Immunosuppressants Flashcards
Cyclosporine mech
Calcineurin inhibitor
Binds cyclophilin
Blocks T cell activation by preventing NFAT/IL-2 Tx/gene expression
ANTI-REJECTION
Cyclosporine use
Transplant rejection prophylaxis
Psoriasis
RA
Cyclosporine toxicity
NEPHROTOXICITY (distinguished from graft failure) HTN Hyperlipidemia Neurotoxicity Givival hyperplasia Hirsutism
Tacrolimus (FK506) mech
Calcineurin inhbitior
Binds FK506 binding protin
Blocks T cell activation by preventing NFAT/IL-2 Tx
Tacrolimus use
ANTI-REJECTION
Transplant rejection prophylaxis
100x more potent than cyclosporine
Tacrolimus toxicity
NEPHROTOXICITY
Increased risk of diabetes and neurotoxicity
No gingival hyperplasia or hirsutism
Sirolimus (Rapamycin) mech
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***
Sirolimus (Rapamycin) use
ANTI-REJECTION
Kidney transplatn rejection prophylaxis
Synergistic with cyclosporine
Sirolimus (Rapamycin) toxicity
Anemia Thrombocytopenia Leukopenia Insulin resistance Hyperlipidemia NOT NEPHROTOXIC (nephrotoxic when combined with cyclosporine) Increased risk lymphomas and infections substrate of CYP3A4
Daclizumab
Basiliximab mech
mabs to block IL-2R (CD25)
Daclizumab
Basiliximab use
Kidney transplant rejection prophylaxis
Daclizumab
Basiliximab toxicity
Edema, hypertension, tremor
Risk of hypersensitivity
Azathioprine mech
Antimetabolite precursors or 6-mercaptopurine
Inhibits lympocyte proliferation by blocking nucleotide synthesis
Say azathioPURINE*
6-MP degraded by xanthine oxidase; toxicity increased by allopurinol
Azathioprine use
Transplant rejection prophylaixs RA Crohn disease Glomerulonephritis Other AI
Azathioprine toxicity
Pancytopenia (a, thro, leuk)
6-MP degraded by xanthine oxidase; toxicity increased by allopurinol
Glucocorticoids mech
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
Glucocorticoids use
Transplant rejection prophylaxis (immunosuppression)
Many AI disorders
Inflammation
Hemolytic disease of newborn
Glucocorticoid toxicity
Hyperglycemia Osteoporosis Central obesity Muscle breakdown Pscyhosis Acne HTN Catarcts Avascular necrosis Can cause Iatrogenic Cushing syndrome
Immunosuppressive therapy used to…
dampen immune response in: organ transplantation AI disease hypersensitivity Hemolytic anemia of the newborn
Suppress immune response so won’t get…
immune mediated tissue damage –> more inflammatory response
Limitations of immunosuppressive therapy
Increase risk of infections
Increased risk of lymphomas and related malignancies
Major classes of immunosuppressants
Glucocorticoids (anti-inflammatory steroids)
Calcineurin inhibitors
Antiproliferative/antimetabolic drugs
Antibodies
Adrenal cortex synthesis two classes of steroids:
corticosteroids
androgens
Corticosteroids have two types of activity:
glucocorticoid (carbohydrate metabolism regulating) activity
mineralocorticoid (electrolyte balance regulating) activity
Prototype of glucocorticoids
cortisol
endogenous, oral, parenteral, topical
Prototype of mineralocorticoids
aldosterone
Activity of aldosterone/cortisol regarding:
sodium retention
liver glycogen deposition
anti-inflammatory
Aldosterone:
+ sodium retention
- liver glycogen deposition
- anti-inflammatory
Cortisol:
- sodium retention
+ liver glycogen deposition
+ anti-inflammatory
Sodium retention is:
the ability of steroid to reduce sodium excretion by the kidney
Liver glycogen deposition is:
ability of steroid to cause hepatic deposition of glycogen in a fasted animal
Endogenous steroids (Anti-Inflammatory, Sodium Retention, Duration)
Aldosterone (0.3, 3000, X)
Corticoterone (0.35, 15, X)
Cortisol (Hydrocortisone) (1, 1, S)
Synthetic steroids used as anti-inflammatory drugs (Anti-Inflammatory, Sodium Retention, Duration)
Betamethasone (25, 0, L)
Dexamethasone (25, 0, L)
Methylprednisolone (5, 0.5, I)
Prednisone (4, 0.8, I)
Short
Intermediate
Long
(in hours)
8-12
12-36
36-72
D, M, and E of glucocorticoids
D: local, but always a little systemic
M: liver
E: kidney
Steroid receptors and molecules
CR: glucocorticoid receptor
CBG: corticosteroid binding globulin
IP: immunophilin
GRE: glucocorticoid response elements
Glucocorticoid mech
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
Actions in humans: cell movement + synthesis/release inflammatory mediators
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)
Cortisol and its analogs prevent or suppress:
redness
swelling
heat
pain
*no matter if inciting agent is radiant, mechanical, chemical ,infectious, or immunological
Therapeutic principles of glucocorticoids
- correct doses are trial and error
- single dose virtually harmless
- few days of corticosteroid tx harmless except high doses
- prologantion of tx increases incidence of potentially lethal effects
- treating only the symptoms
- risk ADRENAL INSUFFICIENCY with abrupt cessation of prolonged, high-dose tx
Toxicity of glucocorticoids
*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
Acute adrenal insufficiency
Fever Myalgia Arthralgia Malaise DEATH can occur with HYPOTENSION and SHOCK
Antiproliferative/antimetabolic drugs
Sirolimus
Mycophenolate Mofetil
*prevent clonal expansion of B and T cells
Mycophenolate Mofetil mech
Mafia: IMPDH code
Inhibitor of inosine monophosphate dehydrogenase IMPDH (important in guanine nucleotide synth)
***T and B cells highly depend on this pathway
Mycophenolate Mofetil use
Organ transplantation
Mycophenolate Mofetil toxicity
Hematologic GI Leukopenia Diarrhea Vomiting
Antibodies causing immunosuppression
Anti-thymocyte globulin (ATG)
Muromonab-CD3
Daclizumab/Basiliximab
Anti-thymocyte globulin (ATG) mech and tox
Binds to thymocytes in circulation –> lymphopenia and impaired T cell imm response
Serum sickness
Nephritis
Maybe anaphylaxis
Muromonab-CD3 mech
Mouse mab that binds to epsilon chain CD3 glycoprotein of TCR complex –> TCR complex internalized –> prevents ag recognition
Muromonab-CD3 use and tox
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
Why can’t use repeatedly?
Because is a mouse man and an immune response occurs to mouse ab in second administration
Daclizumab/Basiliximab mech
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
Daclizumab/Basiliximab use and tox
Organ transplantation
No cytokine release syndrome
Anaphylactic reaction can occur
Site of action and mech: Glucocorticoids Muromonab-CD3 Cyclosporine Tacrolimus Mycophenolate mofetil Daclizumab, Basiliximab Sirolimus
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)
