Other immunosuppressants

Other immunosuppressants

Several drugs used for their immunosuppressant effects in patients undergoing allograft transplantation (transplantation between two people who aren’t identical twins) are also used experimentally to treat autoimmune diseases (diseases resulting from an inappropriate immune response directed against the self). They include:

• azathioprine
• basiliximab
• cyclosporine
• daclizumab
• lymphocyte immune globulin (ATG [equine])
• muromonab-CD3
• mycophenolate mofetil
• sirolimus
• tacrolimus
• thymoglobulin (antithymocyte globulin [rabbit]).

Also these

Cyclophosphamide, classified as an alkylating drug, is also used as an immunosuppressant; however, it’s primarily used to treat cancer.

Anakinra is an immunosuppressant used to treat adults with moderate to severe active rheumatoid arthritis who haven’t responded to at least one disease-modifying antirheumatic drug.

Pharmacokinetics

Immunosuppressants take different paths through the body.

Absorption

When administered orally, azathioprine and mycophenolate are readily absorbed from the GI tract, whereas absorption of cyclosporine, tacrolimus, and sirolimus is varied and incomplete.

Only I.V.

Anakinra, ATG, basiliximab, daclizumab, muromonab-CD3, and thymoglobulin are administered only by I.V. injection.

Distribution

The distribution of azathioprine, basiliximab, and daclizumab isn’t fully understood. Cyclosporine and muromonab-CD3 are distributed widely throughout the body. Azathioprine and cyclosporine cross the placental barrier. The distribution of ATG isn’t clear, but it may appear in breast milk. Distribution of tacrolimus depends on several factors; 75% to 99% is protein-bound. Sirolimus is 97% protein-bound.

Metabolism and excretion

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 inactive metabolite, which is excreted in urine and bile. Concentrations of mycophenolate and acyclovir may increase in the presence of nephrotoxicity.

Azathioprine, anakinra, and ATG are excreted in urine; cyclosporine 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 cytochrome P-450 (CYP3A4); 91% is excreted in stool and 2.2% in urine. Metabolism and excretion of basiliximab and daclizumab aren’t understood.

Pharmacodynamics

How certain immunosuppressants achieve their desired effects has yet to be determined.

What’s going on here?

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 formation 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.

They do know this much…

In patients receiving kidney allografts, azathioprine suppresses cell-mediated hypersensitivity reactions and produces various alterations 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 interleukin. 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.

Yea or nay?

Cyclosporine: Miracle drug or death sentence?

Organ transplantation can save a life. However, cyclosporine, an immunosuppressant used to reduce the risk of organ rejection, may also cause cancer.

Does cyclosporine encourage cells to become cancerous?

It has long been believed that when the immune system is weakened by immunosuppressants, it loses its ability to fight and kill cancerous cells. Recent research suggests that cyclosporine may also encourage abnormal cells to become cancerous and perhaps even grow aggressively. This research has raised concern about the use of cyclosporine in organ transplantation.

A double-edged sword

However, this concern needs to be balanced against the life-threatening risk of organ rejection. Scientists are now looking for ways to block this tumor-promoting effect of cyclo-sporine.

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.

Pharmacotherapeutics

Immunosuppressants are used mainly to prevent rejection in patients who undergo organ transplantation. 

Drug interactions

Most drug interactions with this class of drugs involve other immunosuppressant and anti-inflammatory drugs and various antibiotic and antimicrobial drugs.

• 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 metoclopramide.
• The risk of toxicity to the kidneys increases when cyclosporine or sirolimus is taken with acyclovir, aminoglycosides, or amphotericin B.
• Taking anakinra, ATG, basiliximab, cyclosporine, daclizumab, muromonab-CD3, sirolimus, or thymoglobulin with other immunosuppressants (except corticosteroids) increases the risk of infection and lymphoma (neoplasm of the lymph tissue; typically malignant).
• Barbiturates, rifampin, phenytoin, sulfonamides, and trimethoprim 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.

Warning!

Adverse reactions to noncorticosteroid immunosuppressants

All noncorticosteroid immunosuppressants can cause hypersensitivity reactions. Here are adverse reactions to individual drugs.

Azathioprine

• Bone marrow suppression
• Nausea and vomiting
• Liver toxicity

Cyclosporine

• Kidney toxicity
• Hyperkalemia
• Infection
• Liver toxicity
• Nausea and vomiting

Daclizumab

• GI disorders
• Hypertension
• Hypotension
• Chest pain
• Tachycardia
• Edema
• Dyspnea
• Pulmonary edema
• Thrombosis
• Bleeding
• Renal tubular necrosis

Lymphocyte immune globulin

• Fever and chills
• Reduced white blood cell (WBC) or platelet count
• Infection
• Nausea and vomiting

Muromonab-CD3

• Fever and chills
• Nausea and vomiting
• Tremor
• Pulmonary edema
• Infection

Mycophenolate mofetil

• Nausea
• Diarrhea
• Leukopenia
• Headache
• Weakness
• Urinary frequency
• Leg cramps or pain
• Liver function test result abnormalities
• Rash

Sirolimus

• Anemia
• Thrombocytopenia
• Hyperlipidemia
• Hypertension

Tacrolimus

• Nausea and vomiting
• Diarrhea
• Constipation
• Tremor
• Leukopenia
• Hypertension
• Nephrotoxicity
• Hepatotoxicity

Thymoglobulin

• Abdominal pain
• Diarrhea
• Dyspnea
• Fever and chills
• Headache
• Infection
• Nausea and vomiting
• Reduced WBC or platelet count
• Systemic infections
• Dizziness