A Textbook of Clinical Pharmacology and Therapeutics

402 CLINICAL IMMUNOPHARMACOLOGY
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 transcription
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
Ciclosporin is variably absorbed after oral administration. It
undergoes variable presystemic metabolism by gastro-intestinal
cytochrome P450 3A4. The major route of clearance is metabolism
via hepatic CYP3A. Renal dysfunction does not affect
ciclosporin clearance, 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
100–300 μg/L.
Drug interactions
These include allopurinol, cimetidine, ketoconazole (and
other azoles), erythromycin, diltiazem (and other calciumchannel
blockers), anabolic steroids, norethisterone and other
inhibitors of cytochrome P450 3A4, which reduce the hepatic
clearance of ciclosporin leading to increased toxicity. Phenytoin
and rifampicin increase 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 ciclosporin and 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 concentrations
is useful. The side effect and drug–drug interaction
profile of tacrolimus is similar to that of ciclosporin, but
it may cause more neurotoxicity and nephrotoxicity.
Key points
Calcineurin inhibitors (e.g. ciclosporin) as immunosuppressants
• First-line immunosuppressive agent in solid-organ
transplant immunosuppression.
• Used in severe refractory psoriasis.
• Inhibits transcription of IL-2 and other proinflammatory
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).
ANTI-PROLIFERATIVE IMMUNOSUPPRESSANTS
AZATHIOPRINE
Azathioprine is a prodrug and is converted to 6-mercaptopurine
(6-MP) by the liver.
Uses
Azathioprine is less widely used now than previously to prevent
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 glucocorticosteroids
alone are inadequate. The azathioprine mechanism
of action, adverse reactions, pharmacokinetics and drug
interactions are those of 6-MP and are detailed in Chapter 48.
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 cyclophosphamide and methotrexate,
see Chapter 48.
MYCOPHENOLATE MOFETIL
Uses
Mycophenolate mofetil is 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,