Hematopoietic Medications PDF

Hematopoietic Medications Wayne Parker, PharmD Learning Objectives 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. Explain the mechanism of action of each drug in each class. Describe the action of iron in iron deficiency anemia. Describe the action of Vit B12 in the synthesis of tetrahydrofolate and of succinyl CoA...

Hematopoietic Medications Wayne Parker, PharmD Learning Objectives 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. Explain the mechanism of action of each drug in each class. Describe the action of iron in iron deficiency anemia. Describe the action of Vit B12 in the synthesis of tetrahydrofolate and of succinyl CoA. Describe the action of hematopoietic growth factors on various circulating blood cells. Describe the absorption, transport, storage and elimination of iron. Describe the absorption of folic acid and Vit B12. Describe the acute and chronic iron toxicity and therapy Describe the main adverse effects of hematopoietic growth factors Describe the use of antianemic drugs in anemias. List the main disorders that can be treated effectively with hematopoietic growth factors Drug Classes and Drugs to consider Agents used in Anemias Oral Iron: Ferrous sulfate (Ferrous gluconate) (Ferrous fumarate) Parenteral Iron: Iron Dextran (Iron sucrose) (Ferric gluconate) (Ferric coarboxymaltose) (Ferumoxytol) Iron antidote Hematopoietic growth factors Erythropoietin (epoetin) (Darbepoetin) Cyanocobalamin (hydroxocobalamin) Folic acid Leucovorin Filgrastim (G-CSF) (Pegfilgrastim) Sargramostim (GM-CSF) Deferoxamine Interleukin-11 (Oprelvekin) Thrombopoietin agonists: Romiplostim Eltrombotag Types of Anemias and Causes Microcytic Normochromic – normocytic Macrocytic Iron deficiency Anemia of Chronic disease Alcohol Use Disorder Anemia of chronic disease Kidney disease Copper deficiency Iron transport deficiency Endocrine failure (thyroid, pituitary) Folate deficiency Inherited sideroblastic anemia Myelodysplasia Liver disease Thalassemia Myelophthisis Malabsorption Pure red blood cell aplasia Vitamin B12 deficiency Undernutrition Taking a Good Patient History üLast normal CBC üPrevious diagnosis of anemia üPrevious transfusion üPrevious jaundice, dark urine üFamily history üMedical history including drug use or abuse üRelated symptoms Dyspnea (functional class) Volume loss (orthostatic hypotension) üBlood loss Menstruation Blood donation GI loss Concealed bleeding üDiet üFever üSigns of other cytopenia üSigns of hemolysis Causes of Iron Deficiency Proposed Mechanisms of Adaptation to Iron Deficiency Iron deficiency is most common cause of chronic anemia. Symptoms include: Pallor, fatigue, dizziness, exertional dyspnea, and other generalized symptoms of tissue hypoxia. Cardiovascular system adapts to chronic anemia with tachycardia, increased cardiac output, vasodilation. 1) Adaptation to iron deficiency are centered on the suppression of the hepatic hormone hepcidin and the tissue hypoxia that develops consequent to anemia. 2) The production of erythropoietin by the kidney increases in response to enhanced levels of hypoxia-inducible factor 2α (HIF-2α). 3) Erythropoiesis is increased and hypochromic microcytic red cells are produced owing to the low availability of iron. 4) Increase in erythropoiesis suppresses the production of hepcidin. 5) HIF-2α increases the expression of the duodenal divalent metal transporter 1 (DMT1) on the apical surface of enterocytes to increase the transfer of dietary iron from the lumen to enterocytes. NEJM 2015;372:1832-1843. The absorption, transport, and storage of iron Free inorganic iron is extremely toxic. Iron is required for essential proteins such as hemoglobin Normally, only a small amount of iron is lost from the body each day so dietary requirements are small and easily fulfilled by iron available in wide variety of food. ferroportin ferric iron ferritin Ferrous iron transferrin Whom To Treat and Notes All patients with iron deficiency anemia and most patients with iron deficiency without anemia should be treated Regardless of the presence of symptoms Role of RBC transfusion Patients with severe, severely symptomatic (symptoms of myocardial ischemia), or life-threatening anemia should be treated with RBC transfusion Expected Response Resolution of symptoms, a modest reticulocytosis (peaking in 7 – 10 days) Normalization of hemoglobin level in 6 – 8 weeks Oral versus IV Iron Certain conditions may affect iron dosing and/or the route of admin of iron GI conditions, pregnancy, can’t take oral meds We generally treat patients who have uncomplicated iron deficiency anemia with ORAL iron due ease of admin and efficacy Usual Conditions of IV Iron Therapy Pregnancy Individuals with IBD (inflammatory bowel disease) Gastric surgery CKD (chronic kidney disease) Ongoing blood loss Copyrights apply RBC Transfusion Copyrights apply Pharmacology of Iron The only function is to be incorporated into heme, a metalloporphyrin which is the prosthetic group for hemoglobin, myoglobin, cytochromes, and some enzymes. Absorption: The main site of absorption are duodenum and proximal jejunum. Iron in heme is readily absorbed (heme is absorbed intact). Non heme iron must be reduced to ferrous iron (Fe2 ) before being absorbed into the intestinal cells by an active transport system. From these cells iron is actively transported into blood. The rate of iron transport is regulated by the amount of iron stored in the intestinal mucosal cells and by iron requirement by the body. (When stores are low and requirement is high more iron is transported into blood. When the opposite occurs, iron is stored as ferritin in the intestinal mucosal cells!) Distribution: Iron is transported in the plasma bound to transferrin. The transferrin-iron complex enters maturing erythroid cells by a receptor mediated endocytosis. Storage: Iron is stored as ferritin in: 1. Intestinal mucosal cells. 2. Macrophages of liver, spleen and bone. 3. Hepatocytes (serum ferritin level can be used to measure total body iron stores!) Elimination: Iron is tenaciously conserved!! Minimal amounts (~ 1 mg daily) are lost with sweat, urine and saliva and by exfoliation of intestinal mucosal cells. Pharmacology of Iron Adverse effects after administration of Iron: 1. Oral iron: nausea, epigastric discomfort, diarrhea or constipation, black stools. 2. Parenteral iron: nausea and vomiting, fever, arthralgias, back pain, flushing urticaria, bronchospasm and (rarely) anaphylactoid reaction. Acute iron toxicity: Necrotizing gastroenteritis (vomiting, abdominal pain, bloody diarrhea) followed by shock, severe metabolic acidosis, coma; death can ensue (therapy: deferoxamine) Chronic iron toxicity: Hemochromatosis (excess iron is deposited in heart, liver, etc.) à organ failure and death (therapy: intermittent phlebotomy, deferoxamine). Contraindications and precautions: 1. Anemias not caused by iron deficiency. 2. State of iron overload (hemochromatosis, accidental ingestion, etc.). 3. Parkinson disease (precaution) ( iron supplements appear to increase the rate at which the disease progresses!). Therapeutic use for the PREVENTION and TREATMENT of iron deficiency anemia 1. Oral iron therapy: Iron salts (ferrous sulfate, gluconate, etc.) (treatment must continue for 3-6 months after the correction of the cause of iron loss, to replenish tissue iron stores!) 2. Parenteral iron therapy: Iron dextran and Iron sodium gluconate complex (less allergenic than iron dextran) (IV Adm may provide the entire dosed needed to correct iron deficiency at one time!) Oral Iron Therapy All oral iron preparations are equally effective Ferrous iron is most efficiently absorbed, so ferrous salts should be used (OTC). Ferrous sulfate, Ferrous gluconate, and Ferrous fumarate Some Commonly Used Oral Iron Preparations Preparation Tablet Size Elemental Iron per Tablet Ferrous sulfate, hydrated Ferrous sulfate, desiccated Ferrous gluconate 325 mg 65 mg Usual Adult Dosage for Treatment of Iron Deficiency (Tablets per Day) 2–4 200 mg 65 mg 2–4 325 mg 36 mg 3–4 Ferrous fumarate 325 mg 106 mg 2–3 Oral Iron Therapy: Ferrous sulfate, gluconate, fumarate Contraindications: Hypersensitivity to drug/class/component Primary Hemochromatosis Hemolytic anemia Hemosiderosis Peptic Ulcer Disease Ulcerative Colitis Use with caution in elderly, for chronic therapy, and hypochlorhydria Side Effects Nausea, epigastric discomfort, abdominal cramps, constipation, and diarrhea Constipation is common so usually given with a stool softener. Effects are usually dose-related Can decrease adverse effects by decreasing daily dose or by taking tablets immediately after or with meals Patients develop black stools ØNo clinical significance ØDoes mask continued gastrointestinal bleeding When do we prefer IV therapy over oral medications? Ongoing blood loss, physiologic or anatomic abnormality that interferes with oral absorption or iron homeostasis, and intolerable gastrointestinal side effects of oral iron. We often use IV iron when treating pregnant women and individuals with inflammatory bowel disease, gastric surgery, or chronic kidney disease. Camaschella C. N Engl J Med 2015;372:1832-1843. Parenteral Iron Therapy MOA & Contraindications – same as oral iron Indication: Patients with documented iron deficiency who are unable to tolerate or absorb oral iron therapy. Patients with extensive chronic anemia who can’t be maintained with oral iron alone: 1.Prolonged salicylate therapy 2.Patients with advanced chronic renal disease requiring hemodialysis and treatment with erythropoietin (dialysis patient) 3.GI causes – Malabsorption, gastric surgery patients, inflammatory bowel disease (IBD) Side Effects: Localized pain and tissue staining at injection site, headache, lightheadedness, fever, nausea, flushing, urticaria, bronchospasm, anaphylaxis, and death. Advantage: Bypasses regulatory mechanism so body stores are increased Disadvantage: Inorganic free ferric iron produces serious dose-dependent toxicity à limited dose that can be administered Parenteral Iron Therapy: Iron Dextran, Iron sucrose, Ferumoxytol , Ferric carboxymaltose, Ferric gluconate In addition, patients with a history of inflammatory arthritis (e.g., rheumatoid arthritis) commonly experience a flare of their arthritis during IV iron infusion, which is usually well-controlled with glucocorticoid premedication and/or a brief course of glucocorticoids (three to four days) following the infusion. For individuals with asthma or multiple drug allergies, we generally limit premedication to a glucocorticoid alone (methylprednisolone) Iron Dextran Stable complex of ferric oxyhydroxide and dextran polymers containing 50 mg elemental iron/ml. Given by deep IM injection or IV infusion (IV route is used more commonly!) If given IM, must give using Z-track method to prevent leakage of medication into subcutaneous space (prevents staining of skin, local pain, and ensures full dosage!!). Allows for delivery of ONE entire dose of iron necessary to correct iron deficiency Must give a test dose BEFORE each full dose!!! WHY??? Adverse effects of IV injection include headache, light-headedness, fever, arthralgia, nausea, vomiting, back pain, flushing, urticaria, bronchospasm, anaphylaxis, and death. More likely to have a hypersensitivity reaction in patients previously treated!! Higher risk of anaphylaxis with high molecular weight iron dextran (observational studies!). Ferric gluconate complex and Iron-sucrose complex Only give by IV route Less likely to cause hypersensitivity reactions, but administer slowly at first and observe patients for infusion reactions Patients treated chronically with parenteral iron, monitor iron storage levels to avoid serious toxicity. Iron sucrose- used for dialysis patients , non-dialysis chronic kidney disease, inflammatory bowel disease, chemotherapy-induced anemia, the peripartum period, gastric bypass, heavy uterine bleeding, etc. Ferric gluconate – used primarily in dialysis patients Ferumoxytol and Ferric carboxymaltose Ferumoxytol Composed of superparamagnetic iron oxide nanoparticles coated with a LMW semisynthetic carbohydrate Infusion related reactions (hypotension) can occur.. recommend giving slowly!! Can cause a brighter signal on magnetic resonance imaging (MRI) scans, which is important to be aware of but does not negatively affect interpretation of the scan. If an MRI is planned within three months of administration, the radiologist should be notified that the patient has received ferumoxytol. Ferric carboxymaltose Colloidal iron hydroxide complex with tighter binding of elemental iron to the carbohydrate polymer. Neither formulation are used very often Acute Iron Toxicity Most often seen in children who accidentally ingest iron tablets. As few as ten tablets of any commonly available oral iron preparations can be lethal in young children!! Adults should be advised to store tablets in child-proof containers out of reach of children (Also, keep children’s multivitamins out of reach!!). Children present with iron toxicity experience necrotizing gastroenteritis, vomiting, abdominal pain, bloody diarrhea followed by shock, lethargy, dyspnea. Sometimes patients may clinically improve before experiencing severe metabolic acidosis, coma, and death. Treatment Time is of the essence – URGENT Deferoxamine - antidote Activated charcoal is INEFFECTIVE Whole bowel irrigation or gastric lavage* not routinely used! Ipecac syrup – risk versus benefit May endanger patient’s airway as an aspiration risk and may mask sign on iron toxicity (vomiting) Supportive therapy for gastrointestinal bleeding, metabolic acidosis, and shock Deferoxamine An iron chelator (i.e., a chemical that can bind metals). MOA: Drug has a very high affinity for ferric ion. Drug can bind iron to three atoms of the molecule forming a chelate complex which is pharmacologically inactive. Drug can remove iron from hemosiderin, ferritin and transferrin. Drug cannot remove iron from hemoglobin and cytochromes. Pharmacokinetics: Very low oral bioavailability, administration: IM, IV. Excreted in the urine, changes urine to orange-red color. Adverse effects: Hypotension (with rapid IV injection), allergic reactions (rash, urticaria). Therapeutic uses: Iron poisoning (Acute and Chronic) Transfusional iron overload (thalassemia, sickle cell disease, etc.) Folic Acid Folic acid is pteroylglutamic acid. Essential cofactor for synthesis of amino acids, purines, and DNA The richest source of folates are green vegetables, liver and kidney. Pharmacodynamics: It is converted to tetrahydrofolate (THF) to be transformed to several THF cofactors which participate in several one-carbon unit transfer reactions. The reaction needed for purine and DNA synthesis is catalyzed by thymidylate synthetase. In rapidly proliferating tissues considerable amounts of THF are consumed in the reaction and continued DNA synthesis requires continued regeneration of THF. These reactions are catalyzed by dihydrofolate reductase. NEJM 2015;373:1649-1658. Pharmacology of Folic Acid continued Pharmacokinetics: Normal daily requirements of folic acid ~ 50-200 mcg Unaltered folic acid is completely absorbed by proximal jejunum. Folic acid is stored in modest amounts (5-20 mg) mainly in the liver. Inside cells N5-methyltetrahydrofolate is converted to THF by a demethylation reaction that requires Vit B12. Adverse effects are virtually absent. Contraindications: Do not give alone in patients with pernicious anemia without knowing whether they also have vitamin B12 deficiency* *The danger is that folic acid supplements can mask the signs of vitamin B12 deficiency, yet not prevent the development of irreversible neurological disease due to Vitamin B12 deficiency. Therapeutic Uses of Folic Acid Megaloblastic anemia due to folic acid deficiency, mainly related to: Inadequate intake (alcoholism, total parenteral nutrition, etc.) Impaired absorption (celiac disease, mal-absorption syndromes, barbiturates, phenytoin) Increased demand (pregnancy, infancy) During pregnancy (to decrease the risk of neural tube defects in the fetus). Leucovorin Leucovorin (aka folinic acid ) is 5-formyltetrahydrofolate (just think of leucovorin as folic acid with extra benefits) Pharmacodynamics: Drug is a THF cofactor Inside the cells the drug is metabolized to other reduced folate cofactors These reduced folates are polyglutamated, which helps to retain them inside the cells. They replete the folate pool and continue the folic acid cycle. Leucovorin bypasses the dihydrofolate reductase step in the synthesis of THF and so can be used to rescue cells exposed to folate antagonists (methotrexate, trimethoprim, pyrimethamine). Pharmacokinetics: Leucovorin is completely absorbed from the small intestine and converted to its active metabolites inside the GI cells. Adverse effects are virtually absent! Therapeutic uses: Prophylaxis of methotrexate toxicity (aka “leucovorin rescue”) During fluorouracil therapy Vitamin B12 Vit B12 (cyanocobalamin) and hydroxocobalamin are the cobalamins on the market. Methylcobalamin is the active form of cobalamins in humans. Pharmacokinetics: Normal daily requirements of Vit B12 ~ 2 mcg. Vit B12 combines in the stomach with intrinsic factor and the complex is absorbed in the distal ileum by active transport. Some absorption can also occur via passive diffusion. Vit B12 is stored in large amounts (3-5 mg) mainly in the liver (it would take ~ 5 years to deplete the stores and develop megaloblastic anemia if Vit B12 absorption is stopped!!) Vitamin B12 Adverse effects; are extremely rare and follow mainly parenteral treatment. Hypersensitivity reactions (to cobalt) Hypokalemia and thrombocytosis (after conversion of severe megaloblastic anemia to normal erythropoiesis) Therapeutic uses: Megaloblastic anemia due to impaired absorption of vit B12 caused by: a) Lack of intrinsic factor (gastric atrophy of pernicious anemia, gastric surgery, endocrinopathy) b) Damage of the distal ileum region that absorbs the complex vit B12intrinsic factor (IBD, malignancy, chronic pancreatitis, surgical resection of ileum) c) Decreased availability (fish tapeworm infestation, blind loop syndrome with bacterial overgrowth). Hematopoetic growth factors All are glycoproteins and belong to the cytokine superfamily. Most of these growth factors are today produced by recombinant DNA technology. MOA: They activate specific receptors belonging to the JAK/STAT (Janus-kinase linked) superfamily of cytokine receptors. These can regulate the proliferation and differentiation of hematopoietic progenitor cell in the bone marrow. Pharmacokinetics: Usually administered IV, with distribution in most tissues, but not in the CNS. Half-lives are often very long (several hours or days). Adverse effects: Anaphylactic (or anaphylactoid) reaction ( rash, coughing, sneezing, wheezing, difficulty in breathing, urticaria, angioedema, abdominal cramping, hypotension, palpitations) are rare but can be very serious (Other major adverse effects are drug-specific!!). Erythropoietin (epoetin) Drug is recombinant human erythropoietin. Endogenous erythropoietin is primarily produced by the kidney in response to states of hypoxia. Darbopoetin alpha (Aranesp ®) is a glycosylated form of erythropoietin that differs only in having a 2-3-fold longer half-life Pharmacodynamics: Drug activates specific receptors on red cell progenitors. The activation causes stimulation of erythroid proliferation and differentiation. Adverse effects: Hypertension and thrombotic complications (both are related to the rapid increase in hematocrit!!) Therapeutic uses: Anemias of chronic renal failure Pure RBC aplasia Secondary anemias (due to cancer, AIDS, chronic inflammation, etc.) Erythropoietin Rapid increase in Hg and Hct can cause hypertension and thrombotic complications Black Box Warning Increased risk of death, cardiovascular, and thromboembolic complications Increased risk of tumor progression or recurrence In cancer patients, you want to use the lowest dose needed to avoid RBC transfusions Only use for treatment of anemia due to myelosuppressive chemotherapy Do not use for patients receiving myelosuppressive chemotherapy when the outcome is a cure. In peri-surgery patients, there is an increased risk of deep vein thrombosis in patients not receiving prophylactic anticoagulation Pharmacology of Myeloid Growth Factors Filgrastim is a granulocyte CSF (a lineage specific growth factor) Sargramostim is a granulocyte macrophage CSF( a multilineage growth factor) Pharmacodynamics: Drugs activate specific receptors on myeloid cell progenitors à to the following effects: Filgrastim; leads to stimulation of proliferation and differentiation of progenitors of neutrophils. Activation of phagocytic activity of neutrophils. Mobilization of hematopoietic stem cells (blood concentration of these cells is increased!!) Sargramostim; leads to stimulation of proliferation and differentiation of progenitors of neutrophils, megakaryocytes and erythroid cells. Activation of phagocytic activity of neutrophils. Stimulation of T cell proliferation. Pharmacology of Myeloid Growth Factors Adverse effects: Throbbing bone pain (up to 30%) Leukocytosis (therapy must be stopped if neutrophils rise above 100000/mm3) Hyperuricemia (>20%) with (filgrastim) Splenic rupture (rare but life threatening) (filgrastim) Arthralgias, myalgias, fever, peripheral edema (sargramostim) Therapeutic uses: Chemotherapy induced neutropenia (therapy can be effective but improved survival rate in cancer patient unclear !!) Other severe forms of neutropenia (febrile, congenital, drug induced, etc.) Peripheral blood stem cell mobilization (for autologous stem cell transplantation) Aplastic anemia Megakaryocyte Growth Factors Thrombopoietin and interleukin-11 are key endogenous regulators of platelet production Interleukin-11: 65-85 kDa protein produced by fibroblasts and stromal cells in the bone marrow. Oprelvekin is a recombinant version of interleukin 11 Two thrombopoietin agonists: Romiplostim: New class of drugs called “peptibodies” (Biologic agent that activates the thrombopoietin receptor!). Eltrombopag: Orally active small molecule agonist at thrombopoietin receptor. Pharmacodynamics: Interleukin 11: activates specific receptors on megakaryocytes and megakaryocyte progenitor cells, which leads to: a)Stimulation of proliferation and differentiation of megakaryocytes. b)Stimulation of production of platelets and neutrophils. c)Stimulation of growth of multiple myeloid and lymphoid cells. Romiplostim: High affinity for human Mpl receptor. Causes a dose dependent increase in platelet count. Megakaryocyte Growth Factors Adverse effects: Interleukin-11: Fluid retention (up to 50%), can result in peripheral edema, pleural and pericardial effusion dyspnea on exertion, pulmonary edema. Anemia (due to hemodilution). Transient atrial arrhythmias. Hypokalemia. Romiplostim: Well tolerated, mild headache. Long term use can result in increase in Marrow fibrosis but generally is reversible when the drug is discontinued. Eltrombopag: Hepatotoxicity and hemorrhage. Restricted use to registered physicians and patients. Therapeutic uses: Interleukin-11: Prevention of chemotherapy induced thrombocytopenia. Romiplostim: Use in patients with chronic idiopathic thrombocytopenia who failed to respond to previous treatment with steroids, immunoglobulins, or splenectomy. Eltrombopag: To treat patients with severe idiopathic thrombocytopenia who have failed to respond adequately to first-line therapy.