بسم الله الرحمن الرحيم 1. Yazdanpanah SBMU 1. Agents Used in Anemias 2. Hematopoietic Growth Factors Dr. Yazdanpanah Pharmacology/Toxicology Dept. Shaheed

بسم الله الرحمن الرحيم

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1. Agents Used in Anemias

2. Hematopoietic Growth Factors

Dr. Yazdanpanah

Pharmacology/Toxicology Dept.

Shaheed Beheshti School of Pharmacy

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Outline• Introduction

1. Agents used in Anemia• Iron• Folic acid• Vitamin B12

2. Hematopoietic Growth Factors• Erythropoietin• Myeloid Growth factors• Megakaryocyte Growth factors

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Introduction

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Hematopoiesis– Production from undifferentiated stem cells of circulating

erythrocytes, platelets and leukocytes

– Requires 3 essential nutrients and hematopoietic growth factors

– Blood cells play roles in• Oxygenation of tissues

• Coagulation

• Protection against infections

• Tissue repair

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Deficiency of functional blood cells

• Anemia

• Thrombocytopenia

• Neutropenia

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The pale hand of a woman with severe anemia (right) in comparison to the normal hand of her

husband (left).

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1.1 Iron

1.2 Vitamin B12

1.3 Folic acid

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YazdanpanahSBMU 2. Hematopoietic Growth

Factors

2.1 Erythropoietin

2.2 Myeloid growth factors

2.3 Megakaryocyte growth factors

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IRON

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YazdanpanahSBMU 1.1 IRON: Basic Pharmacology

• Iron forms the nucleus of the iron-porphyrin heme ring

• Iron deficiency

– The most common cause of chronic anemia– Leads to pallor, fatigue, exertional dyspnea, etc.– Cardiovascular adaptations to chronic anemia

– Formation of small erythrocytes with insufficient hemoglobin: microcytic hypochromic

anemia 19

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The protein's α and β subunits are in red and blue, and the iron-containing heme groups in green.

Structure of human hemoglobin

http://en.wikipedia.org/wiki/Heme

YazdanpanahSBMU 1.1 IRON : Pharmacokinetics

• Free inorganic iron: extremely toxic

• An elaborate system for regulating iron absorption, transport and storage

• Iron reclaimed from catalysis of hemoglobin

• Only a small amount of iron lost from the body

• Iron deficiency can develop if …

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YazdanpanahSBMU 1.1 IRON : Pharmacokinetics:

Absorption

• Average diet: 10-15 mg elemental iron daily

• Absorption of 5-10% of iron

• Absorption in duodenum and proximal jejunum

• Increase in iron absorption in response to:• Low iron stores• Increased iron requirements

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Absorption and Transport

• Iron in foods– Meat– Vegetables and grains

• Iron crosses the luminal membrane of the

intestinal mucosal cell by 2 mechanisms

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Figure 33-1. Absorption, transport, and storage of iron 25


Storage

• Storage in:

– Intestinal mucosal cells– Macrophages in liver, spleen, bone– In parenchymal liver cells

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Elimination

• No mechanism for excretion

• Losses account for no more than 1 mg of iron per day

• Regulation of iron balance

• achieved by changing intestinal absorption and storage of iron, in response to the body's needs

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1.1 IRON : Clinical Pharmacology

1. Indications

• Treatment or prevention of iron deficiency anemia

• Iron deficiency– Increased iron requirements– Inadequate iron absorption– Blood loss

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2. Treatment with Oral iron therapy

Drugs as ferrous salts

200 – 400 mg of elemental iron

For 3-6 months after cause correction

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YazdanpanahSBMU 1.1 IRON : Clinical Pharmacology 2. Adverse effects with Oral iron therapy

• Nausea, epigastric discomfort, abdominal cramps,

constipation, and diarrhea

• Usually dose-related, can often be overcome by lowering the daily dose of iron or by taking the tablets immediately after or with meals

• Some patients have less severe gastrointestinal adverse effects with one iron salt than another

• Patients taking oral iron develop black stools31

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1.1 IRON : Clinical Pharmacology 3. Treatment with parenteral iron therapy

– Reserved for patients with documented iron deficiency who:

• unable to tolerate or absorb oral iron • for patients with extensive chronic blood loss who cannot be

maintained with oral iron alone:

– patients with various postgastrectomy conditions and previous

small bowel resection

– inflammatory bowel disease

– advanced chronic renal disease

– malabsorption syndromes32

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3. Treatment with parenteral iron therapy

– Iron dextran (IV, deep IM)• Hmw and Lmw forms

• Advantages of IV administration• Adverse effects

– Hypersensitivity reaction to the dextran: anaphylaxis» A small test dose

– Iron-sucrose (IV) – sodium ferric gluconate complex (IV)

• Advantages to HMW??

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YazdanpanahSBMU 1.1 IRON : Clinical Toxicity

1. Acute toxicity– Almost exclusively in young children (10 Tabs =

Death)– Treatment:

• Whole bowel irrigation• Deferoxamine

2. Chronic toxicity (hemochromatosis)– Deposition of excess iron in heart, liver, etc.– Leads to organ failure and death– Treatment: intermittent phlebotomy,

deferoxamine, deferasirox34

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Vitamin B12

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A cofactor for several essential biochemical reactions

Deficiency: Anemia, GI symptoms and neurologic abnormalities

Cause of deficiency: Inadequate supply in the diet: unusual Inadequate absorption of dietary vitamin:

relatively common and easily treated

1.2. Vitamin B12

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A porphyrin-like ring with a central cobalt atom attached to a nucleotide

1.2. Vitamin B12: Chemistry

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Extrinsic and intrinsic factors

Active forms of vitamin in humans Deoxyadenosylcobalamin, methylcobalamin

Cyanocobalamin, Hydroxocobalamin: convert to active forms

Chief dietary source: Meats, eggs, dietary products

1.2. Vitamin B12: Chemistry

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Average diet: 5 – 30 mcg daily

1-5 mcg: usually absorbed

Store primarily in liver (3000 - 5000 mcg)

Normal daily requirement: 2 mcg

Absorbed in the distal ileum after complex with IF By highly-specific receptor-mediated transport system

1.2. Vitamin B12: Pharmacokinetics

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Deficiency:

Malabsorption of vitamin due to

1. Lack of IF

2. Loss or malfunction of the specific absorptive mechanism

Nutritional deficiency: strict vegetarians

Transport to cells bound to transcobalamin I, II, III

Excess: transport to liver for storage

1.2. Vitamin B12: Pharmacokinetics

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YazdanpanahSBMU1.2. Vitamin B12: Pharmacodynamics

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YazdanpanahSBMU1.2. Vitamin B12: Pharmacodynamics

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The most common causes of deficiency:

Pernicious anemia

Gastrectomy

Conditions affecting distal ileum

malabsorption syndrome inflammatory bowel disease or small bowel resection

1.2. Vitamin B12: Clinical Pharmacology

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Clinical manifestation of Vitamin deficiency:

Neurologic syndrome Megaloblastic Macrocytic anemia

Leukopenia, Thrombocytopenia, Hypercelluar bone marrow with an accumulation of

megaloblastic erythroid cells

Megaloblastic anemia: Vitamin B12 or Folic acid deficiency


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Almost all cases of deficiency: Malabsorption of the vitamin

Treatment: Parenteral injection of vitamin

Most patients: require life-long treatment Hydroxocobalamin, Cyanocobalamin 100 -1000 mcg IM for 1-2 weeks (100-100 mcg IM once a

month for life)

Oral doses of 1000 mcg of vitamin in pernicious anemia


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Folic Acid

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Reduced forms of folic acid required for essential biochemical reactions that provide precursors for the synthesis of amino acids, purines, and DNA

Folate deficiency: not uncommon

The deficiency easily corrected by administration of folic acid

The folate deficiency: Anemia Implicated as a cause of congenital malformations in newborns May play a role in vascular disease

1.3. Folic Acid

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YazdanpanahSBMU 1.3. Folic Acid: Chemistry

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• The average diet in the USA: 500-700 µg daily

• Pregnant women absorb as much as 300-400 µg of folic acid daily

• Various forms of folic acid present in a wide variety of plant and animal tissues– The richest sources: yeast, liver, kidney, and green

vegetables

• Normally, 5-20 mg of folates stored in the liver and other tissues

1.3. Folic Acid: Pharmacokinetics

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• Excreted in the urine and stool

• Destroyed by catabolism

• Serum levels fall within a few days when intake diminished

• Body stores relatively low and daily requirements high

• Folic acid deficiency and megaloblastic anemia:• within 1-6 months after stopping the intake of folic acid


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• Unaltered folic acid readily and completely absorbed in the proximal jejunum

• Dietary folates consist primarily of polyglutamate

forms of N5-methyltetrahydrofolate

• Before absorption, all but one of the glutamyl residues of the polyglutamates hydrolyzed

– by the enzyme α-1-glutamyl transferase ("conjugase")

within the brush border of the intestinal mucosa


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llustration of the brush border membrane of small intestinal villi

Duodenum with brush border

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• The monoglutamate N5-methyltetrahydrofolate transported into the bloodstream by

– both active and passive transport – widely distributed throughout the body

• Inside cells, N5-methyltetrahydrofolate converted to tetrahydrofolate by the demethylation reaction that requires vitamin B12


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• Megaloblastic anemia from folate deficiency:

• microscopically indistinguishable from the anemia caused by vitamin B12 deficiency

• Folate deficiency does not cause the characteristic neurologic syndrome seen in vitamin B12 deficiency

• Folate status

• assays for serum folate • assays for red blood cell folate

1.3. Folic Acid: Clinical Pharmacology

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• Folic acid deficiency • often caused by inadequate dietary intake of folates

• Development of folic acid deficiency:– Alcohol dependence and liver disease– Pregnant women and hemolytic anemia– Malabsorption syndromes– Renal dialysis– Drugs ??

• Maternal folate deficiency • Occurrence of fetal neural tube defects (spina bifida)


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• Parenteral administration rarely necessary

• Oral folic acid well absorbed even in patients with malabsorption syndromes

• A dose of 1 mg folic acid orally daily sufficient to:

– reverse megaloblastic anemia– restore normal serum folate levels– replenish body stores of folates


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• Therapy should be continued until the underlying cause of the deficiency removed or corrected

• Therapy may be required indefinitely for patients with malabsorption or dietary inadequacy

• Folic acid supplementation to prevent folic acid deficiency should be considered in high-risk patients including:

– pregnant women– hemolytic anemia– liver disease– patients on renal dialysis


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Folic Acid Supplementation

• From 1998, all products made from enriched grains in the USA were required to be supplemented with folic acid

• Epidemiologic studies show a strong correlation between maternal folic acid deficiency and the incidence of NTDs such as anencephaly

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Folic Acid Supplementation • Supplemented grains with folic acid

• associated with a significant (30–75%) reduction in NTD rates

• The reduction in NTDs is dose-dependent

• Supplementation of grains in the USA with higher levels of folic acid could result in an even greater reduction in the rate of NTDs

• Rates of other types of congenital anomalies (heart and orofacial) have fallen after supplementation

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• Glycoprotein hormones that regulate the proliferation and differentiation of hematopoietic progenitor cells in the bone marrow

• The first growth factors to be identified were called colony-stimulating factors

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2.1 Erythropoietin

2.2 Myeloid growth factors

2.3 Megakaryocyte growth factors

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Erythropoietin

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• A 34-39 kDa glycoprotein • Recombinant human erythropoietin (rHuEPO,

epoetin alfa)

• IV administration: serum half-life of 4-13 hours in patients with chronic renal failure

• Darbepoetin alfa:• A twofold to threefold longer half-life

• Methoxy polyethylene glycol epoetin ??

2.1. Erythropoietin: Chemistry and pharmacokinetics

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• Stimulates erythroid proliferation and differentiation by interacting with specific erythropoietin receptors on red cell progenitors

• Induces release of reticulocytes from the bone marrow

• Endogenous erythropoietin primarily produced in the kidney– In response to tissue hypoxia, more erythropoietin produced results

in correction of the anemia

2.1. Erythropoietin: Pharmacodynamics

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• Normally, an inverse relationship exists between the hematocrit or hemoglobin level and the serum erythropoietin level

• Exception: anemia of chronic renal failure

Erythropoietin levels usually lowMost likely to respond to treatment with exogenous

erythropoietin

• In most primary bone marrow disorders and most nutritional and secondary anemias• Endogenous erythropoietin levels are high

2.1. Erythropoietin: Pharmacodynamics

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• Consistently improve the hematocrit and hemoglobin level • Usually eliminate the need for transfusions• Reliably improve quality of life indices

1. For patients with anemia of chronic renal failure

– Oral or parenteral iron

– Folate supplementation

2.1. Erythropoiesis-stimulating agents: Clinical Pharmacology

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2. Useful for the treatment of anemia due to

Primary bone marrow disorders and secondary anemias including patients with:

• aplastic anemia and other bone marrow failure states

• myeloproliferative and myelodysplastic disorders

• multiple myeloma

• the anemias associated with chronic inflammation, AIDS, and myelosuppresive cancer chemotherapy

2.1. Erythropoietin: Clinical Pharmacology

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3. Other uses • used successfully to offset the anemia produced by

zidovudine treatment in patients with HIV infection and in the treatment of the anemia of prematurity

• can also be used to reduce the need for transfusion in high-risk patients undergoing elective, noncardiac,

nonvascular surgery; to accelerate erythropoiesis after phlebotomies for autologous transfusion for elective

surgery; or for treatment of iron overload

2.1. Erythropoietin: Clinical Pharmacology

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The most common adverse effects– hypertension and thrombotic complications

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Myeloid growth factors

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• Recombinant human G-CSF (rHuG-CSF; filgrastim)

• Recombinant human GM-CSF (rHuGM-CSF; sargramostim)

• Pegfilgrastim: – much longer serum half-life than recombinant G-CSF

2.2. Myeloid growth factors: Chemistry and pharmacokinetics

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• Stimulate proliferation and differentiation by interacting with specific receptors found on various myeloid progenitor cells

G-CSF– Stimulates proliferation and differentiation of progenitors

already committed to the neutrophil lineage

– Activates the phagocytic activity of mature neutrophils and prolongs their survival in the circulation

– A remarkable ability to mobilize hematopoietic stem cells (increase their concentration in peripheral blood)

• Use of peripheral blood stem cells rather than bone marrow stem cells for autologous and allogeneic hematopoietic stem cell transplantation

2.2. Myeloid growth factors: Pharmacodynamics

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GM-CSF

– broader biologic actions than G-CSF

– stimulates proliferation and differentiation of granulocytic progenitor cells, erythroid progenitors and megakaryocyte progenitors

– stimulates the function of mature neutrophils

– acts together with interleukin-2 to stimulate T-cell proliferation

– locally active factor at the site of inflammation

– mobilizes peripheral blood stem cells (significantly less efficacious than G-CSF) 79

2.2. Myeloid growth factors: Pharmacodynamics

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• G-CSF and pegfilgrastim

• used more frequently (better tolerated)• cause bone pain

• GM-CSF

• cause more severe side effects, particularly at higher doses

– fever, malaise, arthralgias, myalgias, etc.

2.2. Myeloid growth factors: Toxicity

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Megakaryocyte growth factors

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• Interleukin-11 (IL-11) • A 65-85 kDa protein• The half-life: 7-8 hours: sc injection

• Oprelvekin• recombinant form of interleukin-11

• Peptide agonists of thrombopoietin receptor– Romiplostim: sc route

– Eltrombopag: oral route

2.3. Megakaryocyte growth factors: Chemistry and pharmacokinetics

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2.3. Megakaryocyte growth factors: Pharmacodynamics

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IL-11

• Acts through a specific cell surface cytokine receptor to stimulate the growth of multiple lymphoid and myeloid cells

• Acts synergistically with other growth factors

• to stimulate the growth of primitive megakaryocytic progenitors• increases the number of peripheral platelets and neutrophils

Romiplostim

• high affinity for the thrombopoietin receptor

• a dose-dependent increase in platelet count

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• The most common adverse effects of interleukin-11

– Fatigue, headache, dizziness, and cardiovascular effects

• The cardiovascular effects: anemia, dyspnea transient atrial arrhythmias

• Hypokalemia

• All of these adverse effects appear to be reversible

2.3. Megakaryocyte growth factors: Toxicity

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Documents

بسم الله الرحمن الرحيم 1. Yazdanpanah SBMU 1. Agents Used in Anemias 2. Hematopoietic Growth Factors Dr. Yazdanpanah Pharmacology/Toxicology Dept. Shaheed