10 22 - Anti-Anemia Drugs PDF

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Anti-Anemia Drugs...

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Anti-Anemia Drugs Anemia ● Decrease in the number, size, or hemoglobin content of erythrocytes (RBCs) ● Causes Include ○ Deficiencies of substances essential for RBC formation and maturation ■ Iron ■ Folic acid ■ Vitamin B12 ○ Blood loss ○ Hemolysis ○ Bone marrow dysfunction Red Blood Cells - Requirements for Development 1. Iron 2. Folic acid 3. Vitamine B12 4. Healthy bone marrow 5. Erythropoietin (blood cell development) 6. Granulocyte colony stimulating factor (G-CSF) 7. Megakaryocyte GF 8. Thrombopoietin receptor agonists Iron ● ● ●

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Dietary sources = meats, leafy greens, grains, egg yolks 100-160 mg/dL for healthy level Regulation ○ Excess Fe supply = increase ferritin, decreased transferrin receptor ■ Ferritin protects cells against excessive Fe2+ ○ Low Fe supply = decrease ferritin, increase transferrin receptor ■ Takes up iron directly into cell ○ With anemia, can absorb up to 60% of a Fe supplement Elimination ○ No mechanism for excretion ○ Trace amounts (1mg/day) in bile, urine, sweat, intestinal cells

Iron Supplement Absorption

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Iron is absorbed under acidic conditions Stored in mucosal cells 70% sent to RBCs, some to liver

Iron Deficient Anemia ● Reduced oxygen-carrying capacity ● Microcytic and hypochromic (small and pale) erythrocytes ○ Diagnostic criteria ● Absence of hemosiderin (aggregated ferritin) in bone marrow ● Increased iron binding capacity (IBC) ○ Examine serum levels of ferritin and transferrin saturation Iron Preparations - Oral ● Dietary sources ○ Meats ○ Green leafy veggies ○ Grains ○ Beans ○ Egg yolks ● Multiple administrations / day of salts for steady state availability (% elemental) ○ Ferrous fumarate = Femiron; 33% bioavailability ■ 120 mg/d of elemental iron x 33% bioavailability = 360 mg/d ferrous fumarate (this dose is for anemic patients) ■ 200mg/d elemental iron for severe conditions ○ Ferrous sulfate (anhydrous); 30% ○ Ferrous sulfate (hydrated); 20% ○ Ferrous gluconate = Fergon; 12% ○ Sulfates cost less and have equal efficacy and tolerability

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Elemental Iron ○ Carbonyl iron (Feosol) (Fe) ■ Micronized ■ Distributes much smaller so it stays 100% iron ○ Steady bioavailability ○ Reduced likelihood of toxicity ○ Expensive ○ Very corrosive - must be encapsulated in some kind of glucose to not cause GI irritation

Ferrous Oral preparations are absorbed the same way

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Follows the same absorption and metabolism and Iron Supplements Must be absorbed under acidic conditions!!!

Side Effects - Oral Iron ● Oral formulations are safer than parenteral ● GI Irritation - most common ○ Nausea ○ Constipation ○ Stomach / abdominal pain ○ Black, red, tarry stool ○ Vomiting ○ Diarrhea ● Stains teeth ● Lowering dose usually relieves these conditions Iron Preparations - Parenteral ● Used for those who GI irritation is too severe ● Usually administered at a clinical ● Iron Dextran = DexFerrum, INFeD ○ IV or IM ○ Iron deficient anemia when oral formulation is contraindicated

○ Requires 3-10 doses Iron Sucrose = Venofer ○ IV ○ Chronic kidney disease (CKD) dialysis ■ Kidneys generate protein that makes RBCs ○ Requires 3-10 doses ● Sodium-Ferric Gluconate Complex (Ferrlecit) ○ IV ○ CKD Dialysis ○ Requires 3-10 doses ● Ferumoxytol = Feraheme ○ Only requires 2 doses ○ Lasts 3 months ○ Rapid IV infusion ○ CKD ○ Superparamagnetic form of iron oxide ○ Convenient because it requires only 2 doses Side Effects - Parenteral ● Pain upon injection ● Hypotension ○ Sodium ferric gluconate complex (common) ○ Iron dextran (common) ○ Iron sucrose (36%) ○ Ferumoxytol (2%) ● Anaphylactic reactions ○ Iron dextran ●

Iron Preparations Interactions

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Meals, antacids, proton pump inhibitors - decrease acidity, reduce absorption Quinolone antibiotics - chelates to (metal) iron preparations, iron will decrease the absorption of the antibiotic

Toxicity ● Corrosive effects on GI mucosa ● Severe - coma, shock, seizures ● TREATMENTS ○ Deferoxamine - IV; chelation therapy-iron overdose and chronic iron overload) ○ Deferasirox - Oral; chelation therapy-chronic iron overload ○ Carbonate (CO32-) - stomach lavage; iron overdose

Folic Acid Folic Acid, and then you need vitamin B12 to activate Folic Acid ● Sources

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Liver Green veggies Yeast Ruts Cereals

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Fruit Folates are present in food in the form of reduced polyglutamates (5-CH3-folate)

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Absorption, elimination, metabolism

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All but one of the glutamates is removed before absorption Absorption occurs in the mucosal cells in the upper portion of the jejunum and duodenum The glutamates are then added back inside the tissue Folic acid is metabolized in the liver Reabsorbed by the gut ■ Enterohepatic Cycle Excreted in significant amounts every day, so it's important to supplement daily

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5-methyltetrahydrofolate(INACTIVE) is reduced to tetrahydrofolate (ACTIVE) via a series of reactions Chemotherapy drug methotrexate prevents the conversion of folic acid to its active form; cancer patients using this drug will have a folic acid deficiency

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Cont...

○ Folic acid (inactive) --B12→ Folic acid (active) → DNA synthesis → normal erythrocyte maturation ●

Coenzyme THF is active in the transfer of one-carbon units

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Conversion of homocysteine to methionine ■ Too much homocysteine is a CV disease risk

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Conversion of serine to glycine Synthesis of thymidylate Histidine metabolism Synthesis of purines Utilization or generation of formate

Folic Acid Indications ● Megaloblastic or macrocytic anemia (folic acid and B12 deficiencies) ○ Disruption of DNA synthesis to cells undergoing growth and division in bone marrow ○ Megaloblasts - oversized erythroblasts in bone marrow ○ Macrocytes - oversized erythrocytes in blood ● Renal dialysis patients where folates are removed from the plasma during dialysis ● Folic acid deficiency ● Prophylaxis of folate deficiency ○ Especially before and during pregnancy and lactation ○ Maternal folic acid deficiency is implicated with fetal neural tube defects such as spina bifida

Folic Acid Deficiency ● Drugs that inhibit dihydrofolate reductase ○ Methotrexate ● Drugs that interfere with absorption and storage of folate in tissues ○ Long term therapy with antiseizure drugs like phenytoin ● Treatment ○ Inactive - folate; pteroylglutamic acid; folic acid ■ Active after absorption ○ Active - leucovorin calcium; folinic acid; citrovorum factor ■ Used mainly to circumvent inhibitors of dihydrofolate reductase like methotrexate (cancer) ○ Oral folic acid is well absorbed and has no known toxic effect for short term therapy in large dose (15 mg/day) ■ Risk of colorectal, lung, and prostate cancer for long term therapy (1 mg/d) ■ Does not alleviate neurological defects of vitamin B12 deficiency

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Vitamin B12 deficiency - lifelong problems

Vitamin B12 ● A group of compounds with similar structures that contain an atom of cobalt (thus called cobalamins) ○ All drugs have a cobalamin root ● Important for conversion of folic acid into its ACTIVE form ● Essential for DNA synthesis ○ Cobalamin converts methyltetrahydrofolate to THF ○ Folic acid (inactive dietary form) --B12→ folic acid (active) → DNA Synthesis → normal cell growth, maturation, division ● Anemia ○ Deficiencies will cause anemia similar to that seen in folic acid deficiencies

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Some deficiencies caused by low levels of intrinsic factor, meaning B12 can’t be absorbed

B12 Deficiency

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Impaired absorption ○ Enteritis ○ Celiac disease ○ Frequently: atrophy of parietal cells or surgery on stomach (total or partial gastrectomy ○ Antibodies directed against intrinsic factor - pernicious anemia ■ This is when you would have to take an injection preparation ○ Bacterial overgrowth in the stomach ○ Fish tapeworm ● Rare - diet deficiency ○ Strict vegetarian for years ● Disruption of DNA synthesis ○ Cells undergoing growth and division in bone marrow and epithelial cells lining the mouth and GI tract ● Megaloblastic or macrocytic anemia ○ Megaloblasts - oversized erythroblasts in bone marrow ○ Macrocytes - oversized erythrocytes in blood ● Disruption of epithelial cell growth ○ Oral ulceration and GI tract disturbances ● Disruption hematopoiesis (white blood cells) ○ Infections and spontaneous bleeding ● Peripheral and cerebral hypoxia - neurological damage ○ Heart failure and dysrhythmias (cause of death) The role of Vitamin B12 and folic acid in central nervous system degeneration and megaloblastic anemia

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Disruption of the upper signaling cascade could be related to the neurological problems Build up of abnormal fatty acids, which gets incorporated into CNS cell membranes and can disrupt neuronal signaling

Vitamin B12 preparations ● Cyanocobalamin ○ Most preferred preparation ○ Oral, if normal absorption

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○ If absorption is impaired, you would take it as an injection ○ Mega doses 1-10 mg/d ○ Passive diffusion ○ If impaired absorption, doses must be high ○ Rare anaphylaxis reaction ○ New erythrocytes require potassium for development, thus hypokalemia may result Hydroxocobalamin ○ IM ○ This preparation is more highly protein bound and may remain longer in circulation ○ But usage has resulted in the occasional development of antibodies against transcobalamin II-vitamin B12 complex Intranasal Vitamin B12 (Cyanocobalamin - Nascobal) ○ 500 mcg once/week ○ Unsure about how allergies influence concentrations ○ Good for bypassing GI

Hematopoietic Growth Factors 1. What stimulates erythrocyte production in patients with chronic renal failure or for autologous blood transfusion? 2. What accelerates neutrophil repopulation after cancer chemotherapy and bone marrow transplantation? 3. What accelerates platelet repopulation in patients with thrombocytopenia? 4. What accelerates platelet repopulation after cancer chemotherapy? 5. What accelerates bone marrow recovery after autologous bone marrow transplantation? Hematopoietic Growth Factors cont ● Accelerate neutrophil and platelet repopulation after cancer chemotherapy ● Accelerate bone marrow recovery after autologous bone marrow transplantation (BMT) ● Stimulate erythrocyte production in a patient with chronic renal failure

Is there a way to stimulate erythrocyte production in patients with chronic renal failure or for autologous blood transfusion?

HGF cont ● Glycoproteins (cytokines) ○ Regulate the proliferation and differentiation of hematopoietic progenitor cells in the bone marrow ○ Recombinant DNA technology ● Taken IV or SC ● Not taken orally BC proteins will be degraded in GI Erythropoiesis Stimulating Agents (ESA)

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Stimulate production of RBCs GOAL - increase hemoglobin to 10-11 gm/dL Erythropoietin (Epo) ○ Produced in the kidney in response to tissue hypoxia ○ First human hematopoietic growth factor to be isolated ○ Stimulates increase in RBCs

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