LEC 15 Immunopharmacology Flashcards
What do glucocorticoids do?
- mimic natural corticosteroids
- decrease cytokine production
- inhibit T cell proliferation
- decrease inflammation
- decrease ability of WBC (neutrophils) to migrate into tissue
What are some examples of glucocorticoids?
- prednisone
- cortisol
- cortisone
- dexamethasone
What are the negative side effects of prolonged glucocorticoid use?
- Cushings Syndrome (buffalo hump, metabolic syndrome, muscle wasting, bone loss, central obesity, and round “moon” facies)
- psychosis
- adrenal insufficency
- increased risk of infxn
- high blood sugar
- increased risk of DM
- osteoporosis
What do cytostatic agents do?
target T cell growth and proliferation
What are some examples of cytostatic agents?
- methotrexate
- cyclophosphamide
- azathioprine
- mycophenolate
How does methotrexate work?
- folic acid analog
- inhibits dihydrofolate reductase which is crucial for nucleic acid production
- thus, it reduces DNA synthesis
- Indicated for RA, psoriasis, IBD, multiple cancers, and ectopic pregnancies
How does cyclophosphamide work?
- cross-links DNA, suppressing DNA replication
- Indicated for pts w neoplasms, including solid tumors, leukemias, and lymphomas
How does azathioprine work?
- pro-drug of 6-mercaptopurine (6-MP)
- mimics nucleotides and therfore blocks purine nucleotide synthesis and inhibits lymphocyte proliferation
- Indicated for RA, Crohn, glomerulonephritis
How does mycophenolate work?
- reversibly inhibits IMP dehydrogenase which is involved in purine synthesis
- purine synthesis and thus DNA replication reduced in B and T cells
- used in organ transplants (prevention of allograft rejection) and autoimmune diseases
What are the two calcineurin inhibitor drugs?
- Tacrolimus
- Cyclosporine
What does calcineurin do?
- activates T-cell transcription factors that upregulate interleukin 2 (IL-2) production, specifically nuclear factor of activated T cells (NFAT)
- Without calcineurin, IL-2 levels decrease and subsequently T-cell proliferation slows
How does Tacrolimus work?
- binds FK506 binding protein (FKBP)
- inhibits calcineurin and thus decreased IL-2 production and decreased T cell proliferation
- used to prevent transplant rejection
- atopic dermatitis
How does cyclosporine work?
- binds cyclophilin
- inhibits calcineurin, decreased IL-2 production and decreased T cell proliferation
- used to prevent tranplant rejection
- used in severe, active RA that’s not responsive to methotrexate
- severe psoriasis
How does Sirolimus (rapamycin) work?
- Binds FKBP and inhibits the mammalian target of rapamycin (mTOR)- a kinase that plays a role in regulating cellular processes
- blocks T-cell activation and B-cell differentiation by preventing a response to IL-2 (instead of preventing the production of IL-2)
- also used to prevent transplant rejection
What are the negative side effects of calcineurin inhibitors?
- Highly nephrotoxic
- creatinine levels must be monitored
- Sirolimus is less nephrotoxic and may be preferred for pts w existing kidney disease
What are the toxicities associated with Methotrexate?
- bone marrow suppression
- adverse effects on the skin and GI mucosa
- nephrotoxicity
- hepatotoxicity
What are the toxicities associated with mycophenolate?
- Can cause birth defects
- Increased risk of infections and malignancy
- GI disturbances, pancytopenia
- High blood sugar, high cholesterol
What toxicities are associated with azathioprine?
- bone marrow depression
- anemia
How does Infliximab (Remicade) work?
- anti–TNF-α MAb that bind to and directly inhibit the cytokine from binding to its receptor
- Blocks induction of proinflammatory cytokines, decreases leukocyte migration, and reduces activation of neutrophils and eosinophil
- Therapeutic uses - Crohn’s disease, inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, ulcerative colitis
What toxicities are associated with Infliximab?
predisposition to serious infections
How does Etanercept work?
- Fusion protein of TNF receptor to the Fc part of IgG1 – acts as a decoy receptor for TNFa
- FDA-approved for rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, plaque psoriasis
- Black box warning for serious infections
How does Tocilizumab work?
- MAb to human IL-6R, thereby blocking IL-6-associated inflammation
- treatment of rheumatoid arthritis, systemic juvenile idiopathic arthritis, cytokine release syndrome
- Also used for treatment of severe COVID-19 Acute Respiratory Distress Syndrome (ARDS)
- Adverse effects include URTI, nasopharyngitis, headache, high blood pressure
How does Belatacept work?
- Fusion protein of Fc fragment of IgG1 and extracellular domain of CTLA-4
- Blocks T cell costimulation
- Alternative treatment to limit toxicity associated with calcineurin inhibitors (cyclosporine and tacrolimus)
How do Basiliximab & Daclizumab work?
- Block CD25 (IL-2R)
- Basiliximab was FDA approved in 1998
- Daclizumab was discontinued for transplant patients, but was approved for treatment of relapsing multiple sclerosis in 2016