Drugs Used in the Treatment of Iron Deficiency Anaemia, Megaloblastic Anaemia and Pernicious Anaemia

P.C.L 313: Pharmacology of the Gastrointestinal tract, Ocular and Hemopoietic System

Drugs used in the treatment of iron deficiency anaemia, megaloblastic anaemia and pernicious anaemia

By Ms. Ayomide A. Ajibewa

The hematopoietic system

- Hemopoiesis is the production of circulating erythrocytes, platelets, and leukocytes from undifferentiated stem cells.

- The hematopoietic system is made up of the blood cells, bone marrow, lymph nodes, and thymus.

- It is responsible for the production, maturation, and regulation of blood cells.

- It ensures a constant supply of red blood cells, white blood cells, and platelets to maintain oxygen transport, immunity, and haemostasis.

- The primary sites of hemopoiesis include the yolk sac in embryos, the liver and spleen in the fetus, and bone marrow after birth.

- While hemopoiesis forms the cellular components of blood, such as red blood cells, white blood cells, and platelets in the bone marrow, plasma is not formed by stem cell differentiation.

Plasma and Hemopoiesis

- Plasma is the fluid matrix, assembled from water absorbed from the digestive system, interstitial fluids from tissues, and fluids from the lymphatic system lymph vessels.

Image summary: An illustration depicting blood plasma as the liquid vehicle, showing a smiley face plasma drop as the liquid transport medium with blood cells riding along as passengers.

- It transports nutrients, proteins, hormones, waste products, electrolytes, and other substances.

- Hemopoiesis requires a constant supply of three essential nutrients: iron, vitamin B twelve, and folic acid (vitamin B nine), as well as hemopoietic growth factors that regulate the proliferation and differentiation of hemopoietic cells.

The hemopoietic stem cells are pluripotent stem cells capable of self renewal and differentiation.

It gives rise to two major progenitor lines: the myeloid lineage, which includes R.B.C's, platelets, granulocytes, monocytes, eosinophils, and basophils; and the lymphoid lineage, which includes T cells, B cells, and N.K cells.

Image summary: A biological diagram showing the differentiation of a Hematopoietic Stem Cell into two branches. The myeloid progenitor branch leads to red blood cells, platelets, and granulocytes, while the lymphoid progenitor branch leads to T cells, B cells, and natural killer cells.

- The whole process is regulated by growth factors, such as erythropoietin, granulocyte-colony stimulating factors, and thrombopoietin.

- E.P.O is produced by the kidneys when they sense that the blood oxygen levels are low, thus signalling the bone marrow to make more red blood cells.

Blood is:

- Blood is a fluid of life: it carries oxygen from the lungs and carbon dioxide to the lungs.

- It is a fluid of growth, carrying nutrients from the digestive system and hormones from the endocrine system to all parts of the body.

- It is a fluid of health: protecting the body against diseases and getting rid of wastes and unwanted products through the excretory organs.

- It is made up of the blood cells, including red blood cells, white blood cells, and platelets, collectively called the formed elements, as well as plasma, which is the liquid component.

The red blood cells

- R.B.C's, also known as erythrocytes, are non-nucleated formed elements that have characteristic red colouration due to the presence of haemoglobin, which is the colouring pigment.

- They are larger in size compared to the other blood cells and play the major role of transporting respiratory gases.

Development and maturation of R.B.C

- Pluripotent stem cell yields an erythroid burst forming unit, also known as B.F.U-E.

- Erythropoietin, or E.P.O, and cytokines such as interleukin-3 and granulocyte-macrophage colony stimulating factor stimulate this cell to form an erythroid colony-forming unit, or C.F.U-E, in the marrow, during which the nucleus becomes smaller as the cell division progresses.

- Haemoglobin and iron are then incorporated into the red blood cell during the maturation process, which takes about one week, and it is released into the blood stream as a reticulocyte.

- By the time a normal erythrocyte is fully developed from a reticulocyte, the nucleus will have fully disappeared.

- Thus, the red blood cell is a non-nucleated and non-dividing cell and has a survival time of 120 days.

Image summary: A flow chart illustrating the erythrocyte maturation sequence. It shows a step-by-step progression from a pluripotent stem cell through various stages including erythroid burst-forming units, colony-forming units, proerythroblasts, basophilic, polychromatic, and pyknotic erythroblasts. The sequence continues through bone marrow and peripheral reticulocytes, ending with a mature erythrocyte. Key growth factors like GM-CSF, IL-3, and EPO are shown as triggers for the early stages of differentiation.

Erythrocyte maturation sequence. Source: Pharmacotherapy: A pathophysiologic approach.

Anaemia

- Anaemia is a group of conditions characterized by a decrease in either hemoglobin or the red blood cell volume, resulting in decreased oxygen-carrying capacity of the blood.

- It may be due to decreased production of red blood cells, increased destruction of red blood cells, or excess loss of blood from the body.

- All of these are caused either by inherited disorders, nutritional problems, infection, and exposure to drugs or toxins.

Classification of anaemia based on R.B.C size

Image summary: A table categorizes types of anemia by red blood cell size, common cause, and key mechanism. Microcytic anemia involves small cells caused by iron deficiency or chronic disease, where insufficient hemoglobin leads to smaller cells. Normocytic anemia involves normal sized cells caused by acute blood loss, hemolysis, chronic disease, bone marrow failure, or recent blood loss, resulting in fewer cells due to loss or poor production. Macrocytic anemia involves large cells caused by Vitamin B twelve deficiency, folate deficiency, or liver disease, where impaired DNA synthesis causes delayed cell division and larger cells.

Specific types of anemia

Iron Deficiency Anemia, or I.D.A, is characterized by decreased levels of ferritin, which is the iron reservoir, serum iron, and hemoglobin.

- Causes include inadequate iron intake, chronic blood loss, or poor absorption.

- The red blood cell size is microcytic.

- Symptoms include fatigue, a pale appearance known as pallor, brittle nails, and pica, which is a craving for non-food items.

- Treatment involves oral or intravenous iron supplements and treating the underlying cause.

Pernicious Anaemia

- The causes are auto-immune destruction of gastric parietal cells, which leads to a lack of intrinsic factor and impaired Vitamin B 12 absorption.

- The M.C.V classification is macrocytic.

- The mechanism is specifically due to Vitamin B 12 malabsorption.

- Symptoms include neurologic symptoms that may be present and irreversible if Vitamin B 12 deficiency is not treated promptly, as well as memory loss, ataxia, and fatigue.

- Treatment consists of lifelong vitamin B 12 injections.

Aplastic Anemia

- The cause is bone marrow failure or destruction, which can be due to auto-immune issues, drugs, radiation, or infections.

- The M.C.V classification is normocytic.

- The mechanism is a reduced production of all blood cells, known as pancytopenia.

- Symptoms include fatigue, infections, and bleeding or bruising.

- Treatment involves immunosuppressants or a bone marrow transplant.

Hemolytic Anemia

- The cause is red blood cell destruction, which can be auto-immune, hereditary, such as sickle cell or thalassemia, or due to infections.

- The M.C.V classification is normocytic.

- The mechanism is that red blood cells are destroyed faster than they are produced, so the bone marrow tries to compensate by producing more red blood cells, often releasing immature ones called reticulocytes.

- Symptoms include jaundice, dark urine, and splenomegaly.

- Treatment depends on the cause and may include steroids, transfusions, or splenectomy.

Megaloblastic anemia

- The cause is Vitamin B twelve deficiency or Folate deficiency, which can be due to a poor diet, alcoholism, or certain drugs.

- In terms of M.C.V classification, this is macrocytic.

- The mechanism is that a deficiency of Vitamin B twelve or Folate impairs D.N.A synthesis, leading to delayed nuclear maturation while cytoplasmic growth continues. Thus, there is formation of megaloblasts in bone marrow and large, fragile red blood cells in circulation.

- Symptoms include fatigue, pallor, glossitis, which is an inflamed tongue, gastrointestinal disturbances, and neurologic symptoms.

- Treatment involves Vitamin B twelve supplementation.

Hemorrhagic anemia

- The cause is acute or chronic blood loss, for example, through stomach ulcer or menstruation.

- The M.C.V classification is normocytic.

- The mechanism is that blood loss leads to a decrease in circulating red blood cells, reducing oxygen-carrying capacity. The bone marrow compensates by increasing R.B.C production, but persistent loss depletes iron stores.

- Symptoms include fatigue, weakness, pale skin, dizziness, and tachycardia.

- Treatment involves immediate control of bleeding and restoration of blood volume via transfusion or I.V fluids, iron supplementation, and treatment of the underlying cause.

Drugs Used in the Treatment of Iron Deficiency uhneemia, megaloblastic anemia and pernicious anemia

Iron

- Iron is available in a wide variety of foods but is especially abundant in meat.

- It is a transition metal with the ability to exist in several oxidation states and also to form stable coordination complexes.

- It is an essential mineral and an important component of proteins, involved in oxygen transport.

- Because most of the iron in the body is either part of or will be part of haemoglobin, the most obvious clinical result of iron deficiency is anaemia.

Pk

- Iron is present mostly in ferric form, which is converted into ferrous form and then absorbed into the blood.

- It is available as ferrous sulfate, ferrous succinate, gluconate, or fumarate for oral administration.

- Parenteral administration is also available as iron dextran and iron sucrose preparation for patients who cannot absorb the oral preparation, such as those with malabsorption syndrome or surgical procedures involving the gastrointestinal tract, or for those who cannot tolerate it.

- Dextran can be given as an intramuscular injection or a slow intravenous infusion.

- They are stored in intestinal mucosal cells, and primarily in ferritin in macrophages in the liver, spleen and bone.

- There is no mechanism for excretion of iron; small amounts are lost in the faeces by exfoliation of intestinal mucosal cells, and trace amounts are excreted in bile, urine, and sweat.

Indication: prevention or treatment of iron deficiency anaemia.

Contraindication: caution in pregnancy to prevent overload which may pose potential harm to the foetus.

Side effects

Side effects include nausea, abdominal cramps and diarrhoea, concern of infection, severe necrotising gastritis, haemorrhage, diarrhoea, and circulatory collapse.

Chronic toxicity or iron overload also occurs in chronic haemolytic anaemias requiring frequent blood transfusions.

Regarding toxicity, iron toxicity is treated with iron chelators like deferoxamine, which form a complex with ferric iron and are excreted in the urine.

folic acid and vitamin B.12

- Folic acids and Vitamin B.12, also known as cobalamin, are essential constituents of the human diet, being necessary for D.N.A synthesis and consequently for cell proliferation.

- Because red blood cells must be produced continuously, deficiency of cobalamin or folic acid usually manifests as megaloblastic anaemia.

- Mild leukopenia and thrombocytopenia usually accompany the anaemia, and the nuclei of polymorphonuclear leukocytes are abnormal and hypersegmented.

Folic acid

- It is required for the synthesis of D.N.A and effective erythropoiesis.

- In the absence of folic acid, the synthesis of D.N.A decreases, causing failure of maturation.

- This leads to megaloblastic anaemia in which the cells are larger and appear in the megaloblastic, or proerythroblastic, stage.

- Exogenous folic acid does not correct the neurologic defects of cobalamin deficiency; thus, megaloblastic anemia should not be treated with folic acid alone.

Folic Acid

- Folic acid deficiency is most often caused by dietary insufficiency and malabsorption.

- Anemia resulting from folic acid deficiency is readily treated with oral folic acid.

- It is readily available in yeast, liver, kidney, and green vegetables.

Pharmacokinetics:

- It is readily absorbed from the gastrointestinal tract.

- Only modest amounts are stored in the body, so a decrease in dietary intake is followed by anaemia within few months.

Vitamin B.12 (Cyanocobalamin)

- Vitamin B.12, cobalamin, is a cobalt containing molecule.

- Along side folic acid, it is a cofactor in the transfer of carbon atom, a step necessary for the synthesis of D.N.A.

- It is called extrinsic factor since it is obtained mostly from diet; it is also produced in the large intestine by the intestinal flora.

- It is stored mostly in liver and in small quantity in muscle.

- When necessary, it is transported to the bone marrow to promote maturation of Red Blood Cells.

- Deficiency of vitamin B twelve causes pernicious anaemia, thus vitamin B twelve is called antipernicious factor.

- Its deficiency is mostly caused by inadequate absorption; therefore, therapy involves the replacement of cobalamin via parenteral administration.

P.K:

- It is absorbed from the gastrointestinal tract.

- It is stored in the liver in large amounts; a normal individual has enough to last for approximately 5 years.

- It is available as cyanocobalamin and hydroxycobalamin, with the latter having a longer circulating half life.

To do

Briefly discuss the following:

- Iron overload.

- Management of acute iron toxicity.