Pharmacology of Immunosuppressants

Introduction

The immune system is a complex network of cells, tissues, and organs that work together to defend the body against foreign invaders, such as bacteria, viruses, and other pathogens. However, in some cases, the immune system can become overactive or misdirected, leading to autoimmune diseases or rejection of transplanted organs. Immunosuppressants are a class of drugs that are used to suppress or modulate the immune system’s response in order to treat these conditions (Katzung & Trevor, 2018).

Mechanism of Action

Immunosuppressants work by interfering with various stages of the immune response. The immune response involves a series of steps, including antigen recognition, T-cell activation, and proliferation, as well as the production of cytokines and antibodies. Different immunosuppressants target different steps in this process (Brunton, Hilal-Dandan, & Knollmann, 2018).

Types of Immunosuppressants

1. Calcineurin Inhibitors

Calcineurin inhibitors, such as cyclosporine and tacrolimus, work by inhibiting the activity of calcineurin, a protein phosphatase that plays a key role in T-cell activation. By blocking calcineurin, these drugs prevent the production of cytokines, such as interleukin-2 (IL-2), which are necessary for T-cell proliferation and differentiation (Whalen, 2019).

Cyclosporine

Cyclosporine is a cyclic polypeptide that binds to cyclophilin, forming a complex that inhibits calcineurin. It is used to prevent rejection in organ transplantation and to treat autoimmune diseases, such as rheumatoid arthritis and psoriasis (Katzung & Trevor, 2018).

Pharmacokinetics

Cyclosporine is administered orally or intravenously. It is extensively metabolized by the liver via the cytochrome P450 3A4 (CYP3A4) enzyme system. The bioavailability of oral cyclosporine is variable and can be affected by food intake and gastrointestinal motility. Cyclosporine has a narrow therapeutic index, and its dosage must be carefully monitored to avoid toxicity (Brunton et al., 2018).

Adverse Effects

Common adverse effects of cyclosporine include nephrotoxicity, hypertension, hyperlipidemia, and neurotoxicity. Cyclosporine can also increase the risk of infections and malignancies, particularly lymphomas (Whalen, 2019).

Drug Interactions

Cyclosporine is a substrate and inhibitor of CYP3A4 and P-glycoprotein (P-gp). Drugs that induce or inhibit CYP3A4 or P-gp can significantly alter cyclosporine concentrations. For example, rifampin, a potent CYP3A4 inducer, can decrease cyclosporine levels, while ketoconazole, a strong CYP3A4 inhibitor, can increase cyclosporine levels. Other drugs that interact with cyclosporine include diltiazem, verapamil, and grapefruit juice (Katzung & Trevor, 2018).

Therapeutic Drug Monitoring

Due to its narrow therapeutic index and variable pharmacokinetics, cyclosporine requires therapeutic drug monitoring (TDM). TDM involves measuring cyclosporine blood concentrations to ensure that they are within the target range. The target trough concentration (C0) for cyclosporine varies depending on the indication and time after transplantation. In general, the target C0 is 150-300 ng/mL for the first 3 months after kidney transplantation and 100-200 ng/mL thereafter (Brunton et al., 2018).

Tacrolimus

Tacrolimus, also known as FK506, is a macrolide antibiotic that binds to the immunophilin FKBP12, forming a complex that inhibits calcineurin. Like cyclosporine, it is used to prevent organ rejection and treat autoimmune diseases (Katzung & Trevor, 2018).

Pharmacokinetics

Tacrolimus is administered orally or intravenously. It is metabolized by the liver via the CYP3A4 enzyme system. Tacrolimus has a narrow therapeutic index and requires careful monitoring of blood levels to avoid toxicity (Brunton et al., 2018).

Adverse Effects

The adverse effects of tacrolimus are similar to those of cyclosporine, including nephrotoxicity, neurotoxicity, and increased risk of infections and malignancies. Tacrolimus may also cause diabetes mellitus and hyperkalemia (Whalen, 2019).

Drug Interactions

Like cyclosporine, tacrolimus is a substrate and inhibitor of CYP3A4 and P-gp. Drugs that induce or inhibit these enzymes can significantly alter tacrolimus concentrations. Examples of drugs that interact with tacrolimus include rifampin, ketoconazole, diltiazem, and grapefruit juice (Katzung & Trevor, 2018).

Therapeutic Drug Monitoring

Tacrolimus also requires TDM to ensure that blood concentrations are within the target range. The target trough concentration (C0) for tacrolimus varies depending on the indication and time after transplantation. In general, the target C0 is 10-15 ng/mL for the first 3 months after kidney transplantation and 5-10 ng/mL thereafter (Brunton et al., 2018).

2. Antiproliferative Agents

Antiproliferative agents, such as azathioprine and mycophenolate mofetil, work by inhibiting the synthesis of purines or pyrimidines, which are essential for DNA and RNA synthesis. By blocking the proliferation of lymphocytes, these drugs reduce the immune response (Katzung & Trevor, 2018).

Azathioprine

Azathioprine is a prodrug that is converted to 6-mercaptopurine (6-MP) in the body. 6-MP is then metabolized to thioinosinic acid, which inhibits the synthesis of purines. Azathioprine is used to prevent organ rejection and treat autoimmune diseases, such as rheumatoid arthritis and inflammatory bowel disease (Brunton et al., 2018).

Pharmacokinetics

Azathioprine is administered orally. It is rapidly absorbed and converted to 6-MP in the liver. The half-life of azathioprine is approximately 5 hours, while the half-life of 6-MP is 1-2 hours (Whalen, 2019).

Adverse Effects

Common adverse effects of azathioprine include bone marrow suppression, gastrointestinal disturbances, and increased risk of infections. Azathioprine can also cause hepatotoxicity and pancreatitis. Long-term use of azathioprine may increase the risk of malignancies, particularly lymphomas and skin cancers (Katzung & Trevor, 2018).

Drug Interactions

Azathioprine is metabolized by the enzyme thiopurine methyltransferase (TPMT). Patients with low or absent TPMT activity are at increased risk of azathioprine toxicity. Drugs that inhibit TPMT, such as olsalazine and mesalamine, can increase the risk of azathioprine toxicity. Allopurinol, a xanthine oxidase inhibitor, can also increase the risk of azathioprine toxicity by inhibiting the metabolism of 6-MP (Brunton et al., 2018).

Therapeutic Drug Monitoring

TDM is not routinely performed for azathioprine. However, monitoring of complete blood count (CBC) and liver function tests (LFTs) is recommended to detect bone marrow suppression and hepatotoxicity. TPMT genotyping or phenotyping can be performed before starting azathioprine therapy to identify patients at risk for toxicity (Whalen, 2019).

Mycophenolate Mofetil

Mycophenolate mofetil is an ester prodrug that is rapidly hydrolyzed to mycophenolic acid (MPA) in the body. MPA inhibits inosine monophosphate dehydrogenase (IMPDH), an enzyme essential for the de novo synthesis of guanosine nucleotides. By depleting guanosine nucleotides, MPA inhibits the proliferation of T- and B-lymphocytes (Brunton et al., 2018).

Pharmacokinetics

Mycophenolate mofetil is administered orally. It is rapidly absorbed and hydrolyzed to MPA in the liver. The bioavailability of MPA is approximately 95%. MPA undergoes enterohepatic recirculation, which prolongs its half-life to 16-18 hours (Whalen, 2019).

Adverse Effects

The most common adverse effects of mycophenolate mofetil are gastrointestinal disturbances, such as diarrhea, nausea, and vomiting. Mycophenolate mofetil can also cause bone marrow suppression, leading to anemia, leukopenia, and thrombocytopenia. Other adverse effects include increased risk of infections, particularly cytomegalovirus (CMV) and BK virus infections (Katzung & Trevor, 2018).

Drug Interactions

Mycophenolate mofetil is not significantly metabolized by the cytochrome P450 enzyme system. However, it is a substrate for the multidrug resistance-associated protein 2 (MRP2) transporter. Drugs that inhibit MRP2, such as cyclosporine and rifampin, can increase MPA concentrations. Antacids and bile acid sequestrants can decrease MPA absorption (Brunton et al., 2018).

Therapeutic Drug Monitoring

TDM is not routinely performed for mycophenolate mofetil. However, monitoring of CBC is recommended to detect bone marrow suppression. In some cases, such as in patients with high-risk transplants or those experiencing adverse effects, MPA concentration monitoring may be considered (Whalen, 2019).

3. mTOR Inhibitors

Mammalian target of rapamycin (mTOR) inhibitors, such as sirolimus and everolimus, work by binding to the immunophilin FKBP12, forming a complex that inhibits mTOR. mTOR is a serine/threonine kinase that regulates cell growth, proliferation, and survival. By inhibiting mTOR, these drugs reduce the proliferation and differentiation of T-cells (Brunton et al., 2018).

Sirolimus

Sirolimus, also known as rapamycin, is a macrocyclic lactone that binds to FKBP12, forming a complex that inhibits mTOR. It is used to prevent organ rejection, particularly in kidney transplantation (Whalen, 2019).

Pharmacokinetics

Sirolimus is administered orally. It is extensively metabolized by the liver via the CYP3A4 enzyme system. The bioavailability of sirolimus is low and variable, ranging from 10-20%. Sirolimus has a long half-life of approximately 60 hours (Katzung & Trevor, 2018).

Adverse Effects

Common adverse effects of sirolimus include hyperlipidemia, thrombocytopenia, and impaired wound healing. Sirolimus can also cause interstitial lung disease, which may be life-threatening. Other adverse effects include increased risk of infections and malignancies (Brunton et al., 2018).

Drug Interactions

Sirolimus is a substrate and inhibitor of CYP3A4 and P-gp. Drugs that induce or inhibit these enzymes can significantly alter sirolimus concentrations. Examples of drugs that interact with sirolimus include rifampin, ketoconazole, diltiazem, and grapefruit juice (Katzung & Trevor, 2018).

Therapeutic Drug Monitoring

TDM is essential for sirolimus due to its narrow therapeutic index and variable pharmacokinetics. The target trough concentration (C0) for sirolimus varies depending on the indication and time after transplantation. In general, the target C0 is 5-15 ng/mL for the first 2-4 months after kidney transplantation and 5-10 ng/mL thereafter (Brunton et al., 2018).

Everolimus

Everolimus is a derivative of sirolimus that also binds to FKBP12 and inhibits mTOR. It is used to prevent organ rejection and treat certain types of cancer, such as advanced renal cell carcinoma and neuroendocrine tumors (Whalen, 2019).

Pharmacokinetics

Everolimus is administered orally. Like sirolimus, it is metabolized by the liver via the CYP3A4 enzyme system. The bioavailability of everolimus is approximately 16%. Everolimus has a shorter half-life than sirolimus, ranging from 18-35 hours (Katzung & Trevor, 2018).

Adverse Effects

The adverse effects of everolimus are similar to those of sirolimus, including hyperlipidemia, thrombocytopenia, and impaired wound healing. Everolimus may also cause stomatitis, pneumonitis, and increased risk of infections (Brunton et al., 2018).

Drug Interactions

Everolimus is a substrate and inhibitor of CYP3A4 and P-gp, similar to sirolimus. Drugs that induce or inhibit these enzymes can significantly alter everolimus concentrations (Whalen, 2019).

Therapeutic Drug Monitoring

TDM is also essential for everolimus due to its narrow therapeutic index. The target trough concentration (C0) for everolimus varies depending on the indication. For kidney transplantation, the target C0 is 3-8 ng/mL (Brunton et al., 2018).

4. Glucocorticoids

Glucocorticoids, such as prednisone and methylprednisolone, are synthetic analogs of cortisol that have potent anti-inflammatory and immunosuppressive effects. They work by binding to the glucocorticoid receptor, which then translocates to the nucleus and regulates the transcription of various genes involved in the immune response (Whalen, 2019).

Mechanism of Action

Glucocorticoids exert their immunosuppressive effects through several mechanisms, including:

1. Inhibition of cytokine production: Glucocorticoids inhibit the transcription of genes encoding pro-inflammatory cytokines, such as IL-1, IL-6, and TNF-α.
2. Inhibition of leukocyte migration: Glucocorticoids reduce the expression of adhesion molecules on endothelial cells, preventing leukocyte migration to sites of inflammation.
3. Induction of apoptosis: Glucocorticoids induce apoptosis in lymphocytes, particularly T-cells, leading to a reduction in the immune response (Katzung & Trevor, 2018).

Pharmacokinetics

Glucocorticoids are administered orally, intravenously, or topically. They are metabolized by the liver and have variable half-lives, ranging from a few hours to several days, depending on the specific drug and formulation (Brunton et al., 2018).

Adverse Effects

The adverse effects of glucocorticoids are related to their dose and duration of use. Short-term adverse effects include hyperglycemia, hypertension, and electrolyte disturbances. Long-term adverse effects include osteoporosis, cataracts, glaucoma, and increased risk of infections. Glucocorticoids can also cause Cushing’s syndrome, characterized by weight gain, moon face, and central obesity (Whalen, 2019).

Drug Interactions

Glucocorticoids are substrates and inducers of CYP3A4. Drugs that inhibit CYP3A4, such as ketoconazole and ritonavir, can increase glucocorticoid concentrations. Conversely, glucocorticoids can induce the metabolism of other drugs metabolized by CYP3A4, such as cyclosporine and tacrolimus, leading to decreased concentrations of these drugs (Katzung & Trevor, 2018).

Therapeutic Drug Monitoring

TDM is not routinely performed for glucocorticoids. However, monitoring for adverse effects, such as hyperglycemia, hypertension, and electrolyte disturbances, is recommended (Brunton et al., 2018).

5. Biological Agents

Biological agents are a newer class of immunosuppressants that target specific components of the immune system. They include monoclonal antibodies, fusion proteins, and small molecules that inhibit cytokines, cell surface receptors, or signaling pathways involved in the immune response (Katzung & Trevor, 2018).

Examples of biological agents used as immunosuppressants include

1. Tumor necrosis factor (TNF) inhibitors: Infliximab, adalimumab, and etanercept
2. Interleukin-2 receptor (IL-2R) antagonists: Basiliximab and daclizumab
3. B-cell depleting agents: Rituximab and belimumab
4. Janus kinase (JAK) inhibitors: Tofacitinib and baricitinib (Brunton et al., 2018)

Mechanism of Action

Biological agents have diverse mechanisms of action, depending on their specific targets. For example, TNF inhibitors bind to and neutralize TNF-α, a pro-inflammatory cytokine involved in the pathogenesis of various autoimmune diseases. IL-2R antagonists block the binding of IL-2 to its receptor, preventing the activation and proliferation of T-cells (Whalen, 2019).

Pharmacokinetics

Biological agents are administered parenterally, either intravenously or subcutaneously. They have long half-lives, ranging from several days to weeks, allowing for less frequent dosing compared to other immunosuppressants (Katzung & Trevor, 2018).

Adverse Effects

The adverse effects of biological agents are primarily related to their immunosuppressive effects, including increased risk of infections, particularly opportunistic infections such as tuberculosis and fungal infections. Some biological agents may also increase the risk of malignancies, especially lymphomas. Other adverse effects vary depending on the specific agent and may include injection site reactions, infusion reactions, and autoimmune phenomena (Brunton et al., 2018).

Drug Interactions

Biological agents are not significantly metabolized by the cytochrome P450 enzyme system and have limited drug interactions compared to other immunosuppressants. However, they may interact with other immunosuppressants or immunomodulatory agents, potentially increasing the risk of infections or other adverse effects (Whalen, 2019).

Therapeutic Drug Monitoring

TDM is not routinely performed for biological agents. However, monitoring for adverse effects, particularly infections and malignancies, is essential (Katzung & Trevor, 2018).

Immunosuppressant Therapy in Specific Conditions

Solid Organ Transplantation

Immunosuppressants are the cornerstone of therapy in solid organ transplantation, preventing rejection and ensuring graft survival. The choice of immunosuppressants depends on the type of organ transplanted, the time after transplantation, and the patient’s risk factors for rejection and adverse effects (Brunton et al., 2018).

Induction Therapy

Induction therapy refers to the use of high-dose immunosuppressants immediately after transplantation to prevent acute rejection. Agents used for induction therapy include:

1. IL-2R antagonists (basiliximab and daclizumab)
2. Lymphocyte-depleting agents (antithymocyte globulin and alemtuzumab)
3. High-dose glucocorticoids (methylprednisolone) (Whalen, 2019)

Maintenance Therapy

Maintenance therapy involves the long-term use of immunosuppressants to prevent chronic rejection and maintain graft function. The most common maintenance regimens include a combination of:

1. Calcineurin inhibitor (cyclosporine or tacrolimus)
2. Antiproliferative agent (mycophenolate mofetil or azathioprine)
3. Glucocorticoid (prednisone) (Katzung & Trevor, 2018)

mTOR inhibitors (sirolimus and everolimus) may be used as alternatives to calcineurin inhibitors or antiproliferative agents in some cases, particularly in patients with calcineurin inhibitor toxicity or high risk of malignancy (Brunton et al., 2018).

Autoimmune Diseases

Immunosuppressants are used to treat various autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus (SLE), and inflammatory bowel disease (IBD). The choice of immunosuppressants depends on the specific disease, its severity, and the patient’s response to previous therapies (Whalen, 2019).

Rheumatoid Arthritis

The treatment of rheumatoid arthritis typically involves a combination of:

1. Glucocorticoids (prednisone)
2. Conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), such as methotrexate, leflunomide, and sulfasalazine
3. Biological DMARDs (bDMARDs), such as TNF inhibitors (infliximab, adalimumab, and etanercept), IL-6 inhibitors (tocilizumab and sarilumab), and T-cell costimulation modulator (abatacept)
4. Targeted synthetic DMARDs (tsDMARDs), such as JAK inhibitors (tofacitinib and baricitinib) (Katzung & Trevor, 2018)

Systemic Lupus Erythematosus (SLE)

The treatment of SLE often includes:

1. Glucocorticoids (prednisone)
2. Antimalarials (hydroxychloroquine)
3. Immunosuppressants, such as mycophenolate mofetil, azathioprine, and cyclophosphamide
4. Biological agents, such as belimumab (a B-cell activating factor inhibitor) (Brunton et al., 2018)

Inflammatory Bowel Disease

The treatment of IBD, including Crohn’s disease and ulcerative colitis, may involve:

1. Glucocorticoids (prednisone and budesonide)
2. Immunosuppressants, such as azathioprine, 6-mercaptopurine, and methotrexate
3. Biological agents, such as TNF inhibitors (infliximab, adalimumab, and certolizumab pegol), integrin inhibitors (vedolizumab and natalizumab), and IL-12/23 inhibitor (ustekinumab) (Whalen, 2019)
4. Hematologic Malignancies Immunosuppressants are used in the treatment of various hematologic malignancies, particularly in the context of hematopoietic stem cell transplantation (HSCT). The goal of immunosuppression in HSCT is to prevent graft-versus-host disease (GVHD), a condition in which the donor’s immune cells attack the recipient’s tissues (Katzung & Trevor, 2018).

Prophylaxis and Treatment of GVHD

The prevention and treatment of GVHD often involve:

1. Calcineurin inhibitors (cyclosporine and tacrolimus)
2. Methotrexate
3. Mycophenolate mofetil
4. Glucocorticoids (prednisone and methylprednisolone)
5. Antithymocyte globulin
6. Biological agents, such as TNF inhibitors (etanercept and infliximab) and IL-2R antagonists (basiliximab and daclizumab) (Brunton et al., 2018)

Conclusion

Immunosuppressants are a diverse group of drugs that are used to suppress or modulate the immune system’s response in order to treat autoimmune diseases, prevent organ rejection, and manage hematologic malignancies. They include calcineurin inhibitors, antiproliferative agents, mTOR inhibitors, glucocorticoids, and biological agents. Each class of immunosuppressants has a unique mechanism of action, pharmacokinetics, and adverse effect profile. The choice of immunosuppressant depends on the specific condition being treated, the patient’s comorbidities, and the potential for drug interactions. Careful monitoring of immunosuppressant therapy is essential to optimize efficacy and minimize toxicity.

As our understanding of the immune system and the pathogenesis of immune-mediated diseases continues to expand, new immunosuppressants and immunomodulatory agents are being developed. These include small molecules targeting specific signalling pathways, such as JAK inhibitors and sphingosine 1-phosphate receptor modulators, as well as novel biological agents targeting various cytokines and cell surface receptors. The future of immunosuppressant therapy lies in the development of more targeted and personalized approaches that can effectively control the immune response while minimizing adverse effects and long-term complications.

References

Brunton, L. L., Hilal-Dandan, R., & Knollmann, B. C. (2018). Goodman & Gilman’s: The Pharmacological Basis of Therapeutics (13th ed.). McGraw-Hill Education.

Katzung, B. G., & Trevor, A. J. (2018). Basic & Clinical Pharmacology (14th ed.). McGraw-Hill Education.

Whalen, K. (2019). Lippincott Illustrated Reviews: Pharmacology (7th ed.). Wolters Kluwer.