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Phar 303 > Hematoxicology > Flashcards

Hematoxicology Flashcards

1
Q

What is the difference between Primary Hematotoxicity and Secondary Hematotoxicity?

A

Primary: One or more blood components directly affected (common serious effect of xenobiotics, particularly drugs)

Secondary: Toxicity is a consequence of other tissue injuries or systemic disturbances

Consequences of either include hypoxia, hemmorrhage and infection

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2
Q

What are the 6 steps in Erythropoiesis?

A 
Proerythroblast (from myeloid stem cell)
Active synthesis of hemoglobin
Hemoglobin appears
Pyknosis (loss of nucleus)
Reticulocyte (still contains some RNA)
Mature erythrocyte
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3
Q

What is an erythron?

A

All stages of erythrocytes. including developin precursors

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4
Q

What three aspects of erythrocytes can xenobiotics affect?

A

Production
Survival
Function

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5
Q

What is a common effect of xenobiotics on the erythrocyte?

A

Anemia (reduction in number/volume of RBCs)

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6
Q

What are the three groups the various types of annemia are divided into?

A

Caused by blood loss
Decreased or faulty RBC production
Destruction of RBCs

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7
Q

What is the healthy Hematocrit (HCT) level?

note HCT also referred to as Paced Cell Volume or PCV

A

37%-54%

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8
Q

Describe the hemoglobin molecule

A

two alpha chains, two beta chains
Each chain contains one heme
Each heme surrounds one iron ion
Each heme interacts with an O2 molecule

One hemoglobin molecule can “hold” 4 O2 molecules
280 Million Hb molecules in each RBC
Each RBC can carry more than 1 billion molecules of oxygen

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9
Q

What are 3 ways for hemoglobin to not carry oxygen properly?

A
  • Iron deficiency anemia (heme does not contain Fe)
  • Sideroblastic anemia (defect in synthesis of porphyrin ring
  • Thalassemia (disorder caused by inadequate amounts of alpha/beta chains)
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10
Q

Which anemia do drugs that contribute to bleeding cause? How can you avoid this?

A

Iron deficiency anemia, reccomended increase in iron intake

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11
Q

What types of drugs contribute to iron deficiency anemia when taken chronically?

A

NSAIDs

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12
Q

How can you detect iron-deficient erythrocytes histologically?

A

Small, pale RBCs

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13
Q

How can you detect sideroblastic anemic erythrocytes histologically?

A

Prussian blue stain forms a perinuclear ring of blue granules
“sapphire neclace”

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14
Q

What causes sideroblastic anemia (usually)?

A

Exposure to toxic substances, eg Lead/Isoniazid
Pb substitutes for Zinc at ALAD step (second RLS in hemoglobin production)
Isoniazid is a potent Heme inhibitor

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15
Q

What is PLP?

A

Vitamin B6

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16
Q

What causes Decreased production of RBCs?

A

Ineffective hematopoiesis (megaloblastic anemia)

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17
Q

WHat is megaloblastic anemia?

A

RBC count is low
Characterized by RBCs that are larger than normal
Can be congenital or acquired
Any defect that causes a slowing of DNA synthesis

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18
Q

What is the most frequent cause of megaloblastic anemia? Why?

A

Folic acid or cobalamin (vitamin B12) deficiency

Folate/vitamin B12 are essential for DNA replication/repair

19
Q

How is Cobalamin absorbed?

A

By complexing with haptocorrin in the stomach, then transferring to Intrinsic factor-cobalamin complex in small intestine, where the complex binds to cubilin in terminal ileum

The cobelamin then reaches the liver where it enters cells or is stored in haptocorrin-cbl complices in blood

20
Q

How is Folate absorbed?

A

In duodenum/jejunum (monoglu) where it is processed and stored in liver or exported to cells

21
Q

How does alcohol cause megaloblastic anemia?

A

Decreases absorbed folate
Toxic effects on gastric mucosa and production of intrinsic factor
Affects inestinal mucosa to interfere with absorption of folic acid (jejunum) and Vitamin B12 (ileum)

22
Q

What are suicide substrates? What do they do in the context of Folate synthesis?

A

Substrate analogs that bind an enzyme and permanently deactivate the enzyme

In the folate synthesis pathway:
Fluorouracil inhibits thymidylate synthase permanently to inhibit the rate limiting step of DNA synthesis
Methotrexate inhibits dihydrofolate reductase
Neomycin antibiotics inhibit methione synthase (interferes with absorption)

23
Q

What is Aplastic anemia?

A

Stem cells are unable to generate mature blood cells (bone marrow hypoplasia)

Different forms:
Pancytopenia (deficiency in red cells, leukocytes/platelets)
Reticulocytopenia (“aplastic crisis”, low reticulocyte count)

24
Q

What causes aplastic anemia?

A

Can be inherited (rare) or Acquired:

  • Toxic chemicals (pesticides, arsenic, benzene, mercury)
  • Radiation
  • Chemotherapy
  • Medication (chloramphenicol)
25
Q

How are we exposed to benzene? What is its most common exposure route?

A

Cigarettes, automobile exhaust, etc.

Ihnalation is most common exposure route

26
Q

What are the symptoms of acute benzene toxicity?

A

Drowsiness, dizziness, headaches, tremors, confusion, unconsciousness

27
Q

How does benzene cause aplastic anemia?

A

CYP2E/F/A oxidize it into phenol, which creates hydroquinone which can become benzoquinones, which act on ROS in bone marrow to cause toxicity

28
Q

What is hemolytic anemia?

A

The destruction of RBC before their normal lifespan is over (120 days)

29
Q

What are the two types of hemolytic anemia?

A

Immune and nonimmune

30
Q

Describe the cause and effect of immune hemolytic anemia

A

Rare complication of drugs, antibodies (IgM or IgG) against RBCs

Initiates destruction through complement/phagocytotic cells

Xenobiotics can affect antibody binding to the RBC (e.g. penicillin binds RBC surface, immune response against drug-coated RBC)
“Drug absorption mechanism”

31
Q

What is another term for Non-immune hemolytic anemia? What is it associated with?

A

Oxidative hemolytic anemia
Associated with G6PD deficiency (glucose-6-phosphate dehydrogenase) supplies NADPH

Regenerates GSH when it is oxidized
GPx (glutathione peroxidase) used GSH as a substrate to remove H2O2

32
Q

What is Favism?

A

X chromosome linked recessive mutation (males more affected)
G6PD polymorphism
Denatured hemoglobin forms Heinz bodies

33
Q

What are the beta glucosides found in beans?

A

Vicine and convicine

34
Q

What happens to the beta glucosides found in beans after ingestion?

A

Divicine and isouramil are released after ingestion (highly reactive compounds)

ROS

Detoxified in a normal cell (with ample NADPH)
Not detoxified in G6PD-deficient cells

RBC destruction due to oxidative damage

35
Q

What is methemoglobinemia?

A

The oxidation of hemoglobin involving the conversion to the ferrous Fe2+ ion in heme to the ferric Fe3+ ion

Associated with anemia, tissue hypoxia and cyanosis (methemoglobinemia is not capable of binding/transporting oxygen, reduces O2-carrying capacity of blood)

36
Q

What is the lethal level of MetHb (as a percent of Hb)?

A

> 70% death

<= 2% physiologic
2%-15% asymptomatic

37
Q

What causes methemoglobinemia?

A

Nitrites, Nitrates (or inherited cytochrome b5 reductase deficiency, but rare)

38
Q

How do you treat Methemoglobinemia?

A

Methylene blue

Methylene blue activates a redutase which methylene blue to methylene leucoblue, whih reduces MetHb back into Hb

39
Q

What are platelets?

A

Small blood cell fragments that form clots to stop bleeding
Produced in the bone marrow from megakaryocytes
Continuously replaced (lifespan of 9-12 days)

40
Q

What is it called when you have abnormal platelet levels? (too much and too little)

A

Abnormal depletion of platelets: Thrombocytopenia

Excessibe number of platelets:
Therombocytosis

41
Q

What are two possible toxic effects on platelets?

A

Methotrexate (antimetabolite) inhibits production from megakaryocytes

DITP (drug induced thrombocytopenia) decreases production or increases destruction of platelets

42
Q

How can penicillin be toxic to platelets?

A

Can act as a hapten by binding to platelet membranes and eliciting immune response that causes removal of platelets

43
Q

What are the three procoagulants that are NOT synthesized in the liver?

A

Factors III, IV, and VIII

44
Q

How does warfarin inhibit blood clotting?

A

By inhibiting Vitamin K epoxide reductase and vitamin K reductase

Phar 303 (19 decks)

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