Immunosuppressants Flashcards
Cyclosporine
Mechanism: inhibits the activation and proliferation of CD4 and CD8 T cells by preventing IL-2 transcription.
Cyclosporine binds with high affinity to the intracellular protein cyclophilin; the cyclosporin-cyclophillin complex is a potent inhibitor of calcineurin (phosphatase). Inhibition of this phosphatase block the nuclear translocation of a transcription factor (NF-ATc) required for the expression of the IL-2 gene.
Pharmacokinetics: CYP3A4 metabolism
Toxicity: nephrotoxicity, neurotoxicity (tremor, seizure), hypertension, hirsutism, hyperlipidemia, and gingival hyperplasia
Tacrolimus (FK506)
Mechanism: similar to cyclosporine - binds to cytoplasmic protein FKBP-12 to form a complex that also inhibits calcineurin.
Inhibits the activation and proliferation of CD4 and CD8 T cells by preventing IL-2 transcription
Pharmacokinetics: metabolized in the liver
Toxicity: nephrotoxicity, neurotoxicity, hypertension, increased risk of lymphoma, and inhibition of pancreatic beta cell function (can cause diabetes)
Sirolimus (Rapamycin)
Mechanism: blocks T-cell activation and B-cell differentiation by preventing response to IL-2.
Binds FKBP to form a Sirolimus-FKBP complex which inhibits the activity of mTOR (PI3-kinase protein)
Pharmacokinetics: CYP3A4 metabolism
Synergistic with cyclosporine
Toxicity: anemia, thrombocytopenia, leukopenia, insulin resistance, hyperlipidemia
Not nephrotoxic
Mycophenolate mofetil
Mechanism: a prodrug metabolized by liver esterases to mycophenolic acid (MPA).
MPA is a potent inhibitor of monophosphate dehydrogenase which is an enzyme required for de novo purine biosynthesis (purine biosynthesis is required for DNA replication).
The major source of purines in T and B cells are de novo synthesis rather than HPRT mediated salvage.
Toxicity: diarrhea, leukopenia
Azathioprine
Mechanism: prodrug which is metabolized to 6-mercaptopurine (6-MP).
6-mercaptopurine is a purine analog that disrupts de novo purine biosynthesis and inhibits DNA replication.
6-MP is degraded by xanthine oxidase; therefore toxicity increases with allopurinol.
Toxicity: GI distress
Myelosuppression: leukopenia, anemia, thrombocytopenia
Increased toxicity with allopurinol
Glucocorticoids
Mechanism: inhibit NF-kB and suppress both B & T cell function by decreasing the transcription of many cytokines
Toxicity: hyperglycemia, osteoporosis, cushing syndrome, obesity, muscle breakdown, psychosis, hypertension, cataracts, avascular necrosis
Daclizumab
Basiliximab
Mechanism: monoclonal antibodies that bind the alpha chain of the IL-2 receptor (CD25). Inhibits IL-2 mediated T cell activation
Toxicity: edema, hypertension, tremor, hypersensitivity reactions
Methotrexate (MTX)
DMARDs (disease modifying anti-rheumatic drug)
Mechanism: folic acid analog that competitively inhibits dihydrofolate reductase
Reduces thiamine nucleoside production and DNA synthesis
May block T-cell activation due to inhibition of pure in metabolism and adenosine accumulation
Use: severe RA or psoriasis, chemotherapy, abortion (ectopic pregnancy)
Toxicity: teratogen, hepatotoxicity, myelosuppression, oral ulcers, pulmonary fibrosis
Sulfasalazine
DMARDs (disease modifying anti-rheumatic drug)
Mechanism: prodrug processed by gut bacteria into 5-aminosalicyclic acid.
Use: relieves joint pain and swelling and induces remission in active RA
Also used in Crohn’s disease
Toxicity: GI distress, leukopenia, sulfa drug hypersensitivity reaction
Penicillamine
DMARDs (disease modifying anti-rheumatic drug)
Mechanism: dimethylcysteine produced by hydrolysis of penicillin.
Use: metal chelator for wilson’s disease or heavy metal poisoning (copper, arsenic, lead, gold).
Shows anti-rheumatoid activity in 75% of RA patients
Toxicity: Proteinuria (nephrotic syndrome), rashes, stomatitis, GI distress, myopathy
Leflunomide
DMARDs (disease modifying anti-rheumatic drug)
Mechanism: a prodrug whose active metabolite inhibits dihydroorotate dehydrogenase which is an essential mitochondria enzyme in de novo pyrimidine biosynthesis
Prevents replication of activated lymphocytes
Toxicity: GI distress, cytopenia, myelosuppression, rare hepatotoxicity
Infliximab
Adalimumab
Mechanism: monoclonal antibody against TNF-α
Use: IBD, RA, psoriasis, and ankylosing spondylitis
Toxicity: increased susceptibility to infection (reactivation of latent TB, hepatitis B), hepatotoxicity
TNF is important in granuloma formation and stabilization
Etanercept
Mechanism: a TNF decoy receptor
Fusion protein produced by recombinant DNA
Use: RA, psoriasis, ankylosing spondylitis
Toxicity: increased susceptibility to infection (reactivation of latent TB, hepatitis B)
TNF is important in granuloma formation and stabilization
Rituximab
Mechanism: monoclonal antibody against CD20 that promotes complement mediated lysis of CD20 positive B-cells
Uses: NHL, CLL, RA
Natalizumab
Mechanism: monoclonal antibody against α4 subunit of α4β1-integrin that inhibits lymphocytes migration through endothelial cell sites of inflammation
Use: MS, IBD
Risk: JC virus induced progressive multifocal leukoencephalopathy
