INDIVIDUAL DRUGS
USED TO SUPPRESS THE IMMUNE SYSTEM
Cyclosporine (Sandimmune) is a potent inhibitor of
an-tibody- and cell-mediated immune responses and is the immunosuppressant of
choice for the prevention of transplant rejection. It also has application
in the treat-ment of autoimmune diseases.
Cyclosporine is a highly
stable 11–amino acid cyclic polypeptide. The molecule is very lipophilic and
essen-tially is not soluble in water. It can be administered in-travenously,
orally, or by injection.
Cyclosporine can bind to the
cytosolic protein cy-tophilin C. This drug–protein complex inhibits
cal-cineurin phosphatase activity, which leads to a de-creased synthesis and
release of several cytokines, including interleukins IL-2, IL-3, IL-4,
interferon- , and tumor necrosis factor.
Cyclosporine exhibits a high
degree of specificity in its actions on T cells without significantly impairing
B-cell activity. It can inhibit the T cell–dependent limb of antibody
production by lymphocytes by preventing the differentiation of B cells into
antibody-secreting plasma cells. Because T cells appear to require IL-2
stimulation for their continuous growth, cyclosporine impairs the proliferative
response of T cells to antigens. However, once T cells have been stimulated by
antigens to syn-thesize IL-2, cyclosporine cannot suppress the prolifer-ation
of T cells induced by this cytokine.
After oral administration,
cyclosporine is absorbed slowly and incompletely, with great variation among
individuals. Peak plasma concentrations are reached in 3 to 4 hours, and the
plasma half-life is 10 to 27 hours. The drug is extensively metabolized by
hepatic mixed-function oxidase enzymes and is excreted principally via the bile
into the feces. Metabolism results in inactiva-tion of the immunosuppressive
activity. Agents that en-hance or inhibit the mixed-function oxidase enzymes
will alter the therapeutic response to cyclosporine.
Cyclosporine has been
approved for use in allogeneic kidney, liver, and heart transplant patients and
is under study for use in pancreas, bone marrow, single lung, and heart–lung
transplant procedures. It is recommended that corticosteroids, such as
prednisone, be used con-comitantly, although at half or less of their usual
dose. Such combined therapy leads to fewer side effects, a de-creased incidence
of infectious complications, efficacy of lower doses of cyclosporine, and a
better history of patient survival.
Cyclosporine appears to have
promise in the treat-ment of autoimmune diseases. It has a beneficial effect on
the course of rheumatoid arthritis, uveitis, insulin-dependent diabetes,
systemic lupus erythematosus, and psoriatic arthropathies in some patients.
Toxicity is more of a problem in these conditions than during use in
transplantation, since higher doses of cyclosporine are often required to
suppress autoimmune disorders.
Compared with previously
available therapy, the adverse effects associated with cyclosporine are much
less severe but still worthy of concern. Nephrotoxicity, which can oc-cur in up
to 75% of patients, ranges from severe tubular necrosis to chronic interstitial
nephropathy. This effect is generally reversible with dosage reduction.
Vasocon-striction appears to be an important aspect of cyclo-sporine-induced
nephrotoxicity. Hypertension occurs in 25% of the patients and more frequently
in patients with some degree of renal dysfunction; the concomitant use of
antihypertensive drugs may prove useful. Hypergly-cemia, hyperlipidemia,
transient liver dysfunction, and unwanted hair growth are also observed.
Corticosteroids, such as
prednisone (Deltasone, Meti-corten)
and prednisolone (Prelone, Delta-Cortef),
have been used alone or in
combination with other agents in the treatment of autoimmune disorders and for
the pre-vention of allograft rejection. However, the toxicity as-sociated with
their use necessitates prudent administra-tion.
Although corticosteroids possess immunosuppressive properties,
their real value is in controlling the inflamma-tion that can accompany
transplantation and autoim-mune disorders. Virtually all phases of the inflammatory process are affected by these drugs.
Corticosteroid ther-apy alone is successful in only a limited number of
au-toimmune diseases, such as idiopathic thrombocytope-nia, hemolytic anemia,
and polymyalgia rheumatica.
Tacrolimus (Prograf) is a second-generation
immuno-suppressive agent that has been approved for use in liver
transplantation. Its efficacy for other transplanta-tions is being evaluated.
It has properties similar to those of cyclosporine except that weight for
weight it is 10 to 100 times more potent. It is a macrolide antibiotic that selectively
inhibits transcription of a specific set of lymphokine genes in T lymphocytes
(e.g., IL-2, IL-4, and interferon- ) and binds to cytoplasmic proteins in
lym-phocytes. Although the binding proteins (cytophilins) for cyclosporine and
tacrolimus are different, they share similar functions in that the cytophilins
are important for the intracellular folding of proteins. It is speculated that
these proteins are important in regulating gene ex-pression in T lymphocytes
and that both drugs some-how interfere in this process.
Absorption of tacrolimus from
the gastrointestinal (GI) tract is variable. It is extensively metabolized in
the liver and excreted in the urine. As with cyclosporine, nephrotoxicity is
its principal side effect.
Sirolimus (Rapamune) is structurally related to
tacrolimus. It is approved for use as an adjunctive agent in combination with
cyclosporine for prevention of acute renal allograft rejection. It blocks
IL-2-dependent T-cell proliferation by inhibiting a cytoplasmic serine–
threonine kinase. This mechanism of action is different from those of
tacrolimus and cyclosporine. This allows sirolimus to augment the
immunosuppressive effects of these drugs.
Azathioprine (Imuran) is a cytotoxic agent that
prefer-entially destroys any rapidly dividing cell. Since im-munologically
competent cells are generally rapidly di-viding cells, azathioprine is very
effective as an immunosuppressive drug. Unfortunately, any cell that is
replicating is a target for this action. This lack of speci-ficity leads to
serious side effects.
Azathioprine, in combination
with corticosteroids, has historically been used more widely than any other
drug in immunosuppressive therapy. It is classified as a purine antimetabolite
and is a derivative of 6-mercap-topurine .
Azathioprine is a
phase-specific drug that is toxic to cells during nucleic acid synthesis.
Phase-specific drugs are toxic during a specific phase of the mitotic cycle,
usually the S-phase, when DNA synthesis is occurring, as opposed to
cycle-specific drugs that kill both cycling and intermitotic cells.
Azathioprine is converted in
vivo to thioinosinic acid, which competitively inhibits the synthesis of
in-osinic acid, the precursor to adenylic acid and guanylic acid. In this way,
azathioprine inhibits DNA synthesis and therefore suppresses lymphocyte
proliferation. This effectively inhibits both humoral and cell-mediated im-mune
responses.
Azathioprine is well absorbed
following oral adminis-tration, with peak blood levels occurring within 1 to 2
hours. It is rapidly and extensively metabolized to 6-mercaptopurine, which is
further converted in the liver and erythrocytes to a variety of metabolites,
including 6-thiouric acid. Metabolites are excreted in the urine. The half-life
of azathioprine and its metabolites in the blood is about 5 hours.
Azathioprine is a relatively
powerful antiinflammatory agent. Although its beneficial effect in various condi-tions
is principally attributable to its direct immunosup-pressive action, the
antiinflammatory properties of the drug play an important role in its overall
therapeutic ef-fectiveness.
Azathioprine has been used
widely in combination with corticosteroids to inhibit rejection of organ
trans-plants, particularly kidney and liver allografts. However, it is usually
reserved for patients who do not respond to cyclosporine plus corticosteroids
alone.
Azathioprine also has
applications in certain disor-ders with autoimmune components, most commonly
rheumatoid arthritis. It is as effective as cyclophos-phamide in the treatment
of Wegener’s granulomatosis. It has largely been replaced by cyclosporine in
im-munosuppressive therapy. Relative to other cytotoxic agents, the better oral
absorption of azathioprine is the reason for its more widespread clinical use.
The therapeutic use of
azathioprine has been limited by the number and severity of adverse effects
associated with its administration. Bone marrow suppression re-sulting in
leukopenia, thrombocytopenia, or both mayoccur. GI toxicity may be a problem.
It is also mildly he-patotoxic. Because of its immunosuppressive activity,
azathioprine therapy can lead to serious infections. It has been shown to be
mutagenic in animals and humans and carcinogenic in animals.
Mycophenolate mofetil (CellCept), in conjunction with
cyclosporine and corticosteroids, has clinical applica-tions in the prevention
of organ rejection in patients re-ceiving allogeneic renal and cardiac
transplants. By ef-fectively inhibiting de novo purine synthesis, it can impair
the proliferation of both T and B lymphocytes. Following oral administration,
mycophenolate mofetil is almost completely absorbed from the GI tract,
me-tabolized in the liver first to the active compound my-cophenolic acid, and
then further metabolized to an in-active glucuronide.
Early clinical trials
indicate that mycophenolate mofetil in conjunction with cyclosporine and
cortico-steroids is a more effective regimen than azathioprine in preventing
the acute rejection of transplanted organs. GI side effects are most common.
Although azathioprine is the
most popular cytotoxic drug used for immunosuppression, others have been
employed. Among these is cyclophosphamide, a cycle-specific agent that acts by
cross-linking and alkylating DNA, thereby preventing correct duplication during
cell divisions. Methotrexate is a phase-specific agent that acts by inhibiting
folate metabolism. It is highly toxic and appears to offer no advantages over
azathio-prine. Chlorambucil, an alkylating agent, has actions similar to those
of cyclophosphamide. In contrast, its ad-verse effects are fewer in that
alopecia and GI intoler-ance are almost never encountered.
Antiserum can be raised
against lymphocytes or thymo-cytes by the repeated injection of human cells
into an appropriate recipient, usually a horse. The use of such antiserum or
the immune globulin fraction derived from it has been used to produce
immunosuppression. Although antilymphocytic serum can suppress cellular and
often humoral immunity against a variety of tissue graft systems, the responses
are variable, particularly from one batch of serum to another.
Antithymocyte globulin (Atgam) is purified immune globulin
obtained from hyperimmune serum of horses immunized with human thymus
lymphocytes. It has been used successfully alone and in combination with
azathioprine and corticosteroids to prevent renal allo-graft rejection.
Although it has benefits when adminis-tered prophylactically, its use during
rejection episodes may be its greatest value.
Antithymocyte globulin binds
to circulating T lym-phocytes in the blood, which are subsequently removed from
the circulation by the reticuloendothelial system. This globulin also reduces
the number of T lymphocytes in the thymus-dependent areas of the spleen and
lymph nodes.
Since the preparations are
raised in heterologous species, reactions against the foreign proteins may lead
to serum sickness and nephritis. The concomitant use of corticosteroids may
alleviate this response.
Muromonab-(CD3) (Orthoclone OKT3) is a mouse monoclonal
antibody that is a purified IgG. It is used for the prevention of acute
allograft rejection in kid-ney and hepatic transplants and as prophylaxis in
car-diac transplantation. It is also used to deplete T cells in marrow from
donors before bone marrow transplanta-tion.
Muromonab-(CD3) alters the
cell-mediated im-mune response by binding to the CD3 (cluster of
differ-entiation antigen, T3) glycoprotein on T lymphocytes. This binding
inhibits lymphocyte activation so that af-fected T cells cannot recognize
foreign antigen and can-not participate in rejecting an organ graft. Within
min-utes of the first muromonab-(CD3) injection, total circulating T cells are
rapidly depleted from the blood. They later reappear devoid of CD3 and antigen
recog-nition complexes.
Adverse side effects include fever,
pulmonary edema, vomiting, headache, and anaphylaxis. Neutral-izing antibodies
may develop over time and necessitate adjusting the dosage upward to compensate
for the loss of therapeutic activity.
An Rh-negative mother can become
sensitized to Rh antigen during delivery of an Rh-positive infant. This
sensitization may lead to Rh hemolytic disease in future newborns. Rho(D)
immune globulin (RhoGAM) is a
preparation of human IgG that contains a high titer of antibodies against the
Rh(D) red cell antigen. Rho(D) immune globulin functions to prevent the mother
from becoming sensitized to the Rh antigen by binding to and destroying fetal
red blood cells that have entered her blood. It is generally given at 28 weeks
of pregnancy and within 72 hours after delivery. Rh incompatibility can be
identified with routine blood tests.
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