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IHO > Immunosuppressive Drugs > Flashcards

Immunosuppressive Drugs Flashcards

0
Q

In general, glucocorticoids are metabolized by ___ and excreted by ___.

A

The liver

The kidney

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1
Q

What are the 2 classes of steroids synthesized by the adrenal cortex?

A

Corticosteroids (inc glucocorticoids and mineralocorticoids)

Androgens

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2
Q

4 synthetic steroids used as anti-inflammatory drugs

in order of decreasing anti-inflammatory activity

A

Betamethasone, Dexamethasone (25) long
Methylprednisone (5) intermediate
Prednisone (4) intermediate
(with endogenous Cortisol =1, short-acting)

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3
Q

How do steroids exert their effect?

A

Carried in plasma by corticosteroid binding globulin
Diffuses across plasma membrane
Interacts with glucocorticoid receptor in cytoplasm, and they translocate to the nucleus together
Dimerize -> transcription of GRE (glucocorticoid response elements)

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4
Q

Why is there a lag in steroid effects?

A

Time required for transcription, translation.

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5
Q

In the nucleus, the steroid-GR complex also interacts with ____ and ___ –> ____

A

NF-kB and AP-1

act on non-GRE-containing promotors –> repress gene expression

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6
Q

What effect do anti-inflammatory steroids have on neutrophils?

A

More circulating but blockage of extravasation to inflammatory sites
Release from bone marrow accelerated
Half time in circulation increased

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7
Q

What effect do anti-inflammatory steroids have on lymphocytes?

A

Profound lymphopenia

Lymphocytes not lysed - just migrate to extravascular compartments e.g. spleen, lymph nodes, thoracic duct, bone marrow

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8
Q

What effect do anti-inflammatory steroids have on monocytes and eosinophils?

A

Decreased in peripheral blood

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9
Q

Steroid effects

A

reduced expression of COX2
inhibit AA release from phospholipids -> dec PG and LT
inhibit degranulation of mast cells and basophils
inhibit synthesis and release of TNF, IL1, IL2, IFN
etc

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10
Q

Note: administering corticosteroids for inflammation is only treating the symptoms

A

not the cause

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11
Q

Adverse effects of long-term (usually systemic) steroid use

A 
Increased susceptibility to infection
Peptic ulceration
Behavioral disturbances
Cataracts
Osteoporosis and vertebral compression fractures
Inhibition of growth
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12
Q

Withdrawal/discontinuation of steroid effects

A

Symptoms of acute adrenal insufficiency:
Fever, myalgia, arthralgia, malaise
Death with hypotension and shock

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13
Q

2 calcineurin inhibitors

A

Cyclosporine and Tacrolimus (FK506)

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14
Q

What does calcineurin do?

A

Activates T cells

Leads to upregulation of IL2 -> growth and differentiation of T cell response

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15
Q

Cyclosporine:
Common use
Major adverse effect

A 
Long-term therapy for transplantation
Renal toxicity (up to 75% of patients)
16
Q

Compare Tacrolimus to Cyclosporine

A

Tacrolimus is 100x more potent

Similar nephrotoxicity

17
Q

Name 2 antiproliferative/antimetabolic drugs.

What do they do?

A

Prevent clonal expansion of B and T lymphocytes

Sirolimus and Mycophenolate Mofetil

18
Q

How does Sirolimus work?

A

Binds FKBP (cytoplasmic receptor protein) –> inhibits mTOR –> blocks cell cycle progression from G1 to S.

19
Q

Sirolimus toxicity

A

Dose-dependent increase in cholesterol and triglycerides

20
Q

How does mycophenolate mofetil work?

A

Metabolite –> inhibition of inosine monophosphate dehydrogenase -> inhibits de novo guanine nucleotide synthesis -> inhibits proliferation of B and T cells (other cells will use salvage pathways)

21
Q

Mycophenolate Mofetil toxicity

A

Leukopenia, diarrhea, vomiting

22
Q

How does anti-thymocyte globulin work?

A

animals injected with human thymocytes -> Ig
Ig purified and given to humans -> impaired T cell immune response
Tox: serum sickness from ab being recognized as foreign, nephritis

23
Q

How does Muromonab-CD3 work?

A

Mouse ab, binds CD3 -> internalization of TCR -> dampened immune response

24
Q

Why should glucocorticoids be given prior to Muromonab-CD3 administration?

A

Reduces cytokine release syndrome symptoms
When TCR is bound + Fc cross linking from the mouse ab -> initial activation of T cell -> cytokines released
Symptoms range from flu-like illness to life-threatening shock

25
Q

2 IL-2 receptor blockers

A

Daclizumab and Basiliximab

26
Q

How do Daclizumab and Basiliximab work?

How do they compare in toxicity to other immunosuppressive drugs?

A

Bind IL-2 receptor on activated (not resting) T cells and prevent its activity
Tox: no cytokine release syndrome. Lower incidence of lymphoproliferative disorders and opportunistic infections. May have anaphylaxis.

IHO (2 decks)

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