drugs for anemia - humsc

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Drugs for AnemiaPharmacology 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.

5. List pharmacological therapy utilized for the treatment of neutropenia.

6. Describe the role of hydroxyurea in the treatment of sickle cell anemia, its mechanism of action

and overall contribution to disease outcome.


Reference in Textbook

Chapter 42: Drugs for Anemia (pp: 565-571)


Anemia

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


Signs and Symptoms of Anemia


Classification of Anemia


Agents Used to Treat Anemias

• Iron

• Folic acid

• Cyanocobalamin and hydroxocobalamin (vitamin B12)

• Erythropoietin and darbepoetin

• Hydroxyurea

• Transfusion of whole blood


Iron


Iron

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

• Transport (to the bone marrow):transferrin


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 children…..


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 stores


Iron

Oral preparations

❑Ferrous sulfate❑Ferrous fumarate❑Ferrous gluconate❑Polysaccharide-iron

complex❑Carbonyl 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)


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

❑ Drugs that reduce folate absorption, e.g., phenytoin, phenobarbital


Folate deficiency

Folic acid deficiency →↓ synthesis of purines and pyrimidines →

megaloblastic anemia


Folic acid (Folate)

• Absorption: jejunum

• Oral folic acid is not toxic (even at high doses)

• Rare hypersensitivity to IV injection


Vitamin B12


Cyanocobalamin and Hydroxocobalamin(vitamin B12)

• 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

4. Gastric resection


Vitamin B12 deficiency


Vitamin B12 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?

Ileum


Cyanocobalamin and Hydroxocobalamin(vitamin B12)

• Orally: for dietary deficiencies

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

Hydroxocobalamin (IM): rapid response

Cyanocobalamin: daily (high oral doses) or monthly (parenteral)


Erythropoietin and Darbepoetin


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 proerythroblastsPromotes the release of reticulocytesInitiates hemoglobin formation


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

Administered IV

Combined with iron supplements


Darbepoetin

• Long-acting

• Half-life: 3 times > epoetin alpha

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



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

• If hemoglobin levels rise above 10 g/dL dose must be reduced



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)

❖Stimulate granulocyte production in the bone marrow



Therapeutic doses

Prophylaxis against neutropenia following chemotherapy and bone marrow transplantation



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

• Pegfilgrastim: single dose 24 hours after chemotherapy (long-acting)



Adverse effects

Bone pain


Hydroxyurea


Agents Used to Treat Sickle Cell Disease

Hydroxyurea

• Oral

• Ribonucleotide reductase inhibitor

- interferes with DNA synthesis



Mechanism of action

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

• Needs 3-6 months

Green et al, Nature 2013



Mechanism of action

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

• Needs 3-6 months


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

• History of stroke or a high risk for stroke

National Institutes of Health Consensus Development Conference statement: hydroxyurea treatment for sickle cell disease.



Adverse effects

• Myelosuppression

• Cutaneous vasculitis

• etc…

drugs for anemia - humsc

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