Other immunosuppressants
Several drugs used for their immunosuppressant
effects in pa-tients undergoing allograft transplantation (transplantation
be-tween two people who aren’t identical twins) are also used experi-mentally
to treat autoimmune diseases (diseases resulting from an inappropriate immune
response directed against the self). They in-clude:
·
azathioprine
·
basiliximab
·
cyclosporine
·
daclizumab
·
lymphocyte immune globulin (ATG [equine])
·
muromonab-CD3
·
mycophenolate mofetil
·
sirolimus
·
tacrolimus
·
thymoglobulin (antithymocyte globulin [rabbit]).
Cyclophosphamide, classified as an alkylating drug, is also used as an
immunosuppressant; however, it’s primarily used to treat can-cer.
Anakinra is an immunosuppressant used to treat adults with moderate to
severe active rheumatoid arthritis who haven’t re-sponded to at least one
disease-modifying antirheumatic drug.
Immunosuppressants take different paths through the
body.
When administered orally, azathioprine and
mycophenolate are readily absorbed from the GI tract, whereas absorption of
cy-closporine, tacrolimus, and sirolimus is varied and incomplete.
Anakinra, ATG, basiliximab, daclizumab,
muromonab-CD3, and thymoglobulin are administered only by I.V. injection.
The distribution of azathioprine, basiliximab, and daclizumab isn’t
fully understood. Cyclosporine and muromonab-CD3 are distrib-uted widely
throughout the body. Azathioprine and cyclosporine cross the placental barrier.
The distribution of ATG isn’t clear, butit may appear in breast milk.
Distribution of tacrolimus depends on several factors; 75% to 99% is
protein-bound. Sirolimus is 97% protein-bound.
§ Azathioprine and cyclosporine are metabolized
in the liver.
§ Muromonab-CD3 is consumed by T cells
circulating in the blood.
§ The metabolism of ATG is unknown.
·
Mycophenolate is metabolized in the liver to mycophenolate acid, an
active metabolite, and then further metabolized to an in-active metabolite,
which is excreted in urine and bile. Concentra-tions of mycophenolate and
acyclovir may increase in the pres-ence of nephrotoxicity.
·
Azathioprine, anakinra, and ATG are excreted in urine; cy-closporine is
excreted principally in bile. It’s unknown how muromonab-CD3 is excreted.
·
Tacrolimus is extensively metabolized and excreted primarily in bile;
less than 1% is excreted unchanged in urine. Sirolimus is metabolized by the
mixed function oxidase system, primarily cy-tochrome P-450 (CYP3A4); 91% is
excreted in stool and 2.2% in urine. Metabolism and excretion of basiliximab
and daclizumab aren’t understood.
How certain immunosuppressants achieve their
desired effects has yet to be determined.
§ The exact mechanism of action of
azathioprine, cyclosporine, and
§ ATG is unknown, but may be explained by these
theories:
§ Azathioprine antagonizes metabolism of the
amino acid purine and, therefore, may inhibit ribonucleic acid and
deoxyribonucleic acid structure and synthesis. It also may inhibit coenzyme
forma-tion and function.
§ Cyclosporine is thought to inhibit helper T
cells and suppressor T cells.
§ ATG may eliminate antigen-reactive T cells in
the blood, alter T-cell function, or both.
In patients receiving kidney allografts,
azathioprine suppresses cell-mediated hypersensitivity reactions and produces
various al-terations in antibody production. Muromonab-CD3, a monoclonal
antibody, is understood to block the function of T cells.Anakinra, basiliximab,
and daclizumab block the activity of in-terleukin. Mycophenolate inhibits
responses of T and B lymphocytes, suppresses antibody formation by B lymphocytes, and may inhibit
recruitment of leukocytes into sites of inflammation and graft rejection.
Sirolimus is an immunosuppressant that inhibits
T-lymphocyte activation and proliferation that occur in response to antigenic
and cytokine stimulation; it also inhibits antibody formation.
Immunosuppressants are used mainly to prevent
rejection in pa-tients who undergo organ transplantation. (See Cyclosporine:Miracle drug or death sentence?)
Drug interactions
Most drug interactions with this class of drugs
involve other im-munosuppressant and anti-inflammatory drugs and various
antibi-otic and antimicrobial drugs. (See Adverse
reactions to noncorti-costeroid immunosuppressants.)
§ Allopurinol increases the blood levels of
azathioprine.
§ Verapamil increases blood levels of
sirolimus.
§ Voriconazole shouldn’t be given with
sirolimus because the combination inhibits CYP3A4 enzymes, resulting in
increased sirolimus levels.
§ When mycophenolate is taken with antacids or
cholestyramine, mycophenolate levels decrease.
§ Coadministration of mycophenolate with
acyclovir, especially in patients with renal impairment, may increase
concentrations of both drugs.
§ Cyclosporine levels may increase if
cyclosporine is taken with ketoconazole, calcium channel blockers, cimetidine,
anabolic steroids, hormonal contraceptives, erythromycin, or metoclo-pramide.
§ The risk of toxicity to the kidneys increases
when cyclosporine or sirolimus is taken with acyclovir, aminoglycosides, or
ampho-tericin B.
§ Taking anakinra, ATG, basiliximab,
cyclosporine, daclizumab, muromonab-CD3, sirolimus, or thymoglobulin with other
immuno-suppressants (except corticosteroids) increases the risk of infec-tion
and lymphoma (neoplasm of the lymph tissue; typically malig-nant).
§ Barbiturates, rifampin, phenytoin,
sulfonamides, and trimetho-prim decrease plasma cyclosporine and sirolimus
levels.
§ Serum digoxin levels may increase when
cyclosporine is taken with digoxin.
§ Anakinra shouldn’t be given to patients with
active infections or neutropenia.
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