Lippincott Chapter 47: Immunosuppressant Flashcards
SELECTIVE INHIBITORS OF CYTOKINE
PRODUCTION AND FUNCTION
Belatacept NULOJIX
Cyclosporine NEORAL, SANDIMMUNE
Everolimus AFINITOR, ZORTRESS
Sirolimus RAPAMUNE
Tacrolimus PROGRAF
IMMUNOSUPPRESSIVE
ANTIMETABOLITES
Azathioprine IMURAN
Mycophenolate mofetil CELLCEPT
Mycophenolate sodium MYFORTIC
ANTIBODIES
Antithymocyte globulins ATGAM,
THYMOGLOBULIN
Basiliximab SIMULECT
ADRENOCORTICOIDS
Methylprednisolone MEDROL
Prednisolone ORAPRED, PRELONE
Prednisone
SELECTIVE INHIBITORS OF CYTOKINE
PRODUCTION AND FUNCTION
Cyclosporine
Cyclosporine [sye-kloe-SPOR-een], a calcineurin inhibitor, is a lipo-
philic cyclic polypeptide extracted from the soil fungus Beauveria
nivea.
1. Mechanism of action: Cyclosporine preferentially suppresses
cell-mediated immune reactions, whereas humoral immunity is
affected to a far lesser extent. After diffusing into the T cell, cyclo-
sporine binds to a cyclophilin (more generally called an immu-
nophilin) to form a complex that binds to calcineurin (Figure 47.3).
Calcineurin is responsible for dephosphorylating NFATc (cytosolic
Nuclear Factor of Activated T cells). Because the cyclosporine–
calcineurin complex cannot perform this reaction, NFATc cannot
enter the nucleus to promote reactions that are required for the
synthesis of cytokines, including IL-2. The end result is a decrease
in IL-2, which is the primary chemical stimulus for increasing the
number of T lymphocytes.
2. Therapeutic uses: Cyclosporine is used to prevent rejection of
kidney, liver, and cardiac allogeneic transplants and is typically
combined in a double-drug or triple-drug regimen with cortico-
steroids and an antimetabolite such as mycophenolate mofetil.
Cyclosporine may also be used for recalcitrant psoriasis.
3. Pharmacokinetics: Cyclosporine may be given either orally or
by intravenous (IV) infusion. Oral absorption is variable due to
metabolism by a cytochrome P450 (CYP3A4) isoenzyme in the
gastrointestinal (GI) tract and efflux by P-glycoprotein (P-gp),
which limits cyclosporine absorption by pumping the drug back
into the gut lumen. About 50% of the drug is bound to erythrocytes.
Cyclosporine is extensively metabolized, primarily by hepatic
CYP3A4. [Note: When other drug substrates for this enzyme are
given concomitantly, many drug interactions have been reported.]
Excretion of the metabolites is primarily through the biliary route
into the feces.
4. Adverse effects: Many of the adverse effects caused by cyclo-
sporine are dose dependent. Therefore, it is important to monitor
blood levels of the drug. Nephrotoxicity is the most common and
important adverse effect of cyclosporine, and it is critical to monitor
kidney function. Reduction of the cyclosporine dosage can result
in reversal of nephrotoxicity in most cases. [Note: Coadministration
of drugs that also can cause kidney dysfunction, such as amino-
glycosides and nonsteroidal anti-inflammatory drugs, can poten-
tiate the nephrotoxicity of cyclosporine.] Because hepatotoxicity
can also occur, liver function should be periodically assessed. In
patients taking cyclosporine, infections are common and may be
life threatening. Viral infections due to the herpes group and cyto-
megalovirus (CMV) are prevalent. Lymphoma may occur in trans-
planted patients due to the net level of immunosuppression. Other
toxicities include hypertension, hyperlipidemia, hyperkalemia
(K+-sparing diuretics should be avoided in these patients), tremor,
hirsutism, glucose intolerance, and gum hyperplasia.
Tacrolimus
Tacrolimus
Tacrolimus [ta-CRAW-lih-mus], another calcineurin inhibitor, is a mac-
rolide that is isolated from the soil fungus Streptomyces tsukubaensis.
This drug is preferred over cyclosporine because of its increased
potency, decreased episodes of rejection (Figure 47.4), and steroid-
sparing effects, thus reducing the likelihood of steroid-associated
adverse effects.
1. Mechanism of action: Tacrolimus exerts its immunosuppressive
effects in the same manner as cyclosporine, except that it binds
to a different immunophilin, FKBP-12 (FK-binding protein; Figure
47.3), and the complex then binds to calcineurin.
2. Therapeutic uses: Tacrolimus is currently approved for prevent-
ing liver and kidney rejections (along with glucocorticoids). It is
also used in heart and pancreas transplants and rescue therapy
in patients after failure of standard rejection therapy. An ointment
preparation is approved for moderate to severe atopic dermatitis
unresponsive to conventional therapies.
3. Pharmacokinetics: Tacrolimus may be administered orally or IV.
The oral route is preferable, but, as with cyclosporine, oral absorption
of tacrolimus is incomplete and variable, requiring tailoring of doses.
Tacrolimus is subject to gut metabolism by CYP3A4/5 isoenzymes
and is a substrate for P-gp. Together, both of these mechanisms limit
the oral bioavailability of tacrolimus. Absorption is decreased if the
drug is taken with high-fat or high-carbohydrate meals. The drug and
its metabolites are primarily eliminated in the feces.
4. Adverse effects: Nephrotoxicity and neurotoxicity (tremor, sei-
zures, and hallucinations) tend to be more severe with tacrolimus
than with cyclosporine, but careful dose adjustment can minimize
this problem. Development of posttransplant insulin-dependent
diabetes mellitus is a problem, especially in black and Hispanic
patients. Other toxicities are similar to cyclosporine, except that
tacrolimus does not cause hirsutism or gingival hyperplasia, but it
can cause alopecia. Compared with cyclosporine, tacrolimus has
a lower incidence of cardiovascular toxicities, such as hyperten-
sion and hyperlipidemia, both of which are common comorbidi-
ties in kidney transplant recipients. Drug interactions are similar to
cyclosporine.
Continuation blocker
Costimulation blocker
Belatacept [bel-AT-a-sept], a second-generation costimulation blocker,
is a recombinant fusion protein that targets signal 2 in the immune
activation cascade. It is used for long-term maintenance immunosup-
pressive therapy.
1. Mechanism of action: Belatacept blocks CD28-mediated costimu-
lation of T lymphocytes (signal 2) by binding to CD80 and CD86 on
APCs. This prevents the downstream stimulatory signals promoting
T-cell survival, proliferation, and IL-2 production.
2. Therapeutic uses: Belatacept is used in kidney transplanta-
tion in combination with basiliximab, mycophenolate mofetil, and corticosteroids. This drug can take the place of the calcineurin
inhibitors in an effort to avoid the detrimental long-term cardiovas-
cular, metabolic, and renal complications seen with cyclosporine
and tacrolimus. [Note: The first-generation costimulation blocker
abatacept is approved for rheumatoid arthritis.]
3. Pharmacokinetics: Belatacept is the first IV maintenance immu-
nosuppressant and is dosed in two phases. The initial high-dose
phase is administered on a more frequent interval. In the main-
tenance phase, the dose is decreased and administered once
a month. Monthly dosing may be beneficial in patients for whom
medication compliance is an issue. Belatacept clearance is not
affected by age, sex, race, renal, or hepatic function.
4. Adverse effects: Belatacept increases the risk of posttransplant
lymphoproliferative disorder (PTLD), particularly of the central
nervous system. Therefore, it is contraindicated in those patients
who have never been exposed to the Epstein-Barr virus (EBV),
a common cause of PTLD. Serological titers to EBV are typically
obtained to confirm exposure. Common adverse events include
anemia, diarrhea, urinary tract infection, and edema.
Sirolimus
Sirolimus
Sirolimus [sih-ROW-lih-mus] (also known as rapamycin) is a mac-
rolide obtained from fermentations of the soil mold Streptomyces
hygroscopicus.
1. Mechanism of action: Sirolimus binds to the same cytoplasmic
FK-binding protein as tacrolimus, but instead of forming a com-
plex with calcineurin, sirolimus binds to mTOR (a serine/threonine
kinase), interfering with signal 3. [Note: TOR proteins are essential
for many cellular functions, such as cell cycle progression, DNA
repair, and as regulators involved in protein translation.] Binding
of sirolimus to mTOR blocks the progression of activated T cells
from the G1
to the S phase of the cell cycle and, consequently, the
proliferation of these cells (Figure 47.5). Unlike cyclosporine and
tacrolimus, sirolimus does not lower IL-2 production but, rather,
inhibits the cellular response to IL-2.
2. Therapeutic uses: Sirolimus is approved for use in renal trans-
plantation, in combination with cyclosporine and corticosteroids,
thereby allowing lower doses of those medications to be used and
lowering their toxic potential. The combination of sirolimus and
cyclosporine is synergistic because sirolimus works later in the
immune activation cascade. To limit the long-term adverse effects
of cyclosporine, sirolimus is often used in calcineurin inhibitor with-
drawal protocols in patients who remain rejection free during the
first 3 months posttransplant. The antiproliferative action of siroli-
mus is also valuable in cardiology where sirolimus-coated stents
are used to inhibit restenosis of the blood vessels by reducing pro-
liferation of the endothelial cells.
3. Pharmacokinetics: The drug is available as an oral solution or tab-
let. Although it is readily absorbed, high-fat meals can decrease the
absorption. Sirolimus has a long half-life (57 to 62 hours), allowing for once-daily dosing. A loading dose is recommended at the time
of initiation of therapy. Like both cyclosporine and tacrolimus, siro-
limus is metabolized by the CYP3A4 isoenzyme, is a substrate for
P-gp, and has similar drug interactions. Sirolimus also increases
the concentrations of cyclosporine, and careful blood level monitor-
ing of both agents must be done to avoid harmful drug toxicities.
4. Adverse effects: A common adverse effect of sirolimus is hyper-
lipidemia (elevated cholesterol and triglycerides), which may
require treatment. The combination of cyclosporine and sirolimus
is more nephrotoxic than cyclosporine alone due to the drug inter-
action between the two, necessitating lower doses. Other untow-
ard problems are headache, nausea and diarrhea, leukopenia,
and thrombocytopenia. Impaired wound healing has been noted
with sirolimus in obese patients and those with diabetes, which
can be especially problematic immediately following the transplant
surgery and in patients receiving corticosteroids.
Everolimus
E. Everolimus
Everolimus [e-ve-RO-li-mus], another mTOR inhibitor, is approved for
use in renal transplantation. It is also indicated for second-line treat-
ment in patients with advanced renal cell carcinoma.
1. Mechanism of action: Everolimus has the same mechanism of
action as sirolimus. It inhibits activation of T cells by forming a com-
plex with FKBP-12 and subsequently blocking mTOR.
2. Therapeutic uses: Everolimus is used to prevent rejection in kid-
ney transplant recipients in combination with basiliximab, cyclo-
sporine, and corticosteroids.
3. Pharmacokinetics: Everolimus is rapidly absorbed, but absorp-
tion is decreased with high-fat meals. Everolimus is a substrate
of CYP3A4 and P-gp and, thus, is subject to the same drug inter-
actions as previously mentioned. Everolimus avidly binds eryth-
rocytes, and monitoring of whole blood trough concentrations is
recommended. It has a much shorter half-life than sirolimus and
requires twice-daily dosing. Everolimus increases drug concentra-
tions of cyclosporine, thereby enhancing the nephrotoxic effects
of cyclosporine, and is, therefore, recommended to be used with
reduced doses of cyclosporine.
4. Adverse effects: Everolimus has adverse effects similar to
sirolimus. An additional adverse effect noted with everolimus is
angioedema, which may increase with concomitant use of angio-
tensin-converting enzyme inhibitors. There is also an increased
risk of kidney arterial and venous thrombosis, resulting in graft
loss, usually in the first 30 days posttransplantation.
IMMUNOSUPPRESSIVE ANTIMETABOLITES
Azathioprine
Azathioprine [ay-za-THYE-oh-preen] was the first agent to achieve
widespread use in organ transplantation. It is a prodrug that is con-
verted first to 6-mercaptopurine (6-MP) and then to the correspond-
ing nucleotide, thioinosinic acid. The immunosuppressive effects of
azathioprine are due to this nucleotide analog. Because of their rapid
proliferation in the immune response and their dependence on the
de novo synthesis of purines required for cell division, lymphocytes
are predominantly affected by the cytotoxic effects of azathioprine. Its
major nonimmune toxicity is bone marrow suppression. Concomitant
use with angiotensin-converting enzyme inhibitors or cotrimoxazole
in renal transplant patients can lead to an exaggerated leukopenic
response. Allopurinol, an agent used to treat gout, significantly inhib-
its the metabolism of azathioprine. Therefore, the dose of azathio-
prine must be reduced. Nausea and vomiting are also encountered.
(See Chapter 46 for a thorough discussion of 6-MP.)
Mycophenolate mofetil [mye-koe-FEN-oh-late MAW-feh-til] has, for
the most part, replaced azathioprine because of its safety and effi-
cacy in prolonging graft survival. It has been successfully used in
heart, kidney, and liver transplants. As an ester, it is rapidly hydro-
lyzed in the GI tract to mycophenolic acid. This is a potent, reversible,
noncompetitive inhibitor of inosine monophosphate dehydrogenase,
which blocks the de novo formation of guanosine phosphate. Thus,
like 6-MP, it deprives the rapidly proliferating T and B cells of a key
component of nucleic acids (Figure 47.6). [Note: Lymphocytes lack
the salvage pathway for purine synthesis and, therefore, are depen-
dent on de novo purine production.] Mycophenolic acid is quickly and
almost completely absorbed after oral administration. The glucuro-
nide metabolite is excreted predominantly in urine. The most common
adverse effects of mycophenolate mofetil are GI, including diarrhea,
nausea, vomiting, and abdominal pain. High doses of mycophenolate
mofetil are associated with a higher risk of CMV infection. Concomitant
administration with antacids containing magnesium or aluminum, or
with cholestyramine, can decrease absorption of the drug.
Enteric-coated mycophenolate sodium
In an effort to minimize the GI effects associated with mycophenolate
mofetil, enteric-coated mycophenolate sodium is contained within a
delayed-release formulation designed to release in the neutral pH of
the small intestine. This formulation is equivalent to mycophenolate
mofetil in the prevention of acute rejection episodes in kidney trans-
plant recipients. However, the rate of GI adverse events is similar to
that with mycophenolate mofetil.
ANTIBODIES
Antithymocyte globulins
Antithymocyte globulins are polyclonal antibodies that are primarily
used at the time of transplantation to prevent early allograft rejection
along with other immunosuppressive agents. They may also be used
to treat severe rejection episodes or corticosteroid-resistant acute
rejection. The antibodies bind to the surface of circulating T lympho-
cytes, which then undergo various reactions, such as complement-
mediated destruction, antibody-dependent cytotoxicity, apoptosis, and
opsonization. The antibody-bound cells are phagocytosed in the liver
and spleen, resulting in lymphopenia and impaired T-cell responses.
The antibodies are slowly infused intravenously, and their half-life
extends from 3 to 9 days. Because the humoral antibody mechanism
remains active, antibodies can be formed against these foreign pro-
teins. [Note: This is less of a problem with the humanized antibodies.]
Other adverse effects include chills and fever, leukopenia and throm-
bocytopenia, infections due to CMV or other viruses, and skin rashes.
Muromonab-CD3 (OKT3)
Muromonab-CD3 [myoo-roe-MOE-nab] is a murine (mouse) mono-
clonal antibody that is directed against the glycoprotein CD3 anti-
gen of human T cells. Muromonab-CD3 was the first monoclonal antibody approved for clinical use in 1986, indicated for the treatment
of corticosteroid-resistant acute rejection of kidney, heart, and liver
allografts. The drug has been discontinued from the market due to
the availability of newer biologic drugs with similar efficacy and fewer
side effects. antibody approved for clinical use in 1986, indicated for the treatment
of corticosteroid-resistant acute rejection of kidney, heart, and liver
allografts. The drug has been discontinued from the market due to
the availability of newer biologic drugs with similar efficacy and fewer
side effects.
Basiliximab
The antigenicity and short serum half-life of the murine monoclonal
antibody have been averted by replacing most of the murine amino
acid sequences with human ones by genetic engineering. Basiliximab
[bah-si-LIK-si-mab] is said to be “chimerized” because it consists of
25% murine and 75% human protein. [Note: “Humanized” monoclo-
nal antibodies (for example, trastuzumab used for breast cancer; see
Chapter 46) have a smaller stretch of nonhuman protein.] Basiliximab
is approved for prophylaxis of acute rejection in renal transplantation
in combination with cyclosporine and corticosteroids. It is not used for
the treatment of ongoing rejection. Basiliximab is an anti-CD25 anti-
body that binds to the α chain of the IL-2 receptor on activated T cells
and, thus, interferes with the proliferation of these cells. Blockade of
this receptor foils the ability of any antigenic stimulus to activate the
T-cell response system. Basiliximab is given as an IV infusion. The
serum half-life of basiliximab is about 7 days. Usually, two doses of
this drug are administered—the first at 2 hours prior to transplantation
and the second at 4 days after the surgery. The drug is generally well
tolerated, with GI toxicity as the main adverse effect.
A summary of the major immunosuppressive drugs is presented in
Figure 47.7.
CORTICOSTEROIDS
The corticosteroids were the first pharmacologic agents to be used as
immunosuppressives, both in transplantation and in various autoimmune
disorders. They are still one of the mainstays for attenuating rejection epi-
sodes. For transplantation, the most common agents are prednisone and
methylprednisolone, whereas prednisone and prednisolone are used for
autoimmune conditions. [Note: In transplantation, they are used in combi-
nation with agents described previously in this chapter.] The steroids are
used to suppress acute rejection of solid organ allografts and in chronic
graft-versus-host disease. In addition, they are effective against a wide
variety of autoimmune conditions, including refractory rheumatoid arthri-
tis, systemic lupus erythematosus, temporal arthritis, and asthma. The
exact mechanism responsible for the immunosuppressive action of the
corticosteroids is unclear. The T lymphocytes are affected most. The ste-
roids are able to rapidly reduce lymphocyte populations by lysis or redis-
tribution. On entering cells, they bind to the glucocorticoid receptor. The
complex passes into the nucleus and regulates the transcription of DNA.
Among the genes affected are those involved in inflammatory responses.
The use of these agents is associated with numerous adverse effects.
For example, they are diabetogenic and can cause hypercholesterol-
emia, cataracts, osteoporosis, and hypertension with prolonged use.
Consequently, efforts are being directed toward reducing or eliminating
the use of steroids in the maintenance of allograft
