How immunosuppressants are tested on Step 1

Expect a transplant patient with rising creatinine, tremor, gingival hyperplasia, hyperlipidemia, or cytopenias, and a question about which drug or mechanism is responsible.

workspace_premium Two drugs, one protein

Tacrolimus and sirolimus both bind FKBP12, but the complexes hit different targets: tacrolimus–FKBP inhibits calcineurin (blocks IL-2 production); sirolimus–FKBP inhibits mTOR (blocks the response to IL-2).

T-cell activation and drug targets

Map each drug onto the steps of T-cell activation.

Signal 1+ 2TCR–MHC;CD28–B7(belatacept)CalcineurinCyclosporine,tacrolimusIL-2 madeNFATtranscriptionIL-2R →mTORBasiliximab,sirolimusCelldivisionMycophenolate,azathioprine
T-cell activation map. Glucocorticoids act broadly, suppressing cytokine transcription through NF-κB.

Drug classes and toxicities

Toxicities distinguish drugs that share a target.

DrugMechanismKey toxicity
CyclosporineBinds cyclophilin → inhibits calcineurinNephrotoxicity, hypertension, hyperlipidemia, gingival hyperplasia, hirsutism, tremor
TacrolimusBinds FKBP12 → inhibits calcineurinNephrotoxicity, neurotoxicity (tremor), hyperglycemia (new-onset diabetes), hypertension
Sirolimus, everolimusBinds FKBP12 → inhibits mTORHyperlipidemia, thrombocytopenia, poor wound healing, pneumonitis — not nephrotoxic
MycophenolateInhibits IMP dehydrogenase (de novo purine synthesis)GI upset, leukopenia, CMV infection; teratogenic
AzathioprinePurine analog (prodrug of 6-MP)Myelosuppression (worse with low TPMT or allopurinol), hepatotoxicity, pancreatitis
GlucocorticoidsInhibit NF-κB and cytokine genesHyperglycemia, osteoporosis, infection, Cushingoid features

Lymphocytes depend on de novo purine synthesis, which is why mycophenolate is relatively lymphocyte-selective.

Calcineurin inhibitorsCyclosporine, tacrolimusBlock IL-2 productionNephrotoxic (afferent vasoconstriction)Hypertension, tremor, hyperkalemiaCYP3A4 substratesmTOR inhibitorsSirolimus, everolimusBlock response to IL-2Not nephrotoxic (renal-sparing)Hyperlipidemia, cytopenias, poor woundhealingCoat drug-eluting stentsvs
Calcineurin vs mTOR. Sirolimus is often used to spare the kidney when calcineurin inhibitor nephrotoxicity develops.

Biologic immunosuppressants

Monoclonal antibodies and fusion proteins target specific immune molecules.

Biologic agentsBasiliximabIL-2 receptor(CD25);inductionBelataceptBinds B7,blocks CD28costimulationThymoglobulinDepletes Tcells;rejectionRituximabCD20 on B cellsTNF-αinhibitorsInfliximab,adalimumab,etanercept
Biologics. Screen for latent TB before TNF-α inhibitors (granulomas depend on TNF-α) and for hepatitis B before rituximab.

Interactions and clinical application

Calcineurin and mTOR inhibitors are CYP3A4 and P-glycoprotein substrates with narrow therapeutic windows.

InteractionEffect
Azoles, macrolides, diltiazem, verapamil, grapefruit↑ Tacrolimus/cyclosporine levels → toxicity
Rifampin, carbamazepine, phenytoin, St John's wort↓ Levels → rejection
Allopurinol + azathioprineSevere myelosuppression (xanthine oxidase blocked)
NSAIDs + calcineurin inhibitorAdditive nephrotoxicity

Trough drug levels guide tacrolimus and cyclosporine dosing.

functions Worked example — the rising creatinine

A kidney transplant recipient on tacrolimus, mycophenolate, and prednisone is treated for oral thrush with fluconazole. A week later creatinine rises from 1.3 to 2.2 mg/dL and she has a new fine tremor. What happened?

  1. Fluconazole inhibits CYP3A4, which metabolizes tacrolimus.
  2. Tacrolimus levels rise, causing afferent arteriolar vasoconstriction (nephrotoxicity) and neurotoxicity (tremor).
  3. Rejection would not cause a tremor; a high tacrolimus trough confirms toxicity.

Answer. Tacrolimus toxicity from a CYP3A4 interaction. Check the trough level, reduce the dose, or use topical nystatin instead of fluconazole.