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Immunosuppressants

Last updated: February 12, 2020

Summary

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 (like rituximab). A common side effect of immunosuppressants is an increased susceptibility to infection and malignancy.

Glucocorticoids are discussed in detail in another article.



Overview

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 → Multiple inflammatory and immune mediators are inhibited.
  • 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
  • Transplant rejection prophylaxis
  • To suppress various allergic, inflammatory, and autoimmune reactions

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) (✓)
Everolimus
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
Other cytostatic and antiproliferative agents Methotrexate
Cyclophosphamide (✓)

✓ = Definite suppression

(✓) = Probable suppression (inconclusive research currently)

– = No suppression

References:[1][2][3][4][5][6]

Biological agents used in immunotherapy

  • 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.
Antibody Type Target Indication

Infliximab

Chimeric TNF-α inhibition

Adalimumab

Humanized
Etanercept Fusion protein

Golimumab

Humanized

Certolizumab

Humanized
Rituximab Chimeric CD20
Cetuximab Chimeric Epidermal growth factor receptor (EGFR inhibitor)
Alemtuzumab Humanized CD52
Natalizumab Humanized Alpha-4 integrin
Omalizumab Humanized IgE
Abciximab Chimeric Antagonist of GP IIb/IIIa receptors
Muromonab-CD3 Mouse antibody CD3 from T cells
Basiliximab Chimeric Alpha chain (CD25 antigen) of the IL-2 receptor of T cells
Daclizumab Humanized
Trastuzumab Humanized HER2/neu
Bevacizumab Humanized VEGF
Eculizumab Humanized Complement protein C5
Ustekinumab Human IL-12, IL-23
Tocilizumab Humanized IL-6 receptor

Adverse effects

Calcineurin inhibitors

Cyclosporine A

Tacrolimus

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

Tacrolimus and cyclosporine A should not be combined because together they could have nephro- and neurotoxic effects!

Purine analog (Azathioprine/Mercaptopurine)

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)

Mycophenolate mofetil

Methotrexate

Salvage therapy (leucovorin rescue therapy)

Biologics (e.g., daclizumab)

Both calcineurin inhibitors (cyclosporine and tacrolimus) are highly nephrotoxic.

Perform testing for latent tuberculosis before initiating anti-TNF-α treatment!

References:[5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]

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

References

  1. Le T, Bhushan V. First Aid for the USMLE Step 1 2015. McGraw-Hill Education ; 2014
  2. Katzung B,Trevor A. Basic and Clinical Pharmacology. McGraw-Hill Education ; 2014
  3. Pellegrino B. Immunosuppression. Immunosuppression. New York, NY: WebMD. http://emedicine.medscape.com/article/432316-overview. Updated: January 4, 2016. Accessed: April 9, 2017.
  4. Everolimus. https://www.drugs.com/ppa/everolimus.html. Updated: April 9, 2017. Accessed: April 9, 2017.
  5. Methotrexate Injection. https://www.drugs.com/pro/methotrexate-injection.html. Updated: April 9, 2017. Accessed: April 9, 2017.
  6. WebMD. Azathioprine (Rx). In: WebMD, Azathioprine (Rx). New York, NY: WebMD. https://reference.medscape.com/drug/azasan-imuran-azathioprine-343191#0. . Accessed: October 22, 2017.
  7. Mycophenolate. https://www.drugs.com/pro/mycophenolate.html. Updated: April 9, 2017. Accessed: April 9, 2017.
  8. Leucovorin. https://www.drugs.com/dosage/leucovorin.html. Updated: April 9, 2017. Accessed: April 9, 2017.
  9. WebMD. Cyclosporine (Rx). In: WebMD, Cyclosporine (Rx). New York, NY: WebMD. https://reference.medscape.com/drug/neoral-sandimmune-cyclosporine-343196#4. . Accessed: October 22, 2017.
  10. WebMD. Tacrolimus (Rx). In: WebMD, Tacrolimus (Rx). New York, NY: WebMD. https://reference.medscape.com/drug/prograf-astagraf-xl-tacrolimus-343207#4. . Accessed: October 22, 2017.
  11. WebMD. Mycophenolate (Rx). In: WebMD, Mycophenolate (Rx). New York, NY: WebMD. https://reference.medscape.com/drug/cellcept-myfortic-mycophenolate-343209#4. . Accessed: October 22, 2017.
  12. WebMD. Methotrexate (Rx). In: WebMD, Methotrexate (Rx). New York, NY: WebMD. https://reference.medscape.com/drug/trexall-methotrexate-343201#4. . Accessed: October 22, 2017.
  13. Tacrolimus Side Effects. https://www.drugs.com/sfx/tacrolimus-side-effects.html. Updated: October 2, 2017. Accessed: October 22, 2017.
  14. Azathioprine Side Effects. https://www.drugs.com/sfx/azathioprine-side-effects.html. Updated: October 2, 2017. Accessed: October 22, 2017.
  15. Sirolimus Side Effects. https://www.drugs.com/sfx/sirolimus-side-effects.html. Updated: October 2, 2017. Accessed: October 22, 2017.
  16. Everolimus Side Effects. https://www.drugs.com/sfx/everolimus-side-effects.html. Updated: October 2, 2017. Accessed: October 22, 2017.
  17. Daclizumab Side Effects. https://www.drugs.com/sfx/daclizumab-side-effects.html. Updated: October 2, 2017. Accessed: October 22, 2017.
  18. UpToDate. Adalimumab (Including Biosimilars of Adalimumab): Drug Information. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. https://www.uptodate.com/contents/adalimumab-including-biosimilars-of-adalimumab-drug-information.Last updated: January 1, 2018. Accessed: November 16, 2018.
  19. Bendtzen K. Tumor Necrosis Factor-Alpha Inhibitors: Induction of Antibodies, Autoantibodies, and Autoimmune Diseases. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. https://www.uptodate.com/contents/tumor-necrosis-factor-alpha-inhibitors-induction-of-antibodies-autoantibodies-and-autoimmune-diseases.Last updated: October 8, 2017. Accessed: November 16, 2018.
  20. Herold G. Internal Medicine. Herold G ; 2014
  21. Kaplan. USMLE Step 1 Lecture Notes 2016: Pharmacology. Kaplan ; 2015