Immunosuppressants Block 4

Front 1

General Uses of Immunosuppressant

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1. organ transplantation - to prevent rejection of transplanted organ
2. treatment of autoimmune disorders
3. prevention of Rh hemolytic disease of the newborn

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Examples of Immunosuppressant drugs

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1. glucocorticoids
2. calcineurin inhibitors (Cyclosporine, Tacrolimus)
3. Proliferation signal inhibitors (Sirolimus)
4.Mycophenolate mofetil
5. Thalidomide
6. Cytotoxic Drugs (Azathioprine, Cyclophosphamide)
7. Antibodies

Front 3

Glucocorticoids - Prednisone

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Produce numerous effects, including immunosuppression.
Side effects: Hyperglycemia, depression, abdominal pain, mental confusion

Front 4

List the 2 calcineurin inhibitors discussed in class.

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Calcineurin Inhibitors:

1) cyclosporine
2) tacrolimus

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Cyclosporine

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Immunosuppressant
-Calcineurin Inhibitor
-MOA: binds cyclophilin --> inhibits phosphatase activity of calcineurin --> decreased activation of transcription factor NF-AT --> decreased production of IL-2 and other factors by stimulated T cells.

-Oral, IV, Metabolized in liver by CYP3A
-Therapeutic drug monitoring
-Used in several organ transplants and some autoimmune dz

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Adverse Effects of Cyclosporine

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--Adverse effects:
-Renal dysfunction
-HTN
-Neurotoxicity - tremor
-Hirsutism - increased hair growth
-Gingival hyperplasia
-Hepatotoxicity
-Hyperkalemia
-Hyperglycemia
-increased risk of infections and malignancies (lymphomas/skin cancer)

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Drug interactions with cyclosporine

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-Potentiation of renal dysfunction
-Drugs that decrease cyclosporine concentration - Phenobarbital, phenytoin, carbamazepine, rifampin, St. John's wort

-Drugs that increase cyclosporine concentration - some Ca-channel blockers, some antifungals (ketoconazole), some antibiotics (erythromycin), methylprednisone

Front 8

Tacrolimus

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Immunosuppant -Calcineurin Inhibitor
-MOA: Binds FK-binding protein --> inhibition of calcineurin -->decreased activation of transcription factor NF-AT --> decreased production of IL-2 and other factors by stimulated T cells.
-Oral, IV, metabolized by CYP3A
-Measure blood levels
-Adverse Effects: renal, HTN, neurotoxicity, hyperglycemia, hyperkalemia, GI problems, increased risk of infections and malignancies

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Sirolimus

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Immunosuppressant - Proliferation signal inhibitor
-MOA: binds FK binding protein 12 --> inhibition of mammalian target of rapamycin (mTOR) --> inhibition of interleukin-driven T-cell proliferation
-Oral
-Metabolized by CYP3A4, measure blood levels
-Adverse Effects: Hyperlipidemia, myelosuppression, pneumonitis, increased risk of infections and malignancy.

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Mycophenolate mofetil

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Immunosuppressant
-MOA: converted to active metabolite mycophenolic acid which inhibits the de novo pathway of guanine nucleotide synthesis by inhibiting the enzyme inosine monophosphate dehydrogenase
-Oral, IV
-Some adverse effects: GI (diarrhea, vomiting), neutropenia, increased risk of infections and malignancies, Teratogenic effects (don't give to pregnant ladies)

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Thalidomide

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Immunosuppressant
-approved for use in multiple myeloma and erythema nodosum leprosum.
-Very strict restrictions due to birth defects in pregnant women
-Adverse effects: Severe human teratogenicity (bad birth defects, death), peripheral neuropathy, risk of venous thromboembolic events"

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Azathioprine

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Cytotoxic immunosuppressant

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Antithymocyte globulin

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Immunosuppressant
-Antibody
-Use in transplantation

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Rh(D) Immune globulin - (Rhogam)

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Immunosuppressant
-Antibody
-Prevention of Rh hemolytic disease of newborn

Front 15

Muromonab-CD3

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Immunosuppressant
-Antibody binds to CD3
-Used in renal transplant rejection

Front 16

Basiliximab

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Immunosuppressant
-antibody that binds to IL-2 receptor (CD25)'
-used in renal transplantations

Front 17

Daclizumab

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Immunosuppressant
-Antibody -binds to IL-2 receptor
-Used in renal transplantations

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Adalimumab

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Immunosuppressant
-Antibody -binds to TNF
-Used in Rheumatoid arthritis, others

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Etanercept

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Immunosuppressant
-Antibody -binds to TNF
-Used in Rheumatoid arthritis, others

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Infliximab

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Immunosuppressant
-Antibody -binds to TNF
-Used in Rheumatoid arthritis, others