2: Immunosuppressants Flashcards
what does immunopharmacology involve?
- production of vaccines and immunization
- treatment of inflammation
- autoimmune disorders
- allergies
- fungal, viral, and bacterial infections
- infections due to parasites
- cancer
what induces autoimmune diseases?
hyperactive T cell immune response
what causes immune suppression and incompetence?
hypoactive response of T cell immunity
role of each:
- helper T cells
- cytotoxic T cells
- suppressor T cells
helper: coordination of immune response
cytotoxic: remove virus-infected cells from the body
suppressor: temper immune response when it’s overactive
purpose of immunosuppressants
inhibit normal immune response following organ transplantation or overactive immune response associated with autoimmune disorders
what part of the immune response do immunosuppressants work best for?
primary immune response
- efficacy depends on the type of immune response
- best results when treatment begun before exposure to Ag
define acute rejection
- occurs 24h to weeks post transplant
- mediated by T cells and cytokine release
how is immunosuppression achieved?
different classes of immunosuppressants that:
- decrease amount of lymphocytes
- divert lymphocyte traffic
- block pathways involved in lymphocytic response
classes of immunosuppressants
- regulators of gene expression
- alkylating agents
- inhibitors of de novo purine synthesis
- inhibitors of de novo pyrimidine synthesis
- kinase and phosphatase inhibitors
- protein immunosuppressants
- others
what drugs are regulators of gene expression?
adrenocortical steroids - prednisone, prednisolone
what parts of immunosuppression are adrenocortical steroids used for?
induction and maintenance therapy
function of adrenocortical steroids
- reduce circulating lymphocyte levels
- block lymphocyte activation required for Ag presentation
- block T cell proliferation
(inhibit IL-2 gene expression, which is required for clonal expansion of B and T cells)
what drugs are alkylating agents?
cyclophosphamide
what drugs are inhibitors of de novo purine synthesis?
azathioprine, 6-mercaptopurine (first gen)
mizoribine, mycophenolate mofetil (MMF) (second gen)
what parts of immunosuppression are alkylating agents and purine synthesis inhibitors used for?
induction and maintenance
function of alkylating agents and purine synthesis inhibitors
- block or interfere with DNA/RNA synthesis and function
- prevent clonal expansion of B and T cells
chemically describe MMF
-ester prodrug -> active form: mycophenolic acid
function of MMF
inhibits inosinse 5’-monophosphate DH
side effects of MMF
GI shit and events related to bone marrow suppression (leukopenia, anemia, thrombocytopenia)
does NOT have CV risk or chronic nephrotoxic secondary effects
what drugs are inhibitors of de novo pyrimidine synthesis?
- brequinar
- leflunomide
- malononitrilamides
MOA of de novo pyrimidine synthesis
inhibit dihydroorotate DH
usefulness of the leflunomide derivative, FK778?
no benefit for using FK778 over MMF - also seems more difficult for patients to tolerate
what drugs are kinase and phosphatase inhibitors?
cyclosporine
tacrolimus
sirolimus/rapamycin
what parts of immunosuppression are kinase and phosphatase inhibitors used for?
induction and maintenance therapy (block signaling pathways that stimulate IL-2 production)
where does cyclosporine come from?
the fungus Tolypocladium inflatum Gams
how is cyclosporine administered? dosing?
IV or p.o.
given 4-24h before transplant, continued after with lower doses at weekly intervals
where does cyclosporine concentrate?
in the red and white blood cells
PK of cyclosporine
metabolized by liver
mainly excreted in feces
toxicity of cyclosporine
renal (proximal tubule) - limiting factor gingival (hyperplasia) neuronal some hepatic may induce systemic HTN
MOA of cyclosporine
associates with calcineurin and inhibits its phosphatase activity, preventing translocation of NFAT members to nucleus, inhibiting production of lymphokines
also blocks JNK and p38 signaling pathways that are induced by antigen recognition in T cells
what is tacrolimus and where does it come from
macrolide abx from Streptomyces tsukubaensis
MOA of tacrolimus
binds cytoplasmic FK506 binding protein 12 (FKBP12), inhibiting phosphatase pathway of calcineurin
also inhibits JNK and p38 pathways
admin of tacrolimus
IV or p.o.
not as widely distributed as cyclosporine, but 100x as potent
PK of tacrolimus
metabolized in liver
mainly excreted in feces
produces similar toxicity to cyclosporine
what specific disease is tacrolimus proposed to be beneficial for?
myasthenia gravis, notably to reduce corticosteroid burden
where does sirolimus/rapamycin come from?
Streptomyces hygroscopicus
MOA of sirolimus
inhibits calcineurin (and blocka response of T cells to cytokines) by binding FKBP12
but complex formation with FKBP12 does not inhibit IL-2 production in contrast to what happens with other drugs in this class
admin of sirolimus
alone or in combo w/: cyclosporine, tacrolimus, or MMF
-efficacy improved when used with cyclosporine
what drugs are protein immunosuppressive drugs?
antilymphocyte globulins:
- muromonab-CD3
- daclizumab
- basiliximab
polyclonal antithymocyte globulin
anti-CD52 or anti-CD20 agents
belatacept
antilymphocyte globulin MOA
inhibit acute graft rejection by binding to lymphocyte surface proteins
- daclizumab/basiliximab = antiCD25 monoclonal Ab’s for induction and induce less T cell depletion than other drugs
- muromonab = antiCD3 mouse monoclonal Ab that binds to T cell receptor-associated CD3 complex and alters T cells - used for induction and treatment of rejection
what is belatacept and what is it equivalent to?
a targeted immunosuppressant drug -costimulatory blocker
equivalent alternative to traditional calcineurin inhibitors for kidney transplant recipients and for replacement of calcineurin inhibitors over time
belatacept MOA
inhibits CD28-mediated T cell costimulation
high affinity mutant form of T-lymphocyte associated antigen 4-IgG1 (CTLA4Ig) that binds to CD80 and CD86 on APCs, blocking engagement of CD28 on T cells and preventing T cell activation
what is special about belatacept?
seems to specifically target immune rxn against transplants
AE of belatacept
anemia neutropenia UTI headache peripheral edema more frequent post-transplant lymphoproliferative disorders compared to other immunosuppressants high cost \$\$$ serious side effects in kids***
what are the two most widely studied costimulatory pathways for studying induction or maintenance of allograft tolerance?
CD28/B7 and CD40/CD154 pathways
what is rapamycine?
macrocyclic lactone from Streptomyces hygroscopicus
MOA of rapamycine
targets mTOR (key regulator of cell proliferation)
uses of rapamycine
-some for treatment of acute transplant rejection
**facilitates maintenance of cardiac and pulmonary transplants by preventing sm. mm. proliferation (in cardiac) and fibroblasts (in pulm) that are detrimental to the proper fxn of the transplanted organs
what is everolimus and what is it used for?
a drug similar to rapamycine- used for renal transplantation b/c little nephrotoxicity
-also being tried in patients with neoplasia and renal insufficiency
why can everolimus not replace calcineurin inhibitors?
b/c its use as sole “immunosuppressant” comes w/ de novo donor-specific alloantibodies associated with Ab-mediated rejection
so, proposed as a reduced dose in combo w/ calcineurin inhibitors
what is fingolimod?
FTY720 - synthetic small molecule related to myricin, a sphingosine analog
fingolimod MOA
reduced circulating T cells by driving them into lymphoid tissues
fingolimod uses
mainly for MS since it reduces infiltration of lymphocytes into the CNS
what can be used for rheumatoid arthritis?
TNF-a inhibitors
