Transcript (8)ANTI ANEMIC

Dr. Sanjib Das MD
VII.Drugs for Treating Anemia
 A. Pharmacology
 Understand the basic concepts of erythropoiesis
and its regulation by erythropoietin and other
hematopoietic factors (e.g., GM-CSF, interleukin3)
 Know the biochemical basis for microcytic
hypochromic anemia and megaloblastic anemia.
 For iron, vitamin B12 and folic acid, know the
following:







Sources
Mechanisms regulating their intestinal absorption
Factors that influence their bioavailability
Transport
Metabolism
Storage
Excretion
 Know the phases of acute and chronic toxicity in iron






poisoning and its treatment
Know how to treat chronic iron overload disease (e.g.,
chronic blood transfusion, iron malabsorption disease
etc.)
Understand the role of vitamin B12 and folic acid in DNA
synthesis and understand the additional role of vitamin
B12 in lipid metabolism
Know the biochemical systems that are impaired in
vitamin B12 and folic acid deficiency and the role of
cyanocobalamin/hydroxocobalamin and folic acid in
correcting these metabolic defects
Understand in biochemical terms why folic acid will
correct the erythropoietic lesion but not the neurologic
lesion in Addisonian pernicious anemia
Know the mechanisms by which various drugs can lead
to folic acid deficiency
Know the potential uses of erythropoietin and other
hematopoietic factors in treating anemia
B. Some Important Drugs
 IRON (FERROUS SULFATE, IRON DEXTRAN)
 DEFEROXAMINE
 ERYTHROPOIETIN
 FOLIC ACID
 VITAMIN B12 (CYANO- AND HYDROXO-
COBALAMIN)
 SARGRAMOSTIM (GM-CSF)
 FILGRAMOSTIM (G-CSF)
 OPRELVEKIN (IL-11)
AGENTS TO TREAT ANEMIA
 Anemia may arise from failure to make sufficient
red blood cells or to synthesize adequate
quantities of hemoglobin
 Types of anemia
 Microcytic
 Macrocytic
 Other anemia’s
Drugs
Used
to
Treat
Anemia
 Microcytic anemia





Ferrous sulfate
Ferrous gluconate
Ferrous fumarate
Iron dextran
Iron Antidote

Deferoxamine
 Macrocytic anemia




Folic acid
Leucovorin
Cyanocobalamin
Hydroxocobalamin
 Other anemia




Epoetin alfa (Erythropoietin)
Sargramostim (GM-CSF)
Filgrastim (G-CSF)
Oprelvekin (IL-11)
Anemia
 Symptoms:





Paleness
Fatigue
Shortness of breath
Exercise intolerance
Increased heart rate
 Causes of anemia:
 A decrease in the amount of hemoglobin per RBC
Microcytic, hypochromic anemia
 A decrease in the number of circulating RBC’s
Megaloblastic, hyperchromic anemia
 A decrease in hemopoietic growth factors, especially
erythropoietin
Normocytic anemia or mixed
MICROCYTIC HYPOCHROMIC ANEMIA
Iron deficiency

Impaired hemoglobin synthesis

Small red cells with insufficient hemoglobin

Microcytic hypochromic anemia
MEGALOBLASTIC ANEMIA
Vitamin B12 or folic acid deficiency

Impaired DNA synthesis

Impaired production and maturation of erythroid precursors

Macrocytic hyperchromic anemia
Iron
 Physiological functions of iron:
 Required for hemoglobin synthesis
 Co-factor in such enzymes as the cytochromes
 Required for myoglobin synthesis
Pharmacokinetic Properties of Iron
 Absorption: in duodenum and proximal jejunum
 Involves active transport of ferrous iron, which is oxidized to ferric iron in the
intestinal mucosa
 Ferric iron can be stored as ferritin in the intestinal mucosa, or it can be
transported by transferrin to other sites
 Only 5-10% of dietary elemental iron (10 to 15 mg/day) is absorbed (mucosal
block)
 Heme-iron from meat can be absorbed with iron in ferric state
 Low iron stores (ferritin in intestinal mucosal cells) increase iron absorption and
the rate of erythropoiesis
 Absorption is decreased by food, metal chelators, antacids, fluoroquinolones, and
tetracycline
 Absorption is increased by hydrochloric and large amounts of ascorbic acid
 Gastric resection or surgical removal of the upper region of the small intestine
impairs iron absorption
Pharmacokinetic
Properties
of
Iron
 Distribution:
 Transferrin is a specific ferric iron transport protein
 Erythroid cells have transferrin receptors, thus, iron is actively
transported into hemoglobin-synthesizing cells in the bone marrow
 Ceruloplasmin converts ferrous iron to the ferric state, and this
copper-containing, plasma protein appears to be important for cellular
uptake of iron
 10-20% total iron stored in ferritin and hemosiderin, which are stored in
macrophages in liver, spleen and bone marrow
 70% in hemoglobin (red cells)
 10% in myoglobin (muscles)
 1% in cytochromes and transferrin
Pharmacokinetic Properties of Iron
 Excretion:
 There is no specific mechanism for excreting iron
 Iron balance is regulated by intestinal absorption
 About 1 mg of iron is lost daily by such processes as
exfoliation of mucosal cells, which contain ferritin
Causes of Iron Deficiency




Inadequate dietary intake: rare in USA
Malabsorption
Increased requirements: growth, pregnancy, and menstruation
Blood loss (bleeding, cancer)
Iron deficiency

Storage iron decreases then disappears
e.g., loss of hemosiderin granules in bone marrow

Serum ferritin decreases (< 10 g/L)
Good indicator of iron status

Serum iron decreases (< 40 g/dL)

Total iron-binding capacity of transferrin increases (> 400 g/dL)
due to decreased saturation (< 10%)

40/400 = 10 %
Onset of anemia
Treatment
of
Iron-deficiency
Anemia
 Oral: ferrous salts are DOC for iron deficiency anemia:
 Ferrous sulfate
 Ferrous gluconate
 Ferrous fumarate
 Treatment results in a rapid increase in reticulocytosis, and a
measurable response to iron therapy should be detectable within one
week
 Normal hemoglobin levels should be reached in 1-3 months

Normal hemoglobin levels:


14-18 g/dL for men
12-16 g/dL for women
 Treatment should last 3-6 months or longer if the dose of iron was
decreased due to intolerance
 Parenteral iron: Iron dextran >>>> should be used rarely
 Patients with gastric or small bowel resections
 Patients with inflammatory bowel disease involving the proximal small
intestine
Adverse
Effects
of
Iron
 Gastrointestinal irritation
 Acute toxicity from oral iron: seen as acute
poisoning in children; treat with iron-chelating drug,
deferoxamine
 Symptoms: G.I. irritation; necrosis; nausea, cyanosis;
hematemesis; green and tarry stools; cardiovascular
collapse; metabolic acidosis
 Acute toxicity from iron dextran: Headache, Light
headedness, Fever, Arthralgia, Nausea, Vomiting,
Back pain, Flushing, Urticaria, Bronchospasm,
Anaphylaxis (rare)
Can cause death
 Small doses of iron dextran should be given first to
check for signs of immediate hypersensitivity
Chronic Toxicity of Iron
 Men with high meat diet?
 Hemochromatosis: Excessive iron absorption (inherited
disorder)
 Hemosiderosis: Result of numerous blood transfusions
 Iron overload may also occur in the presence of anemia
other than that caused by iron deficiency, such as the
anemia of chronic disease or hemolytic anemia.
 Excess iron deposited in heart, liver, pancreas and other
organs.
 In the absence of anemia, iron overload is treated by
phlebotomy. One unit of blood removes 250-mg iron.
Folic Acid
 Physiological functions:
 Essential for normal synthesis of DNA and normal mitosis of proliferating cells
 Conversion of folic acid to cofactors required for purine and pyrimidine synthesis
Dietary
Folate
Requires
B-12 for
Utilization

5-CH3-FH4
Folate (F)  Folate supplements

Dihydrofolate reductase (DHFR)

Dihydrofolate (FH2)

Dihydrofolate reductase (DHFR)

Tetrahydrofolate (FH4)

1-carbon donors
5-CHO-FH4
10-CHO-FH4
5,10-CH2-FH4
5,10-CH+=FH4
Folic
Acid
Sources: Diet (not synthesized) from plants and animals.

 Yeast, liver, kidney and green vegetables
 Pharmacokinetic properties:
 Absorption:
 Readily and completely absorbed from small intestine by active transport
system
 50-200 g folate absorbed daily (10-25% of folate in diet)
 Absorption is increased in pregnancy, but so is demand
Polyglutamate forms of folate (5-CH3-FH4)

Conjugase (glutamyl transferase)

Monoglutamate forms of 5-CH3-FH4 Requires B-12 for
utilization

Active and passive transport in proximal jejunum
Folic Acid
 Distribution:
 Liver and other tissues store 5-20 mg of folate
 Major dietary and storage form is 5-CH3-FH4
 Because the body stores relatively little folic acid
(relative to the high demand), megaloblastic anemia
can develop in 1-6 months following folate deficiency
 Excretion:
 Folates are metabolized
andoccur
excreted
in fast
urine and
Deficiency can
relatively
feces.
 Serum levels decline within days when intake is
diminished.
Deficiency
 Inadequate dietary intake
 Alcoholics
 Occurs frequently
 Increased requirement:
 During pregnancy
 Renal dialysis (blood folates are removed by dialysis)
 Proliferative disorders (e.g., cancer, leukemia, certain chronic
diseases and skin disorders)
 Hemolytic anemia
 Interference with utilization by other drugs: anticonvulsant
drugs such as: phenytoin, primidone, and mephobarbital,
also oral contraceptives and isoniazid
 Malabsorption syndromes: patients with high rates of cell
turnover (hemolytic anemia); alcoholism/poor liver function
Therapeutic
Use
 Treatment of folate deficiency
 Give during pregnancy -- maternal folate deficiency is
associated with neural tube defects (spina bifida)
 Coronary heart disease:
 Hyperhomocystinemia (high levels of homocysteine) is a possible
risk factor
 Conversion of homocysteine to methionine requires folic acid and
vitamin B12
 Thus, low methionine levels with folic acid or B12 deficiency
 Clinical studies are ongoing to determine whether folic acid and/or
vitamin B12 supplements reduce the risk of coronary heart disease
Vitamin B12
 Physiological function: essential for normal
synthesis of DNA and for maintenance of myelin
throughout the nervous system
 DNA synthesis: vitamin B12 is required to convert 5-
CH3-FH4 (the dietary form) to FH4; FH4 (more
specifically its derivative 5,10-CH2-FH4) is required to
convert dUMP to dTMP
 Lipid synthesis: vitamin B12 is required to convert
methylmalonyl-CoA to succinyl-CoA
 Amino acid synthesis: vitamin B12 and folate are
required to convert homocysteine to methionine
Vitamin B12 Deficiency and the
Methylfolate Trap
5-CH3-FH4
(Major dietary and storage form)
 vitamin B12
Tetrahydrofolate (FH4)

Other 1-carbon donors

Nucleotides (dUMP & dTMP)
 In vitamin B12 deficiency, levels of 5-CH3-FH4 increase (trapped) with a
decrease in the other forms of folate required for nucleotide synthesis
 This defect can be circumvented by administration of folic acid, which
can be reduced to tetrahydrofolate by dihydrofolate reductase (DHFR)
 Thus, the defects in nucleotide synthesis caused by vitamin B12
deficiency can be corrected by folic acid treatment
Structure of Vitamin B12
 Porphyrin-like ring system complexed with cobalt
 Different ligands attached to cobalt produce
several forms of cobalamin
 Active form: R = 5’-deoxyadenosyl or methyl group
 Drugs: R = Cyano (CN-) or hydroxy (OH-)group
 Food: R = various ligands
 Drugs and dietary cobalamins are converted to
active forms in the body
Vitamin B12
 Sources:
 Food (microbial origin); meat (liver), eggs and dairy products
 Not synthesized in humans (Extrinsic factor)
 Pharmacokinetic properties:
 Absorption: requires intrinsic factor (IF):



Glycoprotein synthesized by parietal cells of stomach
IF binds vitamin B12, and this complex is absorbed in ileum
Intrinsic factor is not used as a drug
 Distribution:


IF is never used as a drug
Transported via transcobalamin II, a plasma glycoprotein
Excess stored in liver: thus it takes 3-6 years to deplete stores from
body (since it has long half-life, only given once a month in patients
who cannot absorb it from diet)
Deficiency occurs very very slow
 Excretion: occurs in bile but undergoes enterohepatic circulation
and most is reabsorbed from small intestine; when
transcobalamin II is saturated excess is excreted in urine
Causes of Vitamin B12 Deficiency
 Lack of intrinsic factor: pernicious anemia
 Treat with Vitamin B12 not with intrinsic factor
 Lack of receptors for IF/B12 complex in ileum
 Fish tapeworm infections
 Patients with gastrectomy
Therapeutic
Uses
 Therapeutic uses:
 Only approved use is treatment of vitamin B12 deficiency
 Usually given by intramuscular injection
 Vitamin B12 is nontoxic even in large amounts
 Preparations:
 Cyanocobalamin:



Available nasally, orally, and parenterally, usually given parenterally
Unlike hydroxocobalamin, cyanocobalamin does not cause an
antibody response to hydroxocobalamin-transcobalamin II complex
Preferred agent for long-term use
 Hydroxocobalamin:



Is highly protein bound and remains in circulation longer
Some patients produce antibodies against hydroxocobalamintranscobalamin II complex
Also, now used for treatment of cyanide poisoning (known or
suspected)
Vitamin B12 versus Folic Acid
Deficiency
 It is important to diagnosis the cause of
megaloblastic anemia so that corrective therapy
can be initiated appropriately with either vitamin
B12 or folic acid.
 Clinical tests:
 Red cell levels of folic acid (more reliable than
serum levels)
 Serum levels of vitamin B12
Since folic acid can reverse the hematological damage due to vitamin
B12 deficiency but not the neurological changes, one must
differentiate between folate deficiency and vitamin B12 deficiency
Two-stage
Schilling
Test
 Used to determine the cause of vitamin B
deficiency.
12
 The test involves the oral administration of radioactive
vitamin B12 with and without pig intrinsic factor, after
which the presence of radioactivity in the urine is
determined (a positive result proving that vitamin B12
was absorbed).
 A negative result (i.e., impaired absorption) of both
free vitamin B12 and vitamin B12 complexed with pig
intrinsic factor indicates malabsorption in the distal
ileum (perhaps due to inflammatory bowel disease
or small bowel resection).
 A negative result (i.e., impaired absorption) of just
vitamin B12 indicates malabsorption due to lack of
intrinsic factor (perhaps due to gastrectomy or
pernicious anemia).
(Addisonian) Pernicious Anemia
 Megaloblastic anemia due to B12 deficiency resulting from
lack of production of intrinsic factor by the parietal cells of the
gastric mucosa.
 Accompanied by achlorhydria.  Often seen first
 Generally observed in older men and women of northern
European extraction (e.g., Scandinavians).
 Five years or more may elapse between loss of intrinsic
factor and the development of megaloblastic anemia, which
is how long it takes to deplete liver stores of vitamin B12.
 Treatment with parenteral vitamin B12 should not be
delayed after gastrectomy (or surgical procedures and
diseases that would impair B12 absorption), and should be
continued for life.
Other Anemias
 Bone marrow failure, causing decreased red cell
production, may result from:
 Myelofibrosis and Multiple myeloma: affect bone
marrow directly
 Myelosuppressive chemotherapy: antitumor
agents; drugs used to treat AIDS;
immunosuppressive agents
 Deficiency of hematopoietic growth factors:
chronic renal failure (erythropoietin deficiency)
Drugs Used to Treat Bone Marrow
Failure
 Epoetin alpha (Erythropoietin):
 A glycoprotein that stimulates red cell production
 Derived from genetically modified cells of Chinese hamster ovary
 Used in treatment of anemia patients with chronic renal failure and in cancer patients
receiving chemotherapy
 Sargramostim (GM-CSF):
 Recombinant granulocytic-macrophage colony stimulating factor
 Promotes myeloid recovery in patients with non-Hodgkin's lymphoma, acute
lymphoblastic leukemia, and Hodgkin's disease who are undergoing bone marrow
transplantation
 Promotes myeloid recovery after standard-dose chemotherapy
 Treats drug-induced bone marrow toxicity or neutropenia associated with AIDS
 Filgrastim (G-CSF):
 Recombinant colony stimulating factor
 Prevents and treats chemotherapy-related febrile neutropenia, for promotion of myeloid
recovery in patients undergoing bone marrow transplantation

Oprelvekin (IL-11)
 Promotes megakaryopoiesis
 See Immunopharmacological Agents
Summary on Agents Used to Treat Anemia
Cause
Inadequate iron
Inadequate globin synthesis
Inadequate
RBC synthesis
Deficiency
Iron
Folic acid
Low stores,
quick onset
Erythropoietin
Differential
Diagnosis
Microcytic
Hypochromic
Low iron, ferritin
Megaloblastic
Major factors
Blood loss
Decrease intake
Dietary insufficiency
Malabsorption
Impaired metabolism
DHFR inhibitors
Increased utilization
Pregnancy
Malignancy
Hemolytic anemia
Renal dialysis
Decreased intake
No intrinsic factor
Malabsorption
Kidney failure
Chronic disease
Cancer
Infection
Inflammation
Cytotoxic drugs
Treatment
Ferrous iron
Folic acid
Cyanocobalamin
Erythropoietin
Low folic acid
Vitamin B12
Large stores,
slow onset
Megaloblastic plus
neurologic defects
Low vitamin B12
Schilling test
Normocytic/normochromic
Mixed-type anemia
Low erythropoietin
Drugs used to treat anemia
Microcytic anemia
Macrocytic anemia
Other anemia
Ferrous sulfate
Folic acid
Cyanocobalamin
Epoetin alpha (Erythropoietin)
Sargramostim (GM-CSF)
Filgrastim (G-CSF)
Oprelvekin (IL-11)
Antidote
Deferoxamine
Folate vs. B-12 deficiency
Which of the following would be most
appropriate for the treatment of normocytic
anemia in a 62-year-old woman with chronic
renal failure?
A. Erythropoietin
B. Ferrous sulfate
C. Folic acid
D. Oprelvekin
E. Vitamin B-12
Answer: A
Erythropoietin is made in the
kidney; lack of it causes
normocytic anemia
A 25-year-old pregnant woman in her 4th
month of pregnancy was diagnosed with
macrocytic anemia. Which of the following
would her infant have a higher than normal
risk of?
A. Cardiac abnormality
B. Congenital neutropenia
C. Liver damage
D. Limb deformity
E. Neural tube defect
Answer: E
Folic acid deficiency
leads to neural tube
defects