IMMUNOSUPPRESSANT DRUGS

Classification, Mechanism of Action, Therapeutic Uses, and Adverse Effects

INTRODUCTION

1. Organ transplantation - to prevent graft rejection
2. Autoimmune diseases - to control abnormal immune responses

CLASSIFICATION OF IMMUNOSUPPRESSANT DRUGS

Classification by Role in Transplant Therapy:

(Source: Lippincott Illustrated Reviews: Pharmacology)

Classification by Mechanism of Action:

MECHANISM OF ACTION (Detailed)

(Source: Lippincott Illustrated Reviews: Pharmacology)

1. CALCINEURIN INHIBITORS (CNIs)

• T-cell activation requires calcineurin (a phosphatase enzyme) to activate NFAT (Nuclear Factor of Activated T-cells), which promotes IL-2 gene transcription.
• Cyclosporine binds to Cyclophilin-1 (an intracellular receptor).
• Tacrolimus binds to FKBP-12 (FK-binding protein).
• Both drug-receptor complexes inhibit calcineurin.
• Result: Inhibition of IL-2, IL-3, IL-4, TNF-α, and IFN-γ transcription → T-cell activation is blocked.
• Tacrolimus is 10-100x more potent than cyclosporine.

• Prevention of solid organ rejection (kidney, liver, heart, lung transplants)
• Treatment of rheumatoid arthritis, psoriasis, SLE
• Voclosporin: specifically approved for SLE nephritis

• Nephrotoxicity (major, dose-limiting) - most important!
• Hypertension, headache, tremor
• Cyclosporine specific: Hirsutism (excessive hair growth), gingival hyperplasia, hyperlipidemia
• Tacrolimus specific: Diabetes mellitus (new-onset), alopecia, neurotoxicity
• Both: Infections, CYP3A4 drug interactions, narrow therapeutic index (requires TDM)

Note for exams: Both CNIs are metabolized by CYP3A4 - so numerous drug interactions occur. Grapefruit juice increases cyclosporine bioavailability by 62%.

2. mTOR INHIBITORS

• After IL-2 binds to its receptor (Signal 3), it activates the mTOR pathway.
• Sirolimus and everolimus bind to FKBP-12 → the complex then inhibits mTOR (mammalian target of rapamycin).
• mTOR inhibition blocks the cell cycle (G1 → S transition), preventing T-cell proliferation.
• Note: Unlike CNIs, they do NOT inhibit calcineurin or IL-2 production - they block the cell's response to IL-2.

• Rejection prophylaxis for organ transplantation (kidney, heart)
• Prevention and treatment of graft-versus-host disease (GVHD) - Sirolimus
• Sirolimus-coated coronary stents - prevent restenosis
• Everolimus: also used in oncology (renal cell carcinoma, breast cancer, neuroendocrine tumors)
• Commonly used to reduce CNI dose and minimize nephrotoxicity

• Metabolic: Hypercholesterolemia, hypertriglyceridemia
• Hematologic: Leukopenia, thrombocytopenia, anemia
• GI: Nausea, vomiting, diarrhea
• New-onset diabetes mellitus (long-term use)
• Poor wound healing (avoid in perioperative period)
• Mouth ulcers (aphthous stomatitis)
• Substrate of CYP3A4 - multiple drug interactions; TDM required

3. ANTIPROLIFERATIVES (ANTIMETABOLITES)

A. Azathioprine

• A prodrug converted to 6-mercaptopurine (6-MP), then to thioinosinic acid (nucleotide analogue).
• This analogue is incorporated into DNA chains and blocks DNA elongation - preventing lymphocyte proliferation.
• Important interaction: Xanthine oxidase inhibitors (allopurinol, febuxostat) inhibit azathioprine metabolism → increased toxicity. Concomitant use with febuxostat is contraindicated.
• Adverse effects: Bone marrow suppression (dose-limiting), hepatotoxicity, GI disturbances, increased risk of infections and malignancy.

B. Mycophenolate Mofetil (MMF)

• MMF is a prodrug converted to Mycophenolic acid (MPA) in the liver.
• MPA is a potent, reversible, noncompetitive inhibitor of inosine monophosphate dehydrogenase (IMPDH).
• This blocks the de novo synthesis of guanosine monophosphate (GMP).
• Lymphocytes (T and B cells) rely entirely on de novo synthesis and cannot use the salvage pathway - making them selectively sensitive.
• Result: Selective T and B cell proliferation is blocked.

(Source: Lippincott Illustrated Reviews: Pharmacology)

• MMF has largely replaced azathioprine due to better efficacy and safety profile.
• EC-MPA (enteric-coated, mycophenolate sodium) reduces GI side effects.
• Adverse effects: Leukopenia, thrombocytopenia, GI distress (nausea, vomiting, diarrhea), opportunistic infections.

4. CORTICOSTEROIDS

• First pharmacologic agents used as immunosuppressives.
• Enter cells and bind to the glucocorticoid receptor → complex enters nucleus → regulates DNA transcription.
• Result: Nonspecific inhibition of interleukins and TNF-α. Rapidly reduce lymphocyte populations by lysis or redistribution.
• T-lymphocytes are most affected.
• Methylprednisolone is used for transplant induction and rejection episodes; Prednisone/prednisolone for autoimmune conditions.

• Solid organ transplant (induction, maintenance, acute rejection)
• Chronic GVHD
• Autoimmune diseases: Rheumatoid arthritis, SLE, temporal arteritis, asthma, inflammatory bowel disease, multiple sclerosis

• Short-term: Hyperglycemia, hypertension, edema, mood swings/insomnia, increased infections
• Long-term: Osteoporosis, myopathy, cataracts, impaired wound healing, Cushingoid appearance, adrenal suppression, peptic ulcer

5. BIOLOGICAL AGENTS - MONOCLONAL ANTIBODIES

A. Basiliximab (IL-2 Receptor Antagonist)

• Chimeric monoclonal antibody targeting CD25 (IL-2 receptor α chain) on activated T-cells.
• Blocks IL-2 from binding → prevents T-cell activation and proliferation (non-depleting).
• Used for induction in kidney transplantation.
• Well tolerated; minimal adverse effects compared to other biologics.

B. Alemtuzumab

• Humanized monoclonal antibody targeting CD52 on T and B lymphocytes.
• Causes profound and prolonged T and B cell depletion.
• Used for induction and rejection therapy.
• Adverse effects: Infusion reactions, severe leukopenia, neutropenia, thrombocytopenia, CMV and viral infections.

C. Rituximab

• Chimeric monoclonal antibody targeting CD20 on B lymphocytes.
• Mediates B cell lysis and depletion via CDC (complement-dependent cytotoxicity) and ADCC.
• Used for induction, antibody-mediated rejection (AMR), and autoimmune conditions (RA, lupus).
• Adverse effects: Infusion reactions, leukopenia, risk of PML (progressive multifocal leukoencephalopathy).

D. Belatacept (Costimulation Blocker)

• Recombinant fusion protein of CTLA-4.
• Binds to CD80/CD86 on antigen-presenting cells → blocks CD28 from binding → inhibits Signal 2 of T-cell activation.
• Approved for kidney transplant as CNI substitute to avoid nephrotoxicity.
• Risk of PTLD (post-transplant lymphoproliferative disorder), especially CNS. Contraindicated in EBV-seronegative patients.

E. Belimumab

• Fully human monoclonal antibody against BLyS (B lymphocyte stimulator protein).
• Blocks B-cell survival and differentiation into immunoglobulin-secreting plasma cells.
• Approved for systemic lupus erythematosus (SLE).
• Available as SC or IV formulation.
• Warnings: serious infections, PML, depression/suicidality.

6. POLYCLONAL ANTIBODIES - ANTITHYMOCYTE GLOBULIN (ATG)

• Prepared by immunizing horses or rabbits with human thymocytes.
• Contains multiple antibodies → causes T-cell depletion by complement-mediated lysis.
• Used for transplant induction and treatment of acute rejection.
• Adverse effects: Infusion reactions (fever, chills), leukopenia, thrombocytopenia, pulmonary edema, CMV infections.

7. BORTEZOMIB (Proteasome Inhibitor)

• Inhibits the 26S proteasome → leads to plasma cell depletion.
• Used in the treatment of antibody-mediated rejection (AMR).
• Adverse effects: Leukopenia, anemia, thrombocytopenia, peripheral neuropathy, nausea/vomiting, hepatotoxicity.

PHARMACOLOGY IN ORGAN TRANSPLANTATION - TRIPLE THERAPY

• Each drug targets a different step in the immune cascade → synergistic immunosuppression.
• Allows dose reduction of each drug → fewer adverse effects.
• Notably, CNI dose is often reduced to spare nephrotoxicity.

PHARMACOLOGY IN AUTOIMMUNE DISEASES

ADVERSE EFFECTS SUMMARY TABLE

THERAPEUTIC DRUG MONITORING (TDM)

• Cyclosporine
• Tacrolimus
• Sirolimus
• Everolimus

KEY POINTS FOR EXAM (Memory Tips)

CONCLUSION