Anti-Anemic Drugs 2024 PDF

PHARM 233 Pharmacology Drug Used for Treatment of Anemia Ayman El-Kadi, PhD Faculty of Pharmacy and Pharmaceutical Sciences Winter 2024 Learning Objectives Identify patients who may be at greater risk for developing anemia. Understand different classes of drugs used to treat different types of anemi...

PHARM 233 Pharmacology Drug Used for Treatment of Anemia Ayman El-Kadi, PhD Faculty of Pharmacy and Pharmaceutical Sciences Winter 2024 Learning Objectives Identify patients who may be at greater risk for developing anemia. Understand different classes of drugs used to treat different types of anemia. Understand the mechanisms of different drugs used for treatment of different types of anemia Understand the clinical uses and pharmacokinetics of different drugs used for treatment of different types of anemia Understand the side effects and toxicity of different drugs used for treatment of different types of anemia Types of Anemia A. Iron and Vitamin Deficiency Anemias – Hypochromic, microcytic anemia (small red cells with low hemoglobin; caused by chronic blood loss giving rise to iron deficiency) – Megaloblastic anemia (large red cells, few in number); caused by a deficiency of Vit B12 or folic acid – Pernicious anemia (fewer normal-sized red cells, each with a normal hemoglobin content); caused by a deficiency of Vit B12 due to defect in intrinsic factor B. Other Blood Cell Deficiencies – Erythrocytes, neutrophils and platelets Causes of Anemia Deficiency of nutrients necessary for haemopoiesis, most importantly: – iron – folic acid and vitamin B 12 – B6 (pyridoxine) and vitamin C. Depression of the bone marrow, commonly caused by: – drug toxicity (e.g. anticancer drugs, clozapine ) – exposure to radiation, including radiotherapy – diseases of the bone marrow (e.g. idiopathic aplastic anaemia, leukaemias) – reduced production of, or responsiveness to, erythropoietin (e.g. chronic renal failure, rheumatoid arthritis, AIDS). Excessive destruction of red blood cells (i.e. haemolytic anaemia) Drugs Used for Treatment of Anemia 1. Hematinic agents - Iron - Folic acid and Vit B12 2. Hematopoietic Growth Factors - Erythropoietin Garnulocyte Colony-Stimulating Factor (G-CSF) Garnulocyte-Monocyte Colony-Stimulating Factor (GM-CSF) Megakaryocyte (Thrombopoietic) Growth Factors 1. Hematinic agents: Iron The body of a 70 kg man contains about 4 g of iron 65% of which circulates in the blood as hemoglobin. About one-half of the remainder is stored in the liver, spleen and bone marrow, as ferritin and hemosiderin. Normal daily requirement for iron is 5 mg for men, and 15 mg for growing children and for menstruating women. A pregnant woman needs between 2 and 10 times this amount because of the demands of the fetus. The average diet provides 15–20 mg of iron daily, mostly in meat. Iron in meat is generally present as heme, and about 20– 40% of heme iron is available for absorption. 1. Hematinic agents: Iron 1. Hematinic agents: Iron Ferric iron (Fe3+) must be converted to ferrous iron (Fe2+) for absorption (by ferric reductase enzyme) in the GI tract. Absorption involves active transport into mucosal cells in the duodenum and jejunum (the upper ileum), from where it can be transported into the plasma and/or stored intracellularly as ferritin. Total body iron is controlled exclusively by absorption; in iron deficiency, more is transported into plasma than is stored as ferritin in jejunal mucosa. Iron that is released is transported by transferrin (the transport protein). Transferrin delivers the iron to either the liver for storage or to bone marrow for further hemoglobin and RBC production. 1. Hematinic agents: Iron Iron formulations are used for treatment of iron deficiency. Common Drugs Oral: ferrous sulfate, ferrous fumarate, ferrous gluconate, polysaccharide-iron complex Iv: iron dextran, sodium ferric gluconate, iron sucrose MOA (Mechanism of Action) Most iron is recycled through the body; RBCs contain the majority of iron in hemoglobin. Because the life span of an RBC is about 120 days, in 1 day about 0.8% of the RBCs are broken down, and their iron is recycled: -Senescent (old) RBCs are taken up by the reticular system (spleen and macrophages) and are relieved of their iron 1. Hematinic agents: Iron Pharmacokinetics Ferrous iron (Fe2+) is better absorbed than ferric iron (Fe3+) and is absorbed in the duodenum. About 25% of ferrous iron is absorbed. Iron from animals (heme iron) is ferrous; iron from vegetarian foods (nonheme iron) is ferric, and so a smaller percentage is available for absorption. Iron should be taken on an empty stomach; many foods inhibit iron absorption. Other factors that markedly decrease absorption include antacids, H2 blockers, proton pump antagonists, and calcium supplements. Most ingested iron either is not absorbed or is lost with the enterocytes when their turnover results in shedding into the lumen of the GI tract. Some oral compounds are combined with ascorbic acid, which is designed to enhance absorption. 1. Hematinic agents: Iron Clinical Uses To treat iron deficiency anaemia, which can be caused by: Chronic blood loss (e.g. with menorrhagia, hookworm, colon cancer) Increased demand (e.g. in pregnancy and early infancy) Inadequate dietary intake (uncommon in developed countries) Inadequate absorption (e.g. following gastrectomy, or in diseases such as celiac disease, where the intestinal mucosa is damaged by an immunologically based intolerance to the wheat protein gluten). 1. Hematinic agents: Iron Side Effects Gastrointestinal disturbances. Severe toxic effects occur if large doses are ingested; such acute poisoning can be treated with desferrioxamine, an iron chelator as can chronic iron overload in diseases such as thalassaemia. 1. Hematinic agents: Folic Acid and Vitamin B12 Prototype: B9: Folic acid; B12: Cyanocobalamin, hydroxocobalamin Vitamin B12 and folic acid play key roles in DNA synthesis. Active forms of folic acid serve as enzyme cofactors that play key roles in the synthesis of purines and pyrimidines, as well as amino acids, in the body. A deficiency of folic acid or B12 affect cells that are actively dividing, such as the cells of the bone marrow, which are involved in erythropoiesis. Therefore, the deficiencies of these vitamins is anemia. Specifically, B12 deficiency results in abnormal DNA replication, which prevents cells from maturing properly, leading to production of large, dysfunctional RBC precursors (megaloblasts) that do not leave the marrow, or abnormal cells that do leave the marrow. B12 deficiency can also affect the nervous system, causing inflammation, demyelination, and neuronal cell death. 1. Hematinic agents: Folic Acid and Vitamin B12 MOA: Folic acid: Reduction of folic acid, catalyzed by dihydrofolate reductase in two stages yields dihydrofolate (FH 2 ) and tetrahydrofolate (FH 4 ), co-factors which transfer methyl groups (1carbon transfers) in several important metabolic pathways. FH 4 is essential for DNA synthesis. B12: involves conversion of both methyl-FH 4 to FH 4 and homocysteine to methionine. 1. Hematinic agents: Folic Acid and Vitamin B12 Indications Vitamin B12 Pernicious anemia Megaloblastic and macrocytic anemias caused by poor B12 absorption Folic Acid Megaloblastic and macrocytic anemias Prevention of neural tube defects in neonates Adjunct to methotrexate to prevent methotrexate toxicity Pernicious anemia (combined with B12) 2. Hematopoietic Growth Factors: Erythropoietins Erythropoietins are agents that stimulate the production of red blood cells (RBCs). Prototype: epoetin alfa (also known as recombinant human erythropoietin, rHuEPO or simply, EPO) Other: darbepoetin alfa MOA (Mechanism of Action) Erythropoietin is an endogenous protein that stimulates the production of RBCs (erythrocytes). Erythropoietin is typically released in response to hypoxia and is largely synthesized in the kidneys, with a small amount coming from the liver 2. Hematopoietic Growth Factors: Erythropoietins Patients with a deficiency of erythropoietin will be anemic. This occurs commonly in patients with renal failure. Once released, erythropoietin binds to a receptor on the surface of committed erythroid progenitor cells in the bone marrow. Binding to this receptor mediates a variety of intracellular effects through tyrosine kinases, including the inhibition of apoptosis. Inhibiting apoptosis prevents RBCs from dying at an early stage of development. Erythropoietin also promotes proliferation through Janus protein kinase-2 (JAK2) pathways. 2. Hematopoietic Growth Factors: Erythropoietins Pharmacokinetics Epoetin alpha is administered parenterally by either the SC or the IV route. The elimination half-life of IV Epoetin alpha is approximately 4 to 8 hours. Darbepoetin alfa is a modified form of erythropoietin, with amino acid mutations that have led to a prolonged elimination half-life of approximately 24 hours. Indications Anemia In advanced renal failure Associated with chemotherapy and acquired immunodeficiency syndrome (AIDS) 2. Hematopoietic Growth Factors: Erythropoietins Side Effects Iron deficiency: If iron stores cannot keep up with erythropoiesis, patients may develop a functional iron deficiency. Patients need an iron supplement. Thrombosis: particularly in patients on dialysis. It is recommended that these patients receive anticoagulant therapy as a prophylactic measure. Hypertension: Although increased hematocrit can lead to increased blood pressure, the mechanism is believed to be more likely a result of the interaction between erythropoietin and vasoactive factors such as angiotensin II. Seizures: Seizures have been reported in dialysis patients receiving epoetin alfa. 2. Hematopoietic Growth Factors: ColonyStimulating Factors Colony-stimulating factors (CSFs) are agents that stimulate the production of neutrophils and monocytes. Prototype: Granulocyte Colony-Stimulating Factor (G-CSF): filgrastim, lenograstim, pegfilgrastim Granulocyte-Monocyte Colony-Stimulating Factor (GMCSF): sargramostim 2. Hematopoietic Growth Factors: ColonyStimulating Factors MOA (Mechanism of Action) The CSFs work by binding to receptors on myeloid progenitor cells. These are cells in the bone marrow that make RBCs, platelets, granulocytes, and monocytes. The actions of these receptors are mediated through the Janus protein kinase/signal transducers and activators of transcription (JAK/STAT) pathway. G-CSFs stimulate proliferation and differentiation only of progenitors commited to becoming neutrophils. GM-CSFs stimulate the production of neutrophils and monocytes, as well as the actions (phagocytosis, superoxide production, and cell-mediated toxicity) of neutrophils, monocytes, and eosinophils 2. Hematopoietic Growth Factors: ColonyStimulating Factors Pharmacokinetics The elimination half-life of filgrastim is 3 to 5 hours and is fairly consistent between the IV and SC routes. It is largely cleared through renal excretion. The addition of a polyethylene glycol (PEG) to filgrastim produced pegfilgrastim, which because of its large size is not as readily cleared by the kidneys. Pegfilgrastim therefore has an extended elimination half-life of about 40 hours, compared with filgrastim. Indications Adjunct to myelosuppressive chemotherapy Severe chronic neutropenia Prevention and treatment of neutropenia in human immunodeficiency virus (HIV) infection 2. Hematopoietic Growth Factors: ColonyStimulating Factors Side Effects Bone loss: G-CSF increases osteoclast activity, leading to bone resorption. Joint pain: G-CSF appears to stimulate cytokine release, leading to joint pain. Renal dysfunction: G-CSF causes a transient and reversible renal impairment, believed to be caused by leukostasis (clumping of leukocytes) in the kidneys. Acute respiratory distress: G-CSF can lead to lung injury because of accumulation and activation of neutrophils in the lungs. Splenomegaly or splenic rupture: Cases of splenic rupture have been reported with G-CSF. Sickle cell crises: Sometimes fatal in patients with sickle cell disorders. 2. Hematopoietic Growth Factors: Megakaryocyte (Thrombopoietic) Growth Factors Megakaryocyte (Thrombopoietic) Growth Factors - Oprelvekin (IL-11) - Thrombopoietin Oprelvekin (IL-11) and Thrombopoietin stimulate the growth of megakaryocytic progenitors and increase the number of peripheral platelets. They are used to treat thrombocytopenia following cancer chemotherapy. Eltrombopag (oral) and romiplostim (injectable) are recently approved thrombopoietin agonists. IL-11 treatment is associated with dizziness, headache and fatigue. Recombinant human trombopoietin is supposed to be better tolerated. Iron Overload: Iron overload occurs in chronic hemolytic anaemias requiring frequent blood transfusions, such as; - Thalassaemias (a large group of genetic disorders of globin chain synthesis) - Hemochromatosis (a genetic iron storage disease with increased iron absorption, resulting in damage to liver, islets of Langerhans, joints and skin). Treatment: Iron chelators such as; - Desferrioxamine: form a complex with ferric iron which, unlike unbound iron, is excreted in the urine. - Desferrioxamine is not absorbed from the gut. Therefore, it must be given by slow SC infusion. For acute iron overdose, it is given IM or IV - Deferiprone is an orally absorbed iron chelator, used as an alternative treatment for iron overload in patients who are unable to take desferrioxamine. - Deferasirox is similar, but can cause GI bleeding. References Rang & Dale's Pharmacology 8th Edition Applied Pharmacology 1st Edition