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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
Q

Production:

What drugs cause aplastic anemia?

A
  • sulfonamides
  • carbamazepine
  • gold compounds
  • mercury, arsenic
26
Q

Production:

What other things cause aplastic anemia?

A

radiation, pregnancy, viruses, immune disorders, idiopathic

27
Q

Production:

When can aplastic anemia be predictable?

A

cytotoxic chemotherapy, benzene, radiation

28
Q

Production:

Fatality rate of aplastic anemia

A

high (50%)

29
Q

Production:

onset of aplastic anemia

A

insidious onset (6-7 weeks)

30
Q

Production:

describe the presentation of aplastic anemia

A

-fatigue, weakness, stomatitis, easy bruisability, petechiae, purport, recurrent infections, bleeding

death within 18 months

31
Q

Production:

treatment of aplastic anemia

A
  • withdrawal of drug
  • symptomatic treatment of bleeding, infection
  • immunosuppressive therapy: corticosteroids, cyclosporine, GM-CSF, IL-1, GCSF, antithymocyte globulin
  • bone marrow transplant
32
Q

Production:

describe the presentation of Erythrocytosis

A
  • chest/abdominal pain
  • myalgia, weakness, fatigue
  • headache
  • paresthesias
  • blurred vision/transient loss of vision
  • poor mentation/sense of depersonalization
  • Risk of VTE
33
Q

Production:

describe the mechanisms that cause erythrocytosis

A

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
Q

Function:

What is the antidote for methemoglobinemia?

A

methylene blue

increases rate of methemoglobin reduction

35
Q

Function:

What is methemoglobin

A

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
Q

Survival:

What is a hapten?

A

molecule that does not trigger antibody production on it’s own but when it combines with a protein, it triggers antibody production

37
Q

Survival:

What are drugs as haptens?

A
  • Beta-lactams: penicillins and cephalosporins
  • Tetracycline
  • Antineoplastics: cyclophosphamide, cisplatin
38
Q

Survival:

What drugs form immune complexes?

A

quinidine, phenacetin

39
Q

Survival: List the immune mediated hemolytic anemias (3)

A
  • Drugs as haptens
  • Formation of immune complexes
  • Induce formation of antibodies to cellular components
40
Q

Survival:

What drugs induce formation of antibodies to cellular components?

A
  • Levodopa, methyldopa
  • Procainamide
  • Cimetidine
41
Q

Survival:

Describe oxidative hemolysis that causes hemolytic anemias

A

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
Q

Survival:

Describe G6PD deficiency

A

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
Q

Toxic effects of granulocytes include ____ ____ and ____

A

neutrophils, basophils, eosinophils

44
Q

Drugs may alter what for granulocytes

A
  • Proliferation and kinetics (dose-related)

- Function

45
Q

Describe toxic effects on function of granulocytes

A
  • impairment of phagocytosis
  • inhibition of neutrophil chemotaxis
  • proinflammatory effects of neutrophil activation
46
Q

Describe idiosyncratic toxic neutropenia

A
  • immune-mediated destruction
  • non-immune-mediated
  • not related to pharmacological properties of a drug -> unpredictable
47
Q

Neutrophils proliferate quickly so what drugs will affect these

A

cancer drugs: methotrexate, cytarabine, daunorubicin, cyclophosphamide, cisplatin, nitrosureas

*dose-limiting for many cancer drugs

48
Q

What drugs affect Kinetics of granulocytes

A
  • epinephrine
  • glucocorticoids
  • dexamethasone
49
Q

What impairs phagocytosis?

A
  • EtOH
  • glucocorticoids
  • radiocontrast dye
50
Q

What inhibits neutrophil chemotaxis?

A

macrocodes, zinc salts, mercuric chloride

51
Q

What can cause pro inflammatory effects from neutrophil activation

A

environmental contaminants: sodium sulphite, mercuric chloride

52
Q

What defines agranulocytosis?

A

neutrophils less than 500/mm3

53
Q

Clinical presentation of agranulocytosis

A
  • 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
Q

What drugs can cause agranulocytosis?

A
  • clozapine
  • histamine 2 receptor antagonists (zantac)
  • spironolactone
  • sulfonamides
  • *can be caused by any drug
  • *rare with drug doses less than 10mg/day
55
Q

Describe risk for agranulocytosis and clozapine

A
  • 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
Q

What is the treatment for agranulocytosis

A
  • withdrawal of drug
  • treat infections
  • IV immune globulin
  • G-CSF, GCSF (filgrastim, pegfilgrastim)
  • if clozapine-induced - non-rechallangeable status
57
Q

How can drugs alter production of platelets?

A

anti-proliferative agents

58
Q

How can drugs alter survival of platelets?

A

Immune-mediated destruction

  • penicillin, quinidine, abciximab, gold
  • heparin-induced thrombocytopenia (HIT)

Non-immune-mediated destruction
-Desmopressin

59
Q

What drugs alter function of platelets?

A

NSAIDs
Antibiotics
Clopidogrel, ticagrelor, prasugrel
CCBs

60
Q

Describe the clinical presentation of thrombocytopenia

A

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
Q

What is treatment for thrombocytopenia?

A
  • 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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