A Textbook of Clinical Pharmacology and Therapeutics

Key points
Antigen
recognition
Expression
of IL-2 and
other cytokines
Cell proliferation
and differentiation
Antigen
presenting
cell
Cytokines
B-cell
Plasma
cell
IL-2
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.
Ag
Stimulation of IL-I
CD4 helper cell
CD8 cell
Cytotoxic
T-cell
Figure 50.1: Sites of action of certain immunosuppressive agents.
Primed CD4
helper cell
IL-2
IMMUNOSUPPRESSIVE AGENTS 401
Anti-D (Rh 0) immunoglobulin
Glucocorticosteroids
Antilymphocyte
globulin, OKT 3
and anti-CD4
Ciclosporin,
tacrolimus
Azathioprine, methotrexate,
cyclophosphamide,
rapamycin (sirolimus),
glucocorticosteroids,
mycophenolic acid
Monoclonal
antibodies
(basiliximab and
daclizumab are
antagonists at the
T-lymphocyte IL-2
receptor)
CALCINEURIN INHIBITORS: CICLOSPORIN (AND ITS
CONGENERS)
Ciclosporin is a cyclic hydrophobic decapeptide that was
originally extracted from fungal cultures.
Uses
The main use of ciclosporin is in immunosuppression for
solid-organ transplantation, but it is also effective in refractory
psoriasis and bone marrow transplantation and graft-versushost
disease. A high dose of ciclosporin is 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
Ciclosporin is 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 interleukin-2
(IL-2) and other cytokines by activated lymphocytes.
Ciclosporin binds to a cytosolic protein cyclophilin. This
conjugate subsequently interacts with a Ca2� –calmodulindependent
calcineurin complex and inhibits its phosphorylase