Immunosuppressants
A Step 1 high-yield tour of the immunosuppressants, organized by where each agent interrupts T-cell activation (calcineurin inhibitors, mTOR inhibitor, antimetabolites, glucocorticoids, IL-2R antibody), with signature toxicities, classic drug-specific associations, current first-line regimens, and the shared infection/malignancy risk.
Framework: Where each drug hits the T-cell activation cascade
Immunosuppressants are used to prevent transplant rejection and to treat autoimmune disease. The high-yield way to organize the class is by where the drug interrupts T-cell activation:
- Signal 1 blockers (calcineurin inhibitors) — cyclosporine and tacrolimus. They block calcineurin, preventing dephosphorylation of NFAT, which shuts off IL-2 transcription. Less IL-2 → less T-cell proliferation.
- IL-2 signal / proliferation blockers (mTOR inhibitor) — sirolimus blocks mTOR, so even if IL-2 is made, T cells can't respond (G1→S arrest).
- Antimetabolites — azathioprine and mycophenolate block purine synthesis, starving proliferating lymphocytes of nucleotides.
- Broad transcriptional suppressors — glucocorticoids inhibit NF-κB, lowering many cytokines and inducing lymphocyte apoptosis.
- Biologics — basiliximab is a monoclonal antibody against the IL-2 receptor (CD25).
A shared, testable theme: every agent raises the risk of opportunistic infection and malignancy.
- Cyclosporine binds cyclophilin; tacrolimus (FK506) binds FKBP — both then inhibit calcineurin → ↓ IL-2.
- Both calcineurin inhibitors are nephrotoxic (dose-limiting) and metabolized by CYP3A4 (azoles/macrolides raise levels; rifampin lowers them).
- Gingival hyperplasia + hirsutism = cyclosporine, NOT tacrolimus. Tacrolimus is more linked to neurotoxicity and new-onset diabetes.
- Sirolimus binds FKBP (like tacrolimus) but inhibits mTOR, not calcineurin → it is NOT nephrotoxic, so it can be paired with cyclosporine. Causes pancytopenia (esp. thrombocytopenia) and hyperlipidemia; used in drug-eluting stents.
- Azathioprine → 6-mercaptopurine, degraded by xanthine oxidase → allopurinol dramatically increases toxicity (must reduce dose). TPMT deficiency also predisposes to myelosuppression.
- Mycophenolate inhibits IMP dehydrogenase (IMPDH) → blocks de novo guanine synthesis; lymphocytes lack a salvage pathway, giving selectivity. Main effects: GI upset and teratogenicity.
- Long-term risks: skin squamous cell carcinoma and EBV-driven PTLD/lymphoma; infections include CMV and PJP.
Drug → MOA → use → key toxicity
| Drug | Mechanism | Clinical use | Key toxicity / association |
|---|---|---|---|
| Cyclosporine | Binds cyclophilin → inhibits calcineurin → ↓ IL-2 | Transplant; psoriasis, RA | Nephrotoxicity, HTN, gingival hyperplasia, hirsutism, tremor |
| Tacrolimus | Binds FKBP → inhibits calcineurin → ↓ IL-2 | Transplant — now the first-line CNI in most solid-organ regimens (more potent than cyclosporine) | Nephrotoxicity, neurotoxicity, new-onset diabetes; no gum/hair changes |
| Sirolimus | Binds FKBP → inhibits mTOR → blocks IL-2 signal (G1→S) | Kidney transplant (renal-sparing), drug-eluting stents | Pancytopenia / thrombocytopenia, hyperlipidemia, poor wound healing; NOT nephrotoxic |
| Azathioprine | Prodrug → 6-MP → ↓ purine synthesis | Transplant, IBD, RA, SLE | Myelosuppression; toxicity ↑ with allopurinol (and in TPMT deficiency) |
| Mycophenolate | Inhibits IMPDH → ↓ de novo guanine synthesis | Transplant, lupus nephritis | GI upset (diarrhea), myelosuppression, teratogenic (1st-trimester loss / malformations) |
| Glucocorticoids (prednisone) | Inhibit NF-κB; lymphocyte apoptosis | Transplant, autoimmune, anti-inflammatory | Cushing, osteoporosis, hyperglycemia, cataracts, adrenal suppression |
| Basiliximab | Anti–IL-2 receptor (CD25) mAb | Rejection prophylaxis (induction) | Generally well tolerated |
- Kidney transplant patient develops fine tremor, hypertension, rising creatinine, and overgrown gums. → Cyclosporine (nephrotoxicity + gingival hyperplasia).
- Transplant patient on stable immunosuppression is started on allopurinol for gout and develops profound leukopenia. → Azathioprine (xanthine-oxidase blockade → accumulation of 6-MP).
- Renal transplant patient placed on a regimen specifically chosen to spare kidney function later develops thrombocytopenia and marked hypertriglyceridemia. → Sirolimus (mTOR inhibitor, non-nephrotoxic).
- Transplant patient develops new hyperglycemia and a hand tremor, but has normal gums and no excess hair. → Tacrolimus (diabetogenic, neurotoxic; lacks cyclosporine's cosmetic effects).
- Lupus nephritis patient reports diarrhea; she is counseled to avoid pregnancy. → Mycophenolate (GI toxicity + teratogenic).
- "Cyclosporine → Cyclophilin" (both start Cyclo-); "Tacrolimus = FK506 → FKBP" — the binding proteins are named for the drugs.
- A + A = danger: Azathioprine + Allopurinol. Allopurinol blocks xanthine oxidase, so 6-MP accumulates → severe myelosuppression.
- "Sir does not hurt the kidney" — Sirolimus is not nephrotoxic (hits mTOR, not calcineurin), so it can be combined with cyclosporine.
- Gingival hyperplasia + hirsutism → cyclosporine.
- New-onset diabetes after transplant + neurotoxicity, no cosmetic effects → tacrolimus.
- Non-nephrotoxic + drug-eluting stent + thrombocytopenia + hyperlipidemia → sirolimus.
- Allopurinol drug interaction / TPMT deficiency → azathioprine.
- IMPDH inhibitor / teratogen / diarrhea → mycophenolate.
- Antibody against IL-2 receptor (CD25) → basiliximab.
- Iatrogenic Cushing + avascular necrosis of femoral head + adrenal suppression → glucocorticoids.
Monitoring, interactions, and shared class effects
Calcineurin inhibitors and sirolimus have narrow therapeutic indices and require therapeutic drug-level monitoring. Because cyclosporine and tacrolimus are CYP3A4 substrates, azole antifungals and macrolides (e.g., erythromycin) raise drug levels and nephrotoxicity risk, while enzyme inducers (rifampin, phenytoin) lower levels and risk rejection.
A modern maintenance regimen for most solid-organ transplants is tacrolimus + mycophenolate + a glucocorticoid, with basiliximab for induction — tacrolimus has largely replaced cyclosporine as the first-line calcineurin inhibitor.
Across the entire class, chronic immunosuppression predisposes to opportunistic infections — hence common prophylaxis with TMP-SMX for *Pneumocystis jirovecii* and antivirals for CMV — and to malignancy, classically squamous cell carcinoma of the skin and EBV-associated post-transplant lymphoproliferative disorder (PTLD)/lymphoma. Recognizing these shared toxicities, plus each agent's signature adverse effect, is what the boards reward.
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