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Immunology Block 2 > Pharmacology > Flashcards

Pharmacology Flashcards

1
Q

Immunosuppressants:

A

Defined as drugs that increase the risk of infection, drugs with broad targets/effects, or “old” drugs

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2
Q

Immunomodulators:

A

Defined as drugs that do NOT increase the risk of infection, drugs with narrow targets/effects (like antibody drugs), or “new” drugs

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3
Q

What are eicosanoids?

A

A diverse family of signaling molecules derived from fatty acids. These act as local vasodilators in inflammation; synthesized by most cells.

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4
Q

Release of cytokines, eiconasoids, etc causes a ______ loop which causes a(n) ________

A

positive feedback loop; inflammatory cascade

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5
Q

Which cells are especially important in the inflammatory process?

A

T-helper cells

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6
Q

Prostaglandin E2:

A

An eicosanoid produced by most cells, that is increased in regions of tissue damage

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7
Q

Thromboxane A2:

A

an eicosanoid produced by platelets, that is relevant to toxicities and therapy associated with reduction in clotting while inhibited

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8
Q

Leukotriene E4:

A

An eicosanoid produced by leukocytes

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9
Q

What is the mechanism of action of cyclooxygenase inhibitors?

A

Inhibit the synthesis of prostanoids (prostaglandins and thromboxanes, as well as leukotrienes). Prostanoids play a role in the inflammatory process.

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10
Q

What category of drugs function as cyclooxygenase (COX) inhibitors:

A

NSAIDs

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11
Q

COX1:

A

Constitutive. Normally responsible for normal body homeostatic functions such as renal homeostasis, gastric mucosal protection, and platelet function. As a result, the inhibition of these homeostatic functions can cause toxic effects.

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12
Q

COX2:

A

Is induced at times of tissue damage/infection, and contributes to the inflammatory response normally such as pain, inflammation, fever, and limited homeostatic effects as well as platelet function. . Generally associated with therapeutic effects.

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13
Q

NSAIDs vary in their selectivity for ___ vs. ____ (explain).

A

NSAIDs vary in their selectivity for COX1 vs COX2. Generally, more toxicities (renal, GI, clotting) are associated with NSAIDS that target COX1, vs. fewer toxicities (but not none) associated with COX2

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14
Q

Describe how COX1 results in gastric damage:

A

NSAIDs inhibit PGE2 (a prostaglandin/prostanoid) which functions normally to maintain/produce the mucus lining of the GI tract. With chronic use of NSAIDs, the mucus lining is damaged, resulting in bleeding and ulcers.

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15
Q

Describe the role of NSAIDs and blood clotting

A

NSAIDs inhibit thromboxane A2 (TXA2), which normally promotes platelet activation. Chronic use of NSAIDs cause a decrease in thrombozane, which reduces clotting. This can be considered either a toxicity (bleeding disorder) or therapeutic effect (e.g. daily aspirin to prevent MI or stroke).

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16
Q

_____ is the only NSAID that irreversibly inhibits COX1/COX2 through covalent modification (explain).

A

Aspirin - this covalent modification is permanent; no other NSAIDs do this.

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17
Q

List the approved uses of aspirin:

A
  1. treat ischemic conditions by decreasing clotting, 2. decrease pain 3. decrease inflammation (especially to treat rheumatoid arthritis and osteoarthritis), 4. rheumatic fever
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18
Q

List common off-label uses of aspirin:

A

Treat Kawasaki disease, preeclampsia, and prevent colorectal cancer

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19
Q

Kawasaki disease (description and treatment):

A

Any child with 4/5 criteria of conjunctivitis, swollen lymph nodes, swollen hands/feet, changes in oral mucosa (red, cracked), and rash involving much of the body PLUS fever is diagnosed with Kawasaki, an immune disorder of unknown etiology. Aspirin and intravenous immunoglobulin is the standard treatment.

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20
Q

Preeclampsia (description and treatment):

A

Hypertension associated with pregnancy, affects 2-8% of pregnancies worldwide. Unclear how, but aspirin treatment helps.

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21
Q

Describe how aspirin is used to prevent colorectal cancer:

A

In patient with colorectal cancer, inflammation and PGE2 specifically is associated with development. Aspirin reduces PGE2, which decreases risk. Generally, taking aspirin is not recommended solely for this purpose because of the anti-clotting risk, but in patients who are already taking aspirin for anti-clotting, this is an added perk.

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22
Q

Reye’s Syndrome:

A

Affects children treated with aspirin during viral infections, causes unclear. Recommended to treat with tylenol or advil instead. 20-40% mortality, and long term neurologic effects for many of those that survive.

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23
Q

Aspirin-sensitive asthma:

A

Proposed mechanism: by shutting down COX side of eicosanoid production, this shifts the pathway towards breakdown of amino acids via lipoxygenases, which result in more leukotriene production. Leukotrienes can cause bronchoconstriction. Therefore, some patients with asthma have aspirin-sensitive asthma, which causes acute attacks.

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24
Q

Acute/chronic aspirin poisoning symptoms/outcomes:

A

Acute can result in respiratory and CNS depression, hypotension, coma, and death. Chronic can result in headache, N/V, tinnitus, hyperglycemia, and delirium.

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25
Q

What is the pediatric OD dose for aspirin?

A

>150 mg/kg (most OTC tablets come in 81, 100, or 300mg)

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26
Q

Why is aspirin more easily overdosed on?

A

Many OTC drugs contain aspirin and don’t clearly state on the label. Drugs like pepto-bismol contain bismuth subsalicylate, which is similar to aspirin and results in toxicity. Bengay is a cream that contains aspirin, and is absorbed through the skin, so too much use can result in toxicity.

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27
Q

Compare/contrast ibuprofen and naproxen:

A

naproxen has a longer biologic half life, so fewer doses are suggested per day. Both have low Vds due to plasma protein binding (usually albumin), so they are generally retained in the plasma.

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28
Q

Which cyclooxygenase(s) does ibuprofen inhibit?

A

COX1 and COX2

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29
Q

Which cyclooxygenase(s) does naproxen inhibit?

A

COX1 and COX2

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30
Q

What do Celecoxib and rofecoxib inhibit?

A

COX2 only

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31
Q

Describe the pros/cons of COX1+COX2 vs. COX2 only inhibitors:

A

COX1+COX2 has more GI toxicities than COX2 only. However, COX2 only drugs are associated with more CV toxicities, like MIs.

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32
Q

___ inhibitors are associated with increased risk of MI, why?

A

COX2. These are associated with an inhibition of prostacyclin, an anti-clotting factor. By inhibiting prostacyclin, this reduces the anti-clotting, meaning basically promotes clotting, leading to MIs.

33
Q

What is the mechanism of action of leukotriene inhibitors?

A

Inhibit the synthesis or activity of leukotrienes. Normally leukotrienes are associated with bronchoconstriction, so these are used to prevent bronchoconstriction.

34
Q

Zileuton:

A

LOX (lipooxygenase) inhibitor, which prevents the generation of leukotrienes and reduces bronchoconstriction.

35
Q

Montelukast:

A

LT (leukotriene) antagonist, which prevents bronchoconstriction.

36
Q

Corticosteroids prevent the synthesis of:

A

ALL eicosanoids

37
Q

Cortisol-derived synthetic drugs:

A

Hydrocortisone, prednisone, methylprednisone, and dexamethasone (and more)

38
Q

What are corticosteroids?

A

semi-synthetic derivatives of cortisol

39
Q

How are corticosteroids derived?

A

Derived from cortisol, which is derived from cholsterol

40
Q

What is the mechanism of action of corticosteroids?

A

Alter the transcription of genes in target cells. Steroid hormones are lipid soluble, so they can directly pass through the plasma membrane into the cytoplasm, where they bind their target. The bound complex then enters the nucleus and effects the expression of genes.

41
Q

Corticosteroids inhibit the expression of _____ and induce the expression of _____.

A

Corticosteroids inhibit the expression of PRO-INFLAMMATORY PROTEINS (e.g. TNF-a) and induce the expression of ANTI-INFLAMMATORY PROTEINS (e.g. Lipocortin).

42
Q

What is a key anti-inflammatory protein that is induced by corticosteroids?

A

Lipocortin (also called Annexin 1)

43
Q

Describe how corticosteroids inhibit production of eicosanoids:

A

Corticosteroids inhibit synthesis of all eicosanoids by promoting the synthesis of lipocortin, which is an inhibitor of phospholipase A2 enzyme. The phospholipases are involved in the first step of all eicosanoid synthesis, so lipocortin and corticosteroids inhibit the synthesis of all eicosanoids below this point, As a consequence, have a broader inflammatory effect compared to COX and lipoxygenase inhibitors.

44
Q

Discuss toxicities associated with corticosteroid use:

A

Corticosteroids act as immunosuppressants. Chronic use can immunocompromise a patient and increase the risk of developing a variety of infections. Nature of infection depends on the route of administration of corticosteroids. Inhalation: e.g. for COPD - reduces the effectiveness of immune system in oral cavity and lungs, increasing risk of Thrush or Pneumonia. Oral CS has systemic effects, so act as immunosuppressants for the whole body and puts all at risk.

45
Q

Describe symptoms of Cushing Syndrome:

A

Generalized weight gain, moon face & buffalo hump (fat redistribution), high blood pressure, and thinning/fragility of skin and bones

46
Q

Describe types of corticosteroid toxicities:

A

-Immunosuppression. -Hypercortisolism/Cushing syndrome

47
Q

Why do you get weakened bones and skin with hypercortisolism?

A

Corticosteroids reduce the production of osteocalcin (which normally maintains bones) and keratin (which normally maintains the structure of the skin).

48
Q

Describe the mechanism of Calcineurin inhibitors:

A

Inhibit T-cell activation by APCs; block TCR signaling

49
Q

______ inhibitors come with a very important black box warning for _____.

A

Calcineurin inhibitors have a black box warning for malignancies, especially non-hodgkin’s lymphoma

50
Q

In addition to preventing eicosanoid production, corticosteroids also decrease the transcription of multiple _____ genes

A

cytokine

51
Q

An important cytokine whose production is inhibited by corticosteroids is ____

A

TNF-a

52
Q

What is the mechanism of action of Tofacitinib?

A

JAK/STAT inhibitor. Inhibits signaling through the IL-2 receptor, which inhibits the activation and clonal expansion of T helper and T cytotoxic cells.

53
Q

Describe the mechanism of action of cytokine antibodies:

A

These bind directly to the cytokines outside of the cell and render them inactive before they can bind to target receptors. They don’t inhibit the synthesis or production of the cytokine, but inhibit the function of the inflammatory cytokines.

54
Q

Drugs ending in -mab are:

A

monoclonal antibodies

55
Q

Adalimumab mechanism:

A

Monoclonal antibody, binds TNF-a

56
Q

Effect of adalimumab:

A

TNF-a activates and promotes the activity of various immune cells by binding to its specific receptor on the surface of B cells and initiating signaling pathways that culminate in the nucleus and promote the activation and proliferation of immune cells. In this way it is pro-inflammatory. Adalmumab interferes with this process by binding to soluble TNF-a and preventing it from binding target receptors.

57
Q

How are antibody drugs administered?

A

Because they are large proteins, they must be administered IV or IM

58
Q

Mepolizumab mechanism:

A

Target is IL-5. Binds to soluble IL-5 before it can bind its receptor on the target cell.

59
Q

Mepolizumab effect:

A

IL-5 is primarily responsible for activation of eosinophils, so mepolizumab is an inhibitor of eosinophil activation - really only prescribed for eosinophilic asthma.

60
Q

Tocilizumab mechanism:

A

Binds to IL-6

61
Q

Describe the mechanism of action of DNA synthesis inhibitors:

A

Inhibit leukocyte activation/proliferation, thus inhibiting T cell proliferation by inhibiting the synthesis of DNA precursors (the purine nucleotides) which are necessary for DNA synthesis.

62
Q

What are the purine nucleotides that are inhibited by DNA synthesis inhibitors of leukocyte proliferation/activation drugs

A

Guanosine triphosphate and adenosine triphosphate

63
Q

Azathioprine action:

A

a DNA synthesis inhibitor of leukocyte proliferation/activation. Inhibits purine synthesis

64
Q

Azathioprine toxicity:

A

Potential toxicity of azathioprine because of mutagenicity. If drug derivative (guanine nucleotide derived molecule) gets incorporated in daughter T cell’s DNA and survives, the aberrant nucleotide can lead to production of mutant proteins in daughter T cell which could promote the development of a leukemia, acute myeloid leukemia specifically. If incorporated in lung cells, at risk for developing lung adenocarcinoma.

65
Q

Mycophenolate mechanism of action:

A

Mycophenolate is a DNA synthesis inhibitor of leukocyte proliferation/activation that works by inhibiting the synthesis of GTP. It inhibits inosine monophosphate dehydrogenase, which normally catalyzes a step of GTP synthesis that is necessary for DNA synthesis during S phase of T cell proliferation.

66
Q

Unlike azathioprine, Mycophenolate WHAT

A

Doesn’t insert aberrant nucleotides, so doesn’t increase the risk of cancers

67
Q

Methotrexate mechanism of action:

A

Methotrexate is a DNA synthesis inhibitor of leukocyte proliferation/activation that works by inhibiting DHFR in the folate synthesis pathway. Folate is a necessary cofactor for producing purines. Methotrexate inhibits DHFR which inhibits folate synthesis, which inhibits purine production which inhibits DNA production. Methotrexate acts as a competitive antagonist.

68
Q

Toxicity of DNA synthesis inhibitors (azathioprine, mycophenolate, methotrexate):

A

Pregnancy category D/X, meaning embryotoxic and fetal-toxic. Inhibiting DNA synthesis and cell proliferation during pregnancy is very bad for growth/development. Generally fetally fatal.

69
Q

Sirolimus mechanism of action:

A

Also called rapamycin. mTOR inhibitor. mTOR is an important intermediate in the IL-2 pathway of signaling from the TCR to the genes.

70
Q

Cytokine receptor antibodies mechanism of action:

A

These bind the cytokine receptors on target cells, preventing cytokines from binding and causing effects.

71
Q

Anakinra mechanism/effect:

A

Cytokine receptor antibody. Binds IL-1 receptors, affects various cells.

72
Q

Basilixumab mechanism/effect:

A

Cytokine receptor antibody. Binds IL-2 receptors, affecting T cells.

73
Q

Benralizumab mechanism/effect:

A

Cytokine receptor antibody. Binds IL-5 receptors, affecting eosinophils

74
Q

Omalizumab mechanism/effect:

A

Cytokine receptor antibody. Binds IgE, affecting B cells.

75
Q

Rituximab mechanism/effect:

A

Cytokine receptor antibody. Binds CD20, which is a receptor found on B cells. Inhibits the activation of B cells.

76
Q

Describe what classes of drugs act at which sites in this diagram:

A
77
Q

Which drugs/drug classes target the the T cell receptor or TCR pathway?

A

Cyclosporine, tacrolimus

78
Q

Which drugs/drug classes target the IL-2 receptor/receptor pathway?

A

Anakinra (IL-2 antagonist), Basilixumab (IL-2R antibody), Sirolimus

Immunology Block 2 (9 decks)

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