Pharmacotherapy of Hematologic Disorders PDF

Pharmacotherapy Our Lady of Fatima University of Hematologic College of Pharmacy Disorders PHCP 311 Objectives ☐ To explain the pathophysiology of the Anemia ☐ To identify the factors that may induce and potentiate the disease ☐ To di...

Pharmacotherapy Our Lady of Fatima University of Hematologic College of Pharmacy Disorders PHCP 311 Objectives ☐ To explain the pathophysiology of the Anemia ☐ To identify the factors that may induce and potentiate the disease ☐ To discuss the clinical presentation as well the diagnosis and laboratory evaluation. ☐ To create a therapeutic outcome. Anemia ▪ Anemia is a group of diseases characterized by a decrease in either hemoglobin (Hb) or the volume of red blood cells (RBCs), resulting in decreased oxygen-carrying capacity of blood. ▪ The World Health Organization defines anemia as Hb less than 13 g/dL (130 g/L; 8.07 mmol/L) in men or less than 12 g/dL (120 g/L; 7.45 mmol/L) in women. Functional classification of anemias Common causes of Diseases Causing Anemia of Inflammation Chronic infections: Tuberculosis, Other chronic lung infections (eg, lung abscess, bronchiectasis, Human immunodeficiency virus, Subacute bacterial endocarditis, Osteomyelitis, Chronic urinary tract infections, Chronic inflammation: Rheumatoid arthritis, Systemic lupus erythematosus, Inflammatory bowel disease, Inflammatory osteoarthritis, Gout, Other (collagen vascular) diseases, Chronic inflammatory liver diseases Malignancies: Carcinoma, Lymphoma, Leukemia, Multiple myeloma Morphologic classifications are based on cell size. ☐ Macrocytic cells are larger than normal and are associated with deficiencies of vitamin B12 or folic acid. ☐ Microcytic cells are smaller than normal and are associated with iron deficiency ☐ Normocytic anemia may be associated with recent blood loss or chronic disease Iron-deficiency anemia (IDA), characterized by decreased levels of ferritin (most sensitive marker) and serum iron, and decreased transferrin saturation, can be caused by inadequate dietary intake, inadequate gastrointestinal (GI) absorption, increased iron demand (eg, pregnancy), blood loss, and chronic diseases. Vitamin B12– and folic acid–deficiency anemias, macrocytic in nature, can be caused by inadequate dietary intake, malabsorption syndromes, and inadequate utilization. ☐ Deficiency of intrinsic factor causes decreased absorption of vitamin B12 (ie, pernicious anemia). ☐ Folic acid–deficiency anemia can be caused by hyperutilization due to pregnancy, hemolytic anemia, myelofibrosis, malignancy, chronic inflammatory disorders, long-term dialysis, or growth spurt. ☐ Drugs can cause anemia by reducing absorption of folate (eg, phenytoin) or through folate antagonism (eg, methotrexate). Anemia of inflammation (AI) is a newer term used to describe both anemia of chronic disease and anemia of critical illness. ☐ A diagnosis of exclusion, AI is an anemia that traditionally has been associated with malignant, infectious, or inflammatory processes, tissue injury, and conditions associated with release of proinflammatory cytokines. ☐ Serum iron is decreased but in contrast to IDA, the serum ferritin concentration is normal or increased ▪ Age-related reductions in bone marrow reserve can render elderly patients more susceptible to anemia caused by multiple minor and often unrecognized diseases (eg, nutritional deficiencies) that negatively affect erythropoiesis. ▪ Pediatric anemias are often due to a primary hematologic abnormality. ☐ The risk of IDA is increased by rapid growth spurts and dietary deficiency. ▪ Rapid diagnosis is essential because anemia is often a sign of underlying pathology. ▪ Severity of symptoms does not always correlate with the degree of anemia. ▪ Initial evaluation of anemia involves a complete blood cell count (CBC), reticulocyte index, and examination of the stool for occult blood. Clinical Presentation Signs and symptoms depend on rate of development and age and cardiovascularstatus of the patient. Acute-onset anemia is characterized by cardiorespiratory symptomssuch as palpitations, angina, orthostatic light-headedness, and breathlessness. Chronic anemia is characterized by weakness, fatigue, headache, orthopnea, dyspnea on exertion, vertigo, faintness, cold sensitivity, pallor, and loss of skin tone. IDA is characterized by glossal pain, smooth tongue, reduced salivary flow, pica (compulsive eating of nonfood items), and pagophagia (compulsive eating of ice). Neurologic effects (eg, numbness and paraesthesisas) of vitamin B12 deficiency may precede hematologic changes. Psychiatric findings, including irritability, depression, and memory impairment, may also occur with vitamin B12 deficiency. Anemia with folate deficiency is not associated with neurologic symptoms Diagnosis based on MCV Diagnosis based on MCV Diagnosis based on MCV Treatment Goals of Treatment: The goals are to return hematologic parameters to normal, restore normal function and quality of life, and prevent long-term complications. IRON-DEFICIENCY ANEMIA ▪ Oral iron therapy with soluble ferrous iron salts, which are not enteric coated and not slow or sustained release, is recommended at a daily dosage of 150–200 mg elemental iron in two or three divided doses ▪ Iron is best absorbed from meat, fish, and poultry. ▪ Administer iron at least 1 hour before meals because food interferes with absorption, but administration with food may be needed to improve tolerability. ▪ Consider parenteral iron for patients with iron malabsorption, intolerance of oral iron therapy, or nonadherence. Oral Iron Products Iron dextran, sodium ferric gluconate, iron sucrose, ferumoxytol, and ferric carboxymaltose are available parenteral iron preparations with similar efficacy but different molecular size, pharmacokinetics, bioavailability, and adverse effect profiles VITAMIN B12–DEFICIENCY ANEMIA ▪ Oral vitamin B12 supplementation is as effective as parenteral, even in patients with pernicious anemia, because the alternate vitamin B12 absorption pathway is independent of intrinsic factor. Initiate oral cobalamin at 1–2 mg daily for 1–2 weeks, followed by 1 mg daily. ▪ Parenteral therapy acts more rapidly than oral therapy and is recommended if neurologic symptoms are present. ▪ A popular regimen is IM cyanocobalamin, 1000 mcg daily for 1 week, then weekly for 1 month, and then monthly for maintenance therapy. Initiate daily oral cobalamin administration after symptoms resolve. ▪ Continue vitamin B12 for life in patients with pernicious anemia. FOLATE-DEFICIENCY ANEMIA ▪ Oral folic acid, 1 mg daily for 4 months, is usually sufficient for treatment of folic acid–deficiency anemia, unless the etiology cannot be corrected. ▪ If malabsorption is present, a dose of 1–5 mg daily may be necessary. ▪ Parenteral folic acid is available but rarely necessary. ANEMIA OF INFLAMMATION ▪ Treatment of AI is less specific than that of other anemias and should focus on correcting reversible causes. ▪ Reserve iron therapy for an established IDA; iron is not effective when inflammation is present. RBC transfusions are effective but should be limited to episodes of inadequate oxygen transport and Hb of 7–8 g/dL (70–80 g/L; 4.34–4.97 mmol/L). Erythropoiesis-stimulating agents (ESAs) can be considered, but response can be impaired in patients with AI. The initial dosage for epoetin alfa is 50–100 units/kg three times weekly and darbepoetin alfa 0.45 mcg/kg once weekly. Iron, cobalamin, and folic acid supplementation may improve response to ESA treatment. Potential toxicities of exogenous ESA administration include increases in blood pressure, nausea, headache, fever, bone pain, and fatigue. Hb must be monitored during ESA therapy. ☐ An increase in Hb greater than 12 g/dL (120 g/L; 7.45 mmol/L) with treatment or a rise of greater than 1 g/dL (10 g/L; 0.62 mmol/L) every 2 weeks has been associated with increased mortality and cardiovascular events. In patients with anemia of critical illness, parenteral iron is often used but is associated with a theoretical risk of infection. ANEMIA IN PEDIATRIC POPULATIONS ▪ Infants aged 9–12 months: Administer ferrous sulfate 3–6 mg/kg/day (elemental iron) divided once or twice daily between meals for 4 weeks. ▪ Continue for two additional months in responders to replace storage iron pools. ▪ The dose and schedule of vitamin B12 should be titrated according to clinical and laboratory response. The daily dose of folic acid is 1 mg. EVALUATION OF THERAPEUTIC OUTCOMES IDA: Positive response to oral iron therapy is characterized by modest reticulocytosis in a few days with an increase in Hb seen at 2 weeks. ☐ Reevaluate the patient if reticulocytosis does not occur. ☐ Hb should return to normal after 2 months; continue iron therapy until iron stores are replenished and serum ferritin normalized (up to 12 months). ▪ Megaloblastic anemia: Signs and symptoms usually improve within a few days after starting vitamin B12 or folic acid therapy. ▪ Neurologic symptoms can take longer to improve or can be irreversible, but should not progress during therapy. ▪ Reticulocytosis should occur within 3–5 days. Hb begins to rise a week after starting vitamin B12 therapy and should normalize in 1–2 months. ▪ Hct should rise within 2 weeks after starting folic acid therapy and should normalize within 2 months. ESAs: Reticulocytosis should occur within a few days. Monitor iron, TIBC, transferrin saturation, and ferritin levels at baseline and periodically during therapy. The optimal form and schedule of iron supplementation are unknown. Discontinue ESAs if a clinical response does not occur after 8 weeks Pediatrics: Monitor Hb, Hct, and RBC indices 4–8 weeks after initiation of iron therapy. Monitor Hb or Hct weekly in premature infants. Sickle Cell Anemia Sickle Cell Anemia ▪ Sickle cell syndromes, which can be divided into sickle cell trait (SCT) and sickle cell disease (SCD), are hereditary conditions characterized by the presence of sickle hemoglobin (HbS) in red blood cells (RBCs). ▪ SCT is the heterozygous inheritance of one normal β-globin gene producing hemoglobin A (HbA) and one sickle gene producing HbS (HbAS) gene. Individuals with SCT are asymptomatic. ▪ SCD can be of homozygous or compounded heterozygous inheritance. ▪ Homozygous HbS (HbSS) has historically been referred to as sickle cell anemia (SCA), which now also includes HbSβ0-thal due to similarities in clinical severity. ▪ Heterozygous inheritance of HbS with another qualitative or quantitative β-globin mutation results in sickle cell hemoglobin C (HbSC), sickle cell β-thalassemia (HbSβ+-thal and HbSβ0-thal), and some other rare phenotypes. PATHOPHYSIOLOGY Clinical manifestations of SCD are due to impaired circulation, RBC destruction, and stasis of blood flow and ongoing inflammatory responses. ☐ These changes result from disturbances in RBC polymerization and membrane damage. ☐ In addition to sickling, other factors contributing to the clinical manifestations include functional asplenia (and increased risk of infection by encapsulated organisms), deficient opsonization, and coagulation abnormalities ▪ Polymerization allows deoxygenated hemoglobin to exist as a semisolid gel that protrudes into the cell membrane, distorting RBCs into sickle shapes. Sickle-shaped ▪ RBCs increase blood viscosity and encourage sludging in the capillaries and small vessels, leading to local tissue hypoxia that accentuates the pathologic process. Repeated cycles of sickling, upon deoxygenation, and unsickling, upon oxygenation, damage the RBC membrane and cause irreversible sickling. ☐ Rigid, sickled RBCs are easily trapped, resulting in shortened circulatory survival and chronic hemolysis. CLINICAL PRESENTATION Cardinal features of SCD are hemolytic anemia and vasoocclusion. Symptoms are delayed until 4–6 months of age when HbS replaces fetal hemoglobin (HbF). Common findings include pain with fever, pneumonia, splenomegaly, and, in infants, pain and swelling of the hands and feet (eg, hand-and-foot syndrome or dactylitis). Usual clinical signs and symptoms of SCD include chronic anemia; fever; pallor; arthralgia; scleral icterus; abdominal pain; weakness; anorexia; fatigue; enlarged liver, spleen, and heart; and hematuri Acute complications of SCD include fever and infection (eg, sepsis caused by encapsulated pathogens such as Streptococcus pneumoniae), stroke, acute chest syndrome, and priapism. Acute chest syndrome is characterized by pulmonary infiltration, respiratory symptoms, and equivocal response to antibiotic therapy. Acute episodes of pain can be precipitated by fever, infection, dehydration, hypoxia, acidosis, and sudden temperature changes. The most common type is vasoocclusive pain, which is manifested by pain over the involved areas without change in Hb. Aplastic crisis is characterized by acute decrease in Hb with decreased reticulocyte count manifested as fatigue, dyspnea, pallor, and tachycardia. Acute splenic sequestration is the sudden massive enlargement of the spleen due to sequestration of sickled RBCs. ☐ The trapping of sickled RBCs by the spleen leads to hypotension and shock, and can cause sudden death in young children. ☐ Repeated infarctions lead to autosplenectomy; therefore, incidence declines as adolescence approaches. ▪ Chronic complications involve many organs and include pulmonary hypertension, airway inflammation and hyperresponsiveness, bone and joint destruction, ocular problems, cholelithiasis, cardiovascular abnormalities, depression, hematuria, and other renal complications. ▪ Children experience delayed growth and sexual maturation. ▪ Patients with SCT are usually asymptomatic, except for rare painless hematuria. ▪ Other reported complications associated with SCT are delayed hemorrhage after eye trauma, venous thromboembolism, particularly pulmonary embolism, and chronic kidney disease. DIAGNOSIS SCD is usually identified by routine neonatal screening programs using isoelectric focusing, high-performance liquid chromatography, or electrophoresis. Laboratory findings include: ☐ low hemoglobin; increased reticulocyte, platelet, and white blood cell counts; and sickled red cell forms on the peripheral smear. Prophylactic penicillin is recommended until at least 5 years of age. An effective regimen is penicillin V potassium, 125 mg orally twice daily until 3 years of age and then 250 mg orally twice daily until age 5 years. DISEASE-MODIFYING THERAPIES ▪ HbF directly affects polymer formation. ▪ Increases in HbF correlate with decreased RBC sickling and adhesion. ▪ Patients with low HbF levels have more frequent pain and higher mortality. ▪ HbF levels of 20% or greater reduce the risk of acute sickle cell complications. ▪ Hydroxyurea, a chemotherapeutic agent, stimulates HbF production and increases the number of HbF-containing reticulocytes and intracellular HbF. ▪ It is indicated for patients 2 years of age and older with recurrent moderate to severe painful crises to reduce the frequency of pain crises and the need for blood transfusions. ▪ The recommended single daily dose for adults is 15 mg/kg and 20 mg/kg for children l-Glutamine is approved for SCD patients age 5 and older to reduce the acute complications of SCD. ☐ Dose is weight-based: 5 g twice a day for 65 kg. ▪ Chronic RBC transfusions are indicated for primary and secondary stroke prevention and amelioration of organ damage. ▪ Transfusions are usually given every 3–4 weeks or as needed to maintain desired HbS levels. ▪ The optimal duration of primary prophylactic transfusion therapy in children is unknown. ▪ Risks include alloimmunization, hyperviscosity, viral transmission (requiring hepatitis A and B vaccination), volume and iron overload, and transfusion reactions ▪ Allogeneic hematopoietic stem cell transplantation is the only curative therapy for SCD. ▪ The best candidates are younger than 16 years, have severe complications, and have human leukocyte antigen–matched donors. ▪ Risks must be carefully considered and include mortality, graft rejection, and secondary malignancies. TREATMENT OF COMPLICATIONS ▪ Educate patients to recognize conditions that require urgent evaluation. ▪ Balanced fluid status and oxygen saturation of at least 92% are important to avoid exacerbation during acute illness. ▪ RBC transfusions are indicated for acute exacerbation of baseline anemia (eg, aplastic crisis, hepatic or splenic sequestration, or severe hemolysis), severe vasoocclusive episodes, and procedures requiring general anesthesia. Promptly evaluate fever of 38.5°C (101.3°F) or higher. Empiric antibiotic therapy should provide coverage against encapsulated organisms (eg, ceftriaxone for outpatients and cefotaxime for inpatients; clindamycin for cephalosporin-allergic patients). For acute chest syndrome: ☐ initiate incentive spirometry; appropriate fluid therapy; broad-spectrum antibiotics, including a macrolide or quinolone; and, for hypoxia or acute distress, oxygen therapy. ☐ Other potential therapies include steroids and nitric oxide. Priapism has been treated with analgesics, antianxiety agents, and vasoconstrictors to force blood out of the corpus cavernosum (eg, phenylephrine and epinephrine), and vasodilators to relax smooth muscle (eg, terbutaline and hydralazine). Treatment of aplastic crisis is primarily supportive. Blood transfusions may be indicated for severe or symptomatic anemia. Hydration and blood transfusions are indicated to treat hypovolemia associated with splenic sequestration. ☐ Manage recurrent episodes with observation and splenectomy. ☐ Consider chronic transfusions in children younger than 2 years of age to delay splenectomy until the age of 2 years. ☐ Splenectomy is an option for chronic hypersplenism. Hydration and analgesics are mainstays of treatment for vasoocclusive (painful) crisis. ☐ Administer fluids IV or orally at 1–1.5 times the maintenance requirement; monitor closely to avoid volume overload. ☐ Consider an infectious etiology and initiate empiric therapy if indicated Tailor analgesic therapy to the individual because of the variable frequency and severity of pain. ☐ Pain scales should be used to quantify the degree of pain. ☐ Use nonsteroidal anti-inflammatory drugs (NSAIDs) or acetaminophen for mild to moderate pain. Consider adding an opioid if mild to moderate pain persists. (eg, codeine or hydrocodone). Treat severe pain aggressively with an opioid, such as morphine, hydromorphone, fentanyl, or methadone. ☐ Avoid meperidine due to accumulation of the normeperidine metabolite, which can cause neurotoxicity, especially in patients with impaired renal function. ▪ Treat severe pain with an IV opioid titrated to pain relief and then administered on a scheduled basis with as-needed dosing for breakthrough pain ▪ Patient-controlled analgesia is commonly utilized. ▪ Treatment of chronic pain in SCD requires an interprofessional team approach. ▪ Guidelines for chronic pain management are available. EVALUATION OF THERAPEUTIC OUTCOMES ▪ Evaluate patients on a regular basis to establish baseline symptoms, monitor changes, and provide age-appropriate education. ▪ Evaluate CBC and reticulocyte counts every 3–6 months up to 2 years of age, then every 6–12 months. ▪ Screen HbF level annually until 2 years of age. ▪ Evaluate renal, hepatobiliary, and pulmonary function annually. Screen patients for retinopathy. ▪ Assess efficacy of hydroxyurea by monitoring the number, severity, and duration of sickle cell crises.