Pharmacology for Blood Disorders Flashcards
What are the 4 types of Drug-induced blood dyscrasias that are the leading causes of death?
- Aplastic anemia
- Immune thrombocytopenia
- Agranulocytosis
- Hemolytic anemia
What drugs can cause aplastic anemia and how (mechanism of toxicity)?
- Dose-dependent (Direct): Cancer chemotherapy, chloramphenicol
- Idiosyncratic (Metabolites): Carbamazepine, phenytoin
How to manage aplastic anemia?
- Withdraw causative agent
- Immunosuppressant (CS, Ciclosporin, Cyclophosphamide, azathioprine, antithymocyte immunoglobulin)
- GM-CSF (Sargramostim)
- G-CSF (Filgrastim)
- IL-14
- RBC and platelet transfusion
- Infection treatment (Symptom)
- HSCT (May be necessary)
What drugs can cause immune thrombocytopenia?
- Heparin
- Sulphonamides
- Carbamazepine, phenytoin
- GP IIb/IIIa inhibitors (Abciximab, eptifibatide, tirofiban)
How to manage immune thrombocytopenia?
- Withdraw causative agent
- Immunosuppressants
- Platelet transfusion (for significant bleed)
What drugs can cause agranulocytosis / neutropenia and how (mechanism of toxicity)?
- Direct - Thiamazole, chlorpromazine, ticlopidine, busulfan, zidovudine
- Toxic metabolite - Clozapine, Carbimazole
- Immune (hapten / complement) mediated - Beta lactams, PTU
How to manage agranulocytosis?
- Withdraw causative agent
- Prophylaxis: G-CSF or GM-CSF
- Routine WBC monitoring weekly
What drugs can cause hemolytic anemia (immune and non-immune)?
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
How to manage hemolytic anemia?
- Withdraw causative agent
- RBC transfusion (for low hemoglobin)
- Hemodialysis (for acute renal failure)
- Steroids and immunoglobulins (serious)
- Rituximab Human anti-CD20 mab (for autoimmune hemolytic anemia)
What categories of drugs are used for anemia supportive therapy?
Nutrients
- Iron e.g., ferrous sulphate (PO), iron sucrose (Parenteral)
- Vitamin B12 e.g., hydroxocobalamin
- Folic Acid
ESAs
- Darbepoetin alfa, epoetin alfa
What drugs are used for neutropenia as supportive therapy?
Myeloid growth factors
- Recombinant G-CSF e.g., filgrastim, pegfilgrastim (+ plerixafor)
- Recombinant GM-CSF e.g., sargramostim
What drugs are used for thrombocytopenia as supportive therapy?
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
What are cytopenias?
- Anemia
- Neutropenia
- Thrombocytopenia
What drugs are used for blood cancers (leukemia, myelodysplastic syndrome, lymphoma)?
- Corticosteroids
- Immunosuppressants
- Cytotoxic chemotherapeutic drugs
- Targeted synthetic drugs
- Biologics
- Supportive therapies for cytopenias
How do nutrient deficits lead to anemia? What kind of erythrocytes are produced?
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
Iron ADRs? (Acute and Chronic)
How to treat overdose?
- 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
Which Vitamin B12 parenteral is preferred and why?
Hydroxocobalamin > Cyanocobalamin
More protein binding => Longer retention in circulation
Why is oral vitamin B12 usually not effective?
Deficiencies usually due to GI malabsorption in the first place
Vitamin B12 ADR
- Photosensitivity
- Injection site reaction
- HTN, hot flush, arrhythmias (secondary to hypokalemia)
- GI disturbance
- Dizziness, tremor, headache, paraesthesia
- Chromaturia, acneiform and bullous eruptions, rash and itching
Vitamin B12 DDI
PPIs reduce oral absorption
PK profile of folic acid
- Rapid absorption and peak (1h)
- 100% bioavailability
- Hepatic and plasma metabolism (Convert to 5MTHF) - Enterohepatic circulation
- Urine excretion
When is folic acid contraindicated?
Untreated cobalamin deficiency (Include pernicious anemia untreated)
What special precautions to take for folic acid?
- 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.
Folic acid ADR
- GI disorder, bitter taste, nausea, flatulence
- Immune disorder (Allergy, rare)
- Metabolism and nutrition disorder (Anorexia, rare)
Folic acid DDI
- Anticonvulsant (Have reduced plasma conc)
- Lithium (Have enhanced efficacy)
- Methotrexate (Have reduced effect)
- Aspirin (Have increased elimination)
- Sulfasalazine, triamterene (Have reduced absorption)
- Chloramphenicol, cotrimoxazole (Interfere with folate metabolism)
ESA Contraindications
Uncontrolled HTN
ESA ADRs
- HTN, edema
- Thrombosis, platelet count increased, stroke
- Hyperkalemia
- Seizures
- Myalgia, arthralgia, limb pain
- GI effects (N/V)
- Epoetin alfa: Pruritus
- Darbepoetin alfa: Dyspnoea, cough, bronchitis
G-CSF can be combined with…
Hematopoeitic stem cell mobilizer (Plerixafor)
MOA of Myeloid growth factors
- 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
Myeloid growth factors ADR
- Well tolerated: G-CSF > GM-CSF
- Bone pain (G-CSF) - Reversible
- Fever, malaise, arthralgia, myalgia (GM-CSF)
- Fatal:
* Severe sickle cell crisis, capillary leak syndrome, respiratory failure or acute respiratory distress syndrome (ARDS)
* Rarely, splenic rupture
Special precautions for myeloid growth factors
- 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
Megakaryocyte growth factor ADRs
- Thromboembolism
- Fluid retention, peripheral edema, dyspnea on exertion (Oprelvekin)
Special precaution of megakaryocyte growth factors
- 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
