CYCLOSPORIN

CYCLOSPORIN

• Type of immunosuppressant drug.
• Specific T-cell Inhibitor/ calcineurin Inhibitor.
• Acts on CD4 cells & lymphocytes.

Major pharmacological effects:

Selective inhibition:

• Antigen-stimulated activation & proliferation of T-cells (CD₄ helper cells).
• Expression IL-2 & other cytokines by T cells.
• Affects inducer T-cells response to IL-1, without affecting suppressor T-cells.

Mechanism of action:

• Binding protein – Cyclophilin.
• Inactivates calcineurin.
• Failure of antigenic stimulation by helper T-cell.
• Activates IL-2 inhibitor.
  • Attenuating IL-2 stimulated T-cell proliferation.
  • Block transcription of IL-2.
  • Production of killer lymphocytes.
• Most active before antigen exposure.
• Suppress responses of primed helper T-cells.
• Hence, useful in auto-immune diseases.

Pharmacokinetics:

• Low oral bioavailability  
• Bile-dependent
• Concentrated in WBC’s and RBC’s
• Metabolised in liver; Excreted in bile
• Biphasic plasma t_1/2 – 4-6 hrs & 12-18 hrs

Advantages:

• Selectively suppresses cell-mediated immunity.
• Prevents graft rejection, unaffecting host’s immune system.
• No toxic effects on bone marrow & RE system (unlike cytotoxic immunosuppressants).
• Intact humoral immunity.

Adverse effects:

• Nephrotoxicity.
  • Rise in serum creatinine levels.
  • Reduced GFR.
• Impaired liver function.
• Post-transplant hypertension.
  • Sustained rise in BP.
  • Vasoconstriction & activation of RA system.

Other effects:

Indications:

1. Prevention and treatment of graft rejection reaction  

• Routinely used in renal, hepatic, cardiac, bone marrow and other transplants.
• Initial induction – Orally, 12 hrs prior transplant surgery.
• Maintenance dose – Until needed.

2. Autoimmune diseases – Second line drug.

• Severe rheumatoid arthritis, uveitis, IBD, psoriasis, & suppress acute exacerbations.
• Combined with glucocorticoid.

3. Aplastic anemia 

• Low dose (2-5mg/kg/day).
• Not curative.
• Relapse on withdrawal.

Interactions:

1. Enhanced toxicity:

• Intake of nephrotoxic drugs.
• Vancomycin, Amphotericin B, & NSAIDS.
• Erythromycin & Ketoconazole (CYP3A4 inhibitors) inhibits its metabolism causing toxicity.

2. Excretory interference:

• Excretion of other drugs impaired by decreased renal function.

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