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ANEMIAS - THERAPEUTICS 3

Complete Pharmacotherapy Notes

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1. INTRODUCTION

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2. DEFINITION

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3. CLASSIFICATION

A. Based on MCV (Morphological)

B. Based on Pathophysiology

ANEMIA
├── Decreased Production (Hypoproliferative)
│   ├── Nutritional deficiency → IDA, Megaloblastic
│   ├── Bone marrow failure → Aplastic anemia
│   └── Chronic disease / CKD → ACD
├── Increased Destruction (Hemolytic)
│   ├── Intrinsic → Sickle cell, Thalassemia, G6PD deficiency
│   └── Extrinsic → Autoimmune, TTP, Infection
└── Blood Loss
    ├── Acute → Hemorrhagic anemia
    └── Chronic → Iron deficiency anemia

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4. ETIOLOGY

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5. PATHOPHYSIOLOGY - FLOWCHARTS

A. Iron Deficiency Anemia

LOW DIETARY IRON / CHRONIC BLOOD LOSS / MALABSORPTION
               ↓
    Depletion of Iron Stores (Ferritin ↓)
               ↓
    Reduced Transferrin Saturation (TIBC ↑, Serum iron ↓)
               ↓
    Inadequate iron delivered to erythroblasts in bone marrow
               ↓
    Impaired hemoglobin synthesis
               ↓
    Small, pale (hypochromic, microcytic) RBCs
               ↓
    Reduced oxygen-carrying capacity → ANEMIA

B. Megaloblastic Anemia

B12 / Folate Deficiency
        ↓
Impaired DNA synthesis (thymidylate & purine synthesis blocked)
        ↓
Nuclear maturation arrested; cytoplasm matures normally
("nuclear-cytoplasmic dissociation")
        ↓
Large, abnormal erythroblasts (megaloblasts) in bone marrow
        ↓
Ineffective erythropoiesis → Macrocytic anemia
        ↓
B12 deficiency ONLY: Demyelination of posterior/lateral columns
→ Subacute Combined Degeneration of Spinal Cord (SACD)

C. Hemolytic Anemia (Warm AIHA)

Aberrant immune activation
        ↓
IgG antibodies bind to RBC surface antigens at 37°C
        ↓
Splenic macrophages recognize Fc portion of IgG → Phagocytosis
        ↓
Extravascular hemolysis (spleen, liver)
        ↓
Hb released → Indirect bilirubin ↑ → Jaundice
        ↓
Bone marrow compensates → Reticulocytosis
        ↓
Persistent destruction > Production → ANEMIA

D. Aplastic Anemia

Trigger (drugs, radiation, infection, idiopathic)
        ↓
T-lymphocyte autoreactive activation
        ↓
T-cells destroy hematopoietic stem cells (HSC)
(via IFN-γ, TNF-α mediated apoptosis)
        ↓
Bone marrow hypoplasia / aplasia
        ↓
Pancytopenia: Anemia + Thrombocytopenia + Neutropenia
        ↓
Fatigue + Bleeding + Infections

E. Anemia of Chronic Disease (ACD)

Chronic Inflammation / Infection / Malignancy
        ↓
Cytokines (IL-6, IL-1, TNF-α) released
        ↓
Liver produces HEPCIDIN (key mediator)
        ↓
Hepcidin blocks ferroportin on macrophages & enterocytes
        ↓
Iron sequestered in macrophages → NOT available for erythropoiesis
+ Decreased EPO production and EPO resistance
        ↓
Normocytic, normochromic anemia (may become microcytic)

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6. CLINICAL FEATURES

General Features (All Anemias)

• Fatigue, weakness, lethargy
• Pallor (skin, conjunctiva, palms, nailbeds)
• Dyspnea on exertion
• Palpitations, tachycardia
• Headache, dizziness, fainting
• Reduced exercise tolerance
• In severe cases: angina, heart failure (high-output)

Type-Specific Features

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7. DIAGNOSIS

Laboratory Investigations

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8. TREATMENT GOALS

1. Restore hemoglobin and hematocrit to normal range
2. Replenish depleted stores (iron, B12, folate)
3. Identify and treat the underlying cause
4. Prevent complications (cardiac failure, neurological damage)
5. Improve quality of life, exercise tolerance, and organ function
6. Avoid adverse effects of treatment (iron overload, hypersensitivity)
7. Prevent recurrence through maintenance therapy where appropriate

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9. NON-PHARMACOLOGICAL TREATMENT

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10. PHARMACOLOGICAL TREATMENT

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DRUG GROUP 1: ORAL IRON PREPARATIONS

Mechanism of Action (MOA) - Flowchart

Oral Ferrous Salt Absorbed in Duodenum (as Fe²⁺)
        ↓
Enters mucosal cell via DMT-1 transporter
        ↓
Transported in blood bound to Transferrin (as Fe³⁺)
        ↓
Delivers iron to bone marrow erythroblasts
        ↓
Incorporated into heme → Hemoglobin synthesis ↑
        ↓
RBC production normalized → Correction of IDA

Drug Details

Clinical Pearl: Once-daily dosing on an empty stomach maximizes absorption (avoids hepcidin surge from multiple daily doses). Stool will turn dark/black - reassure patients. Expect Hb rise of ~1-2 g/dL over 3-4 weeks. Continue therapy 3-6 months after Hb normalizes to replenish stores.

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DRUG GROUP 2: PARENTERAL (INTRAVENOUS) IRON

MOA Flowchart

IV Iron administered (as complex colloidal preparation)
        ↓
Taken up by reticuloendothelial system (macrophages)
        ↓
Iron released from complex
        ↓
Stored as ferritin → Released to transferrin when needed
        ↓
Delivered to erythroblasts → Hemoglobin synthesis

Drug Details

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DRUG GROUP 3: VITAMIN B12 (CYANOCOBALAMIN / HYDROXOCOBALAMIN)

MOA Flowchart

B12 (as methylcobalamin) → Cofactor for Methionine Synthase
        ↓
Methylcobalamin + Homocysteine → Methionine + THF (Tetrahydrofolate)
        ↓
THF → 5,10-methylene THF → Thymidylate Synthesis
        ↓
DNA synthesis normalized
        ↓
Megaloblastic maturation arrest reversed
        ↓
Normal RBC production restored

(Also as adenosylcobalamin in mitochondria)
B12 + Methylmalonyl-CoA → Succinyl-CoA
(Maintains myelin sheath integrity → reverses/halts SACD)

Drug Details

Important: Neurological damage from B12 deficiency can be irreversible if not treated promptly. Always check B12 before giving folic acid alone (may mask B12 deficiency while neurological deterioration continues).

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DRUG GROUP 4: FOLIC ACID (FOLATE)

MOA Flowchart

Folic Acid (Pteroylglutamic acid)
        ↓
Reduced by Dihydrofolate Reductase (DHFR)
        ↓
Dihydrofolate (DHF) → Tetrahydrofolate (THF)
        ↓
THF acts as one-carbon donor in:
   ├── Thymidylate synthesis (DNA precursor)
   └── Purine synthesis (DNA/RNA)
        ↓
Normal DNA synthesis → Normal erythropoiesis

Drug Details

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DRUG GROUP 5: ERYTHROPOIESIS-STIMULATING AGENTS (ESAs)

MOA Flowchart

ESA binds to Erythropoietin Receptor (EPOR) on
erythroid progenitor cells (BFU-E, CFU-E) in bone marrow
        ↓
JAK2/STAT5 signaling pathway activated
        ↓
Proliferation and differentiation of erythroid progenitors ↑
        ↓
Anti-apoptotic signals (BCL-XL ↑) → progenitor survival
        ↓
Reticulocyte production ↑ → Mature RBC output ↑
        ↓
Hemoglobin ↑

Drug Details

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DRUG GROUP 6: IMMUNOSUPPRESSIVE AGENTS (Aplastic Anemia)

MOA Flowchart

Horse ATG (antithymocyte globulin)
        ↓
Anti-T-lymphocyte antibody → Lymphocyte depletion
        ↓
Reduces autoreactive T-cell destruction of HSCs
        ↓
Bone marrow suppression reversed → HSC recovery

+

Cyclosporine
        ↓
Inhibits calcineurin → Blocks IL-2 transcription
        ↓
T-cell activation and proliferation suppressed
        ↓
Maintenance of remission after ATG

+

Eltrombopag (Thrombopoietin receptor agonist)
        ↓
Stimulates HSC proliferation directly
        ↓
Enhanced overall + complete response rates

Drug Details

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DRUG GROUP 7: CORTICOSTEROIDS + RITUXIMAB (Hemolytic Anemia - AIHA)

MOA Flowchart

CORTICOSTEROIDS (Prednisone)
        ↓
Bind glucocorticoid receptor → Suppress NF-kB
        ↓
↓ Autoantibody production (B-cell inhibition)
↓ Fcγ receptor expression on splenic macrophages
↓ RBC phagocytosis in spleen
        ↓
Reduced extravascular hemolysis

RITUXIMAB (anti-CD20)
        ↓
Binds CD20 on B-lymphocytes
        ↓
ADCC + CDC → B-cell depletion
        ↓
↓ Autoantibody (IgG) production against RBCs
        ↓
Reduced hemolysis; sustained remission

Drug Details

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11. ADVANCED / NEW THERAPIES

1. Luspatercept (Reblozyl) - TGF-β Trap / Erythroid Maturation Agent

• Class: Activin receptor ligand trap (fusion protein)
• MOA: Binds TGF-β superfamily ligands (GDF11, Activin B) → Enhances late-stage erythroid maturation → Reduces ineffective erythropoiesis
• Indications: Beta-thalassemia (transfusion-dependent and non-transfusion-dependent), myelodysplastic syndromes (MDS) with ring sideroblasts - FDA approved; emerging use in IDA non-responsive to IV iron
• Dose: 1.0-1.25 mg/kg SC every 3 weeks
• ADRs: Hypertension, thromboembolic events, bone pain, dizziness

2. Roxadustat (Evrenzo) - HIF-PHI (Hypoxia-Inducible Factor - Prolyl Hydroxylase Inhibitor)

• Class: HIF-PH Inhibitor (oral small molecule)
• MOA: Inhibits prolyl hydroxylase domain enzymes → HIF-1α stabilization → Mimics hypoxic state → ↑ endogenous EPO production + ↑ intestinal iron absorption + ↓ Hepcidin
• Indications: CKD-associated anemia (dialysis and non-dialysis); approved in EU, Japan, China; FDA rejected for cardiovascular concerns
• Dose: Dialysis: 70-110 mg 3x/week; Non-dialysis: 70 mg 3x/week
• ADRs: Hypertension, thromboembolism, elevated ALT, nasopharyngitis
• Advantage over ESAs: Oral, lowers hepcidin (works in inflammation), lower cost

3. Sutimlimab (Enjaymo) - AIHA / Cold Agglutinin Disease

• Class: Anti-C1s monoclonal antibody (complement inhibitor)
• MOA: Inhibits C1s serine protease → Blocks classical complement pathway activation → Prevents RBC opsonization and hemolysis
• Indications: Cold agglutinin disease (first FDA-approved therapy, 2022)
• Dose: 6.5 g or 7.5 g IV every 2 weeks (weight-based)
• ADRs: Infusion reactions, headache, increased susceptibility to encapsulated organisms (Streptococcus pneumoniae prophylaxis needed)

4. Imetelstat - MDS/Anemia

• Class: Telomerase inhibitor
• MOA: Targets telomerase reverse transcriptase (TERT) → Inhibits proliferation of aberrant clones in MDS
• Indication: MDS-associated anemia (approved 2024 by FDA)

5. Eltrombopag / Avatrombopag - Beyond Aplastic Anemia

• Now explored in ITP, MDS, chemotherapy-induced thrombocytopenia, hepatitis C-related thrombocytopenia.

6. Gene Therapy (Emerging)

• Betibeglogene autotemcel (Zynteglo): Gene therapy for beta-thalassemia (FDA approved 2022) - introduces functional HBB gene via lentiviral vector; curative intent
• Exagamglogene autotemcel (Casgevy): CRISPR-based gene editing for sickle cell disease and beta-thalassemia (FDA approved 2023) - first approved CRISPR therapy

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12. SUMMARY CHART - PHARMACOLOGICAL TREATMENT

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QUICK PHARMACIST REFERENCE - DRUG INTERACTIONS SUMMARY

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