Pharmacology for Blood Disorders

Question 1

What are the 4 types of Drug-induced blood dyscrasias that are the leading causes of death?

Answer 1

1. Aplastic anemia
2. Immune thrombocytopenia
3. Agranulocytosis
4. Hemolytic anemia

Question 2

What drugs can cause aplastic anemia and how (mechanism of toxicity)?

Answer 2

1. Dose-dependent (Direct): Cancer chemotherapy, chloramphenicol
2. Idiosyncratic (Metabolites): Carbamazepine, phenytoin

Question 3

How to manage aplastic anemia?

Answer 3

1. Withdraw causative agent
2. Immunosuppressant (CS, Ciclosporin, Cyclophosphamide, azathioprine, antithymocyte immunoglobulin)
3. GM-CSF (Sargramostim)
4. G-CSF (Filgrastim)
5. IL-14
6. RBC and platelet transfusion
7. Infection treatment (Symptom)
8. HSCT (May be necessary)

Question 4

What drugs can cause immune thrombocytopenia?

Answer 4

1. Heparin
2. Sulphonamides
3. Carbamazepine, phenytoin
4. GP IIb/IIIa inhibitors (Abciximab, eptifibatide, tirofiban)

Question 5

How to manage immune thrombocytopenia?

Answer 5

1. Withdraw causative agent
2. Immunosuppressants
3. Platelet transfusion (for significant bleed)

Question 6

What drugs can cause agranulocytosis / neutropenia and how (mechanism of toxicity)?

Answer 6

1. Direct - Thiamazole, chlorpromazine, ticlopidine, busulfan, zidovudine
2. Toxic metabolite - Clozapine, Carbimazole
3. Immune (hapten / complement) mediated - Beta lactams, PTU

Question 7

How to manage agranulocytosis?

Answer 7

1. Withdraw causative agent
2. Prophylaxis: G-CSF or GM-CSF
3. Routine WBC monitoring weekly

Question 8

What drugs can cause hemolytic anemia (immune and non-immune)?

Answer 8

Immune:
1. Autoantibody production
* Methyldopa (Drug-induced true)
* Quinine. quinidine (Innocent bystander immune complex)
2. Hapten-induced
* Penicillins, cephalosporins, streptomycin

Non-immune
* Protein adsorption - Cisplatin, oxaliplatin, BL inhibitors

Question 9

How to manage hemolytic anemia?

Answer 9

1. Withdraw causative agent
2. RBC transfusion (for low hemoglobin)
3. Hemodialysis (for acute renal failure)
4. Steroids and immunoglobulins (serious)
5. Rituximab Human anti-CD20 mab (for autoimmune hemolytic anemia)

Question 10

What categories of drugs are used for anemia supportive therapy?

Answer 10

Nutrients
- Iron e.g., ferrous sulphate (PO), iron sucrose (Parenteral)
- Vitamin B12 e.g., hydroxocobalamin
- Folic Acid

ESAs
- Darbepoetin alfa, epoetin alfa

Question 11

What drugs are used for neutropenia as supportive therapy?

Answer 11

Myeloid growth factors
- Recombinant G-CSF e.g., filgrastim, pegfilgrastim (+ plerixafor)
- Recombinant GM-CSF e.g., sargramostim

Question 12

What drugs are used for thrombocytopenia as supportive therapy?

Answer 12

Megakaryocyte growth factors / Platelet-Stimulating Agents (PSAs)
- Recombinant IL-11 e.g., oprelvekin
- Fc-fusion protein thrombopoietin receptor agonist e.g., romiplostim
- Oral nonpeptide thrombopoietin receptor agonists e.g., eltrombopag

Question 13

What are cytopenias?

Answer 13

1. Anemia
2. Neutropenia
3. Thrombocytopenia

Question 14

What drugs are used for blood cancers (leukemia, myelodysplastic syndrome, lymphoma)?

Answer 14

• Corticosteroids
• Immunosuppressants
• Cytotoxic chemotherapeutic drugs
• Targeted synthetic drugs
• Biologics
• Supportive therapies for cytopenias

Question 15

How do nutrient deficits lead to anemia? What kind of erythrocytes are produced?

Answer 15

Vitamin B12 and folate deficiency:
- Inhibit DNA synthesis and cell multiplication
- Few large hemoglobin-rich erythrocytes

Iron deficiency:
- Inhibit hemoglobin synthesis
- Few small hemoglobin-poor erythrocytes

Question 16

Iron ADRs? (Acute and Chronic)

How to treat overdose?

Answer 16

• Acute GI: Necrotizing gastroenteritis with vomiting, abdominal pain, and bloody diarrhoea followed by shock, lethargy, dyspnea, metabolic acidosis, coma and death.
• Chronic CV, liver: Haemochromatosis with iron deposited in heart, liver, pancreas and other organs → organ failure, death.
• Parenteral deferoxamine or oral deferasirox iron chelators to treat overdose

Question 17

Which Vitamin B12 parenteral is preferred and why?

Answer 17

Hydroxocobalamin > Cyanocobalamin

More protein binding => Longer retention in circulation

Question 18

Why is oral vitamin B12 usually not effective?

Answer 18

Deficiencies usually due to GI malabsorption in the first place

Question 19

Vitamin B12 ADR

Answer 19

1. Photosensitivity
2. Injection site reaction
3. HTN, hot flush, arrhythmias (secondary to hypokalemia)
4. GI disturbance
5. Dizziness, tremor, headache, paraesthesia
6. Chromaturia, acneiform and bullous eruptions, rash and itching

Question 20

Vitamin B12 DDI

Answer 20

PPIs reduce oral absorption

Question 21

PK profile of folic acid

Answer 21

1. Rapid absorption and peak (1h)
2. 100% bioavailability
3. Hepatic and plasma metabolism (Convert to 5MTHF) - Enterohepatic circulation
4. Urine excretion

Question 22

When is folic acid contraindicated?

Answer 22

Untreated cobalamin deficiency (Include pernicious anemia untreated)

Question 23

What special precautions to take for folic acid?

Answer 23

• Folate-dependent tumours, haemolytic anaemia, alcoholism.
• Women with pre-existing diabetes, obesity, family history of neural tube defects, or previous pregnancy affected by neural tube defect.
• Not appropriate for monotherapy in pernicious, aplastic, or normocytic anaemias when anaemia is present with vitamin B12 deficiency.
• Children. Pregnancy and lactation.

Question 24

Folic acid ADR

Answer 24

1. GI disorder, bitter taste, nausea, flatulence
2. Immune disorder (Allergy, rare)
3. Metabolism and nutrition disorder (Anorexia, rare)

Question 25

Folic acid DDI

Answer 25

1. Anticonvulsant (Have reduced plasma conc) 2. Lithium (Have enhanced efficacy) 3. Methotrexate (Have reduced effect) 4. Aspirin (Have increased elimination) 5. Sulfasalazine, triamterene (Have reduced absorption) 6. Chloramphenicol, cotrimoxazole (Interfere with folate metabolism)

Question 26

ESA Contraindications

Answer 26

Uncontrolled HTN

Question 27

ESA ADRs

Answer 27

1. HTN, edema 2. Thrombosis, platelet count increased, stroke 3. Hyperkalemia 4. Seizures 5. Myalgia, arthralgia, limb pain 6. GI effects (N/V) * Epoetin alfa: Pruritus * Darbepoetin alfa: Dyspnoea, cough, bronchitis

Question 28

G-CSF can be combined with...

Answer 28

Hematopoeitic stem cell mobilizer (Plerixafor)

Question 29

MOA of Myeloid growth factors

Answer 29

* Stimulate myeloid progenitor cells G-CSF * Stimulates proliferation and differentiation of progenitors committed to neutrophil lineage and * Additional activates phagocytic activity of mature neutrophils and prolongs their survival in circulation GM-CSF broader spectrum effects than G-CSF * Stimulates proliferation and differentiation of early and late granulocytic, erythroid and megakaryocyte progenitors

Question 30

Myeloid growth factors ADR

Answer 30

1. Well tolerated: G-CSF > GM-CSF 2. Bone pain (G-CSF) - Reversible 3. Fever, malaise, arthralgia, myalgia (GM-CSF) 4. Fatal: * Severe sickle cell crisis, capillary leak syndrome, respiratory failure or acute respiratory distress syndrome (ARDS) * Rarely, splenic rupture

Question 31

Special precautions for myeloid growth factors

Answer 31

* Patient with pre-malignant or malignant myeloid condition, acute myeloid leukaemia; sickle-cell trait or disease, recent history of pneumonia or lung infiltrates, osteoporotic bone disease * Not indicated for use in chronic myeloid leukaemia or myelodysplastic syndrome

Question 32

Megakaryocyte growth factor ADRs

Answer 32

1. Thromboembolism 2. Fluid retention, peripheral edema, dyspnea on exertion (Oprelvekin)

Question 33

Special precaution of megakaryocyte growth factors

Answer 33

* Patient with or with history of cerebrovascular disease * Risk factors for thromboembolism (e.g., advanced age, prolonged periods of immobilisation, malignancies, surgery/trauma, bleeding, obesity, smoking, contraceptives and hormone replacement therapy) * Eltrombopag: Higher dose required for patients of non-East Asian ancestry (e.g., not Chinese, Koreans, Japanese, Taiwanese, Thai) * Oprelvekin: Chronic heart failure or at risk of developing heart failure; and susceptibility to develop fluid retention