Download Hemato-Poetic Medications

Pharmacology: Pharmacology and Hematopoiesis (Lash)
INTRODUCTION:

General:
Various drugs, hormonal growth factors, vitamins and minerals can affect the blood or blood-forming organs
Blood cells have relatively short life-spans, so you need continuous replacement of cells by hematopoiesis

Anemia:
Significant reduction in functional red cells mass with consequent reduction in O2 carrying capacity
Causes include:
o Blood loss
o Reduced red cell production
o Production of abnormal red cells or precursors
HEMATOPIETIC GROWTH FACTORS (PHYSIOLOGY):

Process of Hematopoiesis:
Pluripotent Stem Cell  Variety of different precursor cells
o Lymphocyte progenitor  B cells, T cells, NK cells
o CFU-GEMM  CFU-E/BFU-E and CFU-GM

CFU-E/BFU-E  RBCs

CFU-GM  Granulocytes (PMNs, Eosinophils, Basophils) and Monocytes
Which precursor cell develops and which path these progenitors follow depends on exposure to a variety of
different hematopoietic growth factors

Erythropoietin:
Synthesis:
o Proximal tubular cells of the kidney (primarily)
o Liver (small amount)
Structure:
o Primary gene product 193 amino acid protein
o First 27 residues cleave during secretion
o Glycosylated (not essential for function but prolongs half-life)
Function:
o Most important regulator of:

Proliferation of committed progenitors (CFU-E)

Maturation of erythroblasts

Release of reticulocytes into circulation
o Synergy with IL-3 and GM-CSF to expand BFU-E population

BFU-E mature to CFU-E, which then mature further into reticulocytes (released)
o Acts by binding specific membrane receptors on the surface of bone marrow cells that are committed
towards synthesis of RBCs
Absence: invariably results in anemia
Diseases/Agents Affecting Production of Erythropoietin:
o In General: anemia or hypoxia cause a RAPID increase (~100 fold) in the renal synthesis and secretion
of erythropoietin
Increase EPO Production
Decrease EPO Production
Disease State
-Kidney (HTN, carcinoma, sarcoma,
-renal artery stenosis etc.)
-Liver (carcinoma)
-Brain (hemangioblastoma)
-Lung (pulmonary insufficiency,
emphysema, carcinoma, fibrosis)
Pharmacological Agent
-Cobalt (↓ tissue O2 use)
-Mercurial diuretics
-Thyroxine
-Estrogens
-Growth Hormone
-Beta2 blockers
-Prolactin
-Adenosine A1 agonist
-ACTH (decreases renal blood flow)
-Calcium ionophores
-Serotonin
-Ca++ channel blockers (chronic use)
-Vasopressin
-Phorbol esters
-Testosterone
-Alkylating agents
-Diacylglycerol
-

EPO Signaling Pathways that Regulate Expression:
o Hypoxia (due to anemia, ischemia, cobalt etc.) is detected by either:

Oxygen sensing cell

EPO producing cell itself
o Detection occurs by changes in signaling molecules (ie. adenosine, prostaglandins etc.)
o Once cell detects hypoxia, change in the cAMP pathway results in the activation of various proteins
that stimulate the production and secretion of EPO
Myeloid (CSFs):
General:
o Glycoproteins that stimulate proliferation and differentiation of several types of hematopoietic
precursor cells AND enhance function of mature leukocytes
Synthesis:
o GM-CSF and IL-3: T lymphocytes
o GM-CSF, G-CSF and M-CSF: monocytes, fibroblasts, endothelial cells
Function:
o Interleukin-3 (IL-3):

Stimulates colony formation of most cell lines

Synergy with GM-CSF to increase number of PMNs, monocytes and eosinophils in the blood

Synergy with EPO to expand BFU-E compartment to stimulate CFU-E proliferation

Influences the function of eosinophils and basophils
o Granulocyte/Macrophage CSF (GM-CSF):

Synergy with IL-3 to stimulate colony formation/proliferation of granulocytes,
monocytes/macrophages, and megakaryocytes

Synergy with EPO to promote formation of BFU-E

Increases phagocytic and cytotoxic potential of mature granulocytes

Reduces motility and clearance from circulation of mature granulocytes

Increases cytotoxicity of eosinophils and leukotriene synthesis
o Granulocyte CSF (G-CSF):

Stimulates granulocyte colony formation and production of PMNs

Synergy with GM-CSF to stimulate granulocyte/macrophage colonies

Synergy with IL-3 to induce formation of IL-3

Induces release of granulocytes from marrow

Increases phagocytic and cytotoxic potential of mature granulocytes
o Macrophage CSF (M-CSF/CSF-1):

Stimulates monocyte/macrophage colony formation (both alone and in synergy with GM-CSF
and IL-3)

Induces synthesis of G-CSF and IL-1

Enhances production of IFN and TNF

Enhances functions of monocytes and macrophages
HEMATOPOIETIC GROWTH FACTORS (PHARMACOLOGY):

Erythropoietin:
Therapeutic Uses:
o Treatment of anemia resulting from chronic renal failure

Transfusion-dependent patients undergoing hemodialysis
 Alleviated requirement for transfusions after several weeks
 Eventually normalized hematocrit

Also corrects anemia in patients who do not require dialysis
o Treatment of anemia associated with AIDS patients of AZT
o Treatment of anemia associated with cancer chemotherapy
o Preoperative increase in red cell production to allow storage of larger volumes of blood for autologous
transfusion
Administration:
o Parenterally (IV or SubQ)
Pharmacokinetics:
o Need to titrate dose

Avoid rapid increase in hematocrit early in therapy

Avoid a rise in hematocrit to >36% during maintenance therapy
o

Proper response to EPO requires adequate iron stores

May need to co-administer oral iron supplement in those with iron deficiency
Toxicities and Side Effects:
o Increase in red cell mass (most common)

Associated with HTN and thrombotic phenomena

Minimized by raisin hematocrit slowly (titrating dose; monitor BP closely)
o Allergic responses infrequent and mild
Myeloid Growth Factors (CSFs):
Therapeutic Uses:
o Correction of insufficient Hematopoiesis:

Anemia

Prevention of chemotherapy induced neutropenia

Possibility of dose intensification of chemotherapy

Autologous bone marrow transplant
o Stimulation of hematopoiesis in primary bone marrow failure:

Aplastic anemia

Congenital neutropenia

Idiopathic cytopenias
o Treatment of leukemias:

AML

Myelodysplastic syndromes
o Expansion and recruitment of circulating progenitor cells:

Peripheral blood stem cell transplantation
o Activation of effector cell function:

Infections

Leukocyte function disorders

AIDS

Tumor cytotoxicity
Toxicities and Side Effects:
o Relatively common with GM-CSF (dose-dependent):

Local induration after SC injection

Thrombophlebitis at site of infusion

Fever

Myalgias

Fatigue

Skin rashs

GI distress

Bone pain
o Dose-limiting side effects of GM-CSF include:

Pericarditis

Pleuritis

Pleural effusions

Pulmonary emboli
o Less side effects with G-CSF:

Bone pain

Vasculitis

Worsening of psoriasis
o By themselves, growth factor may have oncogenic potential!
IRON DEFICIENCY:

Basics: most common cause of nutritional anemia in humans

Causes:
Dietary intake of iron not adequate
Blood loss (GI tract, menstruation; most common cause in the US)
Some interference with iron absorption

Consequences:
Severe Cases: microcytic hypochromic anemia secondary to reduced synthesis of Hb
Does not only affect RBCs: alters muscle metabolism INDEPENDENT of effect on O2 delivery via blood



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Diagnosis:
Presence of microcytic anemia, OR
Quantitation of:
o Transferrin saturation
o Red cell protoporphyrin
o Plasma ferritin content
Iron Transport and Metabolism in Humans:
Iron Stores in the Body:
o Two Forms:

Essential iron-containing compounds

Excess iron (storage form)
o Gender Differences: males have higher stores/kg of body mass than females
o Locations of Iron Sources:

Most: Hb in RBCs

The Rest:
 Myoglobin in muscle
 Storage form bound to ferritin
 Cytochromes and other iron-containing enzymes (trace amounts)
 Transport form bound to transferrin
Ferritin: protein of iron storage
o Apoferritin: not bound to iron; composed of 24 polypeptide chains that form an outer shell with a
storage cavity for iron inside (can bind up to 4000 atoms of Fe)
o Hemosiderin: aggregated ferritin
o Location: predominantly in reticuloendothelial system and liver; small amount in muscle
Transferrin: plasma glycoprotein for iron transport
o Internal exchange of iron: has 2 binding sites for ferric ion; delivers iron to intracellular sites by binding
specific transferrin receptors on cellular plasma membranes
Synthesis of Ferritin/Trasnferrin Receptors in Response to Iron Supply:
o Excess Iron: reduce synthesis of transferrin R; increased synthesis of ferritin
o Low Iron: increased expression of transferrin R; decreased synthesis of ferritin
Iron Requirements and Dietary Availability:
Varies by age, gender and other factors:
o Highest for pregnant women (up to 4x increase in daily requirement)
o Menstruating females (blood loss) and infants (rapid growth) also have high requirements
High Iron Foods: organ meats, brewer’s yeast, wheat germ, egg yolks, oysters, some dried beans and fruits
Low Iron Foods: milk products, non-green vegetables
Bioavailability of Iron:
o Heme Iron: most bioavailable form, but dietary iron is mostly non-heme iron
o Absorption of Non-Heme Iron: facilitated by ascorbate

Forms complex with iron, OR

Reduces ferric  ferrous iron
Treatment of Iron Deficiency:
Oral Therapy:
o Ferrous Sulfate: treatment of choice (~25% of oral iron given in this form is absorbed)
o Duration: usually 3-6 months
o Adverse Effects: nausea, epigastric discomfort, abdominal cramps, constipation, diarrhea

Dose-related

Overcome by lowering dose or taking tablets with meals
Parenteral Thearpy:
o Use:

Patients who can’t tolerate or absorb oral iron

Patients with chronic blood loss
o Repletion of iron stores: more rapid than by oral therapy
VITAMIN B12 AND FOLIC ACID DEFICIEINCES:

Interrelationship Between Vitamin B12 and Folic Acid:
Methionine Synthesis: MeFH4 + B12  methylcobalamin, which then acts as methyl donor produce methionine
Purine Synthesis: requires folate derivatives
DNA Synthesis: requires folate derivatives to methylate dUMP  dTMP (required precursor)
Deficiency of Either B12 or Folate:
o Decreased synthesis of methionine and S-adenosylmethionine
o Interference with protein synthesis
o Interference with numerous methylation reactions
o Redirection of methylation reactions away from nucleic acid synthesis (compromises production of
new cells)
Vitamin B12:
Metabolism:
o Combines with intrinsic factor in stomach and duodenum (secreted by parietal cells of gastric mucosa)
o Requires IF for absorption in the distal ileum (specific receptor-mediated transport)
o Once absorbed, transported to cells of the body bound to plasma glycoprotein (transcobalamin II)
o Excess stored in the liver or excreted in the urine
Sources:
o Cannot be synthesized so needs to be obtained in the diet
o Only original source in nature is microorganisms
o Animal liver is excellent source (primary storage site)
Daily Requirements:
o Small daily requirement
o Daily turnover of liver vitamin B12 is small and therefore deficiency would not develop for 3-4 years
Deficiency
o Affects both hematopoietic AND nervous systems:

Sensitivity of hematopoietic system relates to high rate of cell turnover (requires high rates
of DNA synthesis)
 Not enough B12 leads to highly abnormal DNA synthesis
 Results in morphologically abnormal cells or cells that die during maturation
 Most profound effect on RBCs (abnormally large)- megaloblastic anemia
o Nutritional B12 deficiencies are rare:

Most due to malabsorption (NOT insufficient intake)
 Deficiency in IF (pernicious anemia, gastrectomy)
 Defects in absorption of B12-IF complex by distal ileum
Diagnosis:
o Measurement of B12 in the serum
o Measurement of methylmalonic acid in the serum
Treatment:
o Most are not curable: require lifelong treatment with B12 injections (important to diagnose underlying
cause so proper treatment can occur)
Folic Acid:
Metabolism:
o Taken in via the diet: as reduced polyglutamates

Absorption:
 Requires transport and a pteroyl-γ-glutamyl carboxypeptidase associated with the
intestinal mucosal membrane
 Most occurs in duodenum and upper jejunum (have high activities of dihydrofolate
reductase and methylating activities)

Transport to Tissues:
 Mostly transported to tissues as MeFH4
 Bind plasma proteins
 Taken up into cells by receptor-mediated endocytosis
Sources:
o Diet: almost all foods rich in folate (especially leafy green vegetables, liver, yeast, some fruit)

Important point: cooking can destroy most of the folate content of these foods
Daily Requirements:
o Most people take in much more folate than the minimum daily requirement
Deficiency:
o Often caused by inadequate dietary intake:

Elderly or the poor (lack vegetables, eggs, meat in diet)

Prolonged cooking of folate rich foods
-



Alcoholics and patients with liver disease (poor diet and diminished capacity of the liver to
store folates)
Also causes megaloblastic anemia: difficult to distinguish from B12 deficiency
-
o
Therapy:
o Diagnosis important: potential for mistreating patients with B12 deficiency with folates

Will relieve megaloblastic anemia but will NOT help the neurological defects seen due to B12
deficiency
DEFICIENCIES IN OTHER VITAMINS AND TRACE ELEMENTS AFFECTING HEMATOPOIESIS:

Copper:
Defiency: extremely rare in humans; usually occurs concurrently with other nutritional deficiencies
o No evidence that it needs to be added to the diet
o Clinical states associated with hypocupremia do not have demonstrable effects

For example, sprue, celiac disease, and nephrotic syndrome
o Menke’s Disease (Steely Hair Syndrome) affects the transport of Cu and is associated with decreased
activity of Cu-dependent enzymes, but no hematopoietic effects
o However, anemia due to Cu deficiency has been described:

After intestinal bypass surgery

In people receiving parenteral nutrition

Malnourished infants

Zinc overdose
o When symptoms of deficiency do occur, characterized by:

Leucopenia (particularly granulocytopenia)

Anemia
Therapy: indicated when low levels occur in the presence of leucopenia and anemia
o Oral cupric sulfate
o Parenteral administration

Cobalt:
Deficiency: has not been reported in man
Historical Significance: used to be administered to treat anemia
o No benefit and aplastic anemia
o Beneficial to patients with pure red-cell aplasia (inhibition of enzymes in oxidative metabolism 
tissue hypoxia  increase in secretion of EPO)
o Note: large amounts of Co DEPRESS erythropoiesis

Intoxication in children can cause cyanosis, coma and death

Pyridoxine (Vitamin B6):
Oral Therapy: can increase hematopoiesis in patients with hereditary or acquired sideroblastic anemia
o Anemia characterized by impaired Hb synthesis and accumulation of Fe in mitochondria of erythroid
precurosor cells

Hereditary form is X-linked recessive with variable penetrance and expression

Idiopathic forms associated with use of certain drugs, inflammatory states, neoplastic
disorders and preleukemic syndromes
o Therapy effective for anemia due to certain drugs (isoniazid, pyrazinamide) but not for others

May interfere with beneficial action of other drugs causing the anemia

Riboflavin:
Deficiency:
o Spontaneous red-cell aplasia (rare)
o Induced hypoproliferative anemia
Therapy with Riboflavin:
o Beneficial to patients with red-cell aplasia due to protein depletion