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1. Integrated pharmacotherapy III By Muktar Sano (B.Pharm, MSc in Clinical Pharma c y , Assistant P rof e ssor) 1

2. Course Objective Describe the pathophysiologic processes underlying hematological, psychiatric, neurologic, endocrine and metabolic, gynecology and obstetrics, urologic and dermatologic disorders. Analyze and interpret diagnostic findings relevant to above diseases . Recommend appropriate treatment regimen for patients suffering from above diseases .

3. Introduction Hematological disorders

4. Brain storming Define hematology Explain components of CBC Describe functions of blood 4

5. Hem a tolo g y Study of blood and blood forming tissues Key components of hematologic system are :  Blood  Blood forming tissues Bone marrow Spleen Lymph system 5

6. What Does Blood Do? Transportation  Oxygen  Nutrients  Hormones  Waste Products Regulation  Fluid, electrolyte  Acid-Base balance Protection  Coagulation  Fight Infections 6

7. Components of Blood Plasma - 55% Blood Cells-45% Three types Erythrocytes/RBCs Leukocytes/WBCs Thrombocytes/Platelets 7

8. Components of Blood…

9. Erythrocytes/Red Blood Cells Composed of hemoglobin Erythropoiesis  RBC production Stimulated by hypoxia( decrease in tissue oxygen) Controlled by erythropoietin Hormone synthesized in kidney Allows proliferation and maturation RBCs Induces Hb formation Hemolysis  destruction of RBCs  Releases bilirubin into blood stream  Normal lifespan of RBC = 120 days 9

10. Leukocytes/White Blood Cells 5 types  Basophils  Eosinophils  Neutrophils  Monocytes  L ympho c ytes 10

11. Thromb o cytes/Pl a telet s Must be present for clotting to occur Involved in hemostasis 11

12. Structures of the Hematologic System Bone Marrow Liver Ly m p h Syst e m 12

13. Bone Marrow  Soft substance in core of bones  Blood cell production (Hematopoiesis): The production of all types of blood cells generated by a remarkable self-regulated system. RBC production may also occur in liver and spleen

14. Li v er Receives 24% of the cardiac output (1500 ml of blood each minute) Liver has many functions Hematologic functions :  Liver synthesis plasma proteins including clotting factors and albumin  Liver clears damaged and non-functioning RBCs /erythrocytes from circulation 14

15. Spleen Located in upper Left quadrant of abdomen Functions  Hematopoietic function Produces fetal RBCs  Immune function Lymphocytes, monocytes  Storage function 30% platelets stored in spleen 15

16. Assessment of the Hematologic System  Important Health Information Past health history Medications Surgery or other treatments ― Physical Examination Skin Lymph Nodes, etc., 16

17. Diagnostic Studies :Complete Blood Count WBCs  Normal 4,000 -11,000 /µℓ - leukocytosis  Associated with infection, inflammation, tissue injury or death  Leukopenia --  WBC  Neutropenia --  neutrophil count RBC  ♂ 4.5 – 5.5 x 10 6 /uℓ  ♀ 4.0 – 5.0 x 10 6 /uℓ Hematocrit (Hct)  The hematocrit is the percent of whole blood that is composed of red blood cells .  The hematocrit is a measure of both the number of red blood cells and the size of red blood cells. 17

18. Diagnostic Studies : Complete Blood Count … Platelet count  Normal 150,000- 450,000  Thrombocytopenia-  platelet count  Spontaneous hemorrhage likely when count is below 20,000 Pancytopenia Decrease in number of RBCs, WBCs, and platelets 18

19. Diagnostic Studies of the Hematologic System Radiologic Studies  CT/MRI of lymph tissues Biopsies  Bone Marrow examination  Lymph node biopsies 19

20. 20 Pharmacotherapy of Anemias

21. Introductory case A 27-year-old African American woman scheduled a prenatal visit after a positive home pregnancy test. Previous pregnancies and deliveries were uncomplicated; she has healthy children ages 1.5 and 3 years. No other significant past medical history. Earlier this week she states feeling dizzy and short of breath after walking up stairs. What aspects of this patient’s history suggest she may be anemic? What laboratory assessments are required to make an appropriate diagnosis and therapeutic plan? How would the requested laboratory parameter(s) aid your decision making? 21

22. Learning objectives Upon completion of the chapter, each student will be able to: Identify common causes of anemia. Describe common signs and symptoms of anemia. Describe diagnostic evaluation required to determine the etiology of anemia. Recommend a treatment regimen considering the underlying cause and patient-specific variables. Develop a plan to monitor the outcomes of pharmacotherapy for the treatment of anemia 22

23. Outline Definition Epidemiology and etiology Pathophysiology and classification Clinical presentation and diagnosis Treatment Outcome evaluation 23

24. Introduction 24 Anemia is a group of diseases characterized by a decrease in hemoglobin (Hgb) or RBCs, resulting in decreased oxygen-carrying capacity of blood. Normal values: RBCs Men: 4.2 – 5.4 million/mm 3 Women: 3.6 – 5.0 million/mm 3 WHO defines anemia as  Hgb < 13 g/dL (<8.07 mmol/L) in men or  Hgb < 12 g/dL (<7.45 mmol/L) in women. Normal Hgb values are  Males= 14.0 to 17.5 g/dL (8.69–10.9 mmol/L) and  Females= 12.3 to 15.3 g/dL (7.63–9.50 mmol/L)

25. Epidemiology and Etiology According to the WHO, almost 1.6 billion people ( 25% of the world’s population ) are anemic. Patients with cancer and chronic kidney disease (CKD) have significantly higher rates of anemia. The incidence of anemia in cancer patients=30%-90%. Due to the underlying malignancy and myelosuppressive antineoplastic therapy. in CKD patients; 15% to 20% in patients with CKD stages 1 -stage 3 up to 70% in patients with stage 5. 25

26. Epidemiology and Etiology… Anemia is a common diagnosis  prevalence that varies widely based on age, gender, and race/ethnicity .  More common in blacks 26

27. Epidemiology and Etiology… Age-related reductions in bone marrow reserve can render elderly patients more susceptible to anemia in addition to multiple factors like nutritional deficiencies Pediatric anemias are often due to a primary hematologic abnormality.  The risk of IDA is increased by rapid growth spurts and dietary deficiency 27

28. Etiolo g y… The causes of anemia can be divided into three main categories: decreased production increased destruction, and blood loss 28

29. 29

30. Classification of Anemia… 30

31. Pathophysiology of Anemia Erythropoiesis: begins with a pluripotent stem cell in the bone marrow undergoing differentiation and ends with the appearance of RBCs in peripheral blood Reduction of oxygen-carrying capacity of blood= stimulated by EPO…> RBCs EPO stimulates differentiation of RBC precursors in the bone marrow to become reticulocytes Reticulocytes become erythrocytes after 1 to 2 days in the bloodstream 31

32. The process of erythropoiesis 32

33. Destruction of RBCs 33

34. Pathogenesis of Anemia 1. Decreased-Production Anemias Nutritional Deficiencies  Both folic acid and vitamin B12 are required for the formation of DNA.  Significant decreases in the amount of either nutrient inhibits DNA synthesis and consequently RBC production by hindering the process of erythrocyte maturation.  The deficiency of both can be caused by inadequate dietary intake, decreased absorption, and inadequate utilization. 34

35. Pathogenesis of Anemia… 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) 35

36. Pathogenesis of Anemia… Iron deficiency:  Iron is also essential for RBC production.  It is required for formation of Hgb.  Lack of iron leads to a decrease in Hgb synthesis and decreased RBC production.  Approximately 1 - 2 mg of iron is absorbed through the duodenum daily, and the same amount is lost via blood loss, Menstruation desquamation of mucosal cells, or Utilized by muscles, BM 36

37. Pathogenesis of Anemia… Iron-deficiency anemia (IDA) typically occurs because of inadequate absorption of iron or excessive blood loss.  Common causes include inadequate dietary intake, inadequate GI absorption, increased iron demand (eg, pregnancy), blood loss(excessive menstruation, ulcers or neoplastic lesions, surgery or trauma), and chronic diseases(CKD)  Inadequate absorption occurs in intestinal conditions, like inflammatory bowel disease, celiac disease, or bowel resection. 37

38. Daily Iron requirements Requirements for iron are determined largely by the rate of erythrocyte production Infants and children Adult females Pregnancy 38

39. Pathogenesis of Anemia… Dysregulation of Iron Homeostasis and Impaired Marrow Production  Chronic diseases associated with ACD include Infection, Autoimmune disease, CKD, and Cancer  A major contributing factor for development of ACD is disturbance of iron homeostasis related to activation of the immune system . 39

40. Pathogenesis of Anemia… Anemia of inflammation (AI): is a newer term used to describe both anemia of chronic disease and anemia of critical illness . AI is a hypoproliferative anemia that traditionally has been associated with infectious or inflammatory processes, tissue injury, and conditions associated with release of proinflammatory cytokines 40

41. Diseases Causing Anemia of Inflammation 41

42. Pathogenesis of Anemia… In anemia of critical illness , the mechanism for RBC replenishment and homeostasis is altered by, for example, blood loss or cytokines, which can blunt the erythropoietic response and inhibit RBC production. 42

43. Clin i cal P r esen t a ti o ns Signs and symptoms depend on the rate of development and the age and cardiovascular status of the patient. Acute-onset anemia is characterized by cardio- respiratory symptoms such as tachycardia , lightheadedness , and breathlessness . Chronic anemia is characterized by weakness , fatigue, headache, vertigo, faintness, cold sensitivity, pallor, and loss of skin tone. 43

44. Clinical Presentations … Iron-deficiency anemia is characterized by  glossal pain  smooth tongue  reduced salivary flow  pica (compulsive eating of nonfood items) and  pagophagia (compulsive eating of ice). These symptoms are not usually seen until the Hb concentration is less than 9 g/dL. 44

45. Clinical Presentations … Vitamin B12- and folate-deficiency anemias are characterized by  Pallor  icterus and  gastric mucosal atrophy Vitamin B12 anemia is distinguished by  neuropsychiatric abnormalities (e.g., numbness, paresthesias, irritability) which are absent in patients with folate-deficiency anemia. 45

46. Di a gnosis Rapid diagnosis is essential because anemia is often a sign of underlying pathology. Initial evaluation of anemia involves  a complete blood cell count  reticulocyte index and  examination of the stool for occult blood 46

47. Pertinent Laboratory Tests in the Evaluation of Anemia 4 7

48. Laboratory Tests… 48

49. E x ercise Name: M.K Age: 36 years Sex: male Interpretation:? Causes:? 49 CBC: Results Normal ranges RBC (x10 12 /L) 4.2 4.2-5.4 Hgb (g/dL) 10.6 11.5-15.5 Hct 34.9% 38%-47% MCV (fL/cell) 77.0 80-96 MCH(pg/RBC) 37.5 27-33 MCHC (g/dL) 30.4 32-36

50. Treatment Of Anemia The goal of anemia therapy are  To correct the underlying etiology (eg, restore substrates needed for RBC production), replace body stores to improve red cell oxygen- carrying capacity  To alleviate signs and symptoms  return of normal function and quality of life, and  prevention or reversal of long-term complications such as neurologic complications of vitamin B12 deficiency 50

51. Treatment of Anemia… Goal values To normalize Hgb and Hct 2g/dl increase in Hgb in 3 wks 6% increase in Hct in 3 wks Reticulocytosis will usually occurs within 1 wk * If these indices do not improve within these time frames, the diagnosis should be re-evaluated b. Replete iron stores - Although Hgb and Hct will return to normal within 1-2 months , iron therapy should continue for 3-6 months after Hgb is normalized to replace total body iron stores 51

52. Treatment Of Anemia… General Approach to the Anemic Patient The underlying cause of anemia must be determined and used to guide therapy 52

53. Nonpharmacologic Therapy 1. Transfusion of RBCs .  Safety concerns, cost, and the limited availability of this therapy support efforts to establish the “optimum” threshold for administering RBC transfusions.  Indication for transfusion “trigger for transfusion” for patients without significant cardiovascular disease is 7.0 g/dl 53

54. Nonpharmacologic … 2. Diet ingesting a diet that is rich in iron, folic acid, or vitamin B12 should be encouraged, but is rarely the sole modality of treatment 54

55. Pharmacologic Therapy A) Iron-Deficiency Anemia(IDA) 1. Oral iron therapy: that provides 150 - 200 mg of elemental iron daily .  Reticulocytosis should occur in 7 to 10 days, and Hgb values should rise by about 1.0 g/dl per week.  with soluble ferrous iron salts, not enteric coated, not slow- or sustained- release  Administration on an empty stomach (1 hour before or 2 hours after a meal) is preferred for maximal absorption. 55

56. Pharmacologic Therapy…  Ferrous sulfate=___ % of elemental iron  Ferrous gluconate=  Ferrous fumarate= 56 Oral Iron Products

57. E x ercise If patients develop intolerable GI side effects (ie, heartburn, nausea, bloating) after taking iron on an empty stomach, what to do ? 57

58. Pharmacologic Therapy… Clinically significant drug interactions involving iron products include fluoroquinolones, tetracyclines, and mycophenolate mofetil. The absorption of iron is influenced by gastric acidity.  drugs that decrease gastric acidity (antacids, PPIs, and H2RAs) may impair the absorption of iron. 58

59. Pharmacologic Therapy… 2. Parenteral iron therapy indications  Intolerant to oral formulations, or  Noncompliant to oral therapy, or  Failure to respond to oral iron because of malabsorption syndromes Parenteral administration, however, does not hasten the onset of hematologic response. 59

60. Pharmacologic Therapy… 60

61. Pharmacologic Therapy… 61 Equations for Calculating Doses of Parenteral Iron

62. Pharmacologic Therapy… adverse effects of parenteral iron therapy incidence of life-threatening adverse effects, typically anaphylactic-like reactions The newer products, sodium ferric gluconate and iron sucrose , appear to be better tolerated than iron dextran. Other adverse effects include arthralgias, arrhythmias, hypotension, flushing, and pruritus 62

63. Pharmacologic Therapy… 63 B) Vitamin B12 deficiency Anemia Oral vitamin B12 supplementation appears to be 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.

64. Pharmacologic Therapy… Vitamin B12 deficiency Anemia… Parenteral therapy acts more rapidly than oral therapy and is recommended if neurologic symptoms are present. cyanocobalamin 1000mcg IM daily for 1 week, then weekly for 1 month, and then monthly. Initiate daily oral administration after symptoms resolve Adverse events are rare with vitamin B12 therapy 64

65. Pharmacologic Therapy… C) Folate-deficiency Anemia  Oral folate, 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. 65

66. Pharmacologic Therapy… D) Anemia Of Inflammation (AI)  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 Hgb of 8 – 10 g/dl . 66

67. Pharmacologic Therapy… Erythropoiesis-stimulating agents (ESAs) can be considered, but response can be impaired in patients with AI (off-label use). The initial dosage for  Epoetin alfa is 50 -100 units/kg three times weekly and  Darbepoetin alfa 0.45 mcg/kg once weekly ESA use may result in iron deficiency. Many practitioners routinely supplement ESA therapy with oral iron therapy. 67

68. Early treatment of anemia in patients with CKD has been associated with slower disease progression and a lower risk of death once patients receive dialysis

69. Pharmacologic Therapy… In patients with anemia of critical illness , parenteral iron is often used but is associated with a theoretical risk of infection . Routine use of ESAs or RBC transfusions is not supported by clinical studies. 69

70. Pharmacologic Therapy… Anemia In Pediatric Populations Anemia of prematurity is usually treated with RBC transfusions. ESA use is controversial because it has not been shown to clearly reduce transfusion requirements. the daily dose of elemental iron, administered as iron sulfate, is 3 mg/kg for infants and 6 mg/kg for older children for 4 weeks. Continue for 2 additional months in responders to replace storage iron pools. 70

71. Pharmacologic Therapy…. Anemia In Pediatric Populations… The dose and schedule of vitamin B12 should be titrated according to the clinical and laboratory response. The daily dose of folate is 1 – 3 mg Anemia of prematurity is usually treated with RBC transfusions. The use of epoetin alfa is controversial. 71

72. Evaluation Of Therapeutic Outcomes IDA: P o s iti v e r e s p on s e to o r al i r on the r a p y c ha r act e riz e d by modest reticulocytosis in a few days with an increase in Hgb seen at 2 weeks. Reevaluate the patient if reticulocytosis does not occur. Hgb should return to normal after 2 months ; continue iron therapy until iron stores are replenished and serum ferritin normalized (up to 12 months). 72

73. Evaluation Of Therapeutic Outcomes Megaloblastic anemia: Signs and symptoms usually improve within a few days after starting vitamin B12 or folate 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. Hgb 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 folate therapy and should normalize within 2 months. 73

74. Evaluation Of Therapeutic Outcomes 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 Hgb, Hct, and RBC indices 6 to 8 weeks after initiation of iron therapy. Monitor Hgb or Hct weekly in premature infants. 74