Pharmacology of Drugs for Iron Deficiency & Anemia PDF

Pharmacology of Drugs effective in iron Deficiency and other anemias  Learning Objectives Describe the classification, indications, dose, formulations, adverse effects, contraindications and interactions of drugs effective in iron deficiency and other anemias Explain the mecha...

Pharmacology of Drugs effective in iron Deficiency and other anemias  Learning Objectives Describe the classification, indications, dose, formulations, adverse effects, contraindications and interactions of drugs effective in iron deficiency and other anemias Explain the mechanism of action of drugs effective in iron deficiency and other anemias Identify trade and generic names of drugs effective in iron deficiency and other anemias  Learning Objective At the end of this session you will be able to Explain pharmacology of medicines used in treatment of Anemia Describe medical use of hematopoietic growth factors  Introduction Hematopoiesis the production of erythrocytes, platelets, and leukocytes from undifferentiated stem cells produces over 200 billion new blood cells per day in the normal person and even greater numbers of cells in people with conditions that cause loss or destruction of blood cells.  Introduction… Hematopoiesis: The production from undifferentiated stem cells of circulating erythrocytes, platelets, and leukocytes Essential factors: Iron, vitamin B 12, folic acid and hematopoietic growth factors Inadequate supply results in: Anemia, thrombocytopenia and neutropenia 2  Pathophysiology- Classification Macrocytic cells (larger) are associated with deficiencies of vitamin B12 or folate. Microcytic cells (smaller) associated with iron deficiency Normocytic anemia associated with recent blood loss or chronic disease. Iron-deficiency anemia caused by inadequate dietary intake, inadequate GI absorption, increased iron demand (e.g., pregnancy), blood loss, and chronic diseases. Common Classes of Hemolytic Anemias  Anemia? Production? Survival/Destruction? 12  Pathophysiology (Cont’d) Basically, only three causes of anemia exist: blood loss, increased destruction of RBCs (hemolysis), and decreased production of RBCs.  Underproduction Normocytic Microcytic Anemia of chronic Iron deficiency disease Thal. trait Mixed deficiencies Anemia of chronic disease (30-40%) Renal failure sideroblastic anemias  Etiology Genetic Infectious Nutritional Immunologic Physical Drugs Chronic disease Idiosyncratic  Etiology (Cont’d) Drugs or chemicals commonly cause the aplastic and hypoplastic group of disorders. Certain types of these causative agents are dose related and others are idiosyncratic. Any human exposed to a sufficient dose of inorganic arsenic, benzene, radiation, or the usual chemotherapeutic agents used for treatment of neoplastic diseases develops bone marrow depression with pancytopenia.  Etiology (Cont’d) Drugs can cause anemia by reducing absorption of folate (e.g., phenytoin) or By interfering with corresponding metabolic pathways (e.g., methotrexate). Some drugs and chemicals that may cause haemolysis in glucose-6-phosphate dehydrogenase deficient individuals  Etiology (Cont’d) The idiosyncratic causes of bone marrow suppression include multiple drugs in each of the categories that can be prefixed with anti- (eg, antibiotics, antimicrobials, anticonvulsants, antihistamines). The other idiosyncratic causes of known etiology are viral hepatitis and paroxysmal nocturnal hemoglobinuria. In approximately one half of patients presenting with aplastic anemia, a definite etiology cannot be established, and the anemia must be regarded as idiopathic.  Desired Outcome The ultimate goals of treatment in the anemic patient are to alleviate signs and symptoms, correct the underlying etiology (e.g., restore substrates needed for RBC production), and prevent recurrence of anemia.  Treatment 1. Nutritional Therapy and Dietary Considerations Treatment of A. Iron Supplementation B. Vitamin B12 Supplementation infections, inflammations or C. Folic acid supplementation malignancies 2. Nutritional Supplements A. Iron B. Vitamins C. Folic Acid 3. Transfusions Blood and/or blood products- PRBCS, FFP, Cryoprecipitate, Platelets  1. Nutritional and Dietary Considerations Nutritional therapy is used to treat deficiencies of iron, vitamin B-12, and folic acid. Pyridoxine may be useful in the treatment of certain patients with sideroblastic anemia, even though this is not a deficiency disorder. A strict vegetarian diet requires iron and vitamin B-12 supplementation.  Iron Supplementation Recommended Daily Allowance (Elemental Iron) Adult Pediatric 19-50 years 0-6 months: 0.27 mg/day Males: 8 mg/day 6-12 months: 11 mg/day Females: 18 mg/day 1-3 years: 7 mg/day Pregnant females: 27 mg/day 3-8 years: 10 mg/day Lactating females: 9 mg/day 8-13 years: 8 mg/day >50 years >13 years 8 mg/day Males: 11 mg/day Females: 15 mg/day  Iron Supplementation (Cont’d) Good sources of Iron  Vitamin B12 Supplementation Recommended daily allowance (RDA) Adult Pediatrics >19 years: 2.4 mcg 0-6 months: 0.4 mcg Pregnant women: 2.6 mcg 7-12 months: 0.5 mcg Breastfeeding women: 2.8 mcg 1-3 years: 0.9 mcg Dietary supplement: 50-6,000 4-8 years: 1.2 mcg mcg/day 9-13 years: 1.8 mcg >14 years: 2.4 mcg Vitamin B12 Supplementation (Cont’d) Good sources of Vitamin B12  Folic acid supplementation Recommended daily allowance (RDA)- Pediatric Adult 0-6 months: 65 mcg/day PO Males: 400 mcg/day PO 7-12 months: 80 mcg/day PO Females: 400-800 mcg/day PO 1-4 years: 150 mcg/day PO Pregnant women: 600 mcg/day PO 4-9 years: 200 mcg/day PO 9-14 years: 300 mcg/day PO Nursing women: 500 mcg/day PO 14-18 years: 400 mcg/day PO Upper limit: 1 mg/day PO Upper limit: 1-4 years, 300 mcg/day PO; 4-8 years, 400 mcg/day PO Folic acid supplementation (Cont’d) Good sources of folate  2. Nutritional supplements Nutritional supplements include supplementation of Iron Vitamins Folic acid IRON Pharmacokinetics of Iron: Absorption, traansport, and storage of iron  Pharmacokinetics of Iron … Iron sources to support hematopoiesis: catalysis of the hemoglobin in senescent or damaged erythrocytes dietary iron from a wide variety of foods iron requirements can exceed normal dietary supplies in growing children and pregnant women (increased iron requirements) menstruating women (increased losses of iron)  Pharmacokinetics of Iron Absorption 0.5-1 mg/d iron from food by a normal individual 1-2 mg/d in normal menstruating women 3-4 mg/d in pregnant women The iron in meat (heme iron) can be efficiently absorbed Nonheme iron in foods must be reduced to ferrous iron (Fe 2+ ) before it can be absorbed  Pharmacokinetics of Iron … Transport Iron is transported in the plasma bound to transferrin The transferrin-iron complex enters maturing erythroid cells by receptor-mediated endocytosis iron deficiency anemia is associated with an increased concentration of serum transferrin  Pharmacokinetics of Iron … Storage primarily as ferritin in intestinal mucosal cells, macrophages in the liver, spleen, and bone and in parenchymal liver cells the serum ferritin level can be used to estimate total body iron stores Apoferritin (precursor of ferritin) levels is regulated by the levels of free iron ↓ free iron → ↓ apoferritin → ↑ iron binding to transferrin ↑ free iron → ↑ apoferritin → protection of organs from the iron toxic effects  Pharmacokinetics of Iron … Elimination no mechanism for excretion of iron: regulation of iron balance must be achieved by changing intestinal absorption and storage of iron, in response to the body's needs Some factors influencing iron absorption from the gut  Iron Supplementation-Iron products Two types of supplementation Oral iron therapy Parenteral iron therapy  Oral iron therapy Only ferrous salts should be used Ferrous sulfate, ferrous gluconate and ferrous fumarate – Different iron salts provide different amounts of elemental iron Ferrous fumarate> Ferrous sulfate>ferrous gluconate 200-400 mg/d of elemental iron corrects iron deficiency most rapidly 13 Oral Iron Products  Oral Iron Therapy Safer, more convenient, and less expensive than parenteral therapy. Oral iron preparations are salt forms, which vary in elemental iron content, cost, and effectiveness. Iron absorption from ferrous salts is considered better than that from ferric salts. The dosage of the iron product is based on the elemental iron content.  Oral Iron Therapy (Cont’d) Dosing In general, 30 to 40 mg daily elemental iron is used to treat iron deficiency states Since only 10% to 20% of iron is absorbed, 200 to 400 mg of iron would result in absorption of approximately 40 mg elemental iron.  Oral Iron Therapy (Cont’d) Ferrous sulfate tablets contain 20% elemental iron (60 mg iron per 300-mg tablet). The standard dosing of ferrous sulfate is 300 mg three times a day, which provides 180 mg of elemental iron per day. Assuming 20% absorption, only about 40mg of elemental iron will be absorbed.  Oral Iron Therapy (Cont’d) Absorption Maximum absorption occurs if iron is taken before or between meals. Diet plays a significant role because iron is poorly absorbed from vegetables, grain products, dairy products, and eggs; iron is best absorbed from meat, fish, and poultry. Administration of iron therapy with a meal decreases absorption by more than 50% but may be needed to improve tolerability.  Oral Iron Therapy (Cont’d) Absorption… reduced in patients with reduced gastric acid production or prior gastrointestinal surgeries.  Oral iron absorption test When an inability to absorb iron is suspected, an oral iron absorption test should be administered. administering an oral bolus dose of 325 mg ferrous sulfate (65 mg elemental iron) and measuring the serum iron level 2 and 4 hours later. The serum iron level should rise by 21 to 23 μmol per liter (115–128 μg/dL). Failure to attain this response generally indicates decreased absorption.  Oral Iron Therapy (Cont’d) Drug interaction Antacids, histamine-2 blockers, and proton pump inhibitors may also decrease iron absorption  Oral iron therapy… Common adverse effects: nausea, epigastric discomfort, abdominal cramps, constipation, and diarrhea Adverse effects can often be overcome by lowering the daily dose of iron taking the tablets immediately after or with meals Changing from one iron salt to another Patients taking oral iron develop black stools This may obscure the diagnosis of continued gastrointestinal blood loss  Oral Iron Therapy (Cont’d) Side effects… Use of enteric-coated products to minimize gastrointestinal effects is not recommended because the coating prevents dissolution in the stomach, thus minimizing iron absorption. Iron therapy can cause the stools to appear black. Patients should be educated about differences between stool changes from iron and those associated with gastrointestinal bleeding.  Oral Iron Therapy (Cont’d) Iron salt drug interaction A careful medication history should be obtained to check for potential drug interactions before an absorption test or parenteral therapy is initiated  Ferrous gluconate Ferrous gluconate, 325mg P.O. (39mg elemental iron), 1- 2tabs, TID  Ferrous fumarate Ferrous fumarate, 325mg P.O., (107 elemental iron), one tab, daily to twice per day Ferrous fumarate…  Parenteral iron therapy Oral iron may be inadequate in patients who are intolerant to oral iron, noncompliant, have abnormal absorption due to surgery or gastrointestinal conditions, or significant blood loss. Parenteral iron may be necessary in these patients. Parenteral administration, however, does not hasten the onset of hematologic response. The replacement dose depends on etiology of anemia and Hb concentration  Parenteral iron therapy… Parenteral therapy should be reserved for patients unable to tolerate or absorb oral iron patients with extensive chronic blood loss who cannot be maintained with oral iron alone: advanced chronic renal disease including hemodialysis and treatment with erythropoietin Parenteral Iron Preparations  Iron Dextran is a complex of ferric hydroxide and dextran.  Iron Dextran… Dextran products There are two iron dextran products available, which differ in their molecular weight (Dex- ferrum, molecular weight = 265,000; INFeD, molecular weight = 96,000). There does not appear to be any therapeutic advantage with using a higher molecular weight iron dextran preparation, however, the incidence of adverse events appears to be greater compared to the lower molecular weight iron dextran product  Iron Dextran… Action Iron dextran complex replenishes depleted iron stores in the bone marrow, where it is incorporated into hemoglobin. Following administration, the iron dextran complex is separated by the reticuloendothelial system. The iron that is released then binds to transferrin for transport to the liver, spleen, and bone marrow.  Acute Iron Toxicity Seen almost exclusively in young children who accidentally ingest iron tablets Even 10 tablets can be lethal in young children Adult patients should be instructed to store tablets out of the reach of children Manifestations: necrotizing gastroenteritis Vomiting abdominal pain bloody diarrhea Severe metabolic acidosis Coma and death  Acute Iron Toxicity Urgent treatment is necessary Whole bowel irrigation should be performed  Acute Iron Toxicity…. Deferoxamine, a potent iron-chelating compound, can be given systemically to bind iron that has already been absorbed and to promote its excretion in urine and feces  Chronic Iron Toxicity Also known as iron overload or hemochromatosis excess iron is deposited in the heart, liver, pancreas, and other organs It can lead to organ failure and death occurs in patients with inherited hemochromatosis (a disorder characterized by excessive iron absorption) patients who receive many red cell transfusions over a long period of time (e.g. patients with thalassemia major)  Chronic Iron Toxicity In the absence of anemia is treated by intermittent phlebotomy Parenteral deferoxamine is much less efficient deferoxamine can be the only option for iron overload in patients with thalassemia major deferasirox (oral iron chelator) has been approved for treatment of iron overload Deferasirox appears to be as effective as deferoxamine at reducing liver iron concentrations and is much more convenient  Chronic Iron Toxicity Deferasirox (oral iron chelator) has been approved for treatment of iron overload Vitamin B 12  Vitamins Vitamins are used to meet necessary dietary requirements and are used in metabolic pathways, as well as DNA and protein synthesis. Cyanocobalamin (vitamin B12) and folic acid are used to treat megaloblastic and macrocytic anemias secondary to deficiency. Both vitamin B12 and folic acid are required for synthesis of purine nucleotides and metabolism of some amino acids. Each is essential for normal growth and replication.  Vitamin B 12 Vitamin B 12 serves as a cofactor for several essential biochemical reactions in humans Deficiency of vitamin B 12 leads to anemia gastrointestinal symptoms neurologic abnormalities Most common cause of B 12 deficiency: inadequate absorption of dietary vitamin B 12 especially in older adults Active forms of the vitamin in humans: Deoxyadenosylcobalamin Methylcobalamin  VITAMIN B12 supplementation Two types of Vitamin B12 supplementation Oral Vitamin B12 Parenteral vitamin B12  VITAMIN B12 supplementation Oral vitamin B12 supplementation appears to be as effective as parenteral, even in patients with pernicious anemia, because the alternate vitamin B12 absorption pathway is independent of intrinsic factor. Oral cobalamin is initiated at 1 to 2 mg daily for 1 to 2 weeks, followed by 1 mg daily. Parenteral therapy is more rapid acting than oral therapy and should be used if neurologic symptoms are present. A popular regimen is cyanocobalamin 1,000 mcg daily for 1 week, then weekly for 1 month, and then monthly. When symptoms resolve, daily oral administration can be initiated. Adverse events are rare with vitamin B12 therapy.  Oral Vitamin B12 Therapy Preferred when B12 absorption is normal but there is dietary deficiency (e.g., strict vegetarian or restricted diets), oral B12 therapy is the preferred route. Oral B12 therapy may also be used to treat some drug-induced B12 deficiencies (e.g., nitrous oxide). Oral cyanocobalamin is well absorbed with peak serum concentrations being reached 8 to 12 hours after ingestion.  Oral Vitamin B12 Therapy (Cont’d) Absorption 1% of an oral dose of B12 can be absorbed by a nonspecific, non– IF-dependent process, so large oral dosages may provide sufficient B12 to correct the deficiency, replenish stores, and resolve symptoms. Oral cyanocobalamin is well absorbed with peak serum concentrations being reached 8 to 12 hours after ingestion.  Parenteral Vitamin B12 Therapy Treatment of vitamin B 12 deficiency Parenteral injections of vitamin B 12 are required for therapy Vitamin B 12 for parenteral injection is available as cyanocobalamin or hydroxocobalamin  Parenteral Vitamin B12 Therapy Because of the safety of these agents, dosages of 100 to 1,000 μg of B12 can be given. Dosages under 15 μg generally are insufficient to completely correct the later stages of B12 deficiency. All regimens use more frequent dosing initially to correct the deficiency, followed by injections every 1 to 3 months, based on the patient's response, for life. Summary of Various Parenteral B12 Regimens  Parenteral Vitamin B12 Therapy B12 generally is administered intramuscularly, although subcutaneous injection also can be used. Peak serum concentrations after intramuscular injection are reached in about 1 hour. The half-life of the parenteral B12 is about 6 days; its half-life in the liver is 400 days. With impaired liver or kidney function, more frequent dosing is necessary.  Parenteral Vitamin B12 Therapy Two synthetic forms of B12 are available: cyanocobalamin and hydroxocobalamin. After intramuscular administration, cyanocobalamin appears to be excreted more rapidly than hydroxocobalamin, which is more highly protein bound. Therefore, hydroxocobalamin may allow less frequent dosing (every 3 months) during maintenance therapy. Indications for both of these agents are similar, although hydroxocobalamin may be preferred for treating B12 deficiencies because optic neuropathies may worsen with cyanocobalamin administration. Cyanocobalamin ( Calo-Mist, Ener-B, Nascobal)  Cyanocobalamin… Deoxyadenosylcobalamin and hydroxocobalamin are active forms of vitamin B12 in humans. Available as Injection, 100 mcg/ml, 1000 mcg/ml in 1 ml ampoule Indications: treatment of pernicious anemia; vitamin B deficiency; increased B12 12 requirements due to pregnancy, thyrotoxicosis, hemorrhage, malignancy, liver or kidney disease.  Cyanocobalamin – Adult dose B12 Deficiency Initial: 30 mcg IM once daily for 5-10 days Maintenance: 100-200 mcg IM monthly Nasal dose: 500 mcg once weekly  Cyanocobalamin – Adult dose Pernicious Anemia Manufacturer recommendation: 100 mcg IM/SC once daily for 6-7 days, then every other day for 7 doses, then every 3-4 days for 2-3 weeks, then monthly Alternative parenteral dosing: 1000 mcg IM/SC once daily for 7 days, then weekly for 1 month, then monthly Nasal spray: 500 mcg (1 spray in 1 nostril) weekly; if patient is taking hot meals, spray should be administered 1 hour before or after meal  Cyanocobalamin – Pediatric dose Pernicious Anemia 30-50 mcg IM/SC once daily for &ge2 weeks for total dose of 1,000 mcg to 5,000 mcg administer concomitantly with 1 mg/day of folic acid for 1 month Maintenance: 100 mcg IM/SC monthly B12 Deficiency 0.2 mcg/kg for 2 days; follow by 1,000 mcg/day for 2-7 days; follow by 100 mcg/day for 2-7 days; then 100 mcg/week for 1 month Maintenance: 100 mcg IM/SC monthly Hydroxocobalamin  Hydroxocobalamin… Hydroxocobalamin is preferred because it is more tightly protein-bound Initial therapy: 100-1000 mcg of vitamin B 12 IM daily or every other day for 1-2 weeks to replenish body stores Maintenance therapy: 100-1000 mcg IM once a month for life 34 Folic acid  Folic acid Reduced forms of folic acid are required for synthesis of amino acids, purines, and DNA The consequences of folate deficiency: Anemia congenital malformations in newborns  Pharmacokinetics The richest sources of folic acid: yeast, liver, kidney and green vegetables Body stores of folates are relatively low and daily requirements high folic acid deficiency and megaloblastic anemia can develop within 1-6 months after the intake of folic acid stops  Clinical Pharmacology Folate deficiency results in a megaloblastic anemia that is indistinguishable from the anemia caused by vitamin B 12 deficiency folate deficiency does not cause the characteristic neurologic syndrome seen in vitamin B 12 deficiency  Clinical Pharmacology… Causes of folic acid deficiency inadequate dietary intake of folates alcohol dependence liver diseases (diminished hepatic storage of folates) Pregnancy maternal folic acid deficiency may cause fetal neural tube defects e.g. spina bifida hemolytic anemia  Clinical Pharmacology… Causes of folic acid deficiency renal dialysis (folate loss during dialysis) Drugs Methotrexate, trimethoprim and pyrimethamine Leading to megaloblastic anemia Long-term therapy with phenytoin Rarely leading to megaloblastic anemia  Clinical Pharmacology… Drug-Induced Folate Deficiency Reduced absorption Altered metabolism Ethanol Some anticonvulsants Metformin Methotrexate Cholestyramine Trimethoprim Sulfasalazine Sulfamethoxazole Triamterene Oral contraceptives Pentamidine Some anticonvulsants Alcohol  Indications Treatment of folic acid deficiency: 1 mg/d folic acid orally reverses megaloblastic anemia restore normal serum folate levels replenishes body stores of folates Therapy should be continued until the underlying cause of the deficiency is removed or corrected  Indications… Folic acid supplementation to prevent folic acid deficiency should be considered in high-risk patients: pregnant women, patients with alcohol dependence, hemolytic anemia, liver disease, or certain skin diseases, and patients on renal dialysis  Folic acid (Cont’d) Oral folate 1 mg daily for 4 months is usually sufficient for treatment of folate-deficiency anemia, unless the etiology cannot be corrected. If malabsorption is present, the daily dose should be increased to 5 mg. Folic acid (Folvite) -Dose  Folic acid… Adult Folic Acid Deficiency 0.4-1 mg PO/IV/IM/SC once daily Pediatric Folic Acid Deficiency Infants: 15 mcg/kg/day or 50 mcg/day IV/PO/IM/SC 1-10 years: 1 mg/day IV/PO/IM/SC initially, then 0.1-0.4 mg/day  Electrolyte Supplements Serum potassium levels can fall during therapy for severe cobalamin or folate deficiency and can lead to sudden death. Therefore, potassium supplements may be indicated.  3. Transfusion Transfusion of packed red blood cells (RBCs) should be reserved for patients who are actively bleeding and for patients with a severe and symptomatic anemia. Providing red blood cell transfusions for bleeding and/or severe chronic anemia may be lifesaving. Red cell transfusions are the old mainstay, which offers the quickest relief for anemias. Transfusion is palliative and should not be used as a substitute for specific therapy. In chronic diseases associated with anemia of chronic disorders, erythropoietin may be helpful in averting or reducing transfusions of packed RBCs.  Transfusion (Cont’d) Risks of transfusion Allergic reactions Transmissions of infectious agents hepatitis, HIV, and Human Leukemia Virus (HTLV) HBV (hepatitis B virus) - 1 in 63,000 HIV (AIDS) risk-1 in 675,000 HIV 2-