Drugs affecting hematopoiesis

Arvind Singh Panwar

SECTION 5

137Blood138

Drugs Affecting HematopoiesisCHAPTER 1

HEMATINICS

Definition: Hematinics are compounds required in the formation of blood and are employed in the treatment of anemias.

Iron, vitamin B₁₂ and folic acid are essential for normal erythropoiesis.

IRON

Iron is essential for hemoglobin production.

Physiology

The big percentage of iron in body stores is found in hemoglobin.
- The ferric state of iron (Fe³⁺) in methemoglobin is less able to carry oxygen than the ferrous form (Fe²⁺) in hemoglobin.
- Molecular oxygen is bound reversibly by the iron in hemoglobin.
Inorganic iron in the (Fe²⁺) is most readily absorbed from the GIT.
- Men require a nutritional input of about 0.5–1 mg of iron per day.
- Menstruating women require up to 2 mg of iron per day.
- Pregnant women (especially in the last two trimesters of pregnancy) require 5–6 mg of iron per day.
About 1 mg of iron is lost per day in the feces, sweat, and desquamated skin.
- Menstruating women can lose up to 30 mg of iron per menstrual period.
- Pregnant women can lose up to 500 mg of iron per full-term pregnancy.
About 1 g of iron is stored as ferritin and hemosiderin in the bone marrow, liver, and spleen. This stored iron is available for the synthesis of hemoglobin if blood is lost from the body.
Internal exchange of iron is mediated by a plasma transport protein, transferrin. Transferrin receptors on cell membranes mediate endocytosis of the transferrin-iron complex.

Distribution of iron in the body

Hemoglobin	66%
Ferritin, hemosiderin	25%
Myoglobin (in muscles)	03%
Enzymes(cytochromes, etc.)	06%

Daily requirement of iron

Adult male	0.5–1 mg
Adult female	1–2 mg
Pregnancy and lactation	3–5 mg

Dietary sources of iron. Food that is rich in iron are:

Absorption

The average Indian diet provides about 10–20 mg of iron.
10% of this iron is absorbed from the upper gut in the ferrous form.
Ferric iron (Fe³⁺) must be converted to ferrous iron (Fe²⁺) for absorption in the GIT.
During deficiency, absorption is better. Hem iron is better absorbed than inorganic iron.
Absorption involves active transport into mucosal cells, from where it can be transported into the plasma and/or stored intracellularly as ferritin; in iron deficiency, the former route predominates.

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Factors that influence iron absorption

Factors which increases iron absorption	Factors which decreases iron absorption
Ascorbic acid, acidic pH, meat, amino acids	Antacids, phosphates, tetracyclines, phytates, presence of food in the stomach.

Fig. 5.1.1: Illustration showing distribution of iron in the body

Transport and distribution

Iron in plasma is bound to and also transported with the help of a glycoprotein transferrin and stored as ferritin and hemosiderin in liver, spleen and bone marrow (Fig. 5.1.1).
It is mostly used for erythropoiesis.
Iron from, expired erythrocytes enters the plasma for re-use.

Excretion

Daily 0.5–1 mg of iron is excreted.
A large part is lost in shedding of intestinal mucosal cells and small amounts in the bile and desquamated skin. [Iron loss occurs mainly by (casting off) of ferritin-containing mucosal cells; iron is not excreted in the urine].
In females, iron is also lost in menstruation.

Clinical use of iron

Iron-deficiency anemia, which can be due to:
- – Chronic blood loss (e.g. with menorrhagia)
- – Increased demand (e.g. in pregnancy and early infancy)
- – Inadequate dietary intake or absorption (uncommon in developed countries).

Pathophysiology of Iron Deficiency Anemia

Symptoms: Depletion of body iron can be associated with fatigability, anorexia, headache, and a characteristic hypo-chromic, microcytic anemia.

Laboratory findings

A low plasma iron level in iron-deficiency anemia is associated with an elevated total iron-binding capacity of plasma transferring, so that the ratio of serum iron to iron-binding capacity is less than 10%.
Serum iron level: Total iron-binding capacity <10%.

In other words, the serum iron carrier, transferrin, is less than 10% saturated with iron. This ratio in normal individuals is 35% + 15%.

Diagnosis: A definitive diagnosis of iron-deficiency anemia is made by confirming reduced bone marrow iron stores.

Complications: Severe iron deficiency can cause Plummer-Vinson syndrome, which is associated with dysphagia, hypopharyngeal webs, gastritis, and hypochlorhydria.

DRUGS FOR IRON DEFICIENCY ANEMIA

Preparations of iron: Iron is generally given orally—but can be given parenterally.

Oral iron preparations

Dose: Ferrous sulphate 3–4 tablets daily. The elemental iron content of different salts varies.

Ferrous sulfate, containing about 20% elemental iron, is the drug of choice for iron deficiency anemia.
Ferrous fumarate contains 33% elemental iron. It is principally used in multivitamin mineral mixtures.
Ferrous gluconate and ferrous choline citrate both contain 12% elemental iron.
- Ferrous salts are better absorbed than ferric salts and are cheaper.
- The last three preparations are claimed to be better tolerated but are more expensive.
  
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- Expensive preparations of iron with vitamins, liver extract, amino acids, etc. are available but offer no obvious benefits.

Adverse effects of oral iron

Epigastric pain, nausea, vomiting, gastritis, metallic taste, constipation (due to astringent effect) or diarrhea (irritant effect) are the usual adverse effects.
Liquid preparations of iron cause staining of the teeth.

Parenteral Iron Preparations

Indications

When oral preparations are not tolerated
Failure of absorption – as in malabsorption, chronic bowel disease
Noncompliance
Severe deficiency with bleeding.

Preparations

Iron dextran has 50 mg elemental iron/ml (2 ml ampoule) - can be given IM/IV.

(maximum dose: 20 mg/kg/day)
Iron—sorbitol-citric acid complex—contains 50 mg elemental iron/ml; given IM.

Dose is to be calculated using a formula:

This also includes iron needed for replenishment of stores.

Parenteral Iron

Intramuscular injection of iron is given deep IM in the gluteal region (buttoks) using ‘Z’ technique to avoid staining of the skin.
Intravenous iron is given slowly over 5–10 minutes or as infusion after a test dose.
Test dose = 25 mg.

Adverse Effects

If given intramuscularly, iron dextran may cause local discomfort (pain at the site of injection), pigmentation (discoloration) of the skin, sterile abscess and potentially malignant skin changes.
Headache, fever, arthralgias, difficulty in breathing and lymphadenopathy can occur.
Anaphylactic reactions, although rare, can be fatal.

Acute iron poisoning

It is common in infants and children in whom about 10 tablets can be lethal.
Manifestations include vomiting, abdominal pain, hematemesis, bloody diarrhea, shock, drowsiness, convulsions, cyanosis, acidosis, dehydration, cardiovascular collapse and coma.
Immediate diagnosis and treatment are important as death may occur in 6–12 hour.

Treatment

Supportive management and gastric lavage with sodium bicarbonate solution.
Desferrioxamine is the antidote. It is instilled into the stomach after lavage, to prevent iron absorption; dose: (15 µg/kg/hr.) should be injected IV/IM.
Correction of acidosis and shock.
Discuss the case with National Poisons Information Services [NPIS] or Drug Information Centers (DIC)

MEGALOBLASTIC ANEMIA

Megaloblastic anemia is characterized by the presence of Macrocytic red cell precursors (megaloblasts) in the blood and bone marrow.

Etiology of megaloblastic anemia

Megaloblastic anemia is almost always caused by deficiencies of vitamin B₁₂ or folic acid. These vitamins are essential in DNA synthesis, and thus, the high cell turnover in hematopoiesis is dramatically affected by deficiencies.
The most helpful diagnostic tests are evaluations of serum folate and vitamin B₁₂ levels, the Schilling test for urinary vitamin B₁₂ excretion, and analysis of gastric function.

DRUGS FOR MEGALOBLASTIC ANEMIAS

Folic acid and Vitamin B₁₂

Folic acid and Vitamin B₁₂ are water soluble vitamins, belonging to the B-complex group.
They are essential for normal DNA synthesis.
Their deficiency leads to impaired DNA synthesis and abnormal maturation of RBCs and other rapidly dividing cells. This results in megaloblastic anemia.
Vitamin B₁₂ and folic acid are therefore called maturation factors.
Other manifestations of deficiency include glossitis, stomatitis, malabsorption syndrome and neurological manifestations.

Folic acid

Daily requirements
1. Folic acid is found in a variety of foods, Its highest content found in yeast, liver, and green vegetables.
2. The minimum daily adult dietary requirement is 50 µg, although pregnant or lactating women may need 100–200 (mcg) per day.
Physiology
1. Folic acid is completely absorbed in the upper part of the small intestine.
  
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2. Folates present in food are in the reduced polyglutamate form. The mucosa of the duodenum and the upper jejunum contain dihydro-folate reductase, which methylates the reduces folate.
3. Once absorbed, folate is transported to tissues where it is stored within cells as polyglutamate.
4. Supplies are maintained by food intake and by the enterohepatic cycle.
5. Folates and their cleavage products are mainly excreted through urine.
6. Folic acid is a precursor of several coenzymes, and several derivatives of tetrahydrofolic acid are important in single carbon atom transfers, such as the synthesis of thymidylate from deoxyuridylate.
Prolonged cooking with spices destroys folic acid.
Deficiency
1. Folate deficiency can result from (Fig. 5.1.2):
  1. Inadequate dietary supply.
  2. Disease involving the small intestine.
  3. Defects in the folate enterohepatic cycle (e.g., hepatic toxicity from alcoholism).
  4. Low concentration of folate-binding proteins in plasma
  5. Certain drugs (e.g., methotrexate, trimethoprim, anticoagulants, contraceptives)
  6. Normal pregnancy, which produces an increased requirement for folate
2. Folate deficiency can result in megaloblastic anemia.
  1. The onset is more rapid than with a vitamin B₁₂ deficiency.
    
    Fig. 5.1.2: Causes and effects of folic acid depletion
  2. There is no neurological abnormality associated with folate deficiency.
Therapeutic uses

Folic acid is used:
- To treat megaloblastic anemia due to folate deficiency which can be caused by:
  - – Poor diet (commonly in alcoholics)
  - – Malabsorption syndrome
  - – The use of some drugs, e.g. phenytoin
- Folic acid 2–5 mg/day is given orally along with vitamin B₁₂ in folic acid deficiency due to malabsorption syndromes. Folic acid is given IM to treat or prevent toxicity of methotrexate, (folate antagonist)
- Prophylactically in individuals at hazard from developing folate deficiency, for example:
  - – Pregnant women (especially if there is a risk of birth defects).
  - – Premature infants.
  - – Prophylactically in pregnancy, lactation, infancy and other situations with increased requirement of folic acid = 500 mcg daily orally.
- Patients with severe chronic hemolytic anemia, including hemoglobinopathies (e.g. sickle cell anemia).
Preparations and administration
1. Folic acid can be given orally (or parenterally) and usually cures an uncomplicated megaloblastic anemia resulting from folate deficiency.
2. Folic acid injection contains sodium salt and is principally used in acute illness. It is given by intramuscular, intravenous, or deep subcutaneous injections.
Adverse effects
1. The oral form of folic acid is nontoxic at therapeutic doses, but large amounts may counteract the antiepileptic action of phenobarbital, phenytoin, and primidone.
2. There have been rare allergic reactions to parenteral administration.

Vitamin B₁₂: It is essential for cell growth and for maintenance of normal myelin. It is also important for the normal metabolic functions of folate (Fig. 5.1.3).

Physiology
1. Vitamin B₁₂ (cyanocobalmin) is a cobalt-containing compound that is synthesized by the bacterial flora in the colon. However, it cannot be absorbed there, and humans must obtain the vitamin from the dietary intake of meat and vegetables that possess B₁₂.
2. Intrinsic factor, a glycoprotein produced by the gastric parietal cells, is necessary for the gastrointestinal absorption of vitamin B₁₂.
  1. Gastric acid releases the vitamin from proteins, allowing it to form a complex with intrinsic factor.
    
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  2. The vitamin B₁₂-intrinsic factor complex binds to ileal mucosal cell receptors, from where it is transported into the circulation.
3. Once in the circulation, vitamin B₁₂ is transported to the tissues by a plasma β–globulin- transcobalamin II.
4. The liver preferentially stores vitamin B₁₂. A portion of the stored vitamin is secreted into the bile each day and is normally reabsorbed in the ileum.
  
  Fig. 5.1.3: The role of vitamin B₁₂ in the synthesis of folate polyglutamate
Deficiency
1. Vitamin B₁₂ deficiency can result from:
  1. Inadequate secretion of intrinsic factor.
  2. Intestinal disorders, including ileac disease, gastric atrophy, or surgery.
  3. An insufficient dietary supply, although this is very rare.
  4. Congenital absence of transcobalamin II
  5. Interference with the reabsorption of vitamin B₁₂ excreted in the bile.
2. Vitamin B₁₂ deficiency can result in:
  1. Megaloblastic anemia; although this is most common, all blood cell lines can be affected, resulting in pancytopenia.
  2. Demyelination and cell death, which can produce irreversible damage to the central nervous system (CNS) leads to neurological and neuro-psychiatric disorders.
Therapeutic uses
1. The most common therapeutic use for vitamin B₁₂ is the treatment of pernicious anemia (addisonian anemia). This condition is usually caused by atrophy of the gastric mucosa with achlorhydria and failure to secrete intrinsic factor.
2. Lifetime maintenance therapy with vitamin B₁₂ is required.
Preparations and administration
1. If the patient lacks intrinsic factor or has ileac disease, vitamin B₁₂ must be administered parenterally. Cyanocobalamin injection, a bright red solution, is administered by the intramuscular or deep subcutaneous route, but never intravenously.
2. Oral combinations of vitamin B₁₂ with intrinsic factor usually produce unreliable absorption; therefore, this approach is not recommended.
3. Dose : 1000 mcg cobalamine im/week for 4–6 weeks followed by 1000 mcg im/months.
  
  - Oral cobalamine 1000 mcg/day is a safe, effective and inexpensive alternate.
Adverse effects from vitamin B₁₂ administration are rare.

ERYTHROPOIETIN

Physiology

Erythropoietin is a glycoprotein hormone produced by the kidneys and released in response to tissue hypoxemia. It is a primary regulator of erythropoiesis.
Erythropoietin stimulates the proliferation of immature erythroid progenitor cells. These cell give rise to marrow normoblasts, the immediate precursors of reticulocytes and mature red blood cells.
Erythropoietin has been produced by recombinant DNA technology as a 165-amino acid glycoprotein.
1. lt contains the identical amino acid sequence of isolated natural erythropoietin.
2. Antibodies to erythropoietin have not been detected.

Pharmacokinetics

Erythropoietin is administered parenterally (intravenously or subcutaneously) because it is broken down in the gastrointestinal tract.
The half-life ranges from 5–13 hours when administered intravenously to patients in chronic renal failure. The pharmacokinetics of erythropoietin are not affected by dialysis.

Therapeutic uses

Erythropoietin is indicated for the treatment of anemia associated with chronic renal failure, including patients on and off dialysis.
Erythropoietin elevates or maintains red blood cell levels, decreasing the need for transfusions.

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Erythropoietin is not intended for patients needing immediate correction of severe anemia.
Recent data suggest that erythropoietin may also be useful for treating anemia in patients with AIDS who are being treated with zidovudine, but only in patients with low endogenous erythropoietin levels.

Adverse effects

Hypertension may occur.
Seizures may occur, especially during the first 90 days of treatment.
High doses of heparin may be needed for adequate anticoagulation during hemodialysis.

COLONY-STIMULATING FACTORS (CSF)

Physiology

CSFs are naturally occurring cytokine glycoproteins that stimulate the proliferation, differentiation, and activity of neutrophils, monocytes, and macrophages.
1. Granulocyte CSF (G-CSF) affects neutrophils.
2. Granulocyte-macrophage CSF(GM-CSF) affects neutrophils, monocytes, and macrophages.
Recombinant forms of these glycoproteins have been formed by cloning the genes for the CSFs.
1. Filgrastim is the synthetic form of G-CSF.
2. Sargramostim is the synthetic form of GM-CSF.

Filgrastim and Sargramostim

Pharmacological effects
1. When administered to patients with normal bone marrow function, an increase in the number of white blood cells occurs within 2–3 days.
2. In patients with bone marrow suppression, a similar increase occurs within 7–14 days. When these agents are administered to AIDS patients following zidovudine therapy, the number of neutrophils increase but the incidence of opportunistic infections remains the same.
Therapeutic uses
1. These agents are used for the short-term treatment of patients with primary bone marrow deficiency states or following cancer chemotherapy or bone marrow transplantation
2. In patients with aplastic anemia, administration of filgrastim and sargramostim increases the number of neutrophils and decreases infectious complications.
Administration: Filgrastim and sargramostim may be administered subcutaneously or intravenously.
Adverse effects
1. Filgrastim can cause bone pain, splenomegaly, and abnormalities in uric acid concentrations and lactate dehydrogenase.
2. Sargramostim can cause fluid accumulation, including pleural and pericardial effusions.

Chapter Notes

Drugs Affecting HematopoiesisCHAPTER 1