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Heme > Drugs and the Blood (plus additional reading) > Flashcards

Drugs and the Blood (plus additional reading) Flashcards

**Delete any cards from the reading that seem fringe!!

1
Q

What are 3 presentations (drug characteristics) that may result in changes in protein binding to a drug?

A
  1. Highly protein bound (ceftriazone, phenytoin)
  2. High clearance drugs (particularly those cleared by glomerular filtration)
  3. Drugs in which dosing is not titrated to effect (or half-life; i.e. antibiotics)
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2
Q

What is most affected by changes in the concentration of the protein-bound fraction of a drug?

A

The unbound drug concentration

For instance: if the protein-bound drug changes from 99% to 95%, the [unbound] just increased 5 fold

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3
Q

Which has a greater effect: a change from 98% to 94% [protein-bound drug] or from 5% to 1% [protein-bound drug]?

A

98% to 95%
(a change in concentration for a minimally bound drug hardly affects the conc, dist, clearance or pharmacokin of the unbound portion)

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4
Q

What is most affected by changes in the concentration of the unbound fraction of a drug?

A

changes in pharmacokinetics

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5
Q

What are 3 ways in which neonatal drug-protein binding varies from adult?

A

A larger amount of drug remains unbound due to the lower blood concentration of plasma proteins

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6
Q

How will administering a second drug with greater protein affinity affect a previously administered drug?

A

The second drug will displace the first (which will then alter the balance of bound versus unbound drug)

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7
Q

Why are antibiotics as risk of significant changes in drug pharmacokinetics?

A

They have multiple half-lives within a single dosing interval

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8
Q

In high clearance drugs, what is most affected by changes in protein binding?

A

Clearance

Distribution/Vd

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9
Q

What is the most common adverse clinical consequence of G6PD deficiency?

A

drug-induced hemolysis

-NADPH is not regenerated, thus glutathione is not reduced; reactive O intermediate cannot be removed

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10
Q

What is the function of G6PD?

A

Protect RBC from oxidative damage

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11
Q

Medications that are contraindicated in G6PD deficiency:

A

Pegloticase
Quinine
Rasburicase
Sulfamethoxazole

(Did he say we needed to know this?)

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12
Q

What is eryptosis?

A

suicidal erythrocyte death

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13
Q

How does Ca affect the cell (intracellularly)?

A
  1. Activation of Ca-permeable, non-selective cation channels results in increased cytosolic Ca activity
  2. (Inside the cell) Ca activates Ca-sensitive K channels –> K exits, and the cell becomes hyperpolarized –> Cl exits
  3. Loss of KCl = loss of water, cell shrinks
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14
Q

How does Ca affect the cell membrane?

A

Ca stimulates cell membrane scrambling (via inhibition of “scramblase”), which results in breakdown of phospholipid asymmetry and phosphatidylserine exposure at surface

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15
Q

How is Ca involved in eryptosis?

A

Acts directly on RBC to promote Ca entry via ion channel

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16
Q

What factors can cause a low platelet count?

A
  1. Bone marrow doesn’t make enough
  2. Bone marrow makes enough, but the body destroys them
  3. Spleen holds on to too many platelets
    (or a combination of these factors)
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17
Q

What is the primary manifestation in HIT?

A

thrombocytopenia

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18
Q

6 risk factors for HIT:

A
  1. Female sex
  2. IV administration of heparin (versus subcut)
  3. Bovine heparine (versus porcine)
  4. Post-op patients (worse for ortho srx)
  5. Heparin exposure for >4 days
  6. Exposure to unfractioned heparin (versus low-mol-weight)
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19
Q

By what mechanism does HIT occur?

A
  1. Heparin/PD4 binds with anti-heparin/PD4-IgG
    (drug joins glycoprotein and CDR on antibody)
  2. Immune complex binds to Fc receptor on surface of resting platelet, activating it
  3. Activated platelet deposits onto subendothelial matrix
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20
Q

In HIT, what may be variable among patients?

A

severity

timing of onset after heparin

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21
Q

How does non-immune HIT differ from immune HIT?

A
  1. Milder
  2. No antibodies
  3. Low thrombosis risk
  4. Onset occurs <5 days after exposure
  5. Treated via observation (rather than discontinuation of heparin)
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22
Q

What may induce an earlier onset of HIT?

A

administration of heparin in the past 1-3 months

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23
Q

What may cause a delayed onset of HIT?

A

formation of heparin-independent antibodies (drug acts as an intermediate in an otherwise weak reaction)

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24
Q

T?F: Heparin is the only drug capable of inducing immune thrombocytopenia.

A

F (penicillin, quinine, NSAIDs, abciximab, l-dopa, etc)

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25
Q

What is the most common cause of peripheral blood cytopenias in the industrial world?

A

myelosuppression

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26
Q

What dose-limiting side effect is caused by cytotoxic agents?

A

myelosuppression

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27
Q

T/F: Myelosuppression can be an idiosyncratic drug reaction.

A

T

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28
Q

How do drugs cause peripheral cytopenias?

A

shortening the survival of blood cells (does NOT affect marrow cell production)

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29
Q

What are 2 disorders related to drug-induced myelosuppression?

A

Autoimmune hemolytic anemia

Immune Thrombocytopenia

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30
Q

What glycoproteins are available for therapeutic use?

A

G-CSF
GM-CSF
EPO (human recombinant)

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31
Q

What are non-cytotoxic mechanisms that induce myelosuppression?

A
  1. defects in hematopoietic stem cells
  2. damage to stroma (marrow)
  3. inhibition of production/release of hematopoietic growth factors
  4. Immunosuppression of marrow cells
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32
Q

T/F: The immune system plays an important role in immunosuppression via B-cell mediated activity.

A

F: T cell mediated

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33
Q

What are 6 classes of drugs associated with iosyncratic myelosuppression?

A
  1. antimicrobials
  2. antirheumatics
  3. antithyroid
  4. anticonvulsants
  5. psychotropic agents
  6. cardiovascular drugs
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34
Q

The incidence of severe or opportunistic infections increase as _____ levels decrease.

A

neutrophil

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35
Q

What is the best immediate treatment of neutropenic, febrile patients?

A

empirical therapy with broad spectrum antibiotics (IV)

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36
Q

What are 4 causes of agranulocytosis?

A
  1. certain drugs (e.g. antithyroid)
  2. Hypoplastic BM (does not produce cells)
  3. Anti-neutrophil antibodies
    (“immuno-allergic”)
  4. Toxicity to myeloid precursors
    (ATP depletion, reduce glutathione)
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37
Q

What are 2 factors considered when a patient has developed agranulocytosis due to treatment with a particular drug?

A
  • Duration of drug exposure prior to onset of acute agranulocytosis
  • Time between onset of acute agranulocytosis and neut count normalization
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38
Q

When giving drugs that are known to induce agranulocytosis, what should you do as a physician to prevent harm to the patient (and you…)?

A

follow with blood counts

*this won’t occur in every patient

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39
Q

How do aspirin and NSAIDs differ in their anti-platelet activity?

A
  • Aspirin irreversibly acetylates platelets, rendering it nonfunctional (thromboxane)
  • NSAIDs are reversible
  • Clopidogrel act on ADP receptors
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40
Q

How does clopidogrel affect platelets?

A

Antagonizes ADP receptors

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41
Q

Anti-platelet drugs inhibit:

A

platelet aggregation

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42
Q

How does warfarin inhibit coagulation?

A

inhibits vitamin K dependent activation of clotting factors II (thrombin), VII, IX, X

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43
Q

How does heparin inhibit coagulation?

A

catalyzes inactivation of clotting factors II and X

low molecular weight heparin = only X

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44
Q

How does dabigatran inhibit coagulation?

A

inhibits thrombin

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45
Q

Why must warfarin be monitored closely?

A

response to dosing rate will be pharmacogenomically determined

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46
Q

What stimulates EPO synthesis? Where?

A

Hypoxia, kidneys

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47
Q

Why does renal failure cause anemia?

A

decreased EPO production

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48
Q

How does EPO affect cancer growth?

A

Increases metastasis, resistance to chemo and evasion of apoptosis
(*related to increased cancer risk)

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49
Q

How does folic acid deficiency result in glossitis?

A

Inadequate DNA synthesis (which affects rapidly growing tissues such as tongue)

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50
Q

How does folic acid deficiency result in megaloblastic anemia?

A

Reduced DNA synthesis relative to RNA synthesis, causing unbalanced cell growth and omitted cell divisions during erythropoiesis

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51
Q

How does cobalamin deficiency cause neuro disease and degeneration?

A

Causes demyelination

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52
Q

What cytokine plays a role in asthma?

A

GM-CSF

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53
Q

What is the function of cytokines?

A

Control of proliferation of blood components (through signaling and inflammation)

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54
Q

What are the major actions of G-CSF?

A
  • Increase neutrophil production
  • Increase neutrophil survival/adhesion
  • Increased mobilization of blood cells into blood
  • Decreased T cell reactivity, with increased Treg production
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55
Q

What are the major functions of GM-CSF?

A
  • Maturation of dendritic cells
  • Steady-state differentiation of macroph/NK
  • Mobilization of myeloid cells into blood
  • Survival/activation of macro, neut, eosin
56
Q

Cardiovascular adaptations to chronic anemia:

A

tachycardia
increased cardiac output
vasodilation

57
Q

Most common cause of chronic anemia:

A

IRON DEFICIENCY

58
Q

Functions of iron:

A

iron-porphyrin heme ring (component of Hg)

59
Q

How does iron deficiency affect RBC?

A

results small hemoglobin-deficient erythrocytes, which causes microcytic hypochromic anemia

60
Q

T/F: The body reclaims Fe, thus only a small amount is lost every day

A

T

61
Q

What type of iron should be used to treat deficiency?

A

ferrous salts

62
Q

How many mg of elemental iron should be given daily to correct iron deficiency most quickly?

A

200-400 mg

63
Q

Why should oral iron should be continued for 3–6 months after correction of the cause of anemia?

A
  1. correct the anemia

2. replenishes iron stores

64
Q

What are the most common toxic effects of iron supplements?

A

Nausea, epigastric discomfort, abdominal cramps, constipation, and diarrhea

65
Q

How can toxic effects of iron supplements be overcome?

A

lowering the daily dose of iron or by taking with food

also–trying another salt may help

66
Q

Why may obscure the diagnosis of continued GI blood loss?

A

Iron supplements turn stool black

67
Q

What conditions may result in inability to correct anemia with oral iron alone (need parenteral)?

A
  • advanced renal disease
  • gastrectomy or bowel resections
  • inflammatory bowel disease of prox small bowel
  • Malabsorption syndrome
68
Q

What treatment challenge is associated with parenteral administration of inorganic free ferric iron?

A

Dose-dependent toxicity (which limits the dosage that can be given)

69
Q

What is a colloid formulation of iron?

A

carbohydrate surrounding a core of iron oxyhydroxide

70
Q

What iron formulation is most likely to cause hypersensitivity reactions?

A

parenteral IV Iron dextran

thus, you should always give a test dose

71
Q

Why should patients on parenteral iron be tested for iron overload?

A

parenteral route bypasses the absorptive regulatory processes that are involved in oral routes

72
Q

What serum concentrations can be used to determine iron stores?

A

ferritin

transferrin saturation

73
Q

What is total iron-binding capacity?

A

Ratio of total serum iron concentration to total iron-binding capacity

74
Q

What condition may be caused by acute iron toxicity in children?

A 
Necrotizing gastroenteritis
(nausea, vomiting, bloody diarrhea, shock; patients will improve initially, then experience metabolic acidosis, coma or death)
75
Q

What are two ways to detoxify a patient with iron overload?

A

Whole bowel irrigation

Deferoxamine [Desferal] (potent Fe chelator)

76
Q

How is Deferoxamine [Desferal] excreted?

A

Urine (turns it red)

Bile

77
Q

What is hemochromatosis?

A

chronic iron toxicity disorder in which excess iron is deposited in heart, liver, pancreas, etc; can lead to organ failure and death

78
Q

Hemochromatosis is most commonly seen in what type of patients?

A
  1. Patients with inherited hemochromatosis (absorb too much Fe)
  2. Patients who receive lots of transfusions over time (thalassemia)
79
Q

How is chronic iron overload in the absence of anemia is most efficiently treated?

A

intermittent phlebotomy (1 unit/week)

80
Q

What serum levels are increased by Deferasirox [Exjade]?

A

creatinine
hepatic enzymes

*this drug treats chronic iron overload

81
Q

What are common side effects of Deferasirox [Exjade]?

A
  • Diarrhea, nausea, abd pain, headache, pyrexia, cough
  • Auditory and visual disturbances

*this drug treats chronic iron overload

82
Q

What are common causes of B12 deficiency?

A

inadequate supply in diet

inadequate absorption

83
Q

What are 3 symptoms of B12 deficiency?

A

Megaloblastic anemia
Macrocytic anemia
Neurologic syndrome
(paresthesia progressing to ataxia, etc;
B12 halts but not necessarily reverses)

84
Q

What are common causes of B12 deficiency?

A

Pernicious anemia
Partial or total gastrectomy
Conditions affecting distal ileum
(malabsorption, inflamm bowel, resection)

85
Q

What are rare causes of B12 deficiency in adults?

A

Bacterial overgrowth in small bowel
Chronic pancreatitis
Thyroid disease

86
Q

What are rare causes of B12 deficiency in children?

A
  1. congenital deficiency of intrinsic factor

2. defective receptor sites for vitamin B12-intrinsic factor complex (in distal ileum)

87
Q

T/F: Most B12 deficiency diseases are resolved with injected B12.

A

F: “Most patients do not have curable

deficiency syndromes and require lifelong treatment with vitamin B12”

88
Q

Why is hydroxocobalamin preferable to cyanocobalamin?

A

More highly protein-bound, remains longer in the circulation

89
Q

Folic acid deficiency is most commonly found in (5):

A 
Pregnant women
Malabsorption syndromes
Dialysis patients
Alcoholics
Liver disease
90
Q

Reduced forms of folic acid are precursors for:

A

synthesis of amino acids, purines, and DNA

91
Q

Folic acid oral absorption is (high/low)

A

high–even in patients with malabsorption syndrome

92
Q

Trimethoprim and pyrimethamine are (more/less) likely than methotrexate to
produce folate deficiency.

A

less (they have a greater affinity for bacterial and malarial dihydrofolate reductase)

93
Q

What antimicrobial drug causes folate deficiency?

A

Trimethoprim

94
Q

What antiseizure drug causes folate deficiency?

A

Phenytoin

95
Q

What drug rescues cells from the effects of folate antagonists?

A

LEUCOVORIN

96
Q

T/F: Excessively high folate levels have been linked to depression.

A

F: low levels

97
Q

Biologically active form of folate in circulation?

A

Levomefolate

6(S)-5-methyltetrahydrofolate and L-methylfolate

98
Q

What enzyme reduces folate and dihydrofolate?

A

MTHFR (methylenetetrahydrofolate reductase)

99
Q

How does reduced folate enter cells?

A

Once converted to levomefolate, transported across cell membranes by receptor-mediated endocytosis

100
Q

What is the function of levomefolate once it crosses the BBB?

A

modulates formation of monoamines (serotonin, norepinephrine, dopamine)

101
Q

What is the function of epoetin alpha?

A

Agonizes EPO receptors on RBC progenitors, which stimulates RBC prolif/diff
*causes reticulocyte release from BM

102
Q

What is epoetin alpha used to treat?

A
  1. anemia (esp in chronic renal failure, HIV, cancer)

2. prevent the need for transfusion (elective surgery)

103
Q

What does the prefix “peg-“ mean?

A

original drug has been reformulated with addition of polyethylene glycol moieties (extends PKs of the drug, less frequent re-dosing)

104
Q

The erythropoietin receptor is a member of what superfamily of cytokine receptors?

A

JAK/STAT’s

105
Q

What growth factor induces maturation into RBC?

A

EPO

106
Q

What growth factors induce maturation into granulocytes, eosinophils, basophils?

A

GM-CSF and C-CSF

107
Q

What growth factors induce maturation into monocytes?

A

GM-CSF and M-CSF

108
Q

What growth factor induces maturation into megakaryocytes?

A

CFU-Meg

109
Q

What growth factors induce maturation into platelets?

A

IL6, IL11, thrombopoietin

110
Q

How is hypoxia related to EPO production?

A

Gene transcription inversely related to tissue oxygenation levels

111
Q

Severely anemic patients have (high/low) EPO.

A

high

112
Q

Patients with renal disease (are/aren’t) likely to respond to exogenous EPO.

A

ARE likely

113
Q

Patients in renal failure have (high/low) EPO.

A

low–kidneys cannot produce the growth factor

114
Q

Black box warning: Patients with what disorder had greater risk of death, stroke or CV problems when taking erythropoiesis-stimulating agents if their hgb>11?

A

chronic kidney disease

115
Q

Black box warning: Why are erythropoiesis-stimulating agents given in lowest possible dose and used only for anemia from myelosuppressive chemo?

A

shown to shorten overall survival and/or increase risk of tumor progression in some cancers

116
Q

In patients with cancer, what is prophylactically treated if taking erythropoiesis-stimulating agent?

A

DVT

117
Q

Why should methoxy polyethylene glycol epoetin beta not be used for treatment of
anemia caused by chemo?

A

a clinical trial found significantly more deaths among patients receiving this form of erythropoietin

118
Q

What does G-CSF stimulate?

A
  1. proliferation and differentiation of progenitors already committed to the neutrophil lineage
  2. Activation of phagocytic activity of mature neutrophils (and prolongs survival)
  3. Mobilizes hematopoietic stem cells (increase their concentration in periph blood–use in stem cell transplantation)
119
Q

What toxicities are associated with G-CSF?

A 
bone pain (after discontinued)
splenic rupture (rarely, when used for PBSCs)
120
Q

Which myeloid growth factor is more likely to cause fever: G-CSF or GM-CSF?

A

GM-CSF (also more likely to cause arthralgia, myalgia, capillary leak syndrome)

121
Q

What myeloid growth factor stimulates T cell proliferation?

A

GM-CSF (with the help of IL2)

122
Q

What are 3 ways that GM-CSF affects blood cell?

A
  1. stimulates proliferation and differentiation of early and late granulocytic progenitor cells
  2. growth factor for erythroid and megakaryocyte progenitors
  3. stimulates the function of mature neutrophils

(also mobilizes periph blood cells, but less effectively than G-CSF)

123
Q

Why is G-CSF given after dose-intensive chemo?

A

Speeds up rate of neutrophil recovery, which reduces episodes of:

 1. febrile neutropenia 
 2. need for broad-spectrum abx
 3. infections
 4. hospital length of stay
124
Q

T/F: G-CSF improves patient survival rates after chemo.

A

F

125
Q

Explain the benefit of administering G-CSF to a patient that is ABOUT to undergo high-dose chemo.

A

Because the chemo will induce myelosuppression, patients are given G-CSF (to mobilize peripheral blood stem cells) and stem cells are harvested.

After chemo, patients receive an autologous stem cell transplantation (with the cells that were collected) to counteract chemo’s effects.

126
Q

What is often collected as the hematopoietic preparation for autologous transplantation (instead of BM)?

A

PBSCs (peripheral blood stem cells)

127
Q

What drug is the long acting form of G-CSF [filgrastim] that is covalently linked to polyethylene glycol?

A

pegfilgrastim

peg=polyethylene glycol

128
Q

Where does oprelvekin often cause fluid to accumulate?

A

lungs

129
Q

What does oprelvekin [neumega] stimulate?

A

megakaryocytopoiesis and thrombopoiesis

*megak maturation results in increased platelet production

130
Q

To which receptor does oprelvekin bind?

A

IL-11 receptor on megakaryocytes and megakaryocyte progenitor cells
(receptor interactions with signal transducing receptor gp130, whatever that is)

131
Q

What is oprelvekin approved to treat?

A

prevention of thrombocytopenia in patients receiving

cytotoxic chemo for nonmyeloid cancers

132
Q

Oprelvekin is administered subcut in order to:

A

increase platelet count to >50,000

133
Q

What toxic CV effects are associated with oprelvekin?

A

Anemia (due to hemodilution)
Dyspnea (due to fluid accumulation in lungs)
Transient atrial arrhythmias
*all are reversible

134
Q

What are the components of the 2 identical subunits of Romiplostin [Nplate], and what to they do?

A
  1. Peptide sequence: binds/activates TPO receptor

2. Fc: extends half life (remains in circ much longer than endogenous TPO)

135
Q

What removes Romiplostin [Nplate] from circulation?

A

reticuloendothelial system

136
Q

Most common toxicities related to Oprelvekin; rh-IL-11 [Neumega]:

A

fatigue, headache, dizziness

less common = hypokalemia

Heme (38 decks)

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