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AGENTS USED IN ANEMIA Agents Used in Anemia • Anemia ---a deficiency in erythrocytes or hemoglobin. • Normal value • Adult male • Adult famale RBC(104/μL) 12~16 11~15 Hb(g/dL) 400~550 350~500 Types of anemia • Iron-deficiency anemia • megaloblastic anemia • aplastic anemia • hemolytic anemia Agents used in anemias • Iron • Vitamin B12 • Folic acid Iron • Iron deficiency • most common nutritional cause of anemia • result from inadequate iron intake, malabsorption, blood loss, or an increased requirement, as with pregnancy The Body Content of Iron MG/KG OF BODY WEIGHT Male Female Essential iron Hemoglobin Myoglobin and enzymes 31 6 28 5 Storage iron Total 13 50 4 37 Daily Iron Intake and Absorption SUBJECT IRON REQUIRE MENT, mg/kg Infant 67 Child 22 Adolescent (male) 21 Adolescent (female) 20 Adult (male) 13 Adult (female) 21 Mid-to-late pregnancy 80 Iron Cycle • 5 - 10% of ingested iron is absorbed • Once ingested the acid in the stomach: • 1. Aids in ionization of iron • 2. Splits chelated food iron from chelator • 3. Maintains iron in soluble form • 4. Allows iron to remain in the absorbable form Fe3+ Mechanism of Iron Absorption Iron Preparations • Oral Iron • Ferrous Sulfate (Feosol) – 300 mg tid • Side Effects are extremely mild: • Nausea, upper abdominal pain, constipation or diarrhea. • Cheapest form of Iron and one of the most widely used • Parenteral • Iron Dextran (Imferon) – IM or IV • Indicated for patients who cannot tolerate or absorb oral iron or where oral iron is insufficient to treat the condition ie. Malabsorption syndrome, prolonged salicylate therapy, dialysis patients Pharmacokinetics: Absorption: Fe2+ Increase: Vitamin C, amino acid, gastric acid Decrease: phosphorus, calcium,Tannic acid, Antacids, H2-receptor blockers, Proton pump inhibitors, Tetracyclines • Transfer: transferrin • Utilization: transferrin-R on proliferating erythroid cells. • Storage: ferritin(Fe3+) in intestinal mucosal cells and in macrophages in the liver, spleen, and bone. Pharmacological actions: • Iron is part of hemoglobin, the oxygen-carrying component of the blood. Iron-deficient people tire easily because their bodies are starved for oxygen. • Iron is also part of myoglobin. Myoglobin helps muscle cells store oxygen. Therapeutic uses of Iron • Iron Deficient Anemia • Hookworn infestation • Pregnancy • Malabsorption Syndrome • Premature Babies • GI Bleeding due to: • Blood loss • Ulcers • Aspirin • Excess consumption of coffee Oral iron therapy adverse effects • Nausea • Epigastric discomfort • Abdominal cramps • Constipation • Diarrhea Clinical toxicity • Acute iron toxicity • • • • Necrotizing gastroenteritis Vomiting, abdominal pain, bloody diarrhea Followed by shock, lethargy, dyspnea Severe metabolic acidosis, coma, death • Chronic iron toxicity (hemochromatosis) • Deposit of iron in the heart, liver, pancreas • Can lead to organ failure and death Toxicity of Iron Overdose • 5000 deaths/year in the US, usually in children • 20% of children presenting with iron toxicity will die • 1 to 2 grams are sufficient to cause death • At high doses, Iron is absorbed through passive diffusion with no regulation Treatment of Iron Overdose • Toxic levels • ALD – 200-300mgkg, plasma iron > 300ug/dl • Bicarbonate for acidosis • Fluids for blood loss • Ipecac or lavage • Chelation with Deferoxamine Folate deficiency • Nutritional • Malabsorption • Drug related – impaired absorption (eg. Anticonvulsants) folate antagonists (eg. methotrexate) • Increased Folate Requirements Folic Acid • Folic acid (pteroylglutamic acid) is composed of a heterocycle (pteridine), p-aminobenzoic acid, and glutamic acid. • Folic acid is required for the synthesis of amino acids, purines, and DNA. • Megaloblastic anemia of folate deficiency is microscopically indistinguishable from B12 deficiency. • Folate deficiency does not cause neuropathy. The structure and numbering of atoms of folic acid . •Folic acid • Process in body FA → FH2 → FH4 → 5-CH3-FH4 • Machinism: One carbon unit carrier • Reduction of folic acid → ↓dTMP →↓ DNA→megaloblastic anemia ↓amino acid biosynthesis Folate metabolism. Folate is essential for the de novo synthesis of purines, deoxythymidylate monophosphate (dTMP), and methionine, serving as an intermediate carrier of1-carbon fragments used in the biosynthesis of these compounds. Its active form is tetrahydrofolate (THF). THF acquires the 1-carbon fragment principally from serine, which is converted to glycine in the course of the reaction. For purine synthesis, the 1-carbon fragment is first oxidized to the level of formic acid, then transferred to substrate. For methionine synthesis, a cobalamin-requiring reaction, the 1carbon fragment is first reduced to the level of a methyl group, then transferred to homocysteine. In these reactions the cofactor is released as THF, which can immediately participate in another 1-carbon transfer cycle. During the production of dTMP from dUMP, however, the 1carbon fragment is reduced from formaldehyde to a methyl group in the course of the transfer reaction. The hydrogen atoms used for this reduction come from the cofactor, which is therefore released, not as THF, but as dihydrofolate (DHF). To participate further in the 1-carbon transfer cycle, the DHF has to be re-reduced to THF, a reaction catalyzed by dihydrofolate reductase. Enzymatic reactions that use folate Pharmacokinetics •Only 5-20 mg of folates are stored in the liver. •Folates elimination is high, so serum levels fall within a few days when intake is diminished. •Megaloblastic anemia can develop within 1-6 months after the intake of folic acid stops. Folic acid: Clinical pharmacology • Deficiency • result in megaloblastic anemia • Often caused by inadequate dietary intake • Pregnant woman has increased folate requirement • A dose of 1 mg is sufficient Clinical Pharmacology • Folic acid deficiency is seen in: • Alcohol dependence and liver disease (poor diet and diminished hepatic storage) • Pregnancy and hemolytic anemia (increased folate requirement) • Malabsorption syndromes • Renal dialysis (dialysis removes folates) • Some drug ingestion: methotrexate, trimethoprim and pyrimethamine (inhibit dihydrofolate reductase) Therapeutic Uses of Folic Acid • 1. Megaloblastic Anemia due to inadequate dietary intake of folic acid • Can be due to chronic alcoholism, pregnancy, infancy, impaired utilization: uremia, cancer or hepatic disease. • 2. To alleviate anemia that is associated with dihydrofolate reductase inhibitors. • i.e. Methotrexate (Cancer chemotherapy), Pyrimethamine (Antimalarial) • Administration of citrovorum factor (methylated folic acid) alleviates the anemia. Therapeutic Uses of Folic Acid (cont) • 3. Ingestion of drugs that interfere with intestinal absorption and storage of folic acid. • Mechanism- inhibition of the conjugases that break off folic acid from its food chelators. • Ex. – phenytoin, progestin/estrogens (oral contraceptives) • 4. Malabsorption – Sprue, Celiac disease, partial gastrectomy. • 5. Rheumatoid arthritis – increased folic acid demand or utilization. B12 Deficiency • A B12 deficiency will cause peripheral neuropathy and a macrocytic anemia, a pernicious anemia. • Folic Acid administration can correct the macrocytic anemia but will fail to correct the peripheral neuropathy. • To treat the neuropathy, Vit B12 must be utilized. Vitamin B12 Vitamin B12 • Vitamin B12 deficiency causes: • Megaloblastic anemia, thrombocytopenia and/or leukopenia • GI and neurologic abnormalities. • Deficiency of B12 in older adults due to inadequate absorption is a common and easily treated disorder. • Deoxyadenosylcobalamin and methylcobalamin are the active forms of the B12 in humans. • Cyanocobalamin and hydroxocobalamin (available for therapeutic use) are converted to the active forms. Vitamin B12 •The dietary source of vitamin B12 is meat (especially liver), egg, and dairy products. •The ultimate source of B12 is microbial synthesis; B12 is not synthesized by animals or plants. •Vitamin B12 is also called extrinsic factor. Pharmacokinetics • B12 is stored in the liver with a storage pool of 30005000 mcg. • Daily requirements are 2 mcg, it would take 5 years for megaloblastic anemia to develop. • B12 is absorbed only in complex with intrinsic factor (IF) secreted by the parietal cells of the stomach. • The IF-B12 complex is absorbed in the distal ileum. • It is transported in the blood by transcobalamin II. The assimilation of cobalamin. On entering the stomach, dietary cobalamin (Cbl) forms a complex with R binding protein. As this protein is digested in the small intestine, cobalamin is transferred to intrinsic factor (IF). This complex passes through the intestine until it reaches specific receptors on the mucosa of the distal ileum. The internalized Cbl is then transferred to transcobalamin II (TC II), which circulates in the plasma until it binds to receptors on cells throughout the body and is internalized. Relation to Folic Acid •Methylfolate trap is the biochemical step whereby B12 and folic acid are linked. •That is why the anemia of B12 deficiency can be partially corrected by folic acid. •Folic acid will not prevent neuropathies of B12 deficiency. Enzymatic reactions that use folates. Section 1 shows the vitamin B-12 dependent reaction that allows most dietary folates to enter the tetrahydrofolate cofactor pool and becomes the "folate trap" in vitamin B 12deficiency. Section 2 shows the dTMP cycle. Section 3 shows the pathway by which folic acid enters the tetrahydrofolate cofactor pool. Double arrows indicate pathways with more than one intermediate step Enzymatic reactions that use vitamin B .12 Mechanism for Peripheral Neuropathy • Cobalamin is a cofactor for the enzyme Methylmalonyl-CoA mutase which converts methylmalonyl-CoA to succinyl-CoA. • Succinyl-CoA enters the Krebs cycles and goes into nerves to make myelin. • If no Vitamin B12, methylmalonyl-CoA goes on to form abnormal fatty acids and causes subacute degeneration of the nerves. Only B12 can correct this problem. Clinical Pharmacology • The most common causes of vitamin B12 deficiency are: • Pernicious anemia • Partial or total gastrectomy • Abnormality in the distal ileum (malabsorption syndromes, IBD, small bowel resection). • Pernicious anemia results from defective secretion of intrinsic factor. • Patients have gastric atrophy and fail to secrete intrinsic factor and hydrochloric acid. Vitamin B12: clinical pharmacology • Treat or prevent deficiency • Megaloblastic anemia • Neurologic syndrome • Degeneration of myelin sheaths • Disruption of axons in the dorsal and lateral horns of spinal cord and in peripheral nerves Clinical uses: 1. Megaloblastic anemia 2 .Pernicious anemia 3 .Nervous system diseases 4. Hepatopathy Hematopoietic growth factors Erythropoietin (EPO) Granulocyte colony-stimulating factor (G-CSF) Granulocyte-macrophage colony- stimulating factor (GM-CSF) Erythropoietin (EPO) source: produced by the kidney in response to tissue hypoxia. Pharmacological effects: • stimulates erythroid proliferation and differentiation • Stimulates maturation of red blood cell • also induces release of reticulocytes from the bone marrow Clinical uses: • patients with chronic renal failure • patients with aplastic anemia • anemias associated with chronic inflammation, AIDS, and cancer Adverse reaction: • a rapid increase in hemoglobin • hypertension and thrombotic complications. Granulocyte colony-stimulating factor (G-CSF) Pharmacological effects: • stimulates proliferation and differentiation of progenitors to neutrophils • Increase release of neutrophils from bone marrow • activates the phagocytic activity of mature neutrophils and prolongs their survival in the circulation. Clinical uses: neutropenia Granulocyte-macrophage colonyfactor (GM-CSF) stimulating Pharmacological effects: • stimulates proliferation and differentiation of early and late granulocytic progenitor cells as well as erythroid and megakaryocyte progenitors • stimulates the function of mature neutrophils • Clinical uses: neutropenia • Adverse reaction: fevers, malaise, arthralgias, myalgias, peripheral edema and pleural or pericardial effusions, allergic reactions THANK YOU -PHARMA STREET