L4. Pharmacology of Drugs for Anemias PDF

04 Pharmacology Dr. Karim Nagi Pharmacology of Drugs for Anemia 11th March 2020 Mohamed M Tawengi Aseel S Hassona This document covers: 1. “Pharmacology of Drugs for Anemia” Lecture Slides by Dr. Karim Nagi. 2. “Pharmacology, Lippincott 6th edition” Chapter 33. Introduction: This is our first pharma...

04 Pharmacology Dr. Karim Nagi Pharmacology of Drugs for Anemia 11th March 2020 Mohamed M Tawengi Aseel S Hassona This document covers: 1. “Pharmacology of Drugs for Anemia” Lecture Slides by Dr. Karim Nagi. 2. “Pharmacology, Lippincott 6th edition” Chapter 33. Introduction: This is our first pharmacology lecture in unit 4, Blood. We will discuss the drugs used to treat anemia. As usual, such a lecture requires proper memorization and has a lot of concepts that are important for the IFOM exam as well. Stay focused and good luck! Outline: After you finish this lecture, you should be able to: Identify the different causes of anemia. Identify the major methods for treating anemia. Recognize major characteristics for different types of anemia (etiology, symptoms and side effects) and their appropriate treatments. Recognize other types of blood disorders (neutropenia and sickle cell disease) and identify their treatments’ mode of action and side effects. Anemia: o Anemia is defined as a below-normal plasma hemoglobin concentration resulting from a decreased number of circulating red blood cells or an abnormally low total hemoglobin content per unit of blood volume. General signs and symptoms of anemia include fatigue, rapid heartbeat, shortness of breath, pale skin, dizziness, and insomnia. It can be caused by chronic blood loss, bone marrow abnormalities, increased hemolysis, infections, malignancy, endocrine deficiencies, renal failure and a number of other disease states. It can also result from toxic effects of some drugs or dietary deficiencies as well as genetic causes. A temporary treatment may be provided by blood transfusions or pharmacological options which we will discuss shortly. o The normal range of hemoglobin concentration is different between males and females. Men have higher hemoglobin concentrations than women. o One reason behind this is the menstrual cycle in which women lose blood due to the shedding of the endometrium. With this bleeding, menstruating women lose the hemoglobin reservoir; erythrocytes. 2 o However, the main reason behind the difference in hemoglobin concentrations between genders is due to the sex hormones. Estrogen, the primary female sex hormone, reduces hemoglobin levels. o On the other hand, testosterone in men stimulates erythropoiesis which increases the number of erythrocytes and therefore, increases hemoglobin concentration. Remember! The normal hemoglobin range for men is: 13.5 – 17.5 g/dL OR 135 -175 g/L. For women, it is: 12 – 15.5 g/dL OR 120 – 155 g/L. Hemoglobin: o In (Fig.1), you can see an erythrocyte which is also called a red blood cell. The major protein content of the erythrocyte is the hemoglobin. It has 4 subunits, 2 α and 2 β subunits shown in the same figure. (For more information about the structure of hemoglobin, go back to sheet #2; erythropoiesis). o Within the hemoglobin, you can find the heme group. The heme group is the part that is responsible for binding oxygen for transportation. It binds and transports 4 oxygen molecules at a time. For this reason, we say that hemoglobin is the oxygen-carrying protein within the red blood cells; it transports oxygen Figure 1 from the lungs to the different body organs and it also transports carbon dioxide from the body organs back to the lungs. Carbon dioxide is carried back to the lungs by 3 different ways: ① by binding to hemoglobin, ② dissolution directly into the blood or ③ getting carried as a bicarbonate ion. o In short, when a person loses erythrocytes, they are losing hemoglobin, and this will cause anemia; lower levels of hemoglobin. The following figures show the different causes of anemia: 3 o ① Ulcers (‫ )اﻟﻘﺮﺣﺔ‬are open sores on the skin or inside the body that will not heal without treatment. Interestingly, they can be induced by medications. The most common example are the NSAIDs; non-steroidal anti-inflammatory drugs like ibuprofen, aspirin or diclofenac (voltaren). When these drugs are used for a long period of time, they cause peptic ulcer; ulcer located in the stomach which causes GI disturbance and may lead to anemia. o ② Vitamins from different nutrients are required for erythropoiesis which is the process of formation of red blood cells (erythro-: red, -poiesis: formation; formation of red blood cells). o ③ Bone marrow abnormalities can also cause anemia. The bone marrow is the body part responsible for producing stem cells that differentiate into the different body cells. If a person suffers from a bone marrow abnormality, they will produce abnormal stem cells that cannot differentiate properly to form normal blood cells which causes anemia. o ④ For drugs, some antibiotics like cephalosporins or levodopa are known to cause anemia. Other medications than can cause anemia will be discussed later on in this sheet. Keep in mind that when you take these drugs, they make the immune system define the red blood cells as non-self (i.e. antigenic). Consequently, the immune system will attack the red blood cells. This happens in specific cases after taking the drugs for prolonged time and it results in anemia. As soon as you take the medical history of the patient and identify this problem, you must stop giving these drugs and go for other alternatives. o ⑤ Anemia can be from a genetic cause like sickle cell disease and we will study this later on. Note that normal menstrual cycles don’t cause anemia. However, if the monthly iron intake and absorption does not replace the iron lost during the period, it can result in iron deficiency anemia. Treatments of anemia: o To treat an anemic patient, we have 2 options and we choose based on the severity of the case: 1- If you have a patient who is pale, tired and is developing severe anemia, you cannot give him drugs and wait until he improves and makes new red blood cells. In this case, we do a blood transfusion of red blood cells to restore the hemoglobin concentrations. 4 Remember that within the heme group of red blood cells, you have iron. So, when you transfer a lot of blood to the patient, iron will accumulate and exceeds the normal levels, the patient may develop iron toxicity. This is because the body does not get rid of iron easily and it keeps on accumulating within the body. In short, excessive blood transfusion can cause iron overload and other complications. Important concept to keep in mind for the IFOM examination. The treatment for this problem is by giving a drug that facilitates the excretion of iron from the body. 2- The other option is giving supplements/ drugs to compensate for deficiencies in: Iron Folic acid Vitamin B12 Erythropoietin Necessary for normal erythropoiesis Iron, folate and vitamin B12 deficiencies: - Please take a look on the following table and then go to the next page for the explanations. This table is EXTREMELY important, and you will also need it for the IFOM and USMLE examinations. Remember! Don’t forget these notes!! 5 As you saw in the previous table, we will discuss 3 different types of deficiencies: ① iron deficiency, ② folate -also called folic acid- which is a form of vitamin B9 ③ and vitamin B12 deficiency. ① Iron deficiency: Causes: 1- blood loss, 2- heavy menstruation, 3- low intake of food that contains iron and 4pregnancy. Effects: 1- The loss of erythrocytes results in iron deficiency because they are the main reservoir for iron. Consequently, the body tries to compensate for the loss of iron, and it will result in depletion of the iron stores. 2- Another effect of the low iron levels is on the red blood as they become smaller in what we call microcytic anemia (the size is less than 6.7μm and the MCV is >80.0 fL). 3- Smaller red blood cells have less concentrations of hemoglobin which causes hypochromic anemia. The hemoglobin concentration is measured either by the mean corpuscular hemoglobin (MCH) or by mean corpuscular hemoglobin concentration (MCHC). The MCHC is more informative because it takes into consideration the size of the red blood cell. o If the MCHC level is below 32 g/dL, you can expect hypochromic anemia. o If the MCH is below 27 pg/ cell, you can expect hypochromic anemia. Whenever a question says, ‘microcytic anemia’ you should immediately link it to iron deficiency anemia (Fig.2). If you ask why, it is because the other types of anemia are characterized by macrocytic anemia in which the red blood cells are bigger in size. Figure 2 Treatments: 1- There are many drugs that can treat iron deficiency anemia and the difference between them is in the iron formulations. These different formulations have different concentrations of iron. The recommended dose by the CDC is between 150 – 180 mg/ day divided in 2 – 3 times. It is given in this manner because high doses can reduce the iron absorption. Remember that ferrous sulfate is the most used formulation because of its high content of elemental iron and relatively low cost. We will discuss the formulations later on in this sheet. ② Folate/ vitamin B9 deficiency: Causes: 1- Poor absorption, 2- pregnancy, 3- lactation, 4- alcohol and 5- drugs, mainly dihydrofolate reductase inhibitors which will prevent the metabolism of folate and therefore, it 6 will be excreted without using it. For example, methotrexate, pyrimethamine and trimethoprim. (go back to the note below the table in page #5) Effects: 1- Macrocytic anemia, 2- megaloblastic anemia and 3- congenital neurological anomalies (malformations) such as spina bifida Symptoms: 1- Tingling in the hands and feet, 2- Loss of appetite, 3- diarrhea and 4- muscle weakness Treatments: 1- Non-toxic, 2- no side effects and 3- in high dosage, it is excreted in urine/ feces. ③ Vitamin B12 deficiency: Causes: 1- Poor absorption and 2- failure in producing the intrinsic factor by the stomach which decreases intestinal uptake. The intrinsic factor is involved in the transport of vitamin B12; it is expressed in the stomach and it helps in the absorption of vitamin B12. Effects: 1- Macrocytic anemia, and 2- megaloblastic anemia (pernicious anemia). Symptoms: 1- Tingling in the hands and feet, 2- difficulty walking, 3- Dementia ( mental disorder) and 4- Hallucinations, paranoia or schizophrenia in extreme cases Treatments: 1- Non-toxic, 2- cyanocobalamin or hydroxocobalamin which is preferred because it is faster, higher protein binding and longer plasma levels). Note: 1- If you have a patient presenting with macrocytic anemia, you treat them by giving a combination of folate (vitamin B9) and vitamin B12. This is because vitamins are not toxic, and the combination will not cause any harm. Add to that, if we have a deficiency in vitamin B12 and we give the patient folate, the blood test will show an improvement in macrocytic anemia. However, the cause of the anemia is still there, and we did not treat it. In general, when we treat macrocytic anemia, we give the patient a combination of both vitamin B12 and folate. 2- If you have a patient with pernicious anemia, you link it immediately to vitamin B12 deficiency (not both). Further explanation of the treatments is yet to come. 7 Classification of anemia Based on the size of the RBC (size is represented as MCV) Based on the type of RBC maturation Microcytic anemia (MCV 100) Microcytic anemia: It is characterized by the production of red blood cells that are smaller in o size. It is mainly caused by iron deficiency. The smaller size is due to decreased production of hemoglobin, the o predominant constituent of red blood cells, (Fig.3). Macrocytic anemia: Figure 3 Macrocytic anemia is characterized by the inhibition of the synthesis o of nucleobases (mainly thymine, dTMP) which are essential for the synthesis of the DNA. It could be caused by vitamin B12 or folate deficiency. Consequently, the cell cycle cannot progress into mitosis (Fig.4), and o cell division does not take place which forms megaloblastic cells that are big and unfunctional. Did you know that folate Figure 4 is well absorbed in the jejunum? 1 2 Erythroblastic anemia: immature red blood cells. Megaloblastic anemia: mature RBCs but they are not functional because they are bigger in size. 8 Drug induced anemia: o As mentioned before, some drugs can cause anemia as a side effect. Therefore, when we check the hematology lab results and detect anemia, we must take the medical history of the patient. If we find a drug that induces anemia, we must stop this drug and go for an alternative. Some of those drugs are: o Anticonvulsants: (phenytoin – carbamazepine – felbamate) Antibiotics: (chloramphenicol) Antifungal drugs: (polyenes) ACE inhibitors: Antimalarial drugs: (chloroquine) Aplastic anemia. Aplastic anemia / (isoniazid) sideroblastic anemia. induce anemia by decreasing erythropoietin. suppress the production of erythropoietin. hemolytic anemia. Aplastic anemia is an autoimmune disease that causes a deficiency of all blood cell types; red blood cells, white blood cells and platelets. o Sideroblastic anemia happens when the body has enough iron but unable to use it to make hemoglobin. It can be improved by taking moderate to high doses of pyridoxine (vitamin B6). Pernicious anemia: Cause: Pernicious anemia is a type of megaloblastic anemia. As we mentioned before, the intrinsic factor (IF) is a glycoprotein produced by the parietal cells of the stomach and it is involved in transporting vitamin B12. In a normal person, the intrinsic factor will help in the absorption of vitamin B12. However, in case of pernicious anemia, the body will synthesize antibodies that will bind to the intrinsic factor and prevent it from binding to vitamin B12. Figure 5 Effect: Consequently, vitamin B12 gets to the stomach and absorption will not take place and it will be excreted without using it, (Fig.5). Treatments: We have 2 options: 1- since there is a problem in absorption, the oral supplementation (if the patient doesn’t want to take injections) will only be effective in high doses to compete with the antibodies and bind to the IF; cyanocobalamin. 2- the better option is by parenteral administration; hydroxocobalamin given intramuscularly (IM). 9 Symptoms of iron deficiency anemia: o Pica: an abnormal desire to eat substances not normally eaten, such as chalk, dirt or ashes, (Fig.6). o Koilonychias: a condition that affects the shape of the nails in which they look like a spoon, (Fig.6). o Angular stomatitis which is soreness and cracking at the corners of the mouth. Figure 6 Pharmacokinetics of iron deficiency anemia drugs: o As we mentioned before, the drugs used to treat iron deficiency have different formulations. This means that they have different percentages of elemental iron. The following are the main supplements/ drugs used in iron deficiency anemia: 1- Carbonyl iron (100%): if you take 1 mg of carbonyl iron, it means that you are taking 1 mg of iron. 2- Ferrous fumarate (33%): if you take 1 mg of this drug, you are taking 0.33 mg of iron. 3- Ferrous sulfate (20%): if you take 1 mg of this drug, you are taking 0.20 mg of iron. 4- Ferric ammonium citrate (18%): if you take 1 mg of this drug, you are taking 0.18 mg of iron. 5- Ferrous gluconate (12%): if you take 1 mg of this drug, you are taking 0.12 mg of iron. o You need to keep these percentages in mind when you calculate the recommended daily dose of iron supplementation for a patient. o In case of iron deficiency anemia, these drugs can be taken parenterally for rapid and fast treatment. However, it is linked to higher incidence of side effects such as fatal hypersensitivity and anaphylactoid reactions. o Preferably, if you can treat this deficiency on a long period and it is not a severe case, oral administration has less side effects but may take several weeks to have an effect. 10 Iron supplements and drug interactions: o Iron supplements can produce drug interactions. Therefore, before administering these drugs, you need to check the medical history of the patient; If they take any of the following drugs, you need to look for an alternative because the concurrent ingestion of iron causes a marked decrease in the bioavailability of these drugs by forming iron-drug complexes (chelation or binding of iron by the involved drug). The affected drugs include: 1- Antibiotics: Tetracycline antibiotic and tetracycline derivatives: doxycycline, metacycline and oxytetracycline. - Quinolone antibiotics like ciprofloxacin. To avoid this interaction, iron is taken 2 hours before or 2-4 hours after taking antibiotics. 2- Methyldopa: Centrally acting antiadrenergic drugs which are antihypertensive drug. 3- Levodopa / carbidopa: Used to treat Parkinson's disease; they get transformed into dopamine in the body. 4- Bisphosphonates: Used to treat osteoporosis. Some bisphosphonates include alendronate, risedronate, etidronate and others. 5- Thyroxine: Used for low thyroid function. 6- Captopril (ACE inhibitor) and folic acid: Have also been demonstrated to form stable complexes with iron. 11 Iron toxicity: 1- Ingestion of less than 20mg/ kg of elemental iron is non-toxic. 2- Ingestion of 20mg/ kg to 60mg/ kg results in moderate symptoms. 3- Ingestion of more than 60mg/ kg can result in severe toxicity and lead to severe morbidity and mortality. Symptoms of iron toxicity: Acute symptoms mainly appear in children and they include: 1- Severe GI distress necrotizing gastroenteritis. Necrotizing means that it causes necrosis while gastroenteritis refers to inflammation of the GI tract. So, it is the inflammation of the GI tract that induces necrosis in this region. 2- Hematemesis which is vomiting of blood. 3- Bloody diarrhea. 4- Dyspnea; shortness of breath. 5- Metabolic acidosis in which the body produces too much acids. 6- Shock or coma and it may also lead to death. Management of iron toxicity: o Iron toxicity can be reversed by using chelators which are molecules that bind to iron and help in eliminating it from the body. The main one used is deferoxamine which is taken intravenously. Deferoxamine used to be called desferrioxamine. These chelators are administered as a continuous infusion. With recovery, deferoxamine is terminated and typically, the duration of the therapy is 24 hours. The other treatment option is gastric lavage. with high oral iron intake, it is reversed by washing it away by a gastric lavage. o Recall from our introduction that we said: with excess blood transfusion, the patient should take deferoxamine to eliminate the excess iron from the body. Answer the following question before going to the justification in the next page! - A patient with iron deficiency needs to take ferrous sulfate. What is the recommended dosing regimen for this patient? 12 The answer: - Recommendation: 150 – 180 mg of iron/ day divided into 2 – 3 times. (from the table in page #5). - 180mg/ day divided into 2 – 3 administrations means that 60 mg of iron will be administered 3 times daily OR 90 mg of iron 2 times daily. - Remember that the elemental iron % for ferrous sulfate is 20% which means that for every 100 mg of ferrous sulfate, 20 mg of iron is available for absorption by the body. - Therefore, in order to have 60 – 90 mg of iron at each administration, the patient needs to take 300 – 450 mg of ferrous sulfate. - So, the recommended dosing regimen is: 300 mg of ferrous sulfate, 3 times daily OR 450 mg of ferrous sulfate, 2 times daily. o You might be wondering why we don’t administer carbonyl iron as its elemental iron % is 100%. This is because it is not a severe case; carbonyl iron is for severe cases of iron deficiency to have a quick effect. Another reason is because it is not recommended as it may lead to iron toxicity which may have serious consequences as we have discussed before. o If you are looking for a direct answer, yes, we can give the patient 60 – 90 mg of carbonyl iron as a treatment. However, it is safer to use ferrous sulfate. Another logical reason is because the question stated ferrous sulfate!  o Keep in mind that high doses of iron formulations reduces its absorption. To explain this, when the iron levels are high, the body identifies it as a problem and tries to fix it by reducing iron absorption. o (Fig.7) Summarizes iron deficiency anemia: the intestinal epithelial cells absorb the iron; it is transported into the blood by ferroportin. Transferrin then transports the iron to the bone marrow to synthesize hemoglobin or to hepatocytes to store it as ferritin. (For more information about the physiology of iron absorption, transport and storage, go back to sheet #1; iron metabolism). Figure 7 13 Erythropoietin (epoetin alfa) and darbepoetin: - Erythropoietin is a hormone synthesized and released by the kidneys when the peritubular cells of the kidneys detect hypoxia. Erythropoietin stimulates stem cells to differentiate into proerythroblasts and promotes the release of reticulocytes from the bone marrow and the initiation of hemoglobin formation. Erythropoietin, thus, Figure 8 regulates the RBCs proliferation, and differentiation in the bone marrow. (Fig.8). - Therefore, patients who suffer from chronic renal insufficiency or major kidney problems may suffer from anemia. This is why these patients must be treated with exogenous erythropoietin to prevent chronic anemia from developing. There are 2 types of erythropoietin drugs (Fig.9): 1- Human erythropoietin. 2- Darbepoetin, a synthetic version of the human erythropoietin. Figure 9 o The difference between the 2 types of erythropoietin is that darbepoetin has 2 additional carbohydrate chains that improve its biological activity and it binds less to its receptor (lower affinity). This means that you need less binding of the drug to have the physiological effect taking place. Darbepoetin also has a 3 times longer half-life compared to erythropoietin and that is why it is considered a long-lasting version of erythropoietin. This is also why it is not used for acute treatment of anemia. o Side effects of these agents may include elevation in blood pressure and arthralgia in some cases. 14 Recommendation: o Since erythropoietin or darbepoetin regulate red blood cell proliferation and differentiation in the bone marrow, administrating these drugs rapidly increases the hemoglobin levels. That is why these drugs must be titrated by taking a small amount and increasing it carefully. o Following the administration of these agents, it is recommended that: 1- Hemoglobin level does not exceed 12g/ dL. 2- Hemoglobin level should not rise by more than 1g/ dL over a 2-week period. o This is because high hemoglobin concentrations could induce serious cardiovascular events such as thrombosis and severe hypertension and it could increase the risk of death. o With that being said, if the hemoglobin level exceeds 10g/ dL, erythropoietin or darbepoetin should be reduced or completely discontinued. Side effects of specific anemia treatments: Neutropenia o Neutrophils are the most abundant type of white blood cells and they generally serve as the primary defense system against infections by invading pathogens. o Neutropenia is the condition where the concentrations of neutrophils (neutrocytes) is abnormally low; a concentration that is less than 1500/ µL, (Fig.10). Treatment of neutropenia: Figure 10 We have 2 myeloid growth factors currently available for clinical use: 1- Granulocyte Colony–Stimulating Factors (G-CSF): Filgrastim and Pegfilgrastim. 2- Granulocyte–Macrophage Colony–Stimulating Factors (GM-CSF): Sargramostim. 15 They stimulate granulocytes production in the bone marrow to increase the neutrophil count. - The main difference between filgrastim and pegfilgrastim is that filgrastim must be taken daily because of its short half-life. Pegfilgrastim is given as a single dose with a long half-life. The other difference is that pegfilgrastim is given subcutaneously only, while filgrastim can be given subcutaneously or intravenously. - The dosing for Sargramostim is similar to filgrastim. However, Sargramostim produces much more side effects. Therefore, it is preferred to take G-CSF instead of GM-CSF because they are better tolerated and cause less side effects. - The only exception where Sargramostim (GM-CSF) is preferred over the G-CSF is when the patient is anemic, neutropenic, and thrombocytopenic (low platelet count). This is because you need to stimulate the three major cell lines in the bone marrow and this broad-spectrum stimulant effect is only accomplished by Sargramostim. - These agents are typically used prophylactically to reduce risk of neutropenia following chemotherapy and bone marrow transplantation. 16 Pharmacokinetics 1- The bioavailability of subcutaneously administered G-CSF is 54%. 2- Clearance of G-CSF is complex, and it increases as the granulocyte count rises. 3- G-CSF is metabolized in the kidney and liver to its component amino acids, with little or no G-CSF found in urine. - Pegfilgrastim is a covalent conjugation product of filgrastim and it is a form of polyethylene glycol. It has a much longer half-life than the recombinant G-CSF. - Bone pain was reported more frequently in patients treated with higher doses (20 to 100mcg/kg/day administered IV, and less frequently in patients treated with lower subcutaneous doses of filgrastim (3 to 10mcg/kg/day). Sickle cell disease o Sickle cell anemia/ sickle cell disease is a genetic disorder of the blood caused by an inherited abnormal hemoglobin called hemoglobin S (HbS); sickle hemoglobin which makes the red blood cells sickled in shape instead of the normal biconcave shape, as in (Fig.11). o HbS molecules tend to clump together which makes the red blood cells Figure 11 sticky and more fragile. As a consequence, the formed cells are curved and sickle in shape. o Normal red blood cells last about 4 months in the bloodstream. However, the fragile sickle cells break down after only 10 to 20 days which usually causes anemia. o As you can see in (Fig.12B), the abnormal red blood cells form clumps as they travel within the blood vessels because of their shape. This can cause serious problems and must be treated. Figure 12 17 Treatment of sickle cell disease: 1- Hydroxyurea: - Mechanism of action: Hydroxyurea increases the levels of fetal hemoglobin (HbF) which is the main oxygen transport protein in human fetus. By this, it dilutes the abnormal HbS. This process takes several months. The polymerization of HbS is delayed in treated patients, so that painful crises are not caused by sickled cells blocking the capillaries and causing tissue anoxia; absence of oxygen supply despite adequate blood flow. - Side effects: 1- bone marrow suppression (hydroxyurea toxicity). This toxicity is reversible by withholding the medication for two weeks and can be potentially resumed at a lower dose. 2- Cutaneous vasculitis, skin ulcer and skin cancer. 3- Secondary leukemia. 2- Pentoxifylline: - Mechanism of action: Increases the deformability of red blood cells. (Instead of producing new hemoglobin, we try to fix the deformed one). This will: 1- Improve erythrocyte flexibility and reduces the viscosity of the blood. 2- Decrease total systemic vascular resistance. 3- Improve blood flow and enhance tissue oxygenation in patients with peripheral vascular disease. - Side effects: Pentoxifylline is 1- Nausea/ vomiting. available in extended- 2- Thrombocytopenia. release tablets and is 3- Jaundice. taken 3 times a day with food to lessen the side effects. 18 Summary Iron formulations for iron deficiency anemia: Treatments of anemia: 19 Questions 20 Don’t hesitate to contact Mohamed M Tawengi / Aseel S Hassona regarding any clarification, concern or suggestion!