Classification of Immunosuppressant Drugs

Immunosuppressant drugs are critical in the management of autoimmune diseases, prevention of transplant rejection, and certain inflammatory disorders. They act by inhibiting specific components of the immune response, either selectively or broadly. Their use requires careful monitoring due to risks of infections, malignancy, and drug toxicity.

This blog from Pharmacy Freak explains the classification, mechanisms, uses, drug of choice highlights, and key side effects of immunosuppressants with references from KDT, Sparsh Gupta, and Goodman & Gilman.

What is Immunosuppressant Drugs

Immunosuppressant drugs are pharmacological agents that reduce or inhibit the immune system’s activity. They are used to prevent immune-mediated damage, particularly in organ transplantation and autoimmune diseases.

Classification of Immunosuppressant Drugs (KD Tripathi)

• Calcineurin inhibitors: Cyclosporine (Ciclosporin), Tacrolimus
• m-TOR inhibitors: Sirolimus, Everolimus
• Antiproliferative drugs: Azathioprine, Methotrexate, Cyclophosphamide, Chlorambucil, Mycophenolate mofetil
• Glucocorticoids: Prednisolone, others
• Biological agents –
  • TNFα inhibitors: Etanercept, Infliximab, Adalimumab
  • IL-1 receptor antagonist: Anakinra
  • IL-2 receptor antagonists: Daclizumab, Basiliximab
  • Anti-CD3 antibody: Muromonab CD3
  • Polyclonal antibodies: Antithymocyte antibody (ATG), Rho(D) immune globulin

Classification of Immunosuppressant Drugs (General)

1. Calcineurin Inhibitors
   Mechanism: Inhibit calcineurin, preventing IL-2 transcription and T-cell activation
   Drugs: Cyclosporine, Tacrolimus
   Use: Organ transplantation, autoimmune diseases
   Note: Tacrolimus is more potent and preferred in many transplant protocols
2. mTOR Inhibitors
   Mechanism: Inhibit mammalian target of rapamycin (mTOR), blocking T-cell proliferation
   Drugs: Sirolimus (Rapamycin), Everolimus
   Use: Kidney transplantation, coronary stent restenosis prevention
   Note: Not nephrotoxic unlike calcineurin inhibitors
3. Antiproliferative and Antimetabolic Agents
   Mechanism: Inhibit DNA synthesis and lymphocyte proliferation
   Drugs: Azathioprine, Mycophenolate mofetil, Methotrexate, Leflunomide
   Use: Autoimmune diseases (SLE, rheumatoid arthritis), transplantation
   Note: Mycophenolate selectively inhibits guanine synthesis in lymphocytes
4. Glucocorticoids
   Mechanism: Broad anti-inflammatory and immunosuppressive actions; inhibit cytokine production
   Drugs: Prednisolone, Methylprednisolone, Dexamethasone
   Use: Almost all inflammatory and autoimmune diseases, transplant rejection prophylaxis
   Note: First-line for acute rejection episodes
5. Monoclonal Antibodies
   Mechanism: Target specific immune markers (CD3, CD20, IL-2 receptor, TNF-α)
   Examples:

• Muromonab–CD3 – Binds CD3 receptor on T-cells
• Basiliximab, Daclizumab – IL-2 receptor antagonists
• Rituximab – Anti-CD20 for B-cell lymphomas and autoimmune diseases
• Infliximab, Adalimumab – Anti-TNF agents for rheumatoid arthritis and Crohn’s disease

6. Polyclonal Antibodies
   Mechanism: Contain antibodies against multiple T-cell antigens
   Drugs: Antithymocyte globulin (ATG), Antilymphocyte globulin (ALG)
   Use: Induction therapy in transplantation, aplastic anemia
7. Janus Kinase (JAK) Inhibitors
   Mechanism: Block intracellular signaling via JAK-STAT pathway
   Drug: Tofacitinib
   Use: Rheumatoid arthritis, ulcerative colitis
8. Others

• Cyclophosphamide – Alkylating agent used in severe autoimmune diseases like lupus nephritis
• Hydroxychloroquine – Antimalarial with immunomodulatory effects
• Thalidomide – Inhibits TNF-α, used in multiple myeloma and leprosy reactions

Uses

Immunosuppressant drugs are used in a wide range of clinical conditions:

• Solid organ transplantation (kidney, liver, heart)
• Hematopoietic stem cell transplantation
• Autoimmune diseases (rheumatoid arthritis, systemic lupus erythematosus, psoriasis, inflammatory bowel disease)
• Prevention and treatment of graft-versus-host disease
• Nephrotic syndrome and glomerulonephritis
• Certain cancers (as cytotoxic immunosuppressants)

Drug of Choice Highlights

• Kidney transplantation – Tacrolimus + Mycophenolate mofetil + Prednisolone
• Acute transplant rejection – High-dose Methylprednisolone
• Lupus nephritis – Cyclophosphamide or Mycophenolate mofetil
• Rheumatoid arthritis – Methotrexate
• Crohn’s disease or ulcerative colitis – Infliximab
• Multiple sclerosis – Monoclonal antibodies (e.g., Natalizumab)
• Aplastic anemia – Antithymocyte globulin + Cyclosporine
• Autoimmune hemolytic anemia – Prednisolone
• Pemphigus vulgaris – Rituximab or Azathioprine

Side Effects

• Calcineurin inhibitors – Nephrotoxicity, hypertension, neurotoxicity, gingival hyperplasia (with Cyclosporine)
• mTOR inhibitors – Hyperlipidemia, delayed wound healing, mouth ulcers
• Antimetabolites – Bone marrow suppression, GI disturbances, increased infection risk
• Glucocorticoids – Cushingoid features, osteoporosis, hyperglycemia, hypertension
• Monoclonal antibodies – Infusion reactions, cytokine release syndrome, increased risk of malignancy
• Cyclophosphamide – Hemorrhagic cystitis, infertility, secondary malignancies
• JAK inhibitors – Risk of thromboembolism, infections, elevated liver enzymes

Updated Clinical Pearls

• Tacrolimus is preferred over Cyclosporine due to better graft survival and fewer cosmetic side effects.
• Mycophenolate is selectively toxic to lymphocytes and has replaced Azathioprine in many protocols.
• mTOR inhibitors can be used in patients with calcineurin inhibitor-induced nephrotoxicity.
• Glucocorticoids are the mainstay in acute immunologic flares but should be tapered to minimize long-term side effects.
• Biologics require screening for latent infections like tuberculosis and hepatitis before initiation.
• Cyclophosphamide requires hydration and mesna to prevent hemorrhagic cystitis.

References

1. Tripathi KD. Essentials of Medical Pharmacology. 7th ed. New Delhi: Jaypee Brothers Medical Publishers; 2013. p. 799–812
2. Gupta S, Garg A. Review of Pharmacology. 15th ed. New Delhi: Jaypee Brothers Medical Publishers; 2023. p. 266–270
3. Brunton LL, Chabner BA, Knollmann BC, editors. Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 12th ed. New York: McGraw-Hill Education; 2011. p. 979–994