Immunopharmacology Flashcards
What is the general/overall mechanism of immunosuppressant drugs?
They block the proliferation or interaction of immune cells or block actions or release of cytokines
What are the two major uses of immunosuppressant drugs?
Treat autoimmune diseases and prevent allograft rejection
What prototype corticosteroid is used for immunosuppression?
Prednisolone
What 4 cytotoxic agents are prototype immunosuppressants?
- Azathiaprine
- Methotrexate
- Cyclophosphamide
- Mycophenolate Mofetil
What 3 cyclosporine like drugs are prototype immunosuppressants?
- Cyclosporine
- Tacrolimus
- Sirolimus
What type of cell growth do immune cells have? (3 points)
Synchronized bursts of cell growth that is stimulated by antigens/cytokines
What type of cell growth do cancer cells have? (3 points)
Random, unsynchronized, and unstimulated
How is cytotoxic drug therapy used against immune cells? (3 points)
- Used at initial exposure
- Kills selected rapidly proliferating clones
- Low daily dose for prolonged periods
How is cytotoxic drug therapy used against cancer cells?
- Kills rapidly growing cancer cells
- Intermittent therapy to allow immune system to recover
- High doses for short periods
Azathioprine is metabolized into what substance?
6-mercaptopurine
6-mercaptopurine has what effect on rapidly proliferating cells?
Inhibits the denovo synthesis of purines by preventing the production of AMP and GMP
What metabolite of 6-mercaptopurine inhibits the salvage pathway of purine synthesis?
ThioGMP
What part of DNA and subsequently protein synthesis is inhibited by Methotrexate?
Purine synthesis (same step as Azathioprine/6-mercaptopurine)
What is the major side effect of Azathioprine?
Bone marrow suppression
What is the primary therapeutic use of Azathioprine?
Inhibit rejection of transplanted organs and in some autoimmune diseases like rheumatoid arthritis.
What effect does prednisolone have on cell traffic or accumulation?
It reduces access of cells to target tissue
Why does prednisolone produce lymphocytopenia and monocytopenia?
It redistribute cells to outside of the vascular space.
What effect does prednisolone have on neutrophils?
It prevents adherence to endothelium and inhibits the actions of chemotactic factors
What effects does prednisolone have on cell function? (3 items)
- Interferes with macrophage antigen processing
- Blocks the actions of lymphokines
- Inhibits binding to Fc receptors
What are the two primary uses of prednisolone?
- Management of autoimmune diseases
2. Prevent graft rejection
What are the major side effects/toxicity of prednisolone?
- Suppression of adrenal-pituitary axis
- Acute adrenal insufficiency on abrupt withdrawal
- Cushing’s syndrome
What is the major contraindication for prednisolone?
Existing infection
Name the alkylating agent that results in cross-linking of DNA to kill replicating and non-replicating cells.
Cyclophosphamide
What type of cell activity is Cyclophosphamide most effective in suppressing? Why?
Humoral immunity. Its toxic effect is more pronounce on B-cells
What is Cyclophosphamide used for? What is it not effective for?
It is used to treat autoimmune diseases in combination with other drugs. It is not effect in preventing graft rejection.
What is the major side effect of cyclophosphamide?
bone marrow suppression
What medication is an inhibitor of dihydrofolate reductase that inhibits folate dependent steps in purine synthesis and in turn inhibits DNA synthesis?
Methotrexate
What is the mechanism of action of methotrexate?
Inhibition of dihydrofolate reductase which inhibits folate dependent purine synthesis which inhibits DNA synthesis.
What is the major use for methotrexate?
treatment of autoimmune disease like psoriasis
What is methotrexate not used for?
Transplants
What is the major toxic side effect of methotrexate?
hepatic toxicity
Is mycophenolate mofetil active in its given form? If not, what is the active metabolite?
No. Mycophenolic acid is the active metabolite.
What type of immunosuppression does mycophenolate mofetil produce?
Lymphocyte selective immunosuppression
What is the mechanism of action of mycophenolate mofetil?
- It inhibits IMP dehydrogenase preventing IMP conversion to GMP.
- Prevents denovo synthesis of purines.
- No effect on salvage pathway.
Why does inhibition of de novo pathway and not salvage pathway create selectivity for lymphocytes?
Lymphocytes are the only cells not able to make GMP via the salvage pathway
What are the two major effects of mycophenolate mofetil?
- Inhibition of lymphocyte proliferation
2. Inhibition of expression of cell surface adhesion molecules
How does mycophenolate mofetil compare with azathioprine and methotrexate in its selectivity and effectiveness?
It is more selective
It is equally effective
What is mycophenolate mofetil used for and in combination with what other drugs?
It is used for allograft rejection in combination with cyclosporine and corticosteroids
How does mycophenolate mofetil allow for decreased toxicity?
It allows for lower doses of cyclosporine
What can mycophenolate mofetil be used for other than allograft rejection?
Autoimmune disease like rheumatoid arthritis and refractory psoriasis
What type of patients should mycophenolate mofetil be used with caution? (3 items)
- Active GI disease
- Reduced renal function
- Active infection
What are the side effects associated with mycophenolate mofetil? (3 items)
- Increased risk of infection
- Leukopenia
- Anemia
Why should pregnant women not be given mycophenolate mofetil?
- loss of pregnancy
2. Congenital malformation
What lipophilic peptide antibiotic can be used for immunosuppression?
Cyclosporin
What is the mechanism of action of Cyclosporin in immunosuppression?
It binds to the cellular receptor Cyclophilin and inhibits calcium-dependent phosphatase (Calcineurin). This blocks activation of transcription factor (NFAT) necessary for IL-2 production
What secondary action of Cyclosporin also inhibits IL-2?
Inhibition of mRNA synthesis that codes for IL-2 and other lymphokines.
What effect does Cyclosporin blockage of IL-2 synthesis create?
It blocks T-cell helper function and therefore inhibits T-cell proliferation and cytotoxicity
How does cyclosporine alter T-cell response to IL-2?
It doesn’t!
Why is cyclosporine more specific in its action?
It is not lymphotoxic
What are the uses for cyclosporine?
Anti-rejection and some autoimmune diseases
What is the major side effect of cyclosporine?
Is this reversible?
Nephrotoxicity in 25-40%
Yes, with reduction in dosage or discontinuation
What is the mechanism of action for Tacrolimus?
It binds FK binding protein (FK BP-12), a cyclophilin related protein which inhibits calcineurin and subsequently IL-2
What is the relative potency of Tacrolimus to Cyclosporine?
Tacrolimus is 50-100 times more potent
How is the mechanism of action of Sirolimus and Tacrolimus similar and different?
They both bind FK-BP12 and inhibit T-cell activation & IL-2
The sirolimus FKBP12 complex does not affect calcineurin activity. Instead it inhibits mTOR.
What is a unique use of Sirolimus?
Coating of cardiac stents
