Pharmacology RBC WBC Disorders

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HuskerDevil
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44368
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Pharmacology RBC WBC Disorders
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2010-10-23 13:59:46
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DPAP2012 Pharmacology RBC WBC Disorders
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Pharmacology RBC WBC Disorders
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  1. Hematology RBC WBC Disorders
    • Iron Deficiency Anemia
    • Anemia of Chronic Disease
    • Vitamin B-12 Deficiency
    • Folic Acid Deficiency
    • Thalassemia
  2. Iron Deficiency Anemia
    • Due to blood loss until proven otherwise. (GI, menstrual, hemolysis)
    • Total body iron stores: 2-4 grams
    • Majority of iron is in circulation (RBC)
    • 0.5 – 2 grams stored as ferritin, hemosiderin and in macrophages
    • Average diet: 10-15 mg / day
    • ~ 10% absorbed
  3. Increased Blood Losses:
    • Gastric surgery
    • Women: Menstrual, Pregnancy / Lactation, Complete loss of iron stores
    • Chronic Aspirin Use
    • Chronic hemoglobinuria
  4. Iron Formulations
    • Multiple formulations available
    • Elemental iron varies by formulation
    • Examples: Iron Aspartate, Iron Chloride, Iron Dextran, Iron Perchloride, Na Ferric Gluconate Complex, Sodium Ferric Gluconate Complex
  5. Oral Iron
    • Ferrous Sulfate
    • Not well tolerated (GI upset, constipation) – may improve if administered with food
    • May cause constipation – consider concomitant stool softener (esp in pregnancy)
    • Continue therapy 3-6 months after hemoglobin recovery
    • ‘Failure’ – Assess Compliance! Poor compliance may be due to intolerance of tx
    • Other Sources of Iron: Multivitamins (MVI) (read labels!), Eldertonic (MVI + sherry), Some oral contraceptives (‘inert tablets’)
  6. Parenteral Replacement
    • Considered if oral therapy not tolerated, successful or adequately rapid
    • Usually done inpatient
    • Anaphylaxis risk
    • Options: Iron Dextran (INFeD), Sodium Ferric Gluconate Complex (Ferrlecit), Iron Sucrose (Venofur)
  7. Iron Dextran (INFeD 50 mg/ml)
    • Can replace total body loss in one day
    • Test dose required: observe 60 min
    • IV over 4-6 hours
    • Daily slow IV doses may be given in dialysis
    • Deep IM Z track injection technique so it doesn’t leak out
  8. Sodium Ferric Gluconate (Ferrlecit)
    • Approved for use in dialysis patients >6 yo
    • Most patients will require a minimum cumulative dose of 1 gram of elemental iron = 8 doses to achieve a favorable Hgb response
    • Dosing outside of dialysis (off label)
    • May be diluted administered by IV infusion over 1 hour or undiluted as a slow IV injection
  9. Iron Sucrose Injection (Venofer)
    • Indicated for iron replacement in renal failure patients
    • Most patients require 1gram = 10 doses
    • Dosing rec’s outside of renal failure lacking
    • May be administered undiluted or diluted
  10. Anemia of Chronic Disease (ACD)
    • Hypoproliferative anemia
    • Generally associated with symptoms > 1-2 months
    • RBCs have shortened life span
    • EPO response is inadequate to maintain HGB
  11. Common Causes of ACD
    • Chronic Infections: TB, HIV, Osteomyelitis, Chronic Lung Infection, Subacute Bacterial Endocarditis
    • Less Common Causes of ACD: Alcoholic liver dz, CHF, COPD, Thrombophlebitis, =Ischemic heart disease
    • Chronic Inflammation: RA, SLE, Gout, Collagen Vasc dz, Chronic inflam liver dz, Inflam Osteoarthritis
    • Chronic Renal Failure*
    • Malignancies: Carcinomas, Heme Malignancies
  12. ACD Management
    • Treat / remove underlying cause when possible
    • Primary treatment: erythropoietin supplementation + iron
    • Transfusions effective: Minimize use to avoid iron overload
  13. Erythropoietin (EPO)
    • Naturally produced in the kidney
    • Stimulates the division and differentiation of committed erythroid progenitors in the bone marrow, ↑ RBC production
    • Recombinant formulation: Epogen & Procrit
    • Darbepoetin (Aranesp): Recombinant sugar formulation with additional carbohydrate chains. Longer half life → less frequent administration
    • Adequate iron stores required (supplementation)
  14. Vitamin B-12 Deficiency
    • Dietary Sources: 5 mcg / day
    • Bound to intrinsic factor or other cobalamin-binding proteins (R Factors)
    • B-12 bound to R factors not absorbed
  15. Treatment of B-12 Deficiency
    • Oral: 1000 mcg/day
    • Parenteral: 100 mcg IM or deep SC daily for 1 week, then alternate days for 7 doses, then every 3-4 days for another 2-3 week, then 100 mcg monthly for life
    • Nasal: 500 mcg gel or spray into one nostril once weekly
    • Concentrations are different: order in mcg’s
    • Generally well tolerated and can be managed at home.
  16. Folic Acid Deficiency
    • Initial replacement: 1 mg/day IM/IV/SC/PO
    • Maintenance therapy: 0.4 mg/day IM/IV/SC/PO
    • Pregnant and lactating women: 0.8 – 1 mg/day to prevent neural tube defect (spina bifida)
    • Also in fortified breakfast cereals, dried beans, leafy green vegetables and orange juice as folate
  17. Thalassemia
    • Hereditary disorders that affect the production of globulin chains that form hemoglobin
    • Alpha & Beta forms of disorder
    • Alpha thal: usually due to deletions
    • Beta thal: usually due to gene mutations
    • Occurs most frequently in people of Italian, Greek, Middle Eastern, Southern Asian and African ancestry
  18. Thalassemia Treatment
    • Transfusion support
    • Splenectomy
    • HSCT (stem cell transplant)
    • Iron Chelation
  19. Iron Chelation Therapy
    • Small molecules that bind very tightly to metal ions
    • Metal ions bound to the chelator are chemically inert and can then be excreted
    • One property required of clinically useful chelators is specificity. They must bind the target metal ion preferentially over others.
  20. Mechanism of Iron Toxicity
    • Iron can exist in either of two stable oxidation states – either in the ferrous (Fe2+) state or the ferric (Fe3+) state.
    • The shift of electrons between iron and donor molecules is the basis of energy production by controlled oxidation of carbohydrates, proteins, and lipids.
    • Iron is a key element in most of the cytochrome enzymes involved in the oxidative phosphorylation of the Krebs cycle (ATP production = energy)
  21. Ideal Iron Chelator Properties
    • Oral administration
    • Good tissue penetration
    • Easy mobilization of the iron-chelator complex
    • Inexpensive
    • Non-toxic AKA well tolerated
    • Hexidentate binding of iron ions
    • Doesn’t exist!!
  22. Deferoxamine (Desferal )
    • IV iron chelator
    • IV Infusion of 2-4 grams/day
    • SC administration limited to about 2.5 grams/day due to skin irritation
    • Larger doses can result in liver or renal dysfunction
    • Test dose recommended: Infusion reactions can occur
    • Can be administered IV or SQ via ambulatory infusion pump over 12-16 hours per day
    • Monitoring: 24 hour urine for iron, 30 mg or more should be excreted (generally measured on 3rd day of therapy)
    • Serious Acute Side Effects: infusion related rxns, urticaria, & laryngeal edema, itching
    • Patient counseling: use of the pump, urine will be orange, daily use (5+ days/week) generally required
    • Ascorbic Acid (Vitamin C): Ascorbic Acid increases iron excretion when used with deferoxamine, Should be initiated 1-2 months after chelator, HOLD when not receiving deferoxamine
    • Ascorbic Acid Risk with Deferoxamine: ↑ risk of iron related cardiac toxicities (congestive heart failure, conduction defects, and arrhythmia)
  23. Deferasirox (Exjade)
    • Oral Iron Chelator
    • Adjust dose every 3-6 months based on serum ferritin
    • Available in tablets for suspension in liquid which you drink
    • Expensive $$$$
    • Patient Instructions: Dissolve the tablet for suspension in water, orange juice, or apple juice, mix well, then drink the mixture right away. Add more liquid to glass and drink it all. Do not swallow or chew the tablet, and do not use it without mixing it in liquid first.
    • Black Box Warnings: May cause renal or hepatic impairment / failure &/or GI hemorrhage
    • Required: SCr / CrCl prior to therapy, weekly first month, then monthly while on treatment; Serum transaminases & bilirubin prior to, every two weeks first month, then monthly
    • Contraindicated if: CrCl <40 ml/min or SCr > 2X ULN, Platelets < 50,000, Poor performance status & high risk MDS or advanced malignancies
  24. Iron and Opportunistic Infections
    • Withholding iron from potential pathogens is a host defense strategy
    • Transferrin and lactoferrin are bacteriostatic in vitro for a number of bacteria
    • Lactoferrin: prominent component of the granules of polymorphonuclear leukocytes. The protein is released at high concentrations by the cells in areas of infection
    • Iron overload per se compromises the ability of phagocytes to kill microorganisms
    • A combination of problems likely contribute to the increase in susceptibility to infection in these patients
  25. Glucose-6-Phosphate Dehydrogenase Deficiency
    • Lack of glucose-6-phosphate dehydrogenase (enzyme present in RBCs) in the blood, which can cause hemolytic anemia
    • An inherited disorder (X linked)
    • Most common in African American males, also seen in persons from the Mediterranean & Asia
    • Mild cases: only older RBCs are affected.
    • Severe cases: RBC hemolysis is more serious & affects younger cells too
  26. G6PD Deficiency Management
    • Informing ALL healthcare providers that the patient has G6PD deficiency
    • Avoidance of certain medications, foods (fava beans), and environmental exposures (moth balls)
    • Avoid classes of medications that cause natural oxygen chemicals to accumulate. The ‘oxidative stress’ results in hemolytic episodes in people w/ G6PD deficiency
  27. Sample of Meds to Avoid With G6PD Deficiency
    • Aspirin & aspirin containing products
    • Sulfonamide ABX
    • Dapsone
    • Thiazide Diuretics
    • Vitamin K
    • Phenothiazine
    • Probenecid
    • Sulfonylureas
    • Confirm any & ALL new meds prior to prescribing for patient with G6PD deficiency.
  28. Life Spans of Blood Components
    • RBC = 90-120 days
    • Neutrophil = 7-12 hrs
    • Platelet = 7-8 days
  29. Acute Neutropenia
    • Incidence varies: agents/regimens, doses, schedule
    • Chemo most common cause
  30. WBC Therapeutic Options
    • Prophylactic Antibiotics (may help prevent infection)
    • Cytokines: Prevention vs Treatment post chemo
    • Management of Chronic Neutropenia: Antibiotics +/- Cytokines
  31. Cytokines G-CSF and GM-CSF
    • G-CSF: Filgrastim (SC) and PegFilgrastim (SC) (Not recommended for infants or children < 45kg)
    • GM-CSF: Sargramostim (IV or SC)
    • Indications: Chronic Neutropenia (Minimally effective dose schedule), Chemotherapy related (Specific to treatment regimen being used).
    • Decreases duration of neutropenia, but does not prevent occurrence
    • Start smallest dose possible
  32. G/GM-CSF Side Effects
    • Most common: Bone Pain (usually large bones, femur, pelvis, sternum)
    • Otherwise generally well tolerated: Rash, Influenza type illness
    • Rare: splenic rupture from over response, ARDS, SS (sickle cell) Crisis

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