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Immunosuppressants

Last updated: June 9, 2021

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Immunosuppressants use heterogeneous mechanisms of action to suppress the body's cell-mediated and humoral immune response. They may be used as transplant rejection prophylaxis or to treat autoimmune disorders such as lupus, psoriasis, and rheumatoid arthritis. Commonly used immunosuppressants include cyclosporine A, tacrolimus, glucocorticoids, methotrexate, and biological agents (e.g., rituximab). A common side effect of immunosuppressants is an increased susceptibility to infection and malignancy.

Glucocorticoids are discussed in detail in another article.

Overview of immunosuppressants
Immunosuppressant class Common drugs Mechanism of action Suppression of cell-mediated immune response Suppression of humoral immune response Main clinical uses
Glucocorticoids Prednisolone, hydrocortisone, dexamethasone
  • Inhibition of intracellular NF-κB inhibition of multiple inflammatory and immune mediators (e.g., cytokines) → suppression of B cells and T cells function
  • Acute effect (occurs within minutes) → While the mechanism is not entirely clear, a membrane stabilizing effect is hypothesized.
  • Long-term effects (in hours) → direct influence on gene expression
  • Increased T-cell apoptosis

Calcineurin inhibitors (calcineurin = calcium- and calmodulin-dependent serine-threonine phosphatase)

Cyclosporine A
Tacrolimus (also FK-506 or fujimycin)
Pimecrolimus
mTOR inhibitors Sirolimus (also known as rapamycin)
  • Binding to FKBP inhibition of mTOR kinase inhibition of the IL-2-mediated cell cycle → ↓ response to IL-2 T-cell activation and B-cell differentiation IgM, IgG, and IgA production
(✓)
Everolimus [1]
Purine analog

Azathioprine (mercaptopurine)

(✓)
Protein drugs Antibodies
  • Specific binding to relevant structure in the immune cascade (detailed explanation below)
Other biological proteins
IMDH/IMPDH inhibitors Mycophenolate mofetil
  • Reversible inhibition of inosine monophosphate dehydrogenase → blockade of purine synthesis → selective inhibition of lymphocyte proliferation
Other cytostatic and antiproliferative agents Methotrexate [2]
Cyclophosphamide (✓)

✓ = Definite suppression

(✓) = Probable suppression (inconclusive research currently)

– = No suppression

  • Biological agents are recombinant proteins that intervene in immunological processes.
  • Used in autoimmune diseases and malignancies
  • Although complex and costly, they can significantly improve the success of treatment in some cases.
  • The naming of antibodies follows a certain classification scheme:
    • The suffix "-mab": indicates "monoclonal antibody."
    • Second to last syllable: describes the origin (e.g., "xi"=chimeric, "u"=human)
    • Third to last syllable: denotes the target (e.g., li(m)=immune system)
Overview of biologics
Antibody Type Target Indication

Infliximab

  • TNF-α inhibition

Adalimumab

Golimumab

Certolizumab

Etanercept

Rituximab
  • Chimeric
Cetuximab
  • Chimeric

Panitumumab

  • Humanized
Alemtuzumab
  • Humanized
  • CD52
Natalizumab
  • Humanized
  • Alpha-4 integrin (important for WBC adhesion and migration)
Omalizumab
  • Humanized
  • Unbound serum IgE (prevents binding to FcεRI)
Abciximab
  • Chimeric
Muromonab-CD3
Basiliximab
  • Chimeric
Daclizumab
  • Humanized
Trastuzumab
  • Humanized
Bevacizumab
  • Humanized
Eculizumab
  • Humanized
Secukinumab
  • Human
  • IL-17A
Ixekizumab
  • Humanized
Ustekinumab
  • Human
Tocilizumab
  • Humanized
Denosumab
  • Human
Palivizumab
  • Humanized
  • RSV F protein

Ipilimumab

  • Human
Vedolizumab
  • Humanized
Guselkumab
  • Human
  • IL-23
Pembrolizumab
  • Humanized
Nivolumab
  • Human
Cemiplimab
Avelumab
Durvalumab
Atezolizumab
  • Humanized

BeVAcizumab Blocks VAsculature: bevacizumab inhibits angiogenesis

For the most important indication (breast cancer) and the target (HER2) of trastuzumab, think “Her two (HER2) breasts can be treated with trastwozumab.”

To remember the indication for alemtuzumab, think “ALYMtuzumab for chronic LYMphocytic leukemia.”

Calcineurin inhibitors

  • Calcineurin inhibitors become even more neurotoxic and nephrotoxic when combined; for this reason, they should never be coadministered.
  • Because of their neurotoxicity, patients receiving higher doses and those who have decreased renal function should be closely monitored.

Cyclosporine A

Tacrolimus (FK506) [3]

Many side effects of tacrolimus are similar to cyclosporine A, but tacrolimus does not cause gingival hyperplasia or hypertrichosis.

Both calcineurin inhibitors (cyclosporine A and tacrolimus) are highly nephrotoxic. They become even more nephrotoxic when combined and should, therefore, never be administered concurrently!

Purine analogs (azathioprine, mercaptopurine) [5]

To remember that Azathioprine is the precursor of 6-mercaptopurine, think “Azathiopurine.”

Allopurinol causes toxic accumulation of azathioprine! In cases in which concomitant treatment is unavoidable, a dose reduction of azathioprine is necessary!

mTOR inhibitors (sirolimus, everolimus) [6][7]

To remember that sirolimus can cause pancytopenia, think “Sir, don't forget your pants!”

In contrast to calcineurin inhibitors, mTOR inhibitors are not nephrotoxic.

Mycophenolate mofetil [8]

Methotrexate [2]

Salvage therapy (leucovorin rescue therapy) [9]

Biologics (e.g., daclizumab) [10]

Before initiating anti-TNF-α treatment, a test for latent tuberculosis should be performed.

To remember that trastuzumab causes dilated cardiomyopathy, think “If you trust trustuzumub, it might break your heart.”

Contraindications to anti-TNF-α treatment (infliximab, adalimumab, etanercept)

Glucocorticoids

We list the most important adverse effects. The selection is not exhaustive.

  1. Everolimus. https://www.drugs.com/ppa/everolimus.html. Updated: April 9, 2017. Accessed: April 9, 2017.
  2. Methotrexate Injection. https://www.drugs.com/pro/methotrexate-injection.html. Updated: April 9, 2017. Accessed: April 9, 2017.
  3. Tacrolimus Side Effects. https://www.drugs.com/sfx/tacrolimus-side-effects.html. Updated: October 2, 2017. Accessed: October 22, 2017.
  4. Shivaswamy V, Boerner B, Larsen J. Post-Transplant Diabetes Mellitus: Causes, Treatment, and Impact on Outcomes. Endocr Rev. 2015; 37 (1): p.37-61. doi: 10.1210/er.2015-1084 . | Open in Read by QxMD
  5. Azathioprine Side Effects. https://www.drugs.com/sfx/azathioprine-side-effects.html. Updated: October 2, 2017. Accessed: October 22, 2017.
  6. Sirolimus Side Effects. https://www.drugs.com/sfx/sirolimus-side-effects.html. Updated: October 2, 2017. Accessed: October 22, 2017.
  7. Everolimus Side Effects. https://www.drugs.com/sfx/everolimus-side-effects.html. Updated: October 2, 2017. Accessed: October 22, 2017.
  8. Mycophenolate. https://www.drugs.com/pro/mycophenolate.html. Updated: April 9, 2017. Accessed: April 9, 2017.
  9. Leucovorin. https://www.drugs.com/dosage/leucovorin.html. Updated: April 9, 2017. Accessed: April 9, 2017.
  10. Daclizumab Side Effects. https://www.drugs.com/sfx/daclizumab-side-effects.html. Updated: October 2, 2017. Accessed: October 22, 2017.