What are immunosuppressive drugs, their mechanisms of action (MOA), and uses?

Immunosuppressive Drugs: Mechanisms of Action and Clinical Uses

Immunosuppressive drugs are medications that inhibit or prevent immune system activity, primarily used to prevent organ transplant rejection, treat autoimmune disorders, and manage immune-related inflammatory conditions.

Major Classes of Immunosuppressive Drugs

1. Corticosteroids

• Mechanism of Action: Inhibit multiple inflammatory pathways by binding to glucocorticoid receptors, reducing production of pro-inflammatory cytokines (IL-1, IL-6), and suppressing immune cell function 1
• Clinical Uses:
  • First-line therapy for most high-grade immune-related adverse events (irAEs) 2
  • Treatment of autoimmune disorders
  • Prevention and treatment of transplant rejection
• Key Considerations:
  • Short-term use for irAEs has not been shown to reduce antitumor efficacy 2
  • Require careful tapering to prevent recurrence of immune reactions
  • Side effects include hypertension, hyperglycemia, fluid retention, and HPA axis suppression 1

2. Calcineurin Inhibitors (CNIs)

Cyclosporine and Tacrolimus

• Mechanism of Action: Bind to cytoplasmic receptors (cyclophilin for cyclosporine, FK-binding protein 12 for tacrolimus) and inactivate calcineurin, preventing IL-2 gene transcription and T-cell proliferation 2
• Clinical Uses:
  • Cornerstone of immunosuppressive regimens in liver transplantation (97% of liver transplant patients) 2
  • Kidney, heart, and other solid organ transplants
  • Treatment of severe autoimmune conditions
• Key Considerations:
  • Tacrolimus shows better long-term graft and patient survival than cyclosporine 2
  • Require therapeutic drug monitoring due to narrow therapeutic window 3
  • Major side effects include nephrotoxicity, hypertension, neurotoxicity, and increased infection risk 3
  • Multiple drug interactions via cytochrome P450 system 3

3. Antimetabolites

Mycophenolate Mofetil (MMF)

• Mechanism of Action: Inhibits inosine monophosphate dehydrogenase (IMPDH), reducing purine synthesis and lymphocyte proliferation 4
• Clinical Uses:
  • Prevention of organ rejection in combination with CNIs and corticosteroids 4
  • Treatment of autoimmune disorders
  • Has replaced azathioprine as the most commonly used antimetabolite 2
• Key Considerations:
  • Common side effects include gastrointestinal issues (diarrhea, nausea) and bone marrow suppression 4, 5
  • FDA black box warning for embryofetal toxicity 5
  • Increased risk of infections, particularly CMV 5

Azathioprine

• Mechanism of Action: Prodrug converted to 6-mercaptopurine, inhibits purine synthesis and DNA synthesis, especially in immune cells 2
• Clinical Uses:
  • Prevention of transplant rejection
  • Treatment of autoimmune disorders
  • One of few immunosuppressants considered relatively safe during pregnancy 2
• Key Considerations:
  • Requires monitoring for thiopurine methyltransferase deficiency to prevent serious cytopenias 2
  • Side effects include nausea, liver function abnormalities, neutropenia, and anemia 2

4. mTOR Inhibitors (Sirolimus, Everolimus)

• Mechanism of Action: Inhibit mammalian target of rapamycin (mTOR), blocking cytokine-driven T-cell proliferation and activation 2
• Clinical Uses:
  • Prevention of organ rejection
  • Alternative to CNIs in patients with renal dysfunction
• Key Considerations:
  • Require therapeutic drug monitoring
  • Side effects include hyperlipidemia, thrombocytopenia, and impaired wound healing

5. Biological Agents

TNF Inhibitors (e.g., Infliximab)

• Mechanism of Action: Block interaction of TNF-α with its receptors, inhibiting proinflammatory cytokines (IL-1, IL-6) and modulating immune effector activity 2
• Clinical Uses:
  • Treatment of steroid-refractory immune-related adverse events
  • Autoimmune diseases (Crohn's disease, ulcerative colitis, rheumatoid arthritis)
• Key Considerations:
  • Particularly effective for immune-related colitis and inflammatory arthritis 2
  • Not recommended for immune-related hepatitis 2
  • Typically administered as a single dose, with possible second dose after 2 weeks 2

IL-2 Receptor Antagonists (Basiliximab)

• Mechanism of Action: Bind to CD25 on activated T lymphocytes, selectively inhibiting their proliferation 2
• Clinical Uses:
  • Induction therapy in organ transplantation
  • Allow reduction of CNI doses in patients with pre-transplant renal impairment 2
• Key Considerations:
  • Should always be used in combination with CNIs to avoid high incidence of acute rejection 2
  • Potential concern for high costs and possible negative influence on tolerance 2

Polyclonal Antibodies (Anti-thymocyte globulin, ATG)

• Mechanism of Action: Heterologous preparations of rabbit- or equine-derived antibodies against human T cells 2
• Clinical Uses:
  • Induction therapy in transplantation
  • Treatment of steroid-resistant rejection
• Key Considerations:
  • Monitoring for infusion reactions is essential 2
  • Increased risk of infections, including atypical bacterial, fungal, and viral infections 2

Monitoring and Management

Laboratory Monitoring

• Complete blood count with differential to detect bone marrow suppression 2
• Renal and hepatic function tests 2
• Therapeutic drug monitoring for CNIs and mTOR inhibitors 2
• Specific monitoring for individual drugs (e.g., thiopurine methyltransferase for azathioprine) 2

Infection Prevention

• Prophylaxis for Pneumocystis jiroveci pneumonia should be considered for patients on intensive immunosuppression 2
• Screening for latent tuberculosis prior to initiating therapy 2
• Monitoring for viral infections (CMV, BK virus, JC virus) 5

Drug Interactions

• CNIs have numerous drug interactions via the cytochrome P450 system 3
• Common interacting drugs include antifungals, macrolide antibiotics, and anticonvulsants 3
• Blood levels should be checked when starting or stopping potentially interacting medications 2

Conclusion

Immunosuppressive drugs are essential for preventing transplant rejection and treating autoimmune disorders. The choice of agent depends on the specific clinical scenario, patient factors, and risk-benefit profile. Careful monitoring is required to balance adequate immunosuppression with minimizing adverse effects. Combination therapy with agents targeting different immune pathways is often used to achieve optimal outcomes while minimizing toxicity.