A Textbook of Clinical Pharmacology and Therapeutics

CALCINEURIN INHIBITORS:CICLOSPORIN (AND ITS

CONGENERS)

Ciclosporinis a cyclic hydrophobic decapeptide that was

originally extracted from fungal cultures.

Uses

The main use of ciclosporinis in immunosuppression for

solid-organ transplantation, but it is also effective in refractory

psoriasis and bone marrow transplantation and graft-versus-

host disease. A high dose of ciclosporinis given 4–12 hours

before transplantation and then various oral maintenance

dose regimens are used. Therapeutic drug monitoring is used

to optimize therapy.

Mechanism of action

Ciclosporinis a specific T-lymphocyte suppressor, primarily

acting on the T-helper (Th1) cells, with a unique effect on the

primary immune response. It inhibits the production of inter-

leukin-2 (IL-2) and other cytokines by activated lymphocytes.

Ciclosporinbinds to a cytosolic protein cyclophilin. This

conjugate subsequently interacts with a Ca^2 –calmodulin-

dependent calcineurin complex and inhibits its phosphorylase

IMMUNOSUPPRESSIVEAGENTS 401

Key points

Glucocorticosteroids as immunosuppressants

• Topical (e.g. beclometasone) or systemic (e.g.
  prednisolone) glucocorticosteroids are very effective
  immunosuppressants.


• Appropriate dosing schedules of glucocorticoids are
  effective in diseases due to all types of hypersensitivity.


• Cellular pharmacodynamics:
  
  
  • inhibits expression of pro-inflammatory cytokines IL-
    2, 3 and 6, TNF, GM-CSF and IFN-γ;
  
  
  • inhibits production of adhesion molecules – ICAM-1,
    E-selectin and vascortin – leading to reduced
    vascular permeability;
  
  
  • reduces synthesis of arachidonic acid metabolites
    (prostaglandins, leukotrienes) and reduces histamine
    release;
  
  
  • reduces synthesis of Fc and C3 receptors.
  
  
  
  


• Hepatic metabolism (CYP3A), dosed to minimize HPA
  suppression – lowest dose, once a day.


• Adverse effects include:
  
  
  • acute effects – metabolic disturbances (glucose/
    hypokalaemia), CNS (mood disorders, insomnia);
  
  
  • chronic-effects – features of Cushing’s syndrome;
  
  
  • immunosuppression, risk of infection and HPA axis
    suppression.
  
  
  
  

Antigen

recognition

Expression

of IL-2 and

other cytokines

Cell proliferation

and differentiation

Ag

Antigen

presenting

cell

Stimulation of IL-I

Glucocorticosteroids

Antilymphocyte

globulin, OKT 3

and anti-CD4

IL-2

IL-2

CD4 helper cell

Primed CD4

Cytokines helper cell

B-cell CD8 cell

Plasma

cell

Cytotoxic

T-cell

Monoclonal

antibodies

(basiliximab and

daclizumab are

antagonists at the

T-lymphocyte IL-2

receptor)

Anti-D (Rh 0 ) immunoglobulin

Ciclosporin,

tacrolimus

Azathioprine, methotrexate,

cyclophosphamide,

rapamycin (sirolimus),

glucocorticosteroids,

mycophenolic acid

Figure 50.1:Sites of action of certain immunosuppressive agents.