Lecture 20 - DIHD Flashcards
Why are we concerned about blood toxicity?
- blood has many functions - exchanges oxygen and CO2
- maintains fluid balance (controls BP)
- immune function
- blood also transports drugs
What are the blood cells?
- erythrocytes
- granulocytes (leukocytes)
- platelets
How fast are blood cells produced?
produced at a rate of 1 million to 3 million per second
What is hematopoietic tissue sensitive to?
cytoreductive or anti mitotic agents
What will happen from direct or indirect damage to blood?
life threatening (hypoxia, infection, hemorrhage)
Hematotoxicology
study of the adverse effects of exogenous chemicals on blood and blood-forming tissues
What is hematopoiesis?
- occurs in bone marrow in healthy adults
- stem cells stimulated (potions or colony-stimulating factors) to differentiate into committed cells that further mature
DIHD
drug-induced hematological disorders
- *not very common, but can be very severe when they do occur
0. 01% drug-induced agranulocytosis (mortality rates 11-48%)
The earlier the DIHD occurs in the cascade of hematopoiesis, the more _____ the disorder
severe
What drugs suppress bone marrow?
- methotrexate
- cyclophosphamide
- colchicine
- azathioprine
- ganciclovir
Primary hematotoxicity
- direct cytotoxic mechanism
- immunological mechanism
Secondary hematotoxicity
- toxic effect a consequence of other tissue injury or systemic disturbances
- damage caused by reactive/compensatory mechanism
Idiosyncratic hematotoxicity
unknown cause
List some manifestations of hematotoxicity
- anemia
- thrombocytopenia
- leukopenia
- pancytopenia (deficiency of RBC, WBC, and platelets)
- decrease RBC, hemoglobin, platelets, WBC, neutrophils, eosinophils, basophils, all blood cells
Drugs may alter RBC ___, ___, and ____
production, function, and survival
How can production of RBC be altered?
- cell division/hematopoiesis
- hemoglobin synthesis
which can result in:
- iron deficiency anemia
- sideroblastic anemia
- megaloblastic anemia
- aplastic anemia
- polycythemia
How can function of RBC be altered?
through effects on hemoglobin will affect O2/CO2 transport - cause shifts in oxygen dissociation curve
can result in methemoglobinemia (an abnormal amount of methemoglobin is produced)
methemoglobin is a form of hemoglobin
How can survival of RBC be altered?
normally approx 120 days but shortened by:
- oxidative injury
- decreased metabolism
- altered membrane
can result in hemolytic anemias, immune-mediated, oxidative injury, G6PD deficiency
Production:
What is sideroblastic anemia?
interference with heme synthesis
Production:
What drugs can cause sideroblastic anemia?
- EtOH
- isoniazid (without vitamin B6 supplementation)
- chloramphenical
- linezolid
- zinc toxicity (copper deficiency)
- lead
Production:
Is sideroblastic anemia reversible?
yes - upon drug discontinuation
Production:
What is Megaloblastic anemia
abnormal development of RBC precursors (megaloblasts)
Production:
What drugs can cause megaloblastic anemia?
- Drugs with effects on DNA synthesis (antineoplastics, immunosuppressants, allopurinol, anti-retrovirals)
- Folate and/or vitamin B12 deficiency - inadequate dietary intake or drugs
a) which inhibit dihydrofolate reductase -Sulfa trim
b) which inhibit folate absorption/increase in folate catabolism - phenytoin, primidone, phenobarbital
Production:
What is aplastic anemia?
bone marrow failure
- injury to pluripotent stem cell in bone marrow
- pancytopenia, reticulocytopenia, bone marrow hypoplasia
Production:
What drugs cause aplastic anemia?
- sulfonamides
- carbamazepine
- gold compounds
- mercury, arsenic
Production:
What other things cause aplastic anemia?
radiation, pregnancy, viruses, immune disorders, idiopathic
Production:
When can aplastic anemia be predictable?
cytotoxic chemotherapy, benzene, radiation
Production:
Fatality rate of aplastic anemia
high (50%)
Production:
onset of aplastic anemia
insidious onset (6-7 weeks)
Production:
describe the presentation of aplastic anemia
-fatigue, weakness, stomatitis, easy bruisability, petechiae, purport, recurrent infections, bleeding
death within 18 months
Production:
treatment of aplastic anemia
- withdrawal of drug
- symptomatic treatment of bleeding, infection
- immunosuppressive therapy: corticosteroids, cyclosporine, GM-CSF, IL-1, GCSF, antithymocyte globulin
- bone marrow transplant
Production:
describe the presentation of Erythrocytosis
- chest/abdominal pain
- myalgia, weakness, fatigue
- headache
- paresthesias
- blurred vision/transient loss of vision
- poor mentation/sense of depersonalization
- Risk of VTE
Production:
describe the mechanisms that cause erythrocytosis
1) Increased erythropoiesis (production of RBC)
- blood doping
- self-injection of erythropoietin
- testosterone (especially ester injections), anabolic steroids
- chronic/occupational exposure to CO (ex. taxi drivers)
2) Decreased plasma volume
- diuretics
3) Both (ex smoking)
- will cause chronic hypoxia
Function:
What is the antidote for methemoglobinemia?
methylene blue
increases rate of methemoglobin reduction
Function:
What is methemoglobin
heme iron oxidized to ferric state
- cannot bind/transport O2
- normal control mechanisms maintain low methemoglobin concentration
- oxidizing drugs can overwhelm these (nitrites, nitrates, nitroglycerin, topical anesthetics, dapsone)
- street drugs may have oxidizing drugs as additives
Survival:
What is a hapten?
molecule that does not trigger antibody production on it’s own but when it combines with a protein, it triggers antibody production
Survival:
What are drugs as haptens?
- Beta-lactams: penicillins and cephalosporins
- Tetracycline
- Antineoplastics: cyclophosphamide, cisplatin
Survival:
What drugs form immune complexes?
quinidine, phenacetin
Survival: List the immune mediated hemolytic anemias (3)
- Drugs as haptens
- Formation of immune complexes
- Induce formation of antibodies to cellular components
Survival:
What drugs induce formation of antibodies to cellular components?
- Levodopa, methyldopa
- Procainamide
- Cimetidine
Survival:
Describe oxidative hemolysis that causes hemolytic anemias
RBCs constantly under oxidative stress - protective mechanisms
These are overwhelmed by xenobiotics:
- ascorbic acid
- ASA
- Benzocaine
- Chloramphenicol
- Dapsone
- Methylene Blue
- Nitrofuration
- Jaundice, pallor, dark urine
- Onset: 2-4 days
Survival:
Describe G6PD deficiency
G6PD -> NADPH synthesis
- X-linked genetic disorder
- prevalence ranges from <1% (Japanese and Korean) to 60-70% in Kurdish Jews
- Correlated with malaria-endemic regions
- Most individuals are symptomatic but episodes can be trigged by food, infections or drugs (dapsone, methylene blue, nitrofurantoin, phenazopyridine, fava beans)
Toxic effects of granulocytes include ____ ____ and ____
neutrophils, basophils, eosinophils
Drugs may alter what for granulocytes
- Proliferation and kinetics (dose-related)
- Function
Describe toxic effects on function of granulocytes
- impairment of phagocytosis
- inhibition of neutrophil chemotaxis
- proinflammatory effects of neutrophil activation
Describe idiosyncratic toxic neutropenia
- immune-mediated destruction
- non-immune-mediated
- not related to pharmacological properties of a drug -> unpredictable
Neutrophils proliferate quickly so what drugs will affect these
cancer drugs: methotrexate, cytarabine, daunorubicin, cyclophosphamide, cisplatin, nitrosureas
*dose-limiting for many cancer drugs
What drugs affect Kinetics of granulocytes
- epinephrine
- glucocorticoids
- dexamethasone
What impairs phagocytosis?
- EtOH
- glucocorticoids
- radiocontrast dye
What inhibits neutrophil chemotaxis?
macrocodes, zinc salts, mercuric chloride
What can cause pro inflammatory effects from neutrophil activation
environmental contaminants: sodium sulphite, mercuric chloride
What defines agranulocytosis?
neutrophils less than 500/mm3
Clinical presentation of agranulocytosis
- oral ulcers +/- fever
- severe pharyngitis, fever, malaise, weakness and chills
- sepsis
- sometimes predictable (i.e. drugs toxic to bone marrow) but usually not
- twice as common in females than in males, more common with older age, history of allergy (when it’s idiosyncratic)
What drugs can cause agranulocytosis?
- clozapine
- histamine 2 receptor antagonists (zantac)
- spironolactone
- sulfonamides
- *can be caused by any drug
- *rare with drug doses less than 10mg/day
Describe risk for agranulocytosis and clozapine
- 0.7% incidence, usually within first 6 months of tx
- genetic predisposition
- risk higher in women
- hematologic monitoring required (WBC, ANC) - q4 weeks at minimum
What is the treatment for agranulocytosis
- withdrawal of drug
- treat infections
- IV immune globulin
- G-CSF, GCSF (filgrastim, pegfilgrastim)
- if clozapine-induced - non-rechallangeable status
How can drugs alter production of platelets?
anti-proliferative agents
How can drugs alter survival of platelets?
Immune-mediated destruction
- penicillin, quinidine, abciximab, gold
- heparin-induced thrombocytopenia (HIT)
Non-immune-mediated destruction
-Desmopressin
What drugs alter function of platelets?
NSAIDs
Antibiotics
Clopidogrel, ticagrelor, prasugrel
CCBs
Describe the clinical presentation of thrombocytopenia
Early symptoms: bruising, petechiae/ecchymosis, epistaxis
-May be initial manifestation of aplastic anemia
Fever, chills, pruritus, lethargy
Bleeding may be abrupt
7 days are required for the development of the immune response at the first exposure
Develops within 12 hours of a repeated exposure to a sensitizing agent
What is treatment for thrombocytopenia?
- d/c of the drug
- if HIT, start non-heparin anticoagulant (danaparoid, argatroban, fondaparinux, DOACs)
- transfusion
- immunosuppressive therapy
