A Textbook of Clinical Pharmacology and Therapeutics

cardiac) transplantation and is a more effective alternative than
azathioprine.Mycophenolate mofetilmay also be effective in
the treatment of other autoimmune disorders, such as rheuma-
toid arthritis and psoriasis.

Mechanism of action

In vivo the active entity, mycophenolic acid, inhibits inosine
monophosphate dehydrogenase (a pivotal enzyme in purine
synthesis). It suppresses proliferation both of T and B
lymphocytes. In addition, mycophenolic acidinhibits the
production of pro-inflammatory cytokines.

Adverse effects

These include the following:

• gastro-intestinal disturbances – diarrhoea and
  haemorrhage;


• bone marrow suppression, especially leukopenia and
  anaemia;


• CMV infection;


• lymphomas.

Pharmacokinetics

Mycophenolate mofetilis a prodrug ester of mycophenolic
acid, with improved absorption. After oral administration in
humans, the ester is rapidly and completely cleaved to
mycophenolic acid.Mycophenolic acidundergoes hepatic
elimination to its inactive glucuronide metabolite.

Drug interactions

Antacids decrease mycophenolateabsorption.
For novel anti-proliferative agents, such as sirolimusand
everolimus– see Table 50.1.

BIOLOGIC IMMUNOSUPPRESSANTS

POLYCLONAL ANTIBODIES

ANTILYMPHOCYTE GLOBULIN

Antilymphocyte globulin(ALG, also known as antithymo-
cyte globulin) is prepared by injecting human T lymphocytes

into animals (e.g. rabbits or horses) to raise antibodies. The

active immunoglobulin is largely in the IgG fraction and ALG

is a polyclonal antilymphocyte antibody with inherent vari-

ability from batch to batch. The major effect is probably to pre-

vent antigen from accessing the antigen-recognition site on

the T-helper cells. It is given intravenously for acute organ

transplant rejection. Adverse effects include anaphylaxis and

serum sickness.

MONOCLONAL ANTIBODIES

ANTI-CD3 ANTIBODY (MUROMONAB-CD3)

Uses

These monoclonal antibodies are used as adjuvant (often as

second-line) immunosuppressive therapy in patients with

acute transplant rejection. They are IgG2a antibodies produced

from murine hybridoma cells and are given intravenously.

After a 10- to 14-day course, some patients develop neutraliz-

ing antibodies.

Mechanism of action

Anti-CD3 antibodies bind CD3 protein, blocking antigen

binding to the T-cell antigen–recognition complex, and

decreasing the number of circulating CD3-positive lympho-

cytes. In addition, binding of anti-CD3 to its receptor causes

cytokine release (see Adverse effects below). The overall effect

is to reduce T-cell activation in acute solid-organ graft

rejection.

Adverse effects

These include the following:

• cytokine release syndrome, with chest pain, wheezing and
  dyspnoea (pulmonary oedema occurs after the first dose
  in 1% of patients);


• hypersensitivity reactions ranging from anaphylaxis to an
  acute influenza-like syndrome;


• CNS effects – seizures, reversible meningo-encephalitis
  and cerebral oedema.

IMMUNOSUPPRESSIVEAGENTS 403

Table 50.1:Novel anti-proliferative immunosuppressants

Drug Comments on use Side effects Pharmacokinetics

Sirolimus (rapamycin) Used with ciclosporin to Mild gastro-intestinal Well absorbed. Elimination t1/2is

prevent graft rejection disturbances. Thrombocytopenia 57 h. Hepatic metabolism by CYP3A.

leukopenia, anaemia, increased Linear kinetics

cholesterol and triglycerides.

Not nephrotoxic

Molecular target/mechanism: Drug interactions similar to Therapeutic drug monitoring advised

binds and inhibits mTOR, a ciclosporin. Sirolimus AUC

protein kinase involved in increased if given with

cell cycle progression ciclosporin

Everolimus Analogue of sirolimus Shorter t1/2than sirolimus

mTOR, mammalian target of rapamycin.