DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

component in whole blood and contributes >90% of the immunosuppressive
effect. The blood t 1/2
after multiple doses in stable renal
transplant patients is 62 hours (Zimmerman and Kahan, 1997). A
loading dose of three times the maintenance dose will provide nearly
steady-state concentrations within 1 day in most patients.
Therapeutic Uses. Sirolimus is indicated for prophylaxis
of organ transplant rejection usually in combination with
a reduced dose of calcineurin inhibitor and glucocorticoids.
In patients experiencing or at high risk for calcineurin
inhibitor–associated nephrotoxicity, sirolimus
has been used with glucocorticoids and mycophenolate
to avoid permanent renal damage. Sirolimus dosing regimens
are relatively complex with blood levels generally
targeted between 5-15 ng/mL. It is recommended
that the daily maintenance dose be reduced by approximately
one-third in patients with hepatic impairment
(Watson et al., 1999). Sirolimus also has been incorporated
into stents to inhibit local cell proliferation and
blood vessel occlusion.
Toxicity. The use of sirolimus in renal transplant patients is associated
with a dose-dependent increase in serum cholesterol and triglycerides
that may require treatment. Although immunotherapy with
sirolimus per se is not nephrotoxic, patients treated with
cyclosporine plus sirolimus have impaired renal function compared
to patients treated with cyclosporine and either azathioprine or
placebo. Sirolimus also may prolong delayed graft function in
deceased donor kidney transplants, presumably because of its antiproliferative
action (Smith et al., 2003). Renal function therefore
must be monitored closely in such patients. Lymphocele, a known
surgical complication associated with renal transplantation, is
increased in a dose-dependent fashion by sirolimus, requiring close
postoperative follow-up. Other adverse effects include anemia,
leukopenia, thrombocytopenia, mouth ulcer, hypokalemia, proteinuria,
and GI effects. Delayed wound healing may occur with
sirolimus use. As with other immunosuppressive agents, there is an
increased risk of neoplasms, especially lymphomas, and infections.
Sirolimus is not recommended in liver and lung transplants due to
the risk of hepatic artery thrombosis and bronchial anastomotic
dehiscence, respectively.
Drug Interactions. Because sirolimus is a substrate for CYP3A4 and
is transported by P-glycoprotein, close attention to interactions with
other drugs that are metabolized or transported by these proteins is
required. As noted above, cyclosporine and sirolimus interact, and
their administration should be separated by time. Dose adjustment
may be required when sirolimus is co-administered with diltiazem or
rifampin. Dose adjustment apparently is not required when sirolimus
is co-administered with acyclovir, digoxin, glyburide, nifedipine,
norgestrel/ethinyl estradiol, prednisolone, or trimethoprim–
sulfamethoxazole. This list is incomplete, and blood levels and
potential drug interactions must be monitored closely.
Everolimus
Everolimus [40-O-(2-hydroxyethyl)-rapamycin] is
closely related chemically and clinically to sirolimus but
has distinct pharmacokinetics. The main difference is a
shorter t 1/2
and thus a shorter time to achieve steady-state
concentrations of the drug. Dosage on a milligram per
kilogram basis is similar to that of sirolimus. Aside from
the shorter t 1/2
, no studies have compared everolimus with
sirolimus in standard immunosuppressive regimens
(Eisen et al., 2003). As with sirolimus, the combination of
a calcineurin inhibitor and an mTOR inhibitor produces
worse renal function at 1 year than does calcineurin
inhibitor therapy alone, suggesting a drug interaction
between the mTOR inhibitors and the calcineurin
inhibitors that enhances toxicity and reduces rejection.
The toxicity of everolimus and the drug interactions
reported to date seem to be the same as with sirolimus.
Azathioprine
Azathioprine (IMURAN, others) is a purine antimetabolite.
It is an imidazolyl derivative of 6-mercaptopurine
(see Figure 61–11).
Mechanism of Action. Following exposure to nucleophiles such as
glutathione, azathioprine is cleaved to 6-mercaptopurine, which in
turn is converted to additional metabolites that inhibit de novo purine
synthesis (Chapter 61). A fraudulent nucleotide, 6-thio-IMP, is converted
to 6-thio-GMP and finally to 6-thio-GTP, which is incorporated
into DNA. Cell proliferation thereby is inhibited, impairing a
variety of lymphocyte functions. Azathioprine appears to be a more
potent immunosuppressive agent than 6-mercaptopurine, which may
reflect differences in drug uptake or pharmacokinetic differences in
the resulting metabolites.
Disposition and Pharmacokinetics. Azathioprine is well absorbed
orally and reaches maximum blood levels within 1-2 hours after
administration. The t 1/2
of azathioprine is ~10 minutes, while that of
its metabolite, 6-mercaptopurine, is ~1 hour. Other metabolites have
a t 1/2
of up to 5 hours. Blood levels have limited predictive value
because of extensive metabolism, significant activity of many different
metabolites, and high tissue levels attained. Azathioprine and
mercaptopurine are moderately bound to plasma proteins and are
partially dialyzable. Both are rapidly removed from the blood by
oxidation or methylation in the liver and/or erythrocytes. Renal clearance
has little impact on biological effectiveness or toxicity.
Therapeutic Uses. Azathioprine was first introduced as an
immunosuppressive agent in 1961, helping to make allogeneic
kidney transplantation possible. It is indicated as
an adjunct for prevention of organ transplant rejection
and in severe rheumatoid arthritis. Although the dose of
azathioprine required to prevent organ rejection and
minimize toxicity varies, 3-5 mg/kg/day is the usual
starting dose. Lower initial doses (1 mg/kg/day) are used
in treating rheumatoid arthritis. Complete blood count
and liver function tests should be monitored.
Toxicity. The major side effect of azathioprine is bone marrow suppression,
including leukopenia (common), thrombocytopenia (less
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CHAPTER 35
IMMUNOSUPPRESSANTS, TOLEROGENS, AND IMMUNOSTIMULANTS