Immunopharmacology Flashcards
List TWO examples of immunosuppressant calcineurin inhibitors
Ciclosporin, tacrolimus
List TWO examples of immunosuppressant cytotoxic antimetabolites
Azathioprine, mycophenolate
Name an example of an immunosuppressant mTor inhibitor
Sirolimus
Name an example of a polyclonal antibody used for immunosuppression
Rabbit anti-thymocyte globulin
Name an example of a monoclonal antibody targetting the IL-2 receptor that suppresses T cell proliferation
Daclizumab
Name an immunosuppressant drug targetting S1P receptors
Fingolimod
Explain the mechanisms of action of ciclosporin and tacrolimus
- Ciclosporin and tacrolimus bind immunophilins (cyclophilin and FKBP12, respectively)
Complex with immunophilin inhibits calcineurin (activated by T cell receptors) - Prevents dephosphorylation and nuclear translocation of NFAT (nuclear factor of activated T-Cell)
- Prevents nuclear transcription of cytokine genes (e.g., IL-2, TNFalpha and IFNgamma)
- Inhibits T cell proliferation (also proliferation of B cells and cytotoxic T-lymphocytes)
Which is more potent, ciclosporin or tacrolimus?
Tacrolimus is 10x to 100x more potent that ciclosporin
What are the clinical uses of Ciclosporin and tacrolimus?
kidney, pancreas, liver and cardiac transplants,rhumatoid arthritis, psoriasis (a rash with itchy, scaly patches, most commonly on the knees, elbows, trunk and scalp)
Explain the mechanism of action of sirolimus
- Binds the immunophilin FKBP12
- Complex with FKBP12 inhibits mTor
- Arrests cell cycle from G1 to S phase
- Reduces cytokine‐mediated proliferation of T & B cells
To which immunophilin does ciclosporin bind?
Cyclophilin
To which immunophilin do tacrolimus and sirolimus bind?
FKBP12
Describe the mechanism of cytotoxic antimetabolites, Azathioprine
- Azathioprine converted to 6-MP
2.impedes DNA synthesis and de novo purine synthesis which decrease proliferation of lymphocytes
Describe the mechanism of cytotoxic antimetabolites, Mycophenolate
Inhibits De novo purine synthesis by inhibiting IMPDH
More selective anti-proliferative effects for T/B cells
List FOUR major adverse effects of cytotoxic antimetabolite immunosuppresant drugs
- bonemarrow depression: leukopenia, anaemia,
- thrombocytopenia
- GI toxicity
- lymphoma
- neoplasia
- bleeding
Describe the mechanism of action of fingolimod
- Phosphorylated to active metabolite fingolimod‐P
- Potent S1P receptor agonist
BUT Functional antagonist - Reduces lymphocyte egress from lymph nodes; Disrupts cytokine-mediate lymphocyte homing & Reduces circulating lymphocytes
Derived from cordyceps
What is the half-life of fingolimod?
Approximately 8 days
What is the primary indication for fingolimod?
Multiple sclerosis
What is the major adverse effect of fingolimod?
“First-dose” negative cardiac chronotropic effects due to S1P1 and S1P3 activation in sinoatrial cells
List at least THREE targets of rabbit anti‐thymocyte globulin polyclonal antibody used as an immunosuppressant drug
Non‐selective purified IgG targeting T and B lymphocytes, NK cells, and MHC class I and II antigens,
List FOUR side effects of rabbit anti‐thymocyte globulin polyclonal antibody used as an immunosuppressant drug
Side effects:
* first dose effect: cytokine release syndrome (fever, chill, hypotension)
* thrombocytopenia/ leukopenia/serum sickness
* development of anti‐foreign IgG antibodies
* histiocytic lymphoma at site of injection
Describe the mechanism of action of monoclonal antibodies, daclizumab
targets the IL-2 receptor that suppresses T cell proliferation
WHat is the clinical use ofdaclizumab?
Suppression of transplant rejection
