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Hailey - IHO > Immunosuppressants > Flashcards

Immunosuppressants Flashcards

1
Q

Cyclosporine mech

A

Calcineurin inhibitor
Binds cyclophilin
Blocks T cell activation by preventing NFAT/IL-2 Tx/gene expression

ANTI-REJECTION

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2
Q

Cyclosporine use

A

Transplant rejection prophylaxis
Psoriasis
RA

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3
Q

Cyclosporine toxicity

A 
NEPHROTOXICITY (distinguished from graft failure)
HTN
Hyperlipidemia
Neurotoxicity
Givival hyperplasia
Hirsutism
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4
Q

Tacrolimus (FK506) mech

A

Calcineurin inhbitior
Binds FK506 binding protin
Blocks T cell activation by preventing NFAT/IL-2 Tx

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5
Q

Tacrolimus use

A

ANTI-REJECTION
Transplant rejection prophylaxis
100x more potent than cyclosporine

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6
Q

Tacrolimus toxicity

A

NEPHROTOXICITY
Increased risk of diabetes and neurotoxicity
No gingival hyperplasia or hirsutism

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7
Q

Sirolimus (Rapamycin) mech

A

mTOR inhibitor (blocks cell cycle progression from G1 to S)
Binds FKBP
Blocks T-cell activation and B-cell diff by preventing response to IL-2

Prevents clonal expansion of both B and T cells***

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8
Q

Sirolimus (Rapamycin) use

A

ANTI-REJECTION
Kidney transplatn rejection prophylaxis
Synergistic with cyclosporine

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9
Q

Sirolimus (Rapamycin) toxicity

A 
Anemia
Thrombocytopenia
Leukopenia
Insulin resistance
Hyperlipidemia
NOT NEPHROTOXIC (nephrotoxic when combined with cyclosporine)
Increased risk lymphomas and infections
substrate of CYP3A4
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10
Q

Daclizumab

Basiliximab mech

A

mabs to block IL-2R (CD25)

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11
Q

Daclizumab

Basiliximab use

A

Kidney transplant rejection prophylaxis

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12
Q

Daclizumab

Basiliximab toxicity

A

Edema, hypertension, tremor

Risk of hypersensitivity

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13
Q

Azathioprine mech

A

Antimetabolite precursors or 6-mercaptopurine
Inhibits lympocyte proliferation by blocking nucleotide synthesis
Say azathioPURINE*
6-MP degraded by xanthine oxidase; toxicity increased by allopurinol

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14
Q

Azathioprine use

A 
Transplant rejection prophylaixs
RA
Crohn disease
Glomerulonephritis
Other AI
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15
Q

Azathioprine toxicity

A

Pancytopenia (a, thro, leuk)

6-MP degraded by xanthine oxidase; toxicity increased by allopurinol

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16
Q

Glucocorticoids mech

A

Inhibit NF-kB and cytokines: IL-1, IL-2, IL-6, TNF-a

Suppress both B and T cell function by decreased Tx of many cytokines

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17
Q

Glucocorticoids use

A

Transplant rejection prophylaxis (immunosuppression)
Many AI disorders
Inflammation
Hemolytic disease of newborn

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18
Q

Glucocorticoid toxicity

A 
Hyperglycemia
Osteoporosis
Central obesity
Muscle breakdown
Pscyhosis
Acne
HTN
Catarcts
Avascular necrosis
Can cause Iatrogenic Cushing syndrome
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19
Q

Immunosuppressive therapy used to…

A 
dampen immune response in:
organ transplantation
AI disease
hypersensitivity
Hemolytic anemia of the newborn
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20
Q

Suppress immune response so won’t get…

A

immune mediated tissue damage –> more inflammatory response

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21
Q

Limitations of immunosuppressive therapy

A

Increase risk of infections

Increased risk of lymphomas and related malignancies

22
Q

Major classes of immunosuppressants

A

Glucocorticoids (anti-inflammatory steroids)
Calcineurin inhibitors
Antiproliferative/antimetabolic drugs
Antibodies

23
Q

Adrenal cortex synthesis two classes of steroids:

A

corticosteroids

androgens

24
Q

Corticosteroids have two types of activity:

A

glucocorticoid (carbohydrate metabolism regulating) activity

mineralocorticoid (electrolyte balance regulating) activity

25
Q

Prototype of glucocorticoids

A

cortisol

endogenous, oral, parenteral, topical

26
Q

Prototype of mineralocorticoids

A

aldosterone

27
Q

Activity of aldosterone/cortisol regarding:
sodium retention
liver glycogen deposition
anti-inflammatory

A

Aldosterone:
+ sodium retention
- liver glycogen deposition
- anti-inflammatory

Cortisol:
- sodium retention
+ liver glycogen deposition
+ anti-inflammatory

28
Q

Sodium retention is:

A

the ability of steroid to reduce sodium excretion by the kidney

29
Q

Liver glycogen deposition is:

A

ability of steroid to cause hepatic deposition of glycogen in a fasted animal

30
Q

Endogenous steroids (Anti-Inflammatory, Sodium Retention, Duration)

A

Aldosterone (0.3, 3000, X)
Corticoterone (0.35, 15, X)
Cortisol (Hydrocortisone) (1, 1, S)

31
Q

Synthetic steroids used as anti-inflammatory drugs (Anti-Inflammatory, Sodium Retention, Duration)

A

Betamethasone (25, 0, L)
Dexamethasone (25, 0, L)
Methylprednisolone (5, 0.5, I)
Prednisone (4, 0.8, I)

32
Q

Short
Intermediate
Long
(in hours)

A

8-12
12-36
36-72

33
Q

D, M, and E of glucocorticoids

A

D: local, but always a little systemic
M: liver
E: kidney

34
Q

Steroid receptors and molecules

A

CR: glucocorticoid receptor
CBG: corticosteroid binding globulin
IP: immunophilin
GRE: glucocorticoid response elements

35
Q

Glucocorticoid mech

A

Steroid GR complexes interact and attach promoter region GRE –> altered cellular function***

Also interact with transcription factors NF-kB and AP-1 –> act on NON-GRE containing promoters to repress gene expression

36
Q

Actions in humans: cell movement + synthesis/release inflammatory mediators

A

NEUTROPHILS: more circ, marginalization?
LYMPHOCYTES: profound transient lympohpenia (cells move to extravascular compartments like spleen, LNs, BM, etc.)
MONOCYTES AND EOSINOPHILS: decreased in peripheral blood

Steroid effects:

  • reduce expression of COX 2
  • inhibit release of AA from phospholipids, thus affecting LT and PG formation
  • inhibit degranulation of mast cells and basophils
  • inhibit synt and release of TNF, IL-1, IL-2, and IFNy (to make more cortisol)
37
Q

Cortisol and its analogs prevent or suppress:

A

redness
swelling
heat
pain

*no matter if inciting agent is radiant, mechanical, chemical ,infectious, or immunological

38
Q

Therapeutic principles of glucocorticoids

A
  1. correct doses are trial and error
  2. single dose virtually harmless
  3. few days of corticosteroid tx harmless except high doses
  4. prologantion of tx increases incidence of potentially lethal effects
  5. treating only the symptoms
  6. risk ADRENAL INSUFFICIENCY with abrupt cessation of prolonged, high-dose tx
39
Q

Toxicity of glucocorticoids

A 
*primarily assoc with SYSTEMIC administration
Large dose SE:
- increased susceptibility to inf
- peptic ulceration
- behavioral disturbances (psychosis)
- cataracts
- osteoporosis and vertebral compression fractures
- inhibition of growth
- acute adrenal insufficiency
40
Q

Acute adrenal insufficiency

A 
Fever
Myalgia
Arthralgia
Malaise
DEATH can occur with HYPOTENSION and SHOCK
41
Q

Antiproliferative/antimetabolic drugs

A

Sirolimus
Mycophenolate Mofetil
*prevent clonal expansion of B and T cells

42
Q

Mycophenolate Mofetil mech

A

Mafia: IMPDH code

Inhibitor of inosine monophosphate dehydrogenase IMPDH (important in guanine nucleotide synth)
***T and B cells highly depend on this pathway

43
Q

Mycophenolate Mofetil use

A

Organ transplantation

44
Q

Mycophenolate Mofetil toxicity

A 
Hematologic
GI
Leukopenia
Diarrhea
Vomiting
45
Q

Antibodies causing immunosuppression

A

Anti-thymocyte globulin (ATG)
Muromonab-CD3
Daclizumab/Basiliximab

46
Q

Anti-thymocyte globulin (ATG) mech and tox

A

Binds to thymocytes in circulation –> lymphopenia and impaired T cell imm response

Serum sickness
Nephritis
Maybe anaphylaxis

47
Q

Muromonab-CD3 mech

A

Mouse mab that binds to epsilon chain CD3 glycoprotein of TCR complex –> TCR complex internalized –> prevents ag recognition

48
Q

Muromonab-CD3 use and tox

A

Prevent acute rejection of kidney, liver, and heart transplantation

Cytokine release syndrome: mild flu-like illness OR LIFE-THREATENING SHOCK
- Fc Rec mediated crosslinking –> initial activation of cell –> release cytokines

*admin glucocorticoids prior to admin –> reduced symptoms considerably

49
Q

Why can’t use repeatedly?

A

Because is a mouse man and an immune response occurs to mouse ab in second administration

50
Q

Daclizumab/Basiliximab mech

A

Anti-IL-2 Receptor (anti-CD25) ab
Humanized

Binds to IL-2 Receptor on activated T cells –> block IL-2 mediated T cell activation events

51
Q

Daclizumab/Basiliximab use and tox

A

Organ transplantation

No cytokine release syndrome
Anaphylactic reaction can occur

52
Q 
Site of action and mech:
Glucocorticoids
Muromonab-CD3
Cyclosporine
Tacrolimus
Mycophenolate mofetil
Daclizumab, Basiliximab
Sirolimus
A

Site of action:
DNA elements (regulates DNA gene transcription)
TCR comples (blocks ag recognition)
Calcineurin (inhibits phosphatase activity)
Calcineurin (inhibits phosphatase activity)
IMPDH (inhibits IMPDH activity)
IL-2 Rec (blocks IL-2 mediated T cell activation)
mTOR (blocks mTOR/TK activity in cell cycle progression)

Hailey - IHO (5 decks)

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