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Anti-anemic agents Anemia ---a deficiency in erythrocytes or hemoglobin. 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 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+ 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 absorboral iron or where oral iron is insufficient to treat the condition ie. Malabsorption syndrome, prolonged salicylate therapy, dialysis patients P’kinetic 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. Uses Iron Deficient Anemia Pregnancy Premature Babies Blood loss Hookworn infestation Malabsorption Syndrome GI Bleeding due to: Ulcers Aspirin Excess consumption of coffee 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), paminobenzoic 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. 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 P’kinetic 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. 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 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) Uses 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. 3. Ingestion of drugs that interfere with intestinalabsorption 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 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. The dietary source of vitamin B12 is meat (especially liver), egg, and dairy products. The ultimate source of B12is microbial synthesis; B12 is not synthesized by animals or plants. Vitamin B12 is also called extrinsic factor. P’kinetic B12 is stored in the liver with a storage pool of 3000-5000 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. 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. Fig. below = Enzymatic reactions that use vitamin B .21 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. 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. 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 activatesthe phagocytic activity of mature neutrophils and prolongs their survival in the circulation. Clinical uses: neutropenia Granulocyte-macrophage colony - stimulating factor (GM-CSF) 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