Immunosuppressive agents

1. Definition and Overview

• Medications that inhibit or prevent activity of the immune system.

• Used to prevent rejection of transplanted organs/tissues, treat autoimmune diseases, and manage certain inflammatory disorders.

• Function by suppressing one or more components of the immune response, including T-cell activation, B-cell function, cytokine release, or complement activity.

• Can be given short-term (e.g., post-surgery) or long-term (e.g., in chronic autoimmune conditions).

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2. Mechanisms of Action – General Pathways Targeted

• T-cell activation blockade – inhibition of calcineurin or co-stimulatory signals.

• Inhibition of lymphocyte proliferation – antimetabolites or mTOR pathway blockade.

• Cytokine inhibition – suppression of interleukin, TNF-α, or other pro-inflammatory cytokines.

• B-cell depletion – monoclonal antibodies against B-cell markers (e.g., CD20).

• Complement inhibition – prevents complement-mediated cell lysis.

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3. Main Pharmacological Classes and Examples

A. Calcineurin Inhibitors (CNIs)

• Examples: Cyclosporine, Tacrolimus

• Block calcineurin → reduced IL-2 transcription → impaired T-cell activation.

• Used in transplant rejection prophylaxis, autoimmune diseases.

B. mTOR Inhibitors

• Examples: Sirolimus, Everolimus

• Inhibit mammalian target of rapamycin (mTOR) → block cell cycle progression of lymphocytes.

C. Antimetabolites

• Examples: Azathioprine, Mycophenolate mofetil, Mycophenolic acid

• Inhibit purine synthesis → prevent lymphocyte proliferation.

D. Glucocorticoids

• Examples: Prednisone, Methylprednisolone, Dexamethasone

• Broad immunosuppressive effects: inhibit cytokine production, reduce inflammatory mediator release, suppress immune cell migration.

E. Biologic Agents – Monoclonal Antibodies and Fusion Proteins

• Anti-IL agents: basiliximab (anti-IL-2 receptor), ustekinumab (anti-IL-12/23).

• Anti-T-cell antibodies: alemtuzumab (anti-CD52), muromonab-CD3 (anti-CD3).

• B-cell targeted: rituximab (anti-CD20), ocrelizumab (anti-CD20).

• Costimulation blockers: abatacept, belatacept.

• Complement inhibitors: eculizumab (anti-C5).

F. Alkylating Agents

• Examples: Cyclophosphamide, Chlorambucil

• Crosslink DNA → induce apoptosis in rapidly dividing immune cells.

G. JAK Inhibitors

• Examples: Tofacitinib, Baricitinib

• Block Janus kinase enzymes → interfere with cytokine signaling.

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4. Therapeutic Indications

Transplantation

• Solid organ transplants: kidney, liver, heart, lung, pancreas.

• Hematopoietic stem cell transplantation.

Autoimmune and Inflammatory Disorders

• Rheumatoid arthritis, systemic lupus erythematosus (SLE), multiple sclerosis, inflammatory bowel disease, psoriasis, myasthenia gravis.

Other

• Certain hematological conditions (e.g., autoimmune hemolytic anemia).

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5. Contraindications

• Active, uncontrolled infections.

• Known hypersensitivity to drug or formulation components.

• Certain malignancies (risk may outweigh benefit).

• Live vaccines during therapy.

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6. Adverse Effects (General)

Immunosuppression-related

• Increased susceptibility to bacterial, viral, fungal, and opportunistic infections.

• Increased risk of malignancy (especially lymphomas and skin cancers).

Drug-class specific

• CNIs: nephrotoxicity, hypertension, neurotoxicity, tremor, hyperglycemia.

• mTOR inhibitors: hyperlipidemia, delayed wound healing, mouth ulcers.

• Antimetabolites: bone marrow suppression, gastrointestinal upset, hepatotoxicity.

• Glucocorticoids: osteoporosis, hyperglycemia, adrenal suppression, mood changes.

• Biologics: infusion reactions, reactivation of hepatitis B or tuberculosis.

• Alkylating agents: infertility, hemorrhagic cystitis (cyclophosphamide).

• JAK inhibitors: thrombosis risk, lipid elevation.

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7. Drug Interactions

• CNIs and mTOR inhibitors: metabolized by CYP3A4 → interactions with inhibitors (ketoconazole, erythromycin) and inducers (rifampin, carbamazepine).

• Antimetabolites: allopurinol increases toxicity of azathioprine.

• Glucocorticoids: increased GI bleed risk with NSAIDs; altered metabolism with CYP3A4 modifiers.

• Biologics: increased infection risk with other immunosuppressives; avoid live vaccines.

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8. Monitoring Requirements

• Blood counts – monitor for cytopenias.

• Renal and liver function – detect toxicity early.

• Drug trough levels – especially for CNIs and mTOR inhibitors.

• Lipid profile – mTOR inhibitors, JAK inhibitors.

• Blood pressure and blood glucose – glucocorticoids, CNIs.

• Infection screening – TB, hepatitis B before starting biologics.

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9. Advantages and Limitations

Advantages

• Enable long-term survival of transplanted organs.

• Control autoimmune diseases unresponsive to standard therapies.

• Wide range of agents allowing tailored regimens.

Limitations

• Lifelong therapy often required in transplantation.

• High risk of infection and malignancy with chronic use.

• Narrow therapeutic index for some agents (CNIs).

• Cost and monitoring burden for biologics.

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10. Immunosuppressive Regimens in Transplantation

• Usually involve combination therapy to achieve additive effects and allow lower doses of individual drugs, reducing toxicity.

• Common triple therapy:

  • Calcineurin inhibitor + Antimetabolite + Glucocorticoid.

• Induction therapy: biologic agents (e.g., basiliximab) used peri-operatively to achieve rapid immunosuppression.