University of Nizwa College of Pharmacy and Nursing School of Pharmacy

1. University of Nizwa College of Pharmacy and Nursing School of Pharmacy PHARMACOTHERAPY III PHCY 510 Lecture 12Hematologic Disorders“Anemia”Dr. Sabin Thomas, M. Pharm. Ph. D.Assistant Professor in Pharmacy PracticeSchool of Pharmacy, CPNUniversity of Nizwa

2. Course Outcome • Upon completion of this lecture the students will be able to • Classify anemia based on morphology, • Describe pathophysiology, diagnosis, non-pharmacological and pharmacological treatment for Anemia, • Individualize the treatments for different types of Anemia patients.

3. Anemias are a group of diseases characterized by a decrease in hemoglobin (Hb) or red blood cells (RBCs), resulting in decreased oxygen-carrying capacity of blood. Etiology • Causes of anemia are blood loss, impaired erythropoiesis, and abnormal erythrocyte destruction. • Nutritional deficiencies [iron, cobalamin (B12), folate] are the most common cause of anemia . Erythropoiesis • In response to changes in tissue oxygen availability, kidney regulates production and release of erythropoietin that stimulates bone marrow to produce and release red blood cells.

4. Erythrocytes originate from pluripotent stem cells in the bone marrow • Early stages of red cell production -immature nuclei (pronormoblasts and basophilic normoblasts). • As cells mature, Hb is incorporated, the nucleus is extruded, and cell size decreases. Various nutrients are needed for normal erythropoiesis. • Lack of B12 or folatecan interfere with cell maturation, resulting in the release of megaloblasts (macrocytosis). • Iron deficiency interferes with Hb (Heam + globin) production and incorporation into maturing cells, continue to divide, resulting in smaller cells (microcytosis).

6. Classification • Macrocytic anemias • Megaloblasticanemias • Vitamin B12 deficiency • Folic acid deficiency anemia • Microcytic hypochromic anemias • Iron-deficiency anemia • Genetic anomaly • Sickle cell anemia • Thalassemia • Normocytic anemias • Recent blood loss • Hemolysis • Bone marrow failure • Anemia of chronic disease

7. Generally anemia means a lowering of hemoglobin concentration, red cell count, or packed cell volume (Hematocrit) to below `normal' values. • WHO's suggested definition of anemia: • Adult: a hemoglobin concentration below 13 g per 100 mL in men and below 12 g per 100 mL in women. • Children: below 12 g per 100 mL (6 to 14 years), or below 11 g per 100 mL (6 months to 6 years). • Symptoms of anemia are variable: fatigue, pallor, dyspnea, palpitations, faintness, anorexia, tachycardia, heart failure

8. Haemolyticanaemia • Defined as a reduction in the mean life span of RBC (120 days) due to premature destruction of red cells ‐‐‐‐‐ haemolysis. • Haemolyticanaemias may be either congenital or acquired: • The congenital disorders include: Sickle‐cell disease, beta‐thalassaemia and G6PD anaemia. • The acquired disorders include: The immune type e.g penicillin allergy and the non‐immune type e.g. malaria or snake venoms. • Some drugs cause hemolytic anemia eg. Phenobarbital, Phenytoin • those causes direct oxidative hemolytic damage to RBCs eg.Dapsone • Treatment of hemolytic anemia should focus on correcting the underlying cause. • No specific therapy for glucose-6-phosphate dehydrogenase deficiency. • Treatment consists of avoiding oxidant medications and chemicals.

9. Iron‐deficiency Anemia • If loss is increased, and/or intake decreased, a negative iron‐balance may lead to depletion of body iron stores, iron deficiency, and eventually to anemia. • Iron requirements are increased during infancy, puberty, pregnancy, and during menstruation. • Iron‐deficiency anemia's are most common in women and children. • Iron deficiency results in a microcytic, hypochromic anaemia, but the diagnosis should be confirmed by measurement of serum ferritin and total iron binding capacity (transferrin). • Anemia generally resolves after 1 to 2 months of adequate iron therapy. Iron should be continued for at least six months.

10. 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. • Almost all iron‐deficiency anemia's respond readily to treatment with iron. • The treatment of choice is oral administration of a ferrous salt. • Many iron compounds have been used for this purpose, but do not offer any real advantage over the simple ferrous sulfate, fumarate, orgluconate salts. • The usual adult dose is about 100 to 200 mg of elemental iron daily.

11. Parenteral iron may be required for patients with iron malabsorption, intolerance of oral iron therapy, or noncompliance. • The newer products, sodium ferric gluconateand iron sucrose, appear to be better tolerated than iron dextran. • If the intramuscular route is selected, a Z-trackmethod technique is recommended for administration. • This technique involves moving the subcutaneous tissue over the injection site laterally before inserting the needle. • After the iron dextran is administered, the tissue is slowly released as the needle is removed, covering the needle track. • This technique minimizes leakage through the needle track and skin staining.

12. The parenteral administration of iron dextran is associated with significant morbidity and anaphylactic reactions. • A 25 mg test dose of iron dextran is recommended prior to initiating an IV infusion of the drug. • Anaphylactic reactions are believed to be due to the dextran moiety rather than iron. • As a result, iron sucrose and ferric gluconate have become the predominant parenteral iron preparations used. • Ferric gluconate and iron sucrose may be given undiluted as a slow IV injection

13. Adverse effects of Iron: • Gastro‐intestinal irritation can occur with iron salts. • Nausea and epigastric pain are dose‐related. • Oral iron, particularly modified‐release preparations, can exacerbate diarrhoea in patients with inflammatory bowel disease • Iron preparations taken orally can cause constipation, particularly in older patients • If side‐effects occur, the dose may be reduced; or another iron salt may be used. May cause urine discoloration

14. Megaloblasticanaemia • Megaloblasticanaemia is a consequence of impaired DNA biosynthesis. • Usually due to a deficiency of B12 (cobalamins) or folate, both of which are essential for this process. • For immediate treatment, combined therapy for both deficiencies (B12 + Folic) may be started. • The patient may be converted to the appropriate treatment once the cause of the anaemiais known. • Deficiency of folate may be associated with neural tube defects if it occurs in pregnancy.

15. Vitamin B12- and folate-deficiency anemias can be caused by inadequate dietary intake (strict vegetarians), decreased absorption, and inadequate utilization. • Deficiency of intrinsic factor can cause decreased absorption of vitamin B12 (i.e., pernicious anemia). • Drugs can cause anemia by reducing absorption of folate (e.g., phenytoin) or by interfering with corresponding metabolic pathways (e.g., methotrexate) which may be reversed by folinic acid. • Vitamin B12 deficiency may result in neurological damage, including peripheral neuropathy and effects on mental function.

16. Spina bifida "split spine” is a developmental birth defect caused by the incomplete closure of the embryonic neural tube.

17. The treatment is with vitamin B12, almost always by the intramuscular since in most patients absorption from the gastrointestinal tract is inadequate. • Hydroxocobalaminis preferred to cyanocobalamin since it needs be given less often. • Hydroxocobalamin1 mg every 2 to 3 months for life is used to prevent a recurrence of the deficiency as in pernicious anaemia, total gastrectomy. • Oral folate1 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.

18. Women in the high risk group who wish to become pregnant • should take folic acid 5 mg daily to continue until week 12 of pregnancy. • Women with sickle‐cell disease • should continue taking their normal dose of folic acid 5 mg daily throughout pregnancy.

19. Anemia of Chronic Disease • Anemia of chronic disease is a hypo proliferative anemia associated with chronic infectious or inflammatory processes, tissue injury, or conditions that release proinflammatory cytokines. • Eg.Chronic Kidney Disease. • Treatment of anemia of chronic disease is less specific than that of other anemias. • It should focus on correcting reversible causes. • Iron therapy is not effective when inflammation is present.

20. RBC transfusions are effective. • Epoetinalfacan be considered, especially if cardiovascular status is compromised. • The initial dosage is 50 to 100 units/kg three times weekly. • If Hb does not increase after 6 to 8 weeks, the dosage can be increased to 150 units/kg three times weekly. • Reticulocytosisshould occur a few days after starting epoetinalfatherapy. • Iron, TIBC, transferring saturation, or ferritin levels should be monitored at baseline and periodically because iron depletion is a major reason for treatment failure.

21. Sickle cell Diseases • Sickle cell syndromes are hereditary disorders characterized by the presence of sickle hemoglobin (HbS) in red blood cells (RBCs). • Sickle‐cell disease is a formation of an abnormal haemoglobin SS, making the red cell sickle in shape. • The sickle‐cell trait (haemoglobin AS), is generally asymptomatic.

22. Pathophysiology • RBC polymerization allows deoxygenated hemoglobin to exist as a semisolid gel distorting RBCs into sickle shapes. • Sickle-shaped RBCs increase blood viscosity and encourage sludging in capillaries and small vessels causing hypoxia, risk of bacterial infection and coagulation abnormalities. • In addition to shortened survival, the decreased flexibility of deformed erythrocytes can lead to vaso occlusive crisis (VOC).

23. Feature presentations of SCD are hemolytic anemia and vaso occlusion.

24. Clinical Presentations • Vasoocclusive crisis VOC may produce pain due to infarction with no blood supply to the bones, lung, liver, kidney, penis (priapism), and brain (stroke). • Occasionally a large proportion of red cell mass become trapped in spleen or liver (sequestration crisis) with death due to anaemia. • Usual clinical signs and symptoms of SCD are chronic anemia; fever; pallor; arthralgia; scleral icterus; abdominal pain; weakness; anorexia; fatigue; enlarged liver, spleen, and heart; and hematuria.

25. Treatment • Treatment of sickle‐cell disease is essentially symptomatic. • Young children should receive prophylactic penicillin and influenza, meningococcal, pneumococcal vaccines, to reduce the risk of infection. • Infection should be treated early, • Folatesupplementation given because of increased erythropoiesis (RBCs production) • Sickle‐cell crisis requires hospitalization, with rehydration and analgesia (including morphine) for pain. • Blood transfusion is also important to avoid fatal anaemia. • Studies reported that therapy with hydroxycarbamide (hydroxyurea) caused a 44% reduction in the rate of painful crises. • Bone Marrow Transplantation is curative in some patients.

26. Phenoxymethylpenicillin (pen V) 125 mg 12 hourly • Folic acid 5 mg OD • Mefenamicacid 250 mg / Ibuprofen 200 mg TDS / prn. • Morphine BD / Tramadol / co‐codamol 2‐4 times daily prn • Hydroxycarbamide(hydroxyurea) 500 mg BD • reduce the frequency of crises in sickle‐cell disease and reduce the need for blood transfusions. • Hydroxyurea, a chemotherapeutic agent, has many effects on blood cells, including the stimulation of HbF production. • It is indicated for patients with frequent painful episodes, severe symptomatic anemia, acute chest syndrome, or other severe vasoocclusive complications

27. -Thalassemia • Thalassemia major result from faulty mRNA transcription of the gene. • Due to a deficiency in beta globin production and interference with red cell maturation. • The RBCs are trapped and destroyed in the spleen. • The condition is characterised by a hypochromic, microcytic anaemia accompanied by haemolysis. • Heterozygous -thalassemia is much less severe than homozygous forms of the disease.

28. Patients either have a clinically undetectable disorder (‘‘-thalassemia minima’’) or one that results in only mild anemia (‘‘ -thalassemia minor’’ or ‘‘ -thalassemia trait’’). • In thalassaemiatrait/minor where only one of the beta globin genes is affected, the anaemia is mild and clinically insignificant. • Patients with  -thalassemia minima are asymptomatic, blood values (i.e., hemoglobin concentration and MCV) within normal limits, and require no treatment. • Homozygous forms of  -thalassemia can be classified as either ‘‘  -thalassemia intermedia’’ or ‘‘  -thalassemia major’’ (Cooley’s anemia) is associated with severe anemia and requires intensive chronic treatment.

29. Clinical Presentations • Bone marrow hypertrophy with subsequent abnormal skeletal growth usually develops in children from the second year of life through 10 years of age. • Abnormal skeletal changes are most apparent in the craniofacial bones due to maxillary overgrowth, protrusion of teeth, and separation of orbits. • Liver and spleen enlargement • Bone changes – jaw, forehead • Arrhythmias • Pain, lack of appetite, fatigue • Haemoglobin< 8 (10-11g/dL)

30. Treatment include supportive therapy with chronic blood transfusion and iron chelation regimens. • Regular blood transfusion to correct the anaemia. • Transfusions should be started as early as possible in life. Repeated transfusion results in iron overload , leading eventually to haemochromatosis. • The consequences of haemochromatosisinclude liver dysfunction, endocrine dysfunction, hypogonadism, diabetes and hypothyroidism, arrhythmias and heart failure. • If unchecked, the iron build‐up usually leads to death (mainly through heart failure or arrhythmia).

31. Packed red blood cells (PRBCs), rather than whole blood, are used for all thalassemia transfusion protocols. • Each unit of PRBCs (450 mL) contains 200 to 250 mg of elemental iron. • By 12 years of age, a properly transfused patient with thalassemia has likely received over 50 g of iron. • The normal iron content of the body is 2 g, and there is no natural mechanism by which excess amounts may be excreted. • Deferoxamine, a trihydroxamic acid produced by Streptomyces pilosus, remains the primary option for chelating and removing excess iron. • The accumulation of iron can be retarded by the use of the chelating agent desferrioxamine injection. • Deferiproneand deferasiroxhave been used as an oral alternative to desferrioxamine,

32. Due to poor oral absorption, deferoxamine must be given parenteral. • The subcutaneous route is generally considered. • Because of its short half-life (5 to 10 minutes), deferoxamineis usually administered by continuous infusion. • Typical deferoxamine dosing regimens are 30 to 50 mg/kg/day infused subcutaneously over 8 to 12 hours, 5 or 6 days a week.