NCLEX: Immunosuppressants

The importance of the immune system in protecting the body against harmful foreign molecules is well recognized. However, in the case of organ transplantation, the immune system can elicit a damaging immune response, causing rejection of the transplanted tissue. Transplantation of organs and tissues (for example, kidney, heart, or bone marrow) has become routine due to improved surgical techniques and better tissue typing. Also, drugs are now available that more selectively inhibit rejection of transplanted tissues while preventing the patient from becoming immunologically compromised. Earlier drugs were nonselective, and patients frequently succumbed to infection due to suppression of both the antibody-mediated (humoral) and cell-mediated arms of the immune system. Today, the principal approach to immunosuppressive therapy is to alter lymphocyte function using drugs or antibodies against immune proteins. Because of their severe toxicities when used as monotherapy, a combination of immunosuppressive agents, usually at lower doses, is generally employed. Immunosuppressive drug regimens usually consist of anywhere from two to four agents with different mechanisms of action that disrupt various levels of T-cell activation. [Note: Although this chapter focuses on immunosuppressive agents in the context of organ transplantation, these agents may be used in the treatment of other disorders. For example, cyclosporine may be useful in the treatment of psoriasis, and various monoclonal antibodies have applications in a number of disorders, including rheumatoid arthritis, multiple sclerosis, Crohn disease, and ulcerative colitis.]

The immune activation cascade can be described as a three-signal model. Signal 1 constitutes T-cell triggering at the CD3 receptor complex by an antigen on the surface of an antigen-presenting cell (APC). Signal 1 alone is insufficient for T-cell activation and requires signal 2. Signal 2, also referred to as costimulation, occurs when CD80 and CD86 on the surface of APCs engage CD28 on T cells. Both signals 1 and 2 activate several intracellular signal transduction pathways, one of which is the calcium–calcineurin pathway. These pathways trigger the production of cytokines such as interleukin (IL)-2 and T-cell dependent activation of B lymphocytes. IL-2 then binds to the IL-2 receptor (also known as CD25) on the surface of other T cells to activate mammalian target of rapamycin (mTOR), providing signal 3, the stimulus for T-cell proliferation. Immunosuppressive drugs can be categorized by their mechanism of action: 1) interference with cytokine production or action; 2) disruption of cell metabolism, preventing lymphocyte proliferation; and 3) mono- and polyclonal antibodies that block T-cell surface molecules.



Focus topic: Immunosuppressants

Cytokines are soluble, antigen-nonspecific signaling proteins that bind to cell surface receptors on a variety of cells. The term cytokine includes interleukins (ILs), interferons (IFNs), tumor necrosis factors (TNFs), transforming growth factors, and colony-stimulating factors. Of particular interest is IL-2, a growth factor that stimulates the proliferation of antigen-primed (helper) T cells, which subsequently produce more IL-2, IFN-γ, and TNF-α. These cytokines collectively activate natural killer cells, macrophages, and cytotoxic T lymphocytes. Drugs that interfere with the production or activity of IL-2 significantly dampen the immune response and, thereby, decrease graft rejection. These drugs can be further divided into three main classes: 1) calcineurin inhibitors (cyclosporine and tacrolimus), 2) costimulation blockers (belatacept), and 3) mTOR inhibitors (sirolimus and everolimus).


A. Cyclosporine

Cyclosporine [sye-kloe-SPOR-een], a calcineurin inhibitor, is a lipophilic cyclic polypeptide extracted from the soil fungus Beauveria nivea.

  • 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, cyclosporine binds to a cyclophilin (more generally called an immunophilin) to form a complex that binds to calcineurin. 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.
  • 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 corticosteroids and an antimetabolite such as mycophenolate mofetil. Cyclosporine may also be used for recalcitrant psoriasis.
  • 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.
  • Adverse effects: Many of the adverse effects caused by cyclosporine 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 aminoglycosides and nonsteroidal anti-inflammatory drugs, can potentiate 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 cytomegalovirus (CMV) are prevalent. Lymphoma may occur in transplanted 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.


B. Tacrolimus

Tacrolimus [ta-CRAW-lih-mus], another calcineurin inhibitor, is a macrolide that is isolated from the soil fungus Streptomyces tsukubaensis. This drug is preferred over cyclosporine because of its increased potency, decreased episodes of rejection, and steroidsparing effects, thus reducing the likelihood of steroid-associated adverse effects.

  • 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;
  • Therapeutic uses: Tacrolimus is currently approved for preventing 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.
  • 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.
  • Adverse effects: Nephrotoxicity and neurotoxicity (tremor, seizures, 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 hypertension and hyperlipidemia, both of which are common comorbidities in kidney transplant recipients. Drug interactions are similar to cyclosporine.


C. 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 immunosuppressive therapy.

  • Mechanism of action: Belatacept blocks CD28-mediated costimulation 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.
  • Therapeutic uses: Belatacept is used in kidney transplantation 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 cardiovascular, metabolic, and renal complications seen with cyclosporine and tacrolimus. [Note: The first-generation costimulation blocker abatacept is approved for rheumatoid arthritis.]
  • Pharmacokinetics: Belatacept is the first IV maintenance immunosuppressant and is dosed in two phases. The initial high-dose phase is administered on a more frequent interval. In the maintenance 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.
  • 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.

D. Sirolimus

Sirolimus [sih-ROW-lih-mus] (also known as rapamycin) is a macrolide obtained from fermentations of the soil mold Streptomyces hygroscopicus.

  • Mechanism of action: Sirolimus binds to the same cytoplasmic FK-binding protein as tacrolimus, but instead of forming a complex 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. Unlike cyclosporine and tacrolimus, sirolimus does not lower IL-2 production but, rather, inhibits the cellular response to IL-2.
  • Therapeutic uses: Sirolimus is approved for use in renal transplantation, 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 withdrawal protocols in patients who remain rejection free during the first 3 months posttransplant. The antiproliferative action of sirolimus is also valuable in cardiology where sirolimus-coated stents are used to inhibit restenosis of the blood vessels by reducing proliferation of the endothelial cells.
  • Pharmacokinetics: The drug is available as an oral solution or tablet. 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, sirolimus 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 monitoring of both agents must be done to avoid harmful drug toxicities.
  • Adverse effects: A common adverse effect of sirolimus is hyperlipidemia (elevated cholesterol and triglycerides), which may require treatment. The combination of cyclosporine and sirolimus is more nephrotoxic than cyclosporine alone due to the drug interaction between the two, necessitating lower doses. Other untoward 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.


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 treatment
in patients with advanced renal cell carcinoma.

  • Mechanism of action: Everolimus has the same mechanism of action as sirolimus. It inhibits activation of T cells by forming a complex with FKBP-12 and subsequently blocking mTOR.
  • Therapeutic uses: Everolimus is used to prevent rejection in kidney transplant recipients in combination with basiliximab, cyclosporine, and corticosteroids.
  • Pharmacokinetics: Everolimus is rapidly absorbed, but absorption is decreased with high-fat meals. Everolimus is a substrate of CYP3A4 and P-gp and, thus, is subject to the same drug interactions as previously mentioned. Everolimus avidly binds erythrocytes, 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 concentrations of cyclosporine, thereby enhancing the nephrotoxic effects of cyclosporine, and is, therefore, recommended to be used with reduced doses of cyclosporine.
  • 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 angiotensin- 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.


Focus topic: Immunosuppressants

Immunosuppressive antimetabolite agents are generally used in combination with corticosteroids and the calcineurin inhibitors, cyclosporine and tacrolimus.

A. Azathioprine

Azathioprine [ay-za-THYE-oh-preen] was the first agent to achieve widespread use in organ transplantation. It is a prodrug that is converted first to 6-mercaptopurine (6-MP) and then to the corresponding 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 inhibits the metabolism of azathioprine. Therefore, the dose of azathioprine must be reduced. Nausea and vomiting are also encountered.

B. Mycophenolate mofetil

Mycophenolate mofetil [mye-koe-FEN-oh-late MAW-feh-til] has, for the most part, replaced azathioprine because of its safety and efficacy in prolonging graft survival. It has been successfully used in heart, kidney, and liver transplants. As an ester, it is rapidly hydrolyzed 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. [Note: Lymphocytes lack the salvage pathway for purine synthesis and, therefore, are dependent on de novo purine production.] Mycophenolic acid is quickly and almost completely absorbed after oral administration. The glucuronide 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.


C. 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 transplant recipients. However, the rate of GI adverse events is similar to that with mycophenolate mofetil.


Focus topic: Immunosuppressants

The use of antibodies plays a central role in prolonging allograft survival. [Note: An allograft is transplant of an organ or tissue from one person to another who is not genetically identical.] They are prepared by immunization of either rabbits or horses with human lymphoid cells (producing a mixture of polyclonal antibodies or monoclonal antibodies) or by hybridoma technology (producing antigen-specific monoclonal antibodies). Hybridomas are produced by fusing mouse antibody-producing cells with tumor cells. Hybrid cells are selected and cloned, and the antibody specificity of the clones is determined. Clones of interest can be cultured in large quantities to produce clinically useful amounts of the desired antibody. Recombinant DNA technology can also be used to replace part of the mouse gene sequence with human genetic material, thus “humanizing” the antibodies and making them less antigenic. The names of monoclonal antibodies conventionally contain “xi” or “zu” if they are chimerized or humanized, respectively. The suffix “-mab” (monoclonal antibody) identifies the category of drug. The polyclonal antibodies, although relatively inexpensive to produce, are variable and less specific, which is in contrast to monoclonal antibodies, which are homogeneous and specific.

A. 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 lymphocytes, which then undergo various reactions, such as complementmediated 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 proteins. [Note: This is less of a problem with the humanized antibodies.] Other adverse effects include chills and fever, leukopenia and thrombocytopenia, infections due to CMV or other viruses, and skin rashes.

B. Muromonab-CD3 (OKT3)

Muromonab-CD3 [myoo-roe-MOE-nab] is a murine (mouse) monoclonal antibody that is directed against the glycoprotein CD3 antigen 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.

C. 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” monoclonal antibodies (for example, trastuzumab used for breast cancer;] 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 antibody 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.

Immunosuppressants: CORTICOSTEROIDS

Focus topic: Immunosuppressants

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 episodes. 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 combination 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 arthritis, 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 steroids are able to rapidly reduce lymphocyte populations by lysis or redistribution. 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 hypercholesterolemia, cataracts, osteoporosis, and hypertension with prolonged use. Consequently, efforts are being directed toward reducing or eliminating the use of steroids in the maintenance of allografts.




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