Immunosuppressants
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Introduction
Three drug types used to inhibit innate, humoral, and cell-mediated immunity.
slowing proliferation of activated B and T cells (S phase inhibitors)
corticosteroids (anti-inflammatory effects - cytokines)
cyclosporin A, FK 506, rapamycin - inhibit IL-2 transcription, bloccking T cell proliferation and activation
Indications
- used as adjunct for prevention of graft rejections; of little use once graft rejection has begun
- idiopathic pulmonary fibrosis
Common Medications
- cyclosporin A
- azithioprine
- tacrolimus
- mycophenolate
Cyclosporin A
Neoral is oral cyclosporin A
Mechanism
Cyclosporin blocks T cell activation through inhibition of IL-2 and IFN-γ. Molecularly, cyclosporin complexes with cyclophilin, an inhibitor of calcinurin. Calcinurin normally dephosphorylates NF-AT, promoting transcription of cytokines as mentioned above.
Cyclosporin also alters fibroblast metabolism of collagen.
Adverse effects
-
Acute nephrotoxicity can result from renal vasoconstriction.
Hyperkalemia, hypomagnesemia, hypertension, hepatotoxicity, gum hyperplasia, and hirsuitism can all follow cyclosporin.
Chronic nephrotoxicity can be caused by glomerular ischemia and interstitial fibrosis.
long term
contraindications
metabolism and excretion
metabolized by CYP 3A4; drugs that induce cytochrome CYP3A4 lower drug level.
- grapefruit juice, which inhibits CYP3A4
- St John's Wort induces CYP3A4, leading to increased metabolism
clinical usage
Azithioprine
Mechanism
Azathioprine is metabolized to 6-mercaptopurine, inhibiting purine synthesis and thereby DNA synthesis. Cell proliferation is therefore attenuated, particularly in lymphocytes and neutrophils.
- suppresses IL-2
Adverse effects
- leukopenia
- thrombocytopenia
- infection
- nausea
- vomiting
- diarrhea
- fetal harm
- pancreatitis
long term
- renal transplant patients are at risk of neoplasia
contraindications
Allopurinol can cause toxic levels by inhibiting xanthine oxidase.
metabolism and excretion
renal and hepatic excretion
clinical usage
available orally
Tacrolimus
- immunosuppression
- reduces acute rejection
- steroid-sparing
Mechanism
Inhibits calcinurin, preventing transcription of IL-2 and thereby T cell activation.
Adverse effects
- evidence of higher renal toxicity, glucose intolerance, diabetes, cf cyclosporine
- hypertension
long term
contraindications
metabolism and excretion
clinical usage
Mycophenolate
Mycophenolate inhibits inosine monophosphate dehydrogenase, required for DNA synthesis. It inhibits T and B cell function.
adverse effects
- esophagitis, gastritis, and diarrhea
- not bone marrow suppression
Guidance on Use
Resources and References
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