.