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Anemias Pharmacotherapy 4 for PharmD students Prof. Nayla Younes Background According to WHO: 30% of world’s population are anemic Many people can be unaware that they have anemia It is one of the most under-diagnosed conditions worldwide The highest prevalence of anemia is seen in women, elderly & low income persons. Prevalence of anemia in the surgical population is 75% Importance of anemia is often overlooked & untreated. It can affect both length & quality of life. Homework Comparison between once weekly, twice weekly, and daily oral iron therapy in Jordanian children suffering from iron deficiency anemia doi: 10.1007/s10995-012-0981-3 What do you conclude? Homework What id the prevalence of anemia among Bedouin schoolchildren ? doi: 10.1159/000258632 What do you concluse? Homework What is the prevalence of glucose-6-phosphate dehydrogenase (G6PD) deficiency in Jordan ? doi: 10.1159/000339505 What do you concluse? Homework What is the prevalence of folate deficiency anemia among women in Jordan ? doi: 10.1038/ejcn.2014.100 What do you concluse? Homeworks Enlist all Fe supplements with their doses, salts and dosage forms Enlist all folate supplements with their doses, salts and dosage forms Enlist all B12 supplements with their doses, salts and dosage forms Definition Anemias: group of diseases characterized by ↓ in red cell mass: ↓ in number of (RBC)/(mm3) /or ↓ in Hb concentration in blood to level below normal physiologic requirement for adequate tissue oxygenation. WHO definition:<13 g/dL in men & <12 in women Term anemia is not diagnosis, but rather objective sign of disease. Exact diagnosis is important to understanding of problem & to implement specific therapy to correct anemia. Anemias associated with acute blood loss, those that are iron related, & those caused by chronic disease comprise most of all anemias. Classification of anemia Morphology Micro/normo/macro-cytic Hypo/normo chromic Etiology Deficiency Peripheral Central Pathophysiological Loss Production destruction Functional Proliferative Loss Maturation Morphologic Classification of Anemia Macrocytic •Defective maturation with decreased production •Megaloblastic: pernicious (vitamin B12 deficiency), folic acid deficiency Normochromic, normocytic •Recent blood loss •Hemolysis •Chronic disease •Renal failure •Autoimmune •Endocrine Microcytic, hypochromic (provide evidence of impaired Hb synthesis) •Iron deficiency •Genetic abnormalities: sickle cell, thalassemia Etiologic Classification of Anemia Deficiency • Iron • Vitamin B12 • Folic acid • Pyridoxine Central, caused by impaired bone marrow function • • • Anemia of chronic disease Anemia of the elderly Malignant bone marrow disorders Peripheral • Bleeding (hemorrhage) • Hemolysis (hemolytic anemias Pathophysiologic Classification of Anemia Blood Loss •Acute: trauma, ulcer, hemorrhoids, recent hemorrhage •Chronic: ulcer, vaginal bleeding, aspirin ingestion Inadequate Red Blood Cell Production •Nutritional deficiency: B12, folic acid, iron •Erythroblast deficiency: bone marrow failure (aplastic anemia, irradiation, chemotherapy, folic acid antagonists) or bone marrow infiltration (leukemia, lymphoma, myeloma, metastatic solid tumors, myelofibrosis) •Endocrine deficiency: pituitary, adrenal, thyroid, testicular •Chronic disease: renal, liver, infection, granulomatous, collagen vascular Excessive Red Blood Cell Destruction •Intrinsic factors: hereditary (G6PD), abnormal hemoglobin synthesis •Extrinsic factors: autoimmune reactions, drug reactions, infection (endotoxin), physical trauma to RBC Functional classification of anemia Maturation & development of RBCs In adults, RBCs are formed in marrow of vertebrae, ribs, sternum, clavicle, pelvic (iliac) crest & proximal epiphyses of long bones. In children, most bone marrow space is hematopoietically active to meet ↑ RBC requirements. Figure: normal RBC formation. Circulating erythrocyte is nonnucleated, nondividing cell. > 90% of protein content of erythrocyte consists of oxygencarrying molecule Hb. Erythrocytes compose 40-50% of total blood volume & have normal survival time 120 days. Stimulation of erythropoiesis Hormone EPO, 90% of which is produced by kidneys, initiates & stimulates production of RBCs. Erythropoiesis is regulated by feedback loop. Main mechanism of action of EPO is preventing apoptosis, or programmed cell death, of erythroid precursor cells & allowing their proliferation & subsequent maturation. Body iron normal iron content of body is ~3-4 g. significant amount of iron is stored as ferritin or aggregated ferritin (hemosiderin) in reticuloendothelial cells of liver, spleen, & bone marrow & by hepatocytes. ferritin circulates at concentrations that reflect total iron body stores. only small fraction of iron is found in plasma (100-150 mcg/dL), & most is bound to transferrin, transport protein. 70 kg man 60 kg woman Iron stores - transferrin, ferritin, hemosiderin 0.7 g 0.3 g* (average) Hemoglobin 2.5 g 1.9 g Myoglobin 0.14 g 0.13 g Heme enzymes (cytochromes) 0.01 g 0.01 g TOTAL 2.34 g 3.35 g Iron homeostasis Hepcidin is a regulator of intestinal iron absorption, iron recycling and iron mobilization from hepatic stores. Iron absorption Iron, which is absorbed from duodenum & upper jejunum by active transport mechanism, is enhanced in presence of acidic gastric environment. Dietary iron, which is primarily in ferric state, is converted to more readily absorbed ferrous form in acid environment of stomach. Ferrous form binds to transferrin for its journey to bone marrow, where it is incorporated into Hgb of mature erythrocytes. GI absorption of iron is ↑ from usual 10% to 3-5-fold in iron deficiency states or when erythropoiesis occurs more rapidly. Animal sources of iron (heme iron) are better absorbed than plant sources (nonheme iron). Certain foods & drugs can complex with iron →↓absorption. Q1 Dietary iron requirements Age Milk formula Gender Post menopausal Pregnancy status Lactation status Diet type Dietary reference intakes (DRI) for iron AGE mg iron mg iron Females Infants and Children 0 – 6 months AGE 0.27 9 – 13 years 8 14 – 18 years 15 19 - 50 years 18 8 7 – 12 months 11 1 – 3 years 7 51 + years 4 – 8 years 10 Pregnancy Males <18 years 27 >18 years 27 9 – 13 years 8 14 – 18 years 11 < 18 years 10 19 + years 8 > 18 years 9 Vegetarians 16 mg/day Lactation Dietary iron sources Heme iron, which is found in meat, fish, & poultry is ~3 times more absorbable than nonheme iron found in vegetables, fruits, dried beans, nuts, grain products & dietary supplements. 40% percent of iron from animal sources is in heme form. Heme & nonheme iron are absorbed by different receptors on intestinal mucosa. Food Serving Size Amount (mg) Total cereal 1 cup 18 Grape-Nuts cereal 1 cup 18 Instant Cream of Wheat 1 cup 8.2 Instant plain oatmeal 1 cup 6.7 Wheat germ 1 oz. 2.6 Broccoli 1 medium stalk 2.1 Baked potato 1 medium 2.7 Raw tofu 1/2 cup 4 Lentils 1/2 cup 3.3 Beef chuck 3 ounces 3.2 Factors influencing absorption of dietary iron Absorption of heme iron Absorption of nonheme iron Amount of heme iron, especially in Iron status meat Content of calcium in meal (inhibit) Amount of potentially available nonheme iron Food preparation (time, temperature) Balance between +ve & -ve factors Positive factors (enhance absorption) Ascorbic acid Meat or fish Negative factors (inhibit absorption) Phytate (in bran, oats, rye fiber) Polyphenols (in tea, some vegetables & cereals) Dietary calcium Soy protein Incorporation of Iron into Heme Specific plasma transport protein transferrin delivers iron to bone marrow for incorporation into Hb molecule. Transferrin enters cells by binding to transferrin receptors, which circulate & then attach to cells needing iron. There are <transferrin receptors on surface of cells that do not need iron. Circulating transferrin normally is ~30% saturated with iron. Transferrin delivers extra iron to other body storage sites, such as liver, marrow, & spleen, for later use. This iron is stored within macrophages as ferritin or hemosiderin. Normal Destruction of RBCs Phagocytic breakdown destroys older blood cells, primarily in spleen, but also in marrow. Fate of: Globin chains (amino acids) Porphyrin heme (heme oxygenase) Diagnosis of Anemia: History Onset of symptoms (& surrounding events) Because longstanding anemias can indicate hereditary disorders, family history should be noted. Past Hgb or hematocrit (Hct) determinations, transfusion history, as well as occupational, environmental, & social histories may be valuable. Medication history can help eliminate drug reactions or interactions as cause of anemia. Ds: Physical Examination Pallor is most easily observed in the conjunctiva, mucous membranes, nail beds, and palmar creases of the hand. Postural hypotension and tachycardia can be seen when hypovolemia (acute blood loss) is the primary cause of anemia. Patients with B12 deficiency may exhibit neurologic findings, which include changes in deep tendon reflexes, ataxia, and loss of vibration and position sense; all are consistent with nerve fiber demyelination. Patients with anemia from hemolysis may be slightly jaundiced from bilirubin release. Manifestations of hemorrhage can include petechiae, ecchymoses, hematomas, epistaxis, bleeding gums, and blood in the urine or the stool. Signs and Symptoms General Patients may be asymptomatic or have vague complaints Patients with vitamin B12 deficiency may develop neurologic consequences In ACD, S&S of underlying disorder often overshadow those of anemia Symptoms Decreased exercise tolerance Fatigue Dizziness Irritability Weakness Palpitations Vertigo Shortness of breath Chest pain Neurologic symptoms in vitamin B12 deficiency (WHY?) Signs Tachycardia Pale appearance (most prominent in conjunctivae) Decreased mental acuity Increased intensity of some cardiac valvular murmurs Diminished vibratory sense or gait abnormality in vitamin B12 deficiency Note: Presenting S&S of anemias depend on: rate of development (acute vs. slowly developing) age of patient (young vs. elderly) cardiovascular status of patient (healthy myocardium vs. heart disease) Severity of symptoms does not always correlate with degree of anemia. Laboratory Evaluation Full laboratory evaluation is necessary to: confirm diagnosis (together with information gained from history & physical examination), establish its severity, determine its cause. Cornerstone of this evaluation is CBC. Morphologic appearance of RBC provides useful information about nature of anemia. Microscopic evaluation of peripheral blood smear can detect: macrocytic (large) RBC, which usually are present when anemia results from vitamin B12 or folic acid deficiency; microcytic (small) RBC usually are associated with iron deficiency anemia. Acute blood loss generally is associated with normocytic cells. Routine Laboratory Evaluation for Anemia Workup Complete blood count (CBC): Hgb, Hct, RBC count, red cell indices (MCV, MCH, MCHC), WBC count (& differential) Platelet count Red cell morphology Reticulocyte count Bilirubin & LDH Serum iron, TIBC, serum ferritin, transferrin saturation Peripheral blood smear examination Stool examination for occult blood Bone marrow aspiration & biopsya Hct, hematocrit; Hgb, hemoglobin; LDH, lactic dehydrogenase; MCV, mean corpuscular volume; MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular hemoglobin concentration; RBC, red blood cell; TIBC, total iron-binding capacity; WBC, white blood cell. Laboratory tests in the evaluation of anemia Homework If MCV= 100 fL If Hct=50% Then how many RBCs in 1 ml? Other Diagnostic Tests Schilling test may help uncover intrinsic factor deficiency (done in four stages) Bone marrow testing with iron staining can indicate low iron levels in IDA and adequate stores in ACD IDA vs. ACD Summary: Lab tests Hb, hematocrit (Hct), & RBC indices may remain normal early in disease & then decrease as anemia progresses Serum iron is low in IDA & ACD Ferritin levels are low in IDA & normal to increased in ACD TIBC is high in IDA & is low or normal in ACD Mean cell volume is elevated in vitamin B12 deficiency & folate deficiency Vitamin B12 & folate levels are low in their respective types of anemia Homocysteine is elevated in vitamin B12 deficiency & folate deficiency Methylmalonic acid is elevated in vitamin B12 deficiency HW: Coombs’ test? Treatment of Anemia Desired Outcomes Goal: to increase hemoglobin level, which will improve red cell oxygen-carrying capacity, alleviate symptoms, & prevent anemia complications. Patients who experience resolution in their symptoms such as shortness of breath, tachycardia, fatigue, dizziness, & edema may not require aggressive therapy to maintain their hemoglobin values within normal limits. Prevention of complications owing to anemia such as hypoxia & cardiovascular sequelae can be avoided if hemoglobin levels are > 7 g/dL. General Approach to Anemic Patient Underlying cause of anemia (e.g., blood loss; iron, folic acid, or vitamin B12 deficiency; or chronic disease) must be determined & used to guide therapy. Patients should be evaluated initially based on laboratory parameters to determine etiology of anemia. Appropriate pharmacologic treatment should be initiated based on cause of anemia. Iron Deficiency Anemia (IDA) Iron deficiency is state of negative iron balance in which daily iron intake & stores are unable to meet RBC & other body tissue needs. Signs, Symptoms, & Laboratory Tests The most important S&S of IDA are related to cardiovascular system & are reflection of imbalance between ongoing demands for oxygen against diminishing oxygen supply. low serum iron, low serum ferritin, & elevated TIBC are typical laboratory findings associated with IDA. Serum transferrin receptor levels, which reflect amount of RBC precursors available for active proliferation, are increased in iron deficiency. In severe iron deficiency, RBC become hypochromic (low MCHC) & microcytic (low MCV) – when Hgb concentration falls to <12 g/dL in male patients or <10 g/dL in female patients. Laboratory tests in iron deficiency of increasing severity Normal Fe deficiency Fe deficiency without with mild anemia anemia Severe Fe deficiency with severe anemia Marrow reticulo- endothelial iron 2+ to 3+ None None None Serum iron, µg/dL 60 to 150 60 to 150 <60 <40 Iron binding capacity (transferrin), µg/dL 300 to 360 300 to 390 350 to 400 >410 Saturation (SI/TIBC), percent 20 to 50 30 <15 <10 Hemoglobin, g/dL Normal Normal 9 to 12 6 to 7 Red cell morphology Normal Normal Normal or slight Hypochromia and hypochromia microcytosis Plasma or serum ferritin, ng/mL 40 to 200 <40 <20 <10 Erythrocyte protoporphyrin, ng/mL RBC 30 to 70 30 to 70 >100 100 to 200 Other tissue changes None None None Nail and epithelial changes Peripheral blood smear Normal peripheral blood smear Several platelets (black arrows) & normal lymphocyte (blue arrow) can also be seen. Red cells are of relatively uniform size & shape. Diameter of normal red cell should approximate that of nucleus of small lymphocyte; central pallor (red arrow) should equal 1/3 of its diameter. Microcytic hypochromic red cells Iron deficiency: pale small red cells with just scant rim of pink hemoglobin; occasional "pencil" shaped cells. Normal red cells are similar in size to nucleus of small lymphocyte (arrow); thus, many microcytic cells are present in this smear. Thalassemia can produce similar findings. Predisposing Factors Iron Deficiency Anemia nutritional deficiency Causes worldwide. Blood Loss Blood loss is considered one Menstruation, gastrointestinal of the more common causes. (e.g., peptic ulcer), trauma Common causes of chronic Decreased Absorption blood loss include peptic ulcer disease, hemorrhoids, Medications, gastrectomy, ingestion of GI irritants, regional enteritis menstruation, multiple Increased Requirement pregnancies, & multiple blood Infancy, pregnant/lactating donations. women Impaired Utilization Hereditary, Iron use IDA is the most common Treatment: IDA Severity & cause of IDA determine approach to treatment. Because iron deficiency can be early sign of other illnesses, treatment of underlying disease may aid in correction of iron deficiency. Treatment is focused on replenishing iron stores. Dietary iron intake should be analyzed & modified. Dietary Supplementation & Therapeutic Iron Preparations Treatment of IDA usually consists of dietary supplementation & administration of therapeutic iron preparations. Iron is poorly absorbed from vegetables, grain products, dairy products, & eggs; it is best absorbed from meat, fish, & poultry. Beverages have been shown to affect iron absorption. Meat, orange juice, and other ascorbic acid–rich foods should be included with meals, whereas milk & tea should be consumed in moderation between meals. In most cases of IDA, oral administration of iron therapy with soluble Fe2+ iron salts is appropriate. Iron supplementation resolves anemia by replacing iron stores in body that are necessary for RBC production & maturation. Goals of iron therapy to normalize Hgb & Hct concentrations to replete iron stores. Initially, if doses of iron are adequate, reticulocyte count will begin to increase by 3rd-4th day & peak by 7th-10th day of therapy. By the end of 2nd week of iron therapy, reticulocyte count will fall back to normal. Hgb response is convenient index to monitor in outpatients. Hematologic response is usually seen in 2-3 weeks with 1 g/dL increase in Hb & 6% increase in hematocrit. Iron therapy should be continued for 3-6 months after Hb is normalized to replete iron stores. Iron Therapy Initial treatment of IDA is oral iron: 200 mg of elemental iron daily for those who are able to tolerate oral route. Why 200 mg/day? Many different iron products & salt forms are available (Table) Dosing for iron should be divided equally into 2-3 doses daily. Empty stomach (1 hr before or 2 hrs after meal) is preferred for maximal absorption. If treated properly, response (via presence of reticulocytosis) should be seen in 7-10 days, & Hb should rise by ~1 g/dL per week. Patients should be reassessed if Hb does not increase by 2 g/dL in 3 weeks. Iron Therapy - doses Usual adult dose of ferrous sulfate is 325 mg (one tablet) administered three times daily, between meals. If no iron is being lost through bleeding, required daily dose of elemental iron can be calculated using formula that assumes that 0.25 g/dL/day is maximal rate of Hb regeneration. Differences between iron products Ferrous form of iron is absorbed 3 times > readily than ferric form. Although ferrous sulfate, ferrous gluconate & ferrous fumarate are absorbed almost equally, each contains different amount of elemental iron. Product Formulation Product formulation is of considerable importance in product selection. Some believe that more expensive, sustained-release (SR) iron preparations are inherently better. SR preparations fall into three groups: (a) those claimed to increase GI tolerance or decrease side effects?? (b) those formulated to increase bioavailability, (c) those with adjuvants claimed to enhance absorption (e.g. ascorbic acid) or decrease side effects (e.g. stool softener) Because these products can be given once daily, increased compliance is an additional claim. Drug Ferro-Grad 500 (Filmtabs) Vitron C Ferro DSS/Ferro-Sequel DOSS (mg) 0 0 100 Vitamin C (mg) 500 125 0 DOSS, dioctyl sodium sulfosuccinate; docusate sodium; Fe, iron. Fe++ Content (mg) 105 66 50 Causes for failure to respond to oral iron therapy Patient is not taking the medication Medication is being taken but is not being absorbed Diagnosis is incorrect Coexisting disease interfering with marrow response Continued blood loss or need in excess of iron dose Causes for failure to respond to oral iron therapy Coexisting disease interfering with marrow response Infection Inflammatory disorder (eg, rheumatoid arthritis) Concomitant malignancy Coexisting folic acid &/or vitamin B12 deficiency Bone marrow suppression from another cause Diagnosis is incorrect, possible correct diagnoses include Thalassemia Lead poisoning Anemia of chronic disease (anemia of chronic inflammation) Copper deficiency (zinc toxicity) Myelodysplastic syndrome/refractory sideroblastic anemia Patient is not taking the medication Prescription has not been filled Prescription has been filled but patient is no longer taking the medication Causes for failure to respond to oral iron therapy Medication is being taken but is not being absorbed Rapid intestinal transport bypasses area of maximum absorption Enteric coated product: coating is not dissolving Patient has malabsorption for iron (eg, sprue, atrophic gastritis) Medication taken in association with an agent interfering with absorption (eg, antacids, tetracycline, tea) Continued blood loss or need in excess of iron dose ingested Cause of blood loss treatable (eg, bleeding peptic ulcer) Initiate appropriate treatment Cause of blood loss not treatable (eg, Osler Weber Rendu disease) or need cannot be met by oral iron preparation (eg, renal failure responding to erythropoietin) Switch patient to parenteral iron product Patient information Iron should be dispensed in childproof container. Oral iron therapy produces dark stools. Take iron on empty stomach because food, especially dairy products, decreases absorption by 40-50%. Gastric side effects occur in 5-20% of patients & include nausea, epigastric pain, constipation, abdominal cramps, & diarrhea. To minimize gastric intolerance, oral iron therapy can be initiated with single tablet of ferrous sulfate 325 mg/day; dose is increased by increments of 1 tablet per day Q 2-3 days until full therapeutic dose of ferrous sulfate, 325 mg TID daily, can be administered. Patients should be educated about potential drug interactions that can occur with iron therapy. Iron-drug interactions Parenteral Iron Therapy Parenteral iron therapy may be appropriate in: cases where patients are unable to tolerate oral formulation because of toxicities or compliance. those who have documented iron-deficiency anemia & have not responded to oral iron therapy (e.g., because of malabsorption) Iron can be given parenterally as: ferric gluconate (Ferrlecit), iron dextran (INFeD and Dexferrum), iron sucrose (Venofer). Iron dextran Can be administered undiluted IM or by very slow IV injection. Is commonly diluted in 250-1,000 mL 0.9% NaCl & administered by IV infusion. IV administration is preferred to IM administration when: muscle mass available for IM injection is limited; absorption from muscle is impaired (e.g., stasis, edema); uncontrolled bleeding is risk (e.g., secondary to hemophilia, thrombocytopenia, anticoagulation therapy); large doses are indicated for therapy. In few instances, IM iron dextran is preferred treatment (e.g., patients with limited IV access). Upper limit of each daily dose is based on patient's weight & should not be >100 mg/day. Iron dextran Z-track technique Avoid staining the skin IM iron dextran is absorbed in two phases 1st 72 hours, 60% of the dose is absorbed Remaining drug is absorbed over weeks to months. The response time is similar to that of oral iron therapy, Infusion rates of undiluted IV iron dextran Not exceed 50 mg (i.e., 1 mL) per minute. Infusions generally are given over 1 to 6 hours Ferric gluconate & iron sucrose Are FDA approved for treatment of IDA in patients undergoing chronic hemodialysis & receiving supplemental EPO. Iron requirements in these patients typically exceed 1-2 g → multiple doses of ferric gluconate & iron sucrose are needed to achieve total dose of iron. Ferric gluconate can be administered undiluted as slow IV injection (rate < 12.5 mg/minute) or as IV infusion (125 mg ferric gluconate in 100 mL 0.9% NaCl over 1 hour). Iron sucrose can be administered undiluted as slow IV injection (rate not to exceed 20 mg/minute) or as IV infusion (dilute in maximum of 100 mL 0.9% NaCl & infuse at rate of 100 mg over 15 minute). Calculation of parenteral iron dose Required information: Body weight (kilograms) = BW Hemoglobin concentration (g/dL) = Hgb Concentration of elemental iron in the parenteral product (mg/mL) = C* C* = Iron dextran: 50 mg/mL Iron sucrose: 20 mg/mL Ferric gluconate: 12.5 mg/mL Assumptions: Blood volume is 65 mL per kilogram Hemoglobin concentration to be corrected to 14.0 g/dL No additional iron to be given for repletion of body stores Intermediate calculations: Blood volume (dL) = 65 (mL/kg) x body weight (kg) ÷ 100 (mL/dL) Hemoglobin deficit (g/dL) = 14.0 - patient hemoglobin concentration Hemoglobin deficit (g) = hemoglobin deficit (g/dL) x blood volume (dL) Iron deficit (mg) = hemoglobin deficit (g) x 3.3 (mg Fe/g Hgb) Volume of parenteral iron product required (mL) = Iron deficit (mg) ÷ C(mg/mL) Final calculations: Hemoglobin iron deficit (mg) = BW x (14 - Hgb) x (2.145) Volume of product required (mL) = BW x (14 - Hgb) x (2.145) ÷ C Example: 60 kg woman with a hemoglobin concentration of 8 g/dL. Parenteral iron product is iron sucrose (C = 20 mg elemental iron/mL) Hemoglobin iron deficit = 60 x (14 - 8) x (2.145) = 772 mg iron Volume of iron sucrose needed = 60 x (14 - 8) x (2.145) ÷ 20 = 38.6 mL For iron dextran Side effects Anaphylactoid reactions can occur in <1% of patients treated with parenteral iron therapy.This reaction is more commonly associated with iron dextran than with ferric gluconate & iron sucrose. → 25-mg test dose of iron dextran should be given IM or by IV infusion over 5-10 minutes. If headache, chest pain, anxiety, or signs of hypotension are not experienced, remainder of dose can be administered parenterally. Nevertheless, delayed reactions (e.g., fever, urticaria, arthralgias, & lymphadenopathy) have occurred 24-48 hours after large doses of IV iron dextran & have lasted 3-7 days in 1-2% of patients. Test dose is not indicated for ferric gluconate & iron sucrose because of lower incidence of serious anaphylactoid reactions. Other side effects seen with parenteral iron agents include: hypotension, N&V, cramps, & diarrhea. Parenteral iron medications should not be mixed with (or added to) other medications or parenteral nutrition solutions for IV infusion. Transfusions Another form of treatment involves blood transfusions. The decision to manage anemia with blood transfusions is based on evaluation of risks & benefits. Transfusion of allogeneic blood is indicated in Acute situations of blood loss When hemodynamic support is needed. Blood transfusion in chronic anemia Can elevate Hb concentration in short term but does not address underlying disorder. In critically ill patients, risk of infection, length of stay, & economic cost increase with each unit of transfused packed RBCs. Guidelines for transfusion in perisurgical anemias suggest 6-8 g/dL of Hb as a threshold for treatment, with no benefit at levels >10 g/dL. Vitamin B12 & Folic Acid anemia Anemia from vitamin B12 or folic acid deficiency is treated effectively by replacing missing nutrient. Both folic acid & vitamin B12 are essential for erythrocyte production & maturation. Replacing these factors allows for normal DNA synthesis &, consequently, normal erythropoiesis. Role of Vitamin B12 and Folic Acid DHF, dihydrofolate; THF, tetrahydrofolate; 5-MTHF, 5-methyl-tetrahydrofolate; 5,10-MTHF, 5,10-methyl-tetrahydrofolate THF; Peripheral blood smear Peripheral smear shows marked macroovalocytosis in patient with vitamin B12 deficiency. Peripheral blood smear showing hypersegmented neutrophil (7 lobes) & macroovalocytes - pattern that can be seen with cobalamin or folate deficiency. Diagnosis As a first step, serum for determination of BOTH Cbl & folate concentrations should be obtained. If serum folate & Cbl concentrations are >4 ng/mL & >300 pg/mL, respectively, deficiencies of 2 vitamins are unlikely, & additional testing is not required. If above 2 tests are not in the ranges, next step should be evaluation of metabolites methylmalonate (MMA) & total homocysteine: If both test results are within normal range (ie, MMA 70- 270 nmol/L & total homocysteine 5-14 micromol/L), deficiency of both vitamins is ruled out. If concentrations of both metabolites are ↑, Cbl deficiency is confirmed, with sensitivity & specificity of 94 & 99 %, respectively. If MMA is normal & total homocysteine is ↑, folate deficiency is likely, with sensitivity & specificity of 86 & 99%, respectively. If diagnosis of Cbl &/or folate deficiency has been established, it is reasonable to determine, if possible, cause for deficiency in order to not overlook potentially treatable underlying condition Sprue, IBD, Pancreatic insufficiency, Medication Causes of vitamin B12 deficiency 3 major causes of vitamin B12 deficiency are: Inadequate intake, Malabsorption syndromes Inadequate utilization Gastric abnormalities Pernicious anemia Gastrectomy/Bariatric surgery Gastritis Autoimmune metaplastic atrophic gastritis Pancreatitis Pancreatic insufficiency Small bowel disease Malabsorption syndrome Ileal resection or bypass Crohn's disease Blind loops Agents that block absorption Neomycin Biguanides (eg, metformin) PPIs (eg, omeprazole) N2O inhibits methionine synthase Inherited transcobalamin II deficiency Diet Strict vegans Vegetarian diet in pregnancy HW: Medications that cause false decrease in vit. B12 level? use of oral contraceptives, folate deficiency, pregnancy, congenital deficiency of serum haptocorrins and multiple myeloma Schilling test – how is it done? 4 different stages to find cause of low vitamin B12 levels. Stage I: 2 doses of vitamin B12 (cobalamin) are given: small, first dose (a radioactive form of B12) by mouth → second, larger dose by shot 1 hour later →urine is collected over the next 24 hours → urine is checked to see if vitamin B12 is absorbing normally. If Stage I is abnormal, Stage II may be done 3 - 7 days later. Schilling test – how is it done? Stage II: Radioactive B12 is given along with intrinsic factor Stage II can tell whether low vitamin B12 levels are caused by problems in the stomach that prevent it from producing intrinsic factor. If Stage II test is abnormal, Stage III test is performed. Schilling test – how is it done? Stage III: Is done after taking antibiotics for 2 weeks. It can tell whether abnormal bacterial growth has caused low vitamin B12 levels. Stage IV: Determines whether low vitamin B12 levels are caused by problems with pancreas. Pancreatic enzymes are taken for three days, followed by a radioactive dose of vitamin B12. The test can be repeated with addition of missing factors (eg, intrinsic factor, pancreatic extract), or following the use of nonabsorbable antibiotics (blind loops &/or bacterial overgrowth present), or gluten-free diet (celiac disease). 4: One hour after the test dose, a 1000 µg "flushing" dose of non-radioactive B12 is given to saturate B12 binders (transcobalamines). 5: If present, bacteria in "blind loops" in the duodenum or jejunum preferentially utilize vitamin B12, allowing none to be available at the site of absorption. 1: One µg of radioactive crystalline B12 is taken orally. 2: Gastric acid and pepsin free vitamin B12 from food proteins (not required for crystalline form). B12 attaches to "R" binders (R). 3: Pancreatic proteases degrade the "R" binders, allowing formation of the B12-IF complex, the specific form absorbed by the terminal ileum. B12 is excreted in the urine B12/IF complex is absorbed by the terminal ileum Schilling test in various diseases Test Gastrectomy, pernicious anemia Celiac disease* Ileal Bacterial resection overgrowth or disease # Vitamin B12 Low Low Low Low/normal Low Vitamin B12 + intrinsic factor Normal Low Low Low/normal Low Vitamin B12 + antibiotics n/a Low Normal Low/normal Low Vitamin B12 + gluten-free diet n/a Normal n/a Low/normal Low Vitamin B12 + pancreatic enzymes n/a n/a n/a n/a Pancreatic insufficienc y Normal * The Schilling test may be normal in patients with celiac disease because the terminal ileum is frequently spared. n/a, these stages of the Schilling test are not needed for the disorder. # Results depend upon the length of resection or the extent of disease. Values will not normalize with >100 cm of resection. Values may normalize after treatment of active Crohn's disease. Vitamin B12 Vitamin B12 works closely with folate in synthesis of building blocks for DNA & RNA, is essential in maintaining integrity of neurologic system, plays role in fatty acid biosynthesis & energy production. It is water-soluble vitamin obtained exogenously by ingestion of meat, fish, poultry, dairy products & fortified cereals. Body stores range: 2-5 mg, of which ~half is in liver. Recommended daily allowance is 2 mcg in adults & 2.6 mcg in pregnant or breast-feeding women. Vitamin B12 deficiency takes several years to develop following vitamin deprivation because of efficient enterohepatic circulation of vitamin. Sources of Vitamin B12 Food Serving Size Amount (mcg) Beef liver, cooked 3 oz 60 Breakfast cereal, fortified (100%) 3/4 cup 6 Rainbow trout, cooked 3 oz 5.3 Sockeye salmon, cooked 3 oz 4.9 Beef, cooked 3 oz 2.1 Breakfast cereal, fortified (25%) 3/4 cup 1.5 Haddock, cooked 3 oz 1.2 Clams, breaded and fried 3/4 cup 1.1 Oysters, breaded and fried 6 pieces 1 Tuna, canned in water 3 oz 0.9 Milk 1 cup 0.9 Yogurt 8 oz 0.9 Vitamin B12 Parenteral vs. Oral use of parenteral cyanacobalamin is the most common method of vitamin B12 replacement because it may be more reliable & practical. Subcutaneous or intramuscular administration is appropriate. Vitamin B12 is absorbed completely following parenteral administration, whereas oral vitamin B12 is absorbed poorly via GI tract. use of parenteral vitamin B12 to treat megaloblastic anemia may circumvent need to perform Schilling test to diagnose lack of intrinsic factor. Nasal preparation? Nascobal: 500 mcg in one nostril once weekly Cyanocobalmin dosing regimen Typical cyanocobalmin dosing regimen is: 800-1000 mcg/day for 1-2 weeks, /followed by 100-1000 mcg/day every week until Hgb/Hct normalizes maintenance of 100-1000 mcg monthly for life. A number of dosing regimens exist. A number of oral vitamin B12 preparations are available, including many over-the-counter formulations. Cyanocobalmin dosing regimen A common oral dosing regimen is 1000-2000 mcg/day. If parenteral cyanocobalmin is used initially, oral vitamin B12 can be useful as maintenance therapy. Typically, response to therapy is quick. Neurologic symptoms & megaloblastic cells disappear within few days, & Hb levels ↑ after week of therapy. Cyanocobalmin dosing regimen Vitamin B12 generally is well tolerated & exhibits minimal adverse effects. Injection-site pain, pruritus, rash, & diarrhea have been reported. Drug interactions have been observed with omeprazole & ascorbic acid that ↓ oral absorption. N.B. Lexi: reveals no such interactions Causes of folic acid deficiency Nutritional deficiency Poor dietary intake Malabsorption Increased requirements Drugs (various mechanisms) Causes of folic acid deficiency Nutritional deficiency Substance abuse Alcoholism Poor dietary intake Overcooked foods Depressed patients Nursing homes Malabsorption Celiac disease (sprue) Inflammatory bowel disease Infiltrative bowel disease Short bowel syndrome Drugs (various mechanisms) Methotrexate Trimethoprim Ethanol Phenytoin (folate decr conc of phenytoin) Increased requirements Pregnancy, lactation Chronic hemolysis Exfoliative dermatitis Good sources of folate Food Serving Amount (mcg) Chicken liver 3.5 oz 770 Cereal 1/2 to 1 1/2 cups 100–400 Lentils, cooked 1/2 cup 180 Chickpeas 1/2 cup 141 Asparagus 1/2 cup 132 Spinach, cooked 1/2 cup 131 Black beans 1/2 cup 128 Pasta 2 oz 100–120 Kidney beans 1/2 cup 115 Lima beans 1/2 cup 78 White rice, cooked 3/4 cup 60 Tomato juice 1 cup 48 Brussels sprouts 1/2 cup 47 Orange 1 medium 47 Folic Acid When treating folic acid deficiency, initial daily dose of 1 mg/day by mouth typically is effective. Absorption of folic acid Generally is rapid & complete. However, patients with malabsorption syndromes may require larger doses (up to 5 mg/day). Onset of action Resolution of symptoms & reticulocytosis is prompt, occurring within days of commencing therapy. Hgb will start to rise after 2 weeks of therapy & may take 2 -4 months to resolve deficiency completely. Folic Acid If underlying deficiency is corrected, folic acid replacement can be discontinued. In cases where folic acid is consumed rapidly or absorbed poorly, chronic replacement may be required. Some nonspecific ADEs: allergic reactions, flushing, malaise, & rash. Folic acid has been reported to decrease phenytoin levels by inducing its metabolism. Anemia of Chronic Disease These chronic diseases can include cancer, chronic kidney diseases, & chronic inflammatory disorders. IDA vs. ACD ACD treatment In patients with anemia owing to cancer & chronic kidney disease, therapy with epoetin or darbepoetin can: decrease transfusion increase hemoglobin, improve quality of life. Old, now 10 Old, now no increase after 8-9 Management according to cause of anemia:If the cause of anemia is identified during evaluation, treat the underlying cause as indicated. If the likely cause of anemia is cancer-related inflammation and/or myelosuppressive chemotherapy: offer red blood cell transfusion to symptomatic patients (for example, sustained tachycardia) consider red blood cell transfusion for patients at high risk (with rapidly declining Hb due to recent chemotherapy or radiation) or those who are asymptomatic but with comorbidities (for example, cardiac disease) (Weak recommendation) consider an erythropoiesis-stimulating agent (ESA) in patients with non-myeloid malignancies receiving myelosuppressive therapy for noncurative intent (Weak recommendation) consider intravenous iron in patients with evidence of functional Red blood cell (RBC) transfusion consider a RBC transfusion for patients with cancer- and chemotherapy-induced anemia who are at high risk (for example, progressive decline in hemoglobin [Hb] with recent intensive chemotherapy or radiation) or asymptomatic with cardiac disease, chronic pulmonary disease or cerebrovascular disease (Weak recommendation) give a RBC transfusion to symptomatic patients with sustained tachycardia, tachypnea, chest pain, dyspnea on exertion, lightheadedness, syncope, or severe fatigue (Strong recommendation) http://www.dynamed.com/topics/dmp~AN~T909257/Anemia-of-cancer#sec-Overview-and-Recommendations Erythropoiesis-stimulating agent (ESA): while ESAs have been reported to increase hemoglobin and reduce transfusion requirements in many patients with chemotherapy-associated anemia, they are associated with increased risk of thromboembolism, tumor progression and mortality; thus their use has been significantly reduced consider in patients (Weak recommendation): with Hb < 10 g/dL receiving myelosuppressive therapy for noncurative intent without other identifiable causes of anemia, depending on patient preferences undergoing palliative treatment, depending on patient preferences who refuse blood transfusions http://www.dynamed.com/topics/dmp~AN~T909257/Anemia-of-cancer#sec-Overview-and-Recommendations Erythropoiesis-stimulating agent (ESA): contraindications include patients (Weak recommendation): with cancer not receiving therapy (an exception is patients with low-risk myelodysplastic syndrome) receiving nonmyelosuppressive therapy receiving myelosuppressive chemotherapy with curative intent ESAs should be administered following Risk Evaluation and Mitigation Strategy guidelines and include informed consent of patient. target Hb is uncertain, but consider using lowest possible dose needed to avoid transfusions. epoetin and darbepoetin are considered comparable in efficacy and safety profile. http://www.dynamed.com/topics/dmp~AN~T909257/Anemia-of-cancer#sec-Overview-and-Recommendations Package Insert Dosing Schedule for ESAs and FDA Recommendations for Dose Modifications http://www.dynamed.com/topics/dmp~AN~T909257/Anemia-of-cancer#sec-Overview-and-Recommendations Package Insert Dosing Schedule for ESAs and FDA Recommendations for Dose Modifications http://www.dynamed.com/topics/dmp~AN~T909257/Anemia-of-cancer#sec-Overview-and-Recommendations Package Insert Dosing Schedule for ESAs and FDA Recommendations for Dose Modifications alternative ESA dosing regimens may also be considered discontinue ESA therapy if after 8-9 weeks of therapy, there is no response (measured by Hb levels or need for transfusion), or when chemotherapy is discontinued Guidance from professional organizations regarding use of IV iron is conflicting, but consider in patients who are taking erythropoiesis stimulating agents (ESAs) with evidence of functional iron deficiency (Weak recommendation). http://www.dynamed.com/topics/dmp~AN~T909257/Anemia-of-cancer#sec-Overview-and-Recommendations Anemia of Critical Illness •Patients with anemia of critical illness require necessary substrates of iron, folic acid, &vitamin B12 for RBC production. •Parenteral iron is generally preferred in this population because •EPO •RBC transfusions Anemia of Critical Illness •Patients with anemia of critical illness require necessary substrates of iron, folic acid, &vitamin B12 for RBC production. •Because iron stores usually are insufficient to meet physiologic demands, administration of supplemental iron is necessary to support erythropoiesis. •Parenteral iron is generally preferred in this population because • patients often are undergoing enteral therapy or • because of concerns regarding inadequate iron absorption. •Pharmacologic doses of EPO have been used to treat anemia of critical illness. •Many critically ill patients receive RBC transfusions despite inherent risks associated with transfusions. Anemia in Elderly •Although incidence of anemia is high in elderly, anemia should not be regarded as inevitable outcome of aging because underlying cause can be identified in ~2/3 of patients. •Undiagnosed & untreated anemia can have severe ramifications. •Depending on cause of the anemia, treatment in elderly is same as that described for each type of anemia. Anemia in Pediatric Population •IDA is leading cause of infant morbidity & mortality around the world. •Primary prevention of IDA in infants, children, & adolescents is the most appropriate goal because delays in mental & motor development are potentially irreversible. •Interventions likely to prevent anemia include diverse foods with bioavailable forms of iron, food fortification for infants & children, & individual supplementation. •Anemia of prematurity is frequently treated with RBC transfusions. EPO may be used to treat anemia of prematurity, but it is important to note that EPO pharmacokinetics differs depending on developmental age of infant. Use of EPO is controversial because it has not been shown to clearly reduce transfusion requirements TC: transcobalamine; Cbl: cobalamine; MeCbl:methcobalamine; Ado-Cbl: Adenosine cobalamine