A Textbook of Clinical Pharmacology and Therapeutics

activity. This impairs access to the nucleus of the cytosolic
component of the transcription promoter nuclear factor of
activated T cells (NF-ATc), which in turn reduces the trans-
cription of messenger RNA for IL-2, other pro-inflammatory
lymphokines and IL-2 receptors.

Adverse effects

These include the following:

• nephrotoxicity, which may be minimized by concomitant
  use of calcium channel blockers;


• hyperkalaemia;


• nausea and gastro-intestinal disturbances;


• hypertension;


• hirsutism;


• gingival hypertrophy;


• tremor (which can be an early sign of increasing plasma
  concentrations), paraesthesia and fits;


• hepatotoxicity;


• anaphylaxis with intravenous administration.

Pharmacokinetics

Ciclosporinis variably absorbed after oral administration. It
undergoes variable presystemic metabolism by gastro-intestinal
cytochrome P450 3A4. The major route of clearance is metabo-
lism via hepatic CYP3A. Renal dysfunction does not affect
ciclosporinclearance, but caution is needed because of its
nephrotoxicity. Dose reduction is required in patients with
hepatic impairment.

Therapeutic drug monitoring

Ciclosporin is assayed by radioimmunoassay (RIA) or
high-performance liquid chromatography (HPLC). Effective
immunosuppression occurs at trough concentrations of
100–300μg/L.

Drug interactions

These include allopurinol, cimetidine, ketoconazole(and
other azoles), erythromycin,diltiazem(and other calcium-
channel blockers), anabolic steroids, norethisteroneand other
inhibitors of cytochrome P450 3A4, which reduce the hepatic
clearance of ciclosporinleading to increased toxicity. Phenytoin
and rifampicinincrease hepatic clearance, thus reducing
plasma concentrations. Concomitant use of nephrotoxic agents
such as aminoglycosides, vancomycin and amphotericin
increases nephrotoxicity. ACE inhibitors increase the risk of
hyperkalaemia.
Tacrolimus(FK506) is another calcineurin inhibitor. It is
more potent than ciclosporinand often used in patients who
are refractory to ciclosporin. It can be given intravenously or
orally, and has variable absorption, and is metabolized by
hepatic CYP3A4. Therapeutic drug monitoring of trough con-
centrations is useful. The side effect and drug–drug interac-
tion profile of tacrolimusis similar to that of ciclosporin, but
it may cause more neurotoxicity and nephrotoxicity.

ANTI-PROLIFERATIVE IMMUNOSUPPRESSANTS

AZATHIOPRINE

Azathioprineis a prodrug and is converted to 6-mercaptopurine

(6-MP) by the liver.

Uses

Azathioprineis less widely used now than previously to pre-

vent transplant rejection. It may also be used to treat certain

autoimmune diseases (e.g. systemic lupus erythematosus,

rheumatoid arthritis, inflammatory bowel disease, chronic active

hepatitis and some cases of glomerulonephritis). Owing to its

potential toxicity, it is usually reserved for patients in whom glu-

cocorticosteroids alone are inadequate. The azathioprinemech-

anism of action, adverse reactions, pharmacokinetics and drug

interactions are those of 6-MPand are detailed in Chapter 48.

402 CLINICAL IMMUNOPHARMACOLOGY

Key points

Anti-proliferative agents as immunosuppressants

• These include azathioprine (prodrug of 6-MP),
  methotrexate, cyclophosphamide and mycophenolate
  mofetil.


• They are used as components of combination therapy
  with ciclosporin and/or steroids.


• Azathioprine’s haematopoietic suppression is a major
  limitation of its use.


• Sirolimus, which also synergizes with calcineurin
  inhibitors, is an alternative.

CYCLOPHOSPHAMIDE AND METHOTREXATE

For more information on cyclophosphamideandmethotrex-

ate, see Chapter 48.

MYCOPHENOLATE MOFETIL

Uses

Mycophenolate mofetilis an ester of a product of the Penicillium

mould. It is used in combination with immunophilins (e.g

ciclosporin) and glucocorticosteroids in solid-organ (e.g. renal,

Key points

Calcineurin inhibitors (e.g. ciclosporin) as immuno-

suppressants

• First-line immunosuppressive agent in solid-organ
  transplant immunosuppression.


• Used in severe refractory psoriasis.


• Inhibits transcription of IL-2 and other pro-
  inflammatory cytokines by T lymphocytes.


• Given orally or intravenously, shows variable absorption
  and hepatic metabolism (CYP3A) to many inactive
  metabolites.


• Toxicity – nephrotoxicity, nausea, hypertension, CNS
  effects (tremor and seizures).


• Many drug interactions – toxicity potentiated by azoles,
  macrolides and diltiazem.


• Tacrolimus (more potent than ciclosporin, but possibly
  more neurotoxicity).