Specific Intended Learning Objectives

Drugs for Anemia

Pharmacology and Toxicology HLS Module

Second Year Medical Students Tareq Saleh, MD, PhD

Faculty of Medicine The Hashemite University

Specific Intended Learning Objectives

By the end of these lectures the students should be able to:

1. List the different approaches utilized for the treatment of anemia based on its classification.

2. Describe the main characteristics of iron preparations, their therapeutic indications, pharmacokinetics, and major adverse effects.

3. Describe the mechanism of action of folic acid and vitamin B₁₂, their therapeutic indications and major adverse effects.

4. Understand the role of erythropoietin in the treatment of anemia, therapeutic guidelines, and major adverse effects.

Reference in Textbook

Anemia

“decreased (below-normal) plasma hemoglobin concentration resulting from decreased RBCs or abnormally low hemoglobin/blood volume”

Agents Used to Treat Anemias

• Iron

• Folic acid

• Cyanocobalamin and

hydroxocobalamin (vitamin B₁₂) • Erythropoietin and darbepoetin • Hydroxyurea

Iron

• Storage (liver, spleen, bone marrow, intestinal mucosa): ferritin (iron-protein complex)

• Transport (to the bone marrow):

Iron Deficiency Anemia

• Most common nutritional deficiency

• Negative iron balance: depletion of iron stores and/or inadequate intake. • Examples: acute/chronic

blood loss, menstruation, accelerated growth in

Iron

Mechanism of action:

• Replace deficient iron levels

• 150-180 mg/day elemental iron (2-3 doses/day)

Iron

Pharmacokinetics

• Given orally or IV

• Gastric acidity keeps iron in the ferrous form: Fe → Fe+2

• Main site of absorption: duodenum • Extent of absorption depends on

Iron

Takes weeks to replenish stores

Parenteral preparations ❑Iron dextran

❑Sodium ferric gluconate ❑Ferumoxytol

❑Ferric carboxymaltose ❑Iron sucrose

faster

Intravenous iron given when oral iron is not tolerated or in combination with erythropoietin (hemodialysis or chemotherapy)

Iron

Adverse effects

• GI disturbances: pain, constipation, nausea, diarrhea • Dark stool (most common side effect)

• Hypersensitivity/anaphylaxis (iron dextran)

IV iron should be used cautiously in patients with active infections. Why?

Iron toxicity

• Excessive iron can result in toxicities

• Usually results from frequent blood transfusion

• Treatment: deferoxamine (used for chelation of iron in both acute and chronic toxicity.)

Folic acid (Folate)

• Causes of folate deficiency:

1. Increased demand (e.g., pregnancy, lactation) 2. Poor absorption (e.g., intestinal pathology) 3. Alcoholism

4. Drugs:

❑ Dihydrofolate reductase inhibitors, e.g., methotrexate, trimethoprim ❑ DNA synthesis inhibitors, e.g., azathioprine, zidovudine

Folate deficiency

Folic acid deficiency → ↓ synthesis

of purines and pyrimidines →

Folic acid (Folate)

• Absorption: jejunum

• Oral folic acid is not toxic (even at high doses) • Rare hypersensitivity to IV injection

Cyanocobalamin and Hydroxocobalamin

(vitamin B

)

• Causes of vitamin B₁₂ deficiency: 1. Low dietary intake

2. Malabsorption (e.g., pernicious anemia: ↓ intrinsic factor) 3. Loss of activity of intestinal B₁₂ receptor

Vitamin B

₁₂

deficiency

• Which form of anemia detected on blood film is associated with vitamin B₁₂ deficiency?

Megaloblastic anemia

• What happens if folic acid is used to treat vitamin B₁₂ deficiency?

Reverse the hematologic problem but masks vitamin B deficiency

• Where is Vitamin B₁₂ is absorbed in the gut?

Cyanocobalamin and Hydroxocobalamin

(vitamin B

)

• Orally: for dietary deficiencies

• IM, or deep subcutaneously: pernicious anemia, malabsorption, ileal resection

Hydroxocobalamin (IM): rapid response

Erythropoietin and darbepoetin

Which cells secret erythropoietin? _________________________ What is the function of erythropoietin?

1. _____________________ 2. _____________________ 3. _____________________

Peritubular cells in the kidney

Stimulates the differentiation of proerythroblasts Promotes the release of reticulocytes

Human recombinant erythropoietin

(epoietin alpha)

Therapeutic uses:

1. Anemia due to end-stage renal disease 2. Anemia due to HIV infection

3. Anemia due to bone marrow suppression 4. Anemia due to malignancy

Darbepoetin

• Long-acting

• Half-life: 3 times > epoetin alpha

Both epoetin alpha and darbepoetin are NOT useful for the treatment of acute anemia. Why?

Erythropoietin and darbepoetin

Recommendations for patients receiving epoetin alpha or darbepoetin:

• Minimum effective dose that does not exceed hemoglobin level of 12 g/dL

• Minimum effective dose that does not rise hemoglobin level of 1g/dL over a 2-week period

Erythropoietin and darbepoetin

Adverse effects:

• Edema

• Hypertension • Arthralgia

• Thrombosis/increased risk of death (if used to target hemoglobin levels over 11 g/dL)

Agents Used to Treat Neutropenia

• Filgrastim, tbo-filgrastim and pegfilgrastim: granulocyte colony-stimulating factors (G-CSF)

• Sargramostim: granulocyte-macrophage colony-stimulating factors (GM-CSF)

Agents Used to Treat Neutropenia

Therapeutic doses

Prophylaxis against neutropenia following chemotherapy and bone marrow transplantation

Agents Used to Treat Neutropenia

Pharmacokinetcs

• Filgrastim and sargramostim: subcutaneous, IV

• tbo-filgrastim and pegfilgrastim: subcutaneous ONLY

• Filgrastim, tbo-filgrastim and sargramostim: once daily 24-72 hours after chemotherapy until ANC is 5000-10000/μL

Agents Used to Treat Neutropenia

Adverse effects

Agents Used to Treat Sickle Cell Disease

Hydroxyurea • Oral

• Ribonucleotide reductase inhibitor - interferes with DNA synthesis

Agents Used to Treat Sickle Cell Disease

Mechanism of action

• Increases HbF levels → dilutes HbS → reduces polymerization of HbS → reduce sickling and painful crises

Agents Used to Treat Sickle Cell Disease

Mechanism of action

• Increases HbF levels → dilutes HbS → reduces polymerization of HbS → reduce sickling and painful crises

Hydroxyurea is usually prescribed by a hematologist, using rigorous selection criteria. Indications for hydroxyurea include the following:

• Frequent painful episodes (six or more per year) • History of acute chest syndrome

• History of other severe vaso-occlusive events • Severe symptomatic anemia

• Severe unremitting chronic pain that cannot be controlled with conservative measures

Agents Used to Treat Sickle Cell Disease

Adverse effects

• Myelosuppression • Cutaneous vasculitis • etc…