Immunosuppressive Drugs Flashcards
In general, glucocorticoids are metabolized by ___ and excreted by ___.
The liver
The kidney
What are the 2 classes of steroids synthesized by the adrenal cortex?
Corticosteroids (inc glucocorticoids and mineralocorticoids)
Androgens
4 synthetic steroids used as anti-inflammatory drugs
in order of decreasing anti-inflammatory activity
Betamethasone, Dexamethasone (25) long
Methylprednisone (5) intermediate
Prednisone (4) intermediate
(with endogenous Cortisol =1, short-acting)
How do steroids exert their effect?
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)
Why is there a lag in steroid effects?
Time required for transcription, translation.
In the nucleus, the steroid-GR complex also interacts with ____ and ___ –> ____
NF-kB and AP-1
act on non-GRE-containing promotors –> repress gene expression
What effect do anti-inflammatory steroids have on neutrophils?
More circulating but blockage of extravasation to inflammatory sites
Release from bone marrow accelerated
Half time in circulation increased
What effect do anti-inflammatory steroids have on lymphocytes?
Profound lymphopenia
Lymphocytes not lysed - just migrate to extravascular compartments e.g. spleen, lymph nodes, thoracic duct, bone marrow
What effect do anti-inflammatory steroids have on monocytes and eosinophils?
Decreased in peripheral blood
Steroid effects
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
Note: administering corticosteroids for inflammation is only treating the symptoms
not the cause
Adverse effects of long-term (usually systemic) steroid use
Increased susceptibility to infection Peptic ulceration Behavioral disturbances Cataracts Osteoporosis and vertebral compression fractures Inhibition of growth
Withdrawal/discontinuation of steroid effects
Symptoms of acute adrenal insufficiency:
Fever, myalgia, arthralgia, malaise
Death with hypotension and shock
2 calcineurin inhibitors
Cyclosporine and Tacrolimus (FK506)
What does calcineurin do?
Activates T cells
Leads to upregulation of IL2 -> growth and differentiation of T cell response
Cyclosporine:
Common use
Major adverse effect
Long-term therapy for transplantation Renal toxicity (up to 75% of patients)
Compare Tacrolimus to Cyclosporine
Tacrolimus is 100x more potent
Similar nephrotoxicity
Name 2 antiproliferative/antimetabolic drugs.
What do they do?
Prevent clonal expansion of B and T lymphocytes
Sirolimus and Mycophenolate Mofetil
How does Sirolimus work?
Binds FKBP (cytoplasmic receptor protein) –> inhibits mTOR –> blocks cell cycle progression from G1 to S.
Sirolimus toxicity
Dose-dependent increase in cholesterol and triglycerides
How does mycophenolate mofetil work?
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)
Mycophenolate Mofetil toxicity
Leukopenia, diarrhea, vomiting
How does anti-thymocyte globulin work?
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
How does Muromonab-CD3 work?
Mouse ab, binds CD3 -> internalization of TCR -> dampened immune response
