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Flashcards in Immunopharmacology Deck (114):
1

applications of immunosuppression

-hypersensitivity
-autoimmunity
-organ transplantation

2

immune tolerance due to

antigen-specific

3

application of immunostimulation (biological response modifers)

immunodeficiency

4

see diagram and blurb in pdf

see diagram and blurb in pdf

5

name 5 immunosuppressive agents

1. glucocorticoids
2. calcineurin inhibitors
3. antiproliferative/antimetabolic agents
4. agents affeting lymphocyte distribution
5. antibodies

6

what are the most common glucocorticoids used

1. prednisone
2. prednisolone
3. dexamethasone

7

how are glucocorticoids administered

-oral
-IV
-topical

8

what bond is required for glucocorticoid but no mineralocorticoid activity

11Beta-OH

9

addition --- bond selectively increases glucocorticoid activity

1,2 double bond

10

--- bond increases both glucocrticoid and minteralocorticoid activity

9 alpha F

11

substitution at --- eliminates mineralocorticoid activity

C16

12

the glucocorticoid receptor is a member of

the nuclear hormone receptor superfamily

13

the cortisol-receptor complex is translocated to

the nucleus where it binds as homodimers to DNA transcripts that contain glucocorticoid response elements (GREs) and regulates gene expression of those genes

14

cortisol-receptor complex binding influences

transcription factors that act on other response elements. Therefore glucocorticoids influence the expression of genes

15

what are the anti-inflammatory/Immunosuppressive Effects of Glucocorticoids

-decrease cytokines, other inflammatory mediators
-redistribution of peripheral leukocytes
-decrease activity of peripheral leukocyes at site of inflammation
-impaired macrophage, T-cell, B-cell responses
-vasoconstriction
-decrease capillary permeability

16

what are the therapeutic uses for immunosuppression (glucocorticoids)

-prevention and treatment of transplant rejection
-graft-versus-host disease in bone-marrow transplantation
-autoimmune disorder (Rheumatoid and other arthritides, systemic lupus erthematosus)
-systemic dermatomyositis
-psoriasis and other skin conditions
-asthma and other allergic disorders
-inflammatory bowel disease
-inflammatory opthalmic disease
-autoimmune hematologic disorders
-acute exacerbation of MS

17

effective doses of glucocrticoids to relieve symptoms are determined

empirically

18

short term admin of glucocrticoids (up to 10 days) in the absence of contraindictions does not produce

adverse side effects

19

for prolonged use of glucocrticoids , benefits must be weighted against production of

iatrogenic Cushing's

20

high doses of glucocrticoids cause

mineralcorticoid effects - concern in pts with heart disease

21

prolonged use of glucocrticoids causes

-increase susceptibility to infection
-inhibits growth
-induces myopathy, osteoporosis, cataracts

22

what happens when glucocrticoids are used for more than 2 weeks

-adrenal suppression may be induced by negative feedback
-reduced ACTH secretion
-adrenocortical atrophy
-acute adrenal insufficiency in times of stress or upon withdrawal of the corticosteroid

23

what is cyclosporine

-lipid soluble peptide antibiotic

24

cyclosporine also known as

cyclosporin A

25

how is cyclosporine administered

-oral
-IV
-ophthalmic emulsion

26

cyclosporine binds to

cyclophilin C

27

binding of cyclosporine to cyclophilin C causes

-decrease calcineurin (cytoplasmic phosphatase)
-decrease production of cytokines
-decrease response of T cells to antigens

28

therapeutic use of cyclosporine

-graft-versus host disease in bone-marrow transplantation
-aplastic anemia in patients ineligible for transplants
-kidney, liver, heart and heart-lung transplantation
-autoimmune diseases
-dry eye syndrome (opthalmic emulsion)

29

cyclosporine toxicity can cause

-reversible nephrotoxicity (dose limiting)
-vascoconstriction that may lead to hypertension
-neurotoxicity
-hyperlipidemia
-transient hepatotxicity
-stimulates TGF-beta which may lead to an increase risk of cancer

30

cyclosporine is metabolized by

cytochrome P450 (especially CYP3A4)

31

what drugs inhibit metabolism and reduces cyclosporine clearance

-erythromycin
-ketoconazole
-Amphotericin B
-grapefruit juice

"A-KEG"

32

what drugs increase cyclosporine clearance

-phenobarbital
-rifampin

33

what is Tacrolimus

a macrolide antibiotic

34

Tacrolimus binds to

FK506-binding protein-12 (FKBP-12) an immunophilin structurall related to cyclophilin

35

function of Tacrolimus

-inhibits calcineurin
-decreases production of cytokines
-decreases response of T cells to antigens

36

administration of Tacrolimus

-oral
-injection

37

therapeutic use of Tacolimus

SAME AS CYCLOSPORINE:
Graft-versus-host disease in bone-marrow transplantation
Aplastic anemia in patients ineligible for transplants
Kidney, liver, heart and heart-lung transplantation
Autoimmune diseases

38

Tacrolimus is --- times more potent than cyclosporine

10 to 100

39

toxicity and drug interactions of Tacrolimus

same as for cyclosporine

40

what is Sirolimus

macrocyclic lactone

41

Sirolimus binds to

FKBP-12

42

does Sirolimus inhibit calcineurin

no!

43

function of Sirolimus

-inhibits mTOR (mammalian target of rapamycin, key enzyme in cell cycle progression)
-inhibit T-cell activation and proliferation

44

administration of Sirolimus

oral

45

therapeutic use of Sirolimus

-inhibition of transplant rejection (often include combination with a calcineurin inhibitor and glucocorticoid)
-preservation of graft-versus-host reaction
-treatment of autoimmune disease

46

effects of Sirolimus persists for ---- after discontinuing therapy

several months

47

toxicity accompanying the use of Sirolimus includes

-dose-dependent thrombocyopenia
-leukopenia
-hyperlipidemia

48

renal transplant patients on Sirolimus may show

a dose-dependent increase in serum cholesterol and triglycerides

49

adverse side effects of Sirolimus toxicity

-anemia
-hypotension
-hypokalemia or hyperkalemia
-fever
-gastrointestinal effects
-increase risk of lymphomas
-increased infections

50

Sirolimus interacts with what substrate

CYP3A4 - see cyclosporine for interactions

51

what is Azathioprine a derivative of

6 mercaptopurine (6-MP) derivative

52

Azathioprine has a better --- than (6-MP)

oral absorption

53

Azathioprine inhibits

S phase of DNA synthesis

54

Azathioprine is converted to

thioinosinic acid

55

thionosinic acid is a competitive inhibitor of

purine synthesis

56

Therapeutically thionosinic affects

T cells more than B cells

57

administration method of Azathioprine

oral
IV

58

Azathioprine is used in combination with corticosteroids to

inhibit rejection of organ transplants and for rheumatoid arthritis

59

Azathioprine toxicity can lead to

-bone marrow suppression, gastrointesinal toxicity, mild hepatotoxicity
-lead to severe infection
-mutagenic, carcinogenic

60

what happens if Azathioprine is co-administered with allopurional

toxicity may increase

61

Mycophenolate Mofetil is a semisynthetic derivative of

mycophenolic acid

61

therapeutic use of Fingolimod

treatment of patients with relapsing multiple sclerosis to reduce frequency of exacerbations and delay the physical disability

61

function of Mycophenolate Mofetil

-inhibits inosine monophosphate dehydrogenase
-decreases purine biosynthesis
-decreases proliferation of T and B lymphocytes

61

administration of Mycophenolate Mofetil

oral, IV

61

Mycophenolate Mofetil is used in combination with cyclosporine and corticosteroids to

prevent organ rejection in allogenic renal transplant pts and in liver and cardiac transplant patients

61

Mycophenolate Mofetil toxicity causes

-diarrhea
-leukopenia
-cytomegalovirus infections and gastrointestinal hemorrhage

62

what happens when Mycophenolate Mofetil is co-administered with antacids (magnesium, aluminim hydroxides)

decreases absorption

62

Mechanism of action of Fingolimod

-sphingosine 1-phosphate receptor (S1P-R) agonist

63

administration of Fingolimod

-oral

64

what type of vaccine should be avoided when taking Fingolimod

live attenuated vaccines during and for 2 months after stopping due to risk of infection

65

effects of Fingolimod toxicity

-decrease heart rate and/or AV conduction after first dose
-infections
-macular edema
-decrease in pulmonary function
-hepatotoxicity

66

why should women of childbearing potential on Fingolimod use contraception during and for 2 months after stopping

bc Fingolimod increases fetal risk

67

Fingolimod has a pharmacodynamic interaction meaning

Antiarrhythmic drugs and Beta blockers increase risk of additive effects on heart rate

68

Vincristine used to teat

idiopathic thrombocytopenic purpura

69

Fingolimod clearance is decreased by

ketoconazole (inhibitor of CYP4F)

70

other antimetabolites used for immunisuppression

1. cyclophosphamide
2. methotrexate
2. Vincristine

71

Methotrexate used to treat

rheumatoid arthritis

72

Vincristine used to teat

idiopathic thrombocytopenic purpura

73

therapeutic use of ATG

can be used alone or in combination with corticosteroids and azathioprine to prevent renal allograph rejection

74

ATG toxicity can lead to

hypersensitivity
nephritis and anaphylaxis (occurs rarely)

75

what is Muromonab-CD3

a mouse monoclonal Ab

76

mechanism of action of Muromonab-CD3

-blocking Ab
-CD3 localized adjacent to antigen recognition complex, which is blocked as well
-T cells are unable to recognize foreign antigen

77

what is antithymocyte globulin (ATG)

is a purified equine immunoglobulin against human thymus lymphocytes

79

name 2 IL-2 Receptor (Anti-CD25) Antibodies

1. Basiliximab
2. Daclizumab

79

both Basiliximab and Daclizumab are

mouse/human monoclonal antibodies

80

infliximab toxicity causes

-infusion rxn - fever, urticaria, hypotension, dyspnea within 1-2 hrs after administration
-upper respiratory and urinary tract infections
-development of antinuclear Abs, rarely a lupus-like syndrome

81

therapeutic use of Basiliximab and Daclizumab

-prevention of acute renal transplant rejection
-both are given with cyclosporine and corticosteroids

82

Basiliximab and Daclizumab toxicity

well tolerated; no significant drug interactions

83

therapeutic use of Muromonab-CD3

-treatment of acute kidney or hepatic transplant rejection
-prophylaxis in cardiac transplantation
-depletions of T cells in marrow from donors before bone marrow transplantation

84

name an Anti-TNF reagent

infliximab

85

Muromonab-CD3 toxicity causes

-fever
-pulmonary edema
-vomiting
-headache
-anaphylaxis
-infection during chronic therapy

86

what is infliximab

a chimeric anti-TNF -alpha monoclonal antibody

87

sites of action of immunosuppressive agents of T-cell activation (see slide 26)

1. glucocorticoids
2. cyclosporine
3. tacrolimus
4. sirolimus
5. Azathioprine
6. Fingolimod
7. Mycophenolate
8. Muromonab- CD3
9. Daxlizumab, Basiliximab

88

infliximab toxicity causes

-infusion rxn - fever, urticaria, hypotension, dyspnea within 1-2 hrs after administration
-upper respiratory and urinary tract infections
-development of antinuclear Abs, rarely a lupus-like syndrome

89

therapeutic use of Rho immune globulin

prevention of hemolytic disease of Rh-positive newborns

90

mechanism of action of Etanercept

blocks the effects of TNF-alpha

91

therapeutic use of Etanercept

rheumatoid arthritis - patients who do not respond to other treatments

92

Etanercept toxicity cause

-injection site rxns
-infections

93

BCG toxicity leads to

severe hypersensitivity and shock

94

what are immune globulins

-human plasma from donors in the general population or hyperimmunized individuals (for specific exposures such as hepatitis B, rabies, tetanus, varicella-zoster, cytomegalovirus, botulism, respiratory syncytial virus)
-replacing missing Abs

95

what are immunostimulants

biological response modifiers

96

What is Bacillus Calmette-Guerin (BCG)

-an immunostimulant
-viable attenuated strain of Myobacterium bovis

97

mechanism of action of BCG

-has an adjuvant effect to stimulate T cells and natural killer cells

98

therapeutic use of BCG

bladder cancers

99

BCG toxicity leads to

severe hypersensitivity and shock

100

therapeutic use of immune globulin

passive immunization
-immunodeficiencies
-prevention of infection in chronic lymphocytic leukemia
-Kawasake disease (acute multisystem inflammatory disease of children)

101

immune globulin toxicity leads to

-anaphylactoid rxns and severe hypotension
-theoretical risk of infection due to plasma source

102

name 2 recombinant cytokines

1. interleukin-2
2. interferons

109

name 2 Myeloid Colony Stimulating Factors

Granulocyte-macrophage colony stimulating factor (GM-CSF)
Granulocyte stimulating factor (G-CSF)

110

what drugs are calcineurin inhibitors

-cyclosporine
-Tacrolimus

111

what drugs are Antiproliferative & Antimetabolic drugs

-Sirolimus
-Azathioprine
-Mycophenolate Mofetil
-Fingolimod
-Cyclophosphamide
-Methotrexate
-Vincristine

112

what drugs are antibodies

-antithymocyte gloulin (ATG)
-Muromonab -CD3 (Anti-CD3 Monoclonal Ab)
-Basiliximab (IL-2 Receptor Antibodies)
-Daclizumab (IL-2 Receptor Antibodies)
-Infliximab (Anti-TNF Reagents)
-Rho Immune Globulin

113

what drugs are Anti-TNF reagents

-Etanercept

114

what drugs are immunostimulants

immune globulin