Term
switch off multiple inflammatory genes (encoding cytokines, chemokines, adhesion molecules, inflammatory enzymes, receptors, and proteins) that have been activated during a chronic inflammatory process.
in higher concentrations they have additional effects on the synthesis of anti-inflammatory proteins and post-genomic effects
1) receptor-mediated transcription regulation mechanism (down regulates proinflammatory cytokines)
2) T-cells are inhibited from making IL-2 and proliferating
3) the activation of cytotoxic T-cells is inhibited |
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Definition
| MOA of glucocorticoids: prednisone and dexamethasone |
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Term
long term use associated with:
avascular bone necrosis
osteopenia
increased risk of infection
poor wound healing
cataracts
hyperglycemia
hypertension |
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Definition
| ADRs of glucocorticoids: prednisone and dexamethasone |
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Term
prodrug that is gradually cleaved in the body to 6-mercaptopurine from which 6-thioguanosine nucleotides are synthesized
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Definition
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Term
bone marrow suppression is major side effect
also, increased risk of various cancers: due to immunosuppression and also due to mutagenic aspect of the MOA (DNA damage)
thiopurines cause phototoxicity: anions readily absorb UVA light; formation of reactive oxygen species leading to DNA damage and a major source of mutation |
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Definition
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Term
inhibits the 1st enzymatic step of purine salvage
salvage pathway: recover purine bases and reconvert them into the corresponding nucleotide; useful when tissue cannot synthesize purines via the de novo pathway
6-MP is converted to 6-thiouric acid (inactive) by xanthine oxidase
XO is very important in MP metabolism
if taking allopurinol must lower the dose of azathioprine
6-MP is deactivated by TPMT (low or high function)
MeTIMP (metabolite of 6-MP) is a potent inhibitor of de novo purine synthesis
Thio-dGTP (metabolite of 6-MP) results in cytotoxicity from incorporation into DNA and mismatch pair initiation |
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Definition
| metabolism and mechanism of 6-mercaptopurine (active form of azathioprine) |
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Term
inhibits purine biosynthesis
inhibition of the 1st committed step of de novo purine synthesis
MeTIMP is an efficient NON-COMPETITIVE INHIBITOR of aminophosphoribosyl transferase
inhibition reduces supplies of purine nucleotides for DNA and RNA synthesis |
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Definition
| MOA of MeTIMP: methyl thioinosine-5'-monophosphate (metabolite of azathiprine) |
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Term
impairs T-cell proliferation
6-thioGTP is a good substrate for DNA polymerases; coding for 6-TG is ambiguous; C and T are encoded equally
THIS CAN INITIATE THE DNA MIS-MATCH REPAIR (MMR) SYSTEM WHICH RESULTS IN CELL DEATH
6-TG DNA is methylated easily by S-adenosyl methionine
normal surveillance repairs G:T mismatch
Me-6-TG cannot be repaired; NO COMPLEMENTARY BASE
anomalous DNA structures that result are observed as interruptions
during the next S phase lethal DNA structures trigger activation of G2 arrest |
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Definition
| MOA of Me-6-TG: methyl-6-thioguanosine (metabolite of azathioprine) |
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Term
prodrug of mycophenolic acid
BA of MPA ~94% (BA of MM ~0% b/c so rapidly metabolized to MPA)
MPA metabolized by glucuronidation
undergoes enterohepatic recycling |
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Definition
| ADME of mycophenolate mofetil |
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Term
prodrug metabolized to mycophenolic acid
non-competitive inhibition of IMPDH
MPA is NOT a purine analog (like 6-MP) but rather inhibits cofactor binding
IMPDH catalyzes the NAD+ dependent oxidation of IMP to XMP, which is the COMMITTED STEP in guanosine nucleotide biosynthesis (no longer de novo which take you to IMP)
MPA inhibits IMPDH by ACTING AS A REPLACEMENT FOR THE NICOTINAMIDE PORTION OF NAD+ COFACTOR AND A CATALYTIC WATER MOLECULE
the MPA bicyclic ring system attacks on the purine ring (as NAD+ would do) and its PHENOL OCCUPIES THE HYDOLYTIC WATER SITE. this blocks hydrolysis of thioimidate ester adduct of Cys331 and inactivates the enzyme
thus MPA selectively inhibits lymphocyte proliferation and functions, including antibody production, cellular adhesion and migration resulting in immunosuppression |
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Definition
| MOA of mycophenolate mofetil |
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Term
selective suppression of T-cells without the bone marrow toxicities seen with azathioprine
cyclosporin forms a complex with the binding protein cyclophilin and calcineurin; this complex inhibits the enzyme calcineurin
calcineurin plays an essential role in the antigen-induced proliferation of T-cells
cyclosporin also increases expression of inhibitors of IL-2 stimulated T-cell proliferation |
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Definition
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Term
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Definition
| cyclosporin complex binding sites for cyclophilin and calcineurin |
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Term
renal dysfunction
tremor
hirsutism
hypertension
hyperlipidemia
gum hyperplasia
cyclosporin is very lipophilic with a pKa of 4.3
metabolized extensively by CYP3A4 = drug interactions
all metabolites are less active than cyclosporin or inactive |
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Definition
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Term
like cyclosporine, tacrolimus inhibits T-cell activation by inhibiting calcineurin
binds to the intracellular protein, FKBP12, an immunophilin structurally similar to cyclophilin
the tacrolimus/FKBP12/calcium/calcineurin complex forms and caclineurin phosphatate activity is inhibited |
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Definition
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Term
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Definition
| calcineurin binding site on tacrolimus compared to cyclosporin |
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Term
inhibits T-cell activation/proliferation downstream of IL-2 and other T-cell growth factors
forms a complex with immunophilin, FKBP12.
this complex does not inhibit calcineurin activity like tacrolimus and cyclosporin
sirolimus binds to and inhibits mTOR, a key enzyme in cell cycle progression
mTOR is a protein essential for G1 to S traverse in cell cycle |
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Definition
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Term
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Definition
| complex formation of sirolimus/FKBP12/mTOR compared to tacrolimus/FKBP12/calcineurin |
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Term
localizes B and T cells in the lymph nodes, preventing them from circulating and attacking implanted grafts
sequesters lymphocytes but does not affect their function
fingolimod resembles sphingosine, a natural lipid protein signaling agent
fingolimod acts on S1P receptors (present in large amounts on lymphocytes)
when lymphocytes return to the lymph nodes to multiply, the level of these receptors on the membrane is reduced
when they are ready to exit, the level increases, sensitizing them to S1P and provoking migration from the nodes to circulation
fingolimod activates S1P-1 receptors, which become internalized and unavailable for S1P. thus the cell cannot leave the lymph node |
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Definition
| MOA of fingolimod (FTY720) |
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