Immunosuppressants Flashcards
Immunopharmacology focuses on…
Primary and secondary disorders of the immune system and the production of modulators of the immune system
Two types of immunopharmacological drugs
Immunosuppressants
Immunostimulants
The development of the adaptive immune response happens over about….days
8-14
Basophils can release
Histamine Bradykinin Serotonin Hepatin SRSA
Immunosuppressants are used to…
Inhibit normal immune responses
Organ transplant, Autoimmune disorders
What immune response are immunosuppressants most effective with
Primary
Start before antigen exposure
Acute organ rejection =
Rejection that occurs 24 hrs-several weeks after transplant
Acute rejection is mediated primarily by…
T cells and cytokines
Six Classess of Immunosuppressants
- Regulators of Gene Expression
- Alkylating Agents
- Inhibitors of de novo purine synth.
- Inhibitors of de novo pyramidine synth.
- Kinases and phosphatase inhibitors
- Protein immunosuppressive drugs
End result of immunosuppressant regulators of gene expression?
- Reduced Circulating Lymphocytes
- Blocked lymphocyte activation needed for antigen pres.
- Block T-cell proliferation
How do Immunosuppressant regulators of gene expression block T cell proliferation?
Inhibition of IL-2 gene transcription
immunosuppressant regulators of gene expression.
Induction, Maintenance, or both?
Both
Example of immunosuppressant alkylating agent?
Cytotoxic drug cyclophosphamide
First generation immunosuppressant inhibitor of de novo purine synthesis
Azathioprine
6-mercaptopurine
Important non-1st gen immunosuppressant inhibitors of de novo purine synthesis?
Mycophenylate mofetil
Methotrexate
Polygentamate
immunosuppressant inhibitors of de novo purine synthesis.
Induction, Maintenance, or both?
Both
immunosuppressant alkylating agents.
Induction, Maintenance, or both?
Both
Difference between effects of de novo purine and pyrimidine inhibiton
DN pyramadine inhib. has less CV risk and less nephrotoxicity, but they’re also less effective
How do immunosuppressant inhibitors of de novo pyrimidine synthesis work?
Inhibitior of dihydroorotate, a key enzyme in pyramidine synthesis
Three classic examples of immunosuppressant kinases and phosphotase inhibitors
Cyclosporine
Tacrolimus
Sirolimus
Effects of dosing with Cyclosporine or tacrolimus?
They block T-cell signalling pathways that stimulate IL-2
Cyclosporine or tacrolimus
Induction, Maintenance, or both?
Both
Cyclosporine method of administration?
Concentrates in which cells?
IV or Per Os
Dist. widely, but conc. in RBC and WBC
Cyclosporine metabolism?
Metabolized by liver and mainly excreted in feces
Cyclosporine schedule?
Given 4-24 hrs before transplant
Lowered doses at weekly interval afterward
Cyclosporine toxicity?
Mainly renal (proximal tubule)
Gingival
Neuronal
Sometimes hepatic
Cyclosporine Mechanism?
Assoc. w/ Calcineurin and inhibits its phosphotase activity. This prevents translocation of NFAT TFs to the nucleus of lymphocytes. Blocks lymphokine synthesis.
Also blocks JNK and p38
Tacrolimus is what kind of anti-biotic?
Macrolide
Tacrolimus Mechanism?
Binds to cytoplasmic FK506 binding protein, making a complex that inhibits phosphatase activity of calcineurin
Also blocks JNK and p38
How is Tacrolimus dosed?
IV or Per Os
Distribution and metabolism of Tacrolimus?
Loss widely distrib. than cyclosporine
Metabolized by liver and excreted in the feces
Who is more potent, cyclosprorine or Tacrolimus
Tacrolimus is about 100x more potent
Tacrolimus may be useful to treat what specific disease?
Myasthenia gravis
Mechanism of Sirolimus action?
Inhibition of calcineurin (and blocking of T cell resp. to cytokines) by binding onto FKBP12.
Is Sirolimus used alone or in combination treatment?
Yes
Both – better w/ cyclo.
Look up Everolimus in the ppt.
well shit.
page 5 of my notes
How do antilymphocyte globulins work?
Inhibition of acutre graft rejection by binding onto lymphocyte surface proteins
Ex. muromonab for induction and treatment of rejection
Antilymphocyte globulins are used against what targets?
CD 25 (Basiliximab)
CD3 (Muromonab)
CD52, CD20 – Antithymocyte
Diseases with CD20 overexpression?
RA, Hemolytic anemia
Significance of Beltacept?
Equivalent alternative to calcineurin inhibitors for kidney transplant recipients. It is an inhibitor of CD28 mediated T cell costimulation.
Mechanism for Beltacept
Binds to CD80 and 86, blocking CD28 engagement on T cells.
Prevents T cell activation.
Beltacept is associated with…
more frequent post-transplant lymphoproliferative disorders than other suppressants.
Serious side effects in children.
Non-medical downside of Baltacept?
It’s fuckin expensive.
Studies on rejection in kidney transplant with beltacept use suggest that targeting ______ might be more valueable than targeting CD80/86
CD28
Important details for Rapamycine
Macrocyclic Lactone
Targets mTOR (regulator of cell proliferation)
May help by preventing the proliferation of smooth muscle cells and fibroblasts
Everolimus is a related compound
Why can’t Everolimus replace calcineurin inhibitors?
When used alone, it triggers de novo donor-specific alloantibodies associated with antibody mediated rejection
What is FTY720?
First in class synthetic small molecule Reduces circulating Ts by driving them into lymphoid tissues Treats MS
TNF-alpha inhibitors are used primarily to treat…
RA
Which cell usually mediates auto-immunity?
T cell
Examples of Ab mediated auto-immunity
Autoimmune mediated hemolytic anemia
Myasthenia gravis
Hypoadrenocorticism
Disease in which exposure to an antigen will program for search and destruction of the antigen in the future
Thyroiditis
Autoimmune hypothyroidism
Six major drugs for treatment of autoimmune disorders
Corticosteroids Cyclophosphamide Asathioprine Mercaptopurine Leflunomide Cyclosporine
Primary drugs used in any autoimune disease?
Corticosteroids
Why not use Corticosteroids long term?
Infections, Ulcers, Hyperglycemia, Osteoporosis
How does cyclophosphamide work?
Inhibits DNA synthesis and function by alkylation
Affects B Cells more than T cells
How does Azathioprine work?
Purine anti-metabolite that interferes w/ DNA synthesis
Affects all rapidly growing cells
Takes weeks to see results
Effects of Azathioprine cytotoxicity?
Leukopenia
Thrombocytopenia
GI Dysfunction
Possible infections and hepatic lesions
Azathioprine is metabolized into…
Mercaptopurine
Mercaptopurine effects?
Interferes with RNA and DNA synthesis after conversion to a purine antagonist.
Mostly hits humoral immunity
Side effects - BM+GI depletion
Effects of Leflunomide?
Inhibitor of pyrimidine synthesis
Active metabolite has a long half life of several weeks
used for RA
Why are frequent blood measures of Cyclosporine levels necessary?
Variability of Cyclosporine absorption
Cyclosporine saturates tissues, so dosage may need adjusting
Drug interactions
To get the full benefit of Cyclosporine, the patient must…
be on a very strict feeding and dosing schedule.
Diet consistent
Made difficult by loss of appetite
Three drug classes important to the treatment of allergies
Fatty Acids
Antihistamines
Biotin
What is atopy?
Inhalant allergy
Fatty acids used in allergy treatment may include…
linoleic and gamma-linoleic acids
Why give an allergy sufferer fatty acids?
They work in the skin to help reduce the amount/effects of histamine.
Very safe, few side effects
Typical mechanism for anti-histamines?
H1 blockers.
prevent attachment of histamine to its target
Example of a common antihistamine?
Diphenhydramine
If all else fails in allergy treatment and patients are symptomatic more than 4 months per year, what should you consider?
Immunotherapy
Weekly/Monthly injections with allergens to induce desensitization in most treated patients
For patients with severe symptoms of allergies after other options are exhausted, use…
Corticosteroids (ex. dexamethasone, methylprednisone)
Some major risks of imunosuppressants
GVH Infections Reappearance of latent disease (ex. Hep) CV events Neoplasia
