Pharmacology - chapter 40 - Immunosuppressants Flashcards
The immune activation cascade can be described as a three signal model. Discribe this signal pathway.
1 T cell triggering by CD3 receptor-antigen complex on surface of APC
2 Costimulation when CD80 and CD86 of APC bind T cell CD28.
3 Stimulation of T cell poliferation.
Why are several immunosuppressants usually used together in a regime of different drugs, rather than monotheraphy?
Because it’s beneficial to use several drugs at lower doses, rather than one at a higher dose. This is because this group of drugs are associated with severe toxicity when large doses are administered.
Three categories of immunosuppressive drugs, based on theri mechanism of action?
1 interfere with cytokine production or action
2 disrupt cell metabolism, preventing lymphocyte proliferation
3 mono-and polyclonal antibodies block T cell surface molecules.
- Enhances activity of NK cells.
- Attracts neutrophils and macrophages.
Which cytokine be dis?
IL-1
- induces proliferation of antigen-primed T cells
- enhances activity of NK cells.
Which cytokine can this be?
Yes, it is IL-2
- enhances activity of NK cells and macrophages.
- increases expression og MHC molecules.
- Enhances production og IgG2a.
Which cytokine?
Iterferon gamma
- cytotoxic effect on tumor cells.
- induces cytokine secretion in the inflammatory response.
Cytokine?
TNF-alpha
what is the role of IL-2 in immuno suppressive therapy?
it stimulates the proliferation of antigen-primed T helper cells which in turn produce more IL-2, IFN-gamma and TNF-alpha. These cytokines collectively activate NK cells, macrophages, cytotoxic T lymphocytes. Therefore, drugs that interfere with IL-2 production will dampen the immune response.
Cyclosporine, mechanism of action?
binds with cyclophilin to form a complex that binds with calcineurin, thus inhibiting the calcineurin pathway that activates NFATc(cytoplasmic Nuclear Factor of Activated T cells). NFATc is a transcription factor that codes for IL-2.
Cyclosporine, areas of use?
used to prevent rejection of kidney, liver and cardiac allogeneic transplants.
Cyclosporine, metabolism?
Cyclosporine is metabolized by CYP3A4. It is also a substrate for intestinal P-glycoprotein.
Cyclosporine, adverse effects?
Nephrotoxicity is the most common and important adverse effect of cyclosporine.
Drugs by which coadministration will increase the nephrotoxicity of cyclosporine?
1 drugs that can cause renal dysfunction - e.g. aminoglycoside antibiotyka.
2 Anti-inflammatory such as diclofenac, naproxen or sulindac that potentiate the nephrotoxicity of cyclosporine.
One type of diuretics one should not administer along with cyclosporine?
K+ - sparing diuretics, as patients are proned to become hyperkalemic.
Tacrolimus, mechanism of action?
Similar to that of cyclosporine, except Tacrolimus binds with FK-binding protein, another component of the calcineurin pathway.
Tacrolimus, pharmacokinetics?
Metabolized by CYP3A4/5 and is a substrate for P-glycoprotein.
Tcrolimus, adverse effects?
Nephrotoxicity and neurotoxicity. Development of post-transplant insulin dependent diabetes mellitus is a problem, particularily for black and hispanic patients.
Sirolimus, areas of use?
Used in kidney transplant, administered together with cyclosporine and corticosteroids.
Sirolimus-coated stents are inserted into cardiac vasculature to inhibit restenosis of blood vessels by reducing proliferation of endothelial cells.
Sirolimus, mechanism of action?
Sirolimus bind with mTOR, interfering with signal 3: preventing IL-2 signal to induce T cell proliferation and thereby preventing activated T cell from entering S phase.
Sirolimus, pharmacokinetics?
Long half life(57-62 hours)
Metabolized by CYP3A4.
Interacts with the same drugs as do cyclosporine and tacrolimus
Everolimus, mechanism of action?
mTOR inhibitor.
Azathioprine, mechanism of action?
prodrug that is converted first to 6-mercaptopurine and then to thiosinic acid. Thiosinic acid interfere with de novo synthesis of purine, a pathway that lymphocytes are dependent on, as they do not have a purine salvage pathway.
Allopurinol and Azathioprine relationship?
Allopurinol significantly reduce the metabolism of azathioprine(60-70%). Therefore, lowering the dose of azathioprine is required.
Lymphocytes and purine synthesis?
Lymphocytes lack the salvage pathway for purine synthesis and is therefore are dependent on de novo synthesis of purines.
Antithymocyte globulins?
Antibodies that binds to the surface of ciruclating T lymphocytes, which undergo destruction by complement activation, apoptosis, opsoniation or they are phagocytosed in the liver or spleen.
Mauromonab-CD3, mechanism of action?
Bind to CD3 receptors and disrupt the T-lymphocyte function by blocking antigen recognition site. By this mechanism the circulating T cells are depleted.
Mauromonab-CD3, pharmacokinetics?
Intial binding to CD3 receptors transiently activates the T cell and results in cytokine release(cytokine storm)
Mauromonab-CD3, adverse effects?
Anaphylactoid reactions may occur. Symptoms range from mild flu-like illness to a life threatening shock-like reaction.
Basiliximab and Daclizumab, mechanism of action?
IL-2 antagonists. Both compounds are anti-CD25 antibodies and bind to the alpha chain of the IL-2 receptor.
Basiliximab & daclizumab, adverse effects?
Their major toxicity is GI.
Alemtuzumab. mechanism of action?
anti-CD52 antibody that cause depletion of T cells from the peripheral circulation.
Sirolimus, adverse effects?
hyperlipidemia
Name five main groups of immunosuppressants
1 Cytotoxic drugs 2 Calcineurin inhibitors 3 Glucocorticosteroids 4 Cytokin inhibitors 5 Antibodies
Cyclophosphamide, mechanism?
Alkylating agent: adding an alkyle group to DNA preventing replication and cell division.
Methotrexate, mechanism?
inhibits dihydrofolate reductase, an enzyme that reduces dihydrofolic acid to tetrahydrofolic acid - a compound that is necessary in the metabolism of nucleic acids.
Azathioprine, mechanism?
interferes with purinesynthesis –> metabolized to mercaptopurine –>
a purine analogue that inhibits DNA synthesis
Leflunomide mechanism?
inhibits pyrimidine synthase
Mycophenolate mofetil mechanism?
converted to mycophenolic acid in the body —> inhibits inosine monophosphate dehydrogenase which prevent proliferation of B & T lymphocytes
What is calcineurin?
= protein phoshatase 3 that activates the T cells of the immunesystem by:
1 activating NFAT(Nuclear Factor of Activated T-cells)
2 stimulating IL-2 production
3 stimulating cell proliferation and activating
Ciclosporin moa?
inhibits IL-2 production and decreases T-cell proliferation
Tacrolimus moa?
Same as ciclosporin, but more potent
Glucocorticosteroids mechanism?
1 Inhibits transcription factor AP-1 and NF-KB = inhibits COX
2 Activated lipocortin 1 = inhibition of Phospholipase A2
Etanerecept mechanism?
soluble TNF-alpha receptor that prevents TNF-alpha from binding with receptors in the tissues- Like extra non-functional receptors
Infliximab and Adalimuab mechanism?
Monoclonal antibodies against TNF-alpha
Certolizumab mechanism?
antibody against TNF-alpha. Used in ULC and crohns disease
Anakinra mchanism?
IL-1 receptor antagonist. Used in Rheumatid Arthritis
2 x immunosuppressive antibodies against adhesive molecules?
Efalizumab - antibody against integrin alpha1
Alefacept - interfering with CD2 protein(surface protein on NK and T cell)
3 x antibodies against lymphocyte antigen?
1 Anti Thymocyte Globulin - decrease nr of circulating T cells
2 Muronomab - antibody against CD3 on T cells
3 Basiliximab & Daclizumab - antibody aginst IL-2 receptor(CD25 antigen)
