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Year 4 - Toxicology > Lecture 20 - DIHD > Flashcards

Lecture 20 - DIHD Flashcards

1
Q

Why are we concerned about blood toxicity?

A
  • blood has many functions - exchanges oxygen and CO2
  • maintains fluid balance (controls BP)
  • immune function
  • blood also transports drugs
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2
Q

What are the blood cells?

A
  • erythrocytes
  • granulocytes (leukocytes)
  • platelets
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3
Q

How fast are blood cells produced?

A

produced at a rate of 1 million to 3 million per second

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4
Q

What is hematopoietic tissue sensitive to?

A

cytoreductive or anti mitotic agents

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5
Q

What will happen from direct or indirect damage to blood?

A

life threatening (hypoxia, infection, hemorrhage)

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6
Q

Hematotoxicology

A

study of the adverse effects of exogenous chemicals on blood and blood-forming tissues

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7
Q

What is hematopoiesis?

A
  • occurs in bone marrow in healthy adults
  • stem cells stimulated (potions or colony-stimulating factors) to differentiate into committed cells that further mature
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8
Q

DIHD

A

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%)
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9
Q

The earlier the DIHD occurs in the cascade of hematopoiesis, the more _____ the disorder

A

severe

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10
Q

What drugs suppress bone marrow?

A
  • methotrexate
  • cyclophosphamide
  • colchicine
  • azathioprine
  • ganciclovir
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11
Q

Primary hematotoxicity

A
  • direct cytotoxic mechanism

- immunological mechanism

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12
Q

Secondary hematotoxicity

A
  • toxic effect a consequence of other tissue injury or systemic disturbances
  • damage caused by reactive/compensatory mechanism
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13
Q

Idiosyncratic hematotoxicity

A

unknown cause

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14
Q

List some manifestations of hematotoxicity

A
  • anemia
  • thrombocytopenia
  • leukopenia
  • pancytopenia (deficiency of RBC, WBC, and platelets)
  • decrease RBC, hemoglobin, platelets, WBC, neutrophils, eosinophils, basophils, all blood cells
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15
Q

Drugs may alter RBC ___, ___, and ____

A

production, function, and survival

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16
Q

How can production of RBC be altered?

A
  • cell division/hematopoiesis
  • hemoglobin synthesis

which can result in:

  • iron deficiency anemia
  • sideroblastic anemia
  • megaloblastic anemia
  • aplastic anemia
  • polycythemia
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17
Q

How can function of RBC be altered?

A

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

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18
Q

How can survival of RBC be altered?

A

normally approx 120 days but shortened by:

  • oxidative injury
  • decreased metabolism
  • altered membrane

can result in hemolytic anemias, immune-mediated, oxidative injury, G6PD deficiency

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19
Q

Production:

What is sideroblastic anemia?

A

interference with heme synthesis

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20
Q

Production:

What drugs can cause sideroblastic anemia?

A
  • EtOH
  • isoniazid (without vitamin B6 supplementation)
  • chloramphenical
  • linezolid
  • zinc toxicity (copper deficiency)
  • lead
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21
Q

Production:

Is sideroblastic anemia reversible?

A

yes - upon drug discontinuation

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22
Q

Production:

What is Megaloblastic anemia

A

abnormal development of RBC precursors (megaloblasts)

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23
Q

Production:

What drugs can cause megaloblastic anemia?

A
  • 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
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24
Q

Production:

What is aplastic anemia?

A

bone marrow failure

  • injury to pluripotent stem cell in bone marrow
  • pancytopenia, reticulocytopenia, bone marrow hypoplasia
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25
Production: | What drugs cause aplastic anemia?
- sulfonamides - carbamazepine - gold compounds - mercury, arsenic
26
Production: | What other things cause aplastic anemia?
radiation, pregnancy, viruses, immune disorders, idiopathic
27
Production: | When can aplastic anemia be predictable?
cytotoxic chemotherapy, benzene, radiation
28
Production: | Fatality rate of aplastic anemia
high (50%)
29
Production: | onset of aplastic anemia
insidious onset (6-7 weeks)
30
Production: | describe the presentation of aplastic anemia
-fatigue, weakness, stomatitis, easy bruisability, petechiae, purport, recurrent infections, bleeding death within 18 months
31
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
32
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
33
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
34
Function: | What is the antidote for methemoglobinemia?
methylene blue increases rate of methemoglobin reduction
35
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
36
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
37
Survival: | What are drugs as haptens?
- Beta-lactams: penicillins and cephalosporins - Tetracycline - Antineoplastics: cyclophosphamide, cisplatin
38
Survival: | What drugs form immune complexes?
quinidine, phenacetin
39
Survival: List the immune mediated hemolytic anemias (3)
- Drugs as haptens - Formation of immune complexes - Induce formation of antibodies to cellular components
40
Survival: | What drugs induce formation of antibodies to cellular components?
- Levodopa, methyldopa - Procainamide - Cimetidine
41
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
42
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)
43
Toxic effects of granulocytes include ____ ____ and ____
neutrophils, basophils, eosinophils
44
Drugs may alter what for granulocytes
- Proliferation and kinetics (dose-related) | - Function
45
Describe toxic effects on function of granulocytes
- impairment of phagocytosis - inhibition of neutrophil chemotaxis - proinflammatory effects of neutrophil activation
46
Describe idiosyncratic toxic neutropenia
- immune-mediated destruction - non-immune-mediated - not related to pharmacological properties of a drug -> unpredictable
47
Neutrophils proliferate quickly so what drugs will affect these
cancer drugs: methotrexate, cytarabine, daunorubicin, cyclophosphamide, cisplatin, nitrosureas *dose-limiting for many cancer drugs
48
What drugs affect Kinetics of granulocytes
- epinephrine - glucocorticoids - dexamethasone
49
What impairs phagocytosis?
- EtOH - glucocorticoids - radiocontrast dye
50
What inhibits neutrophil chemotaxis?
macrocodes, zinc salts, mercuric chloride
51
What can cause pro inflammatory effects from neutrophil activation
environmental contaminants: sodium sulphite, mercuric chloride
52
What defines agranulocytosis?
neutrophils less than 500/mm3
53
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)
54
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
55
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
56
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
57
How can drugs alter production of platelets?
anti-proliferative agents
58
How can drugs alter survival of platelets?
Immune-mediated destruction - penicillin, quinidine, abciximab, gold - heparin-induced thrombocytopenia (HIT) Non-immune-mediated destruction -Desmopressin
59
What drugs alter function of platelets?
NSAIDs Antibiotics Clopidogrel, ticagrelor, prasugrel CCBs
60
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
61
What is treatment for thrombocytopenia?
- d/c of the drug - if HIT, start non-heparin anticoagulant (danaparoid, argatroban, fondaparinux, DOACs) - transfusion - immunosuppressive therapy

Year 4 - Toxicology (24 decks)

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