- A combination of two to four immunosuppressive drugs is used to target different levels of the immune cascade to prevent allograft rejection and allow lower doses of the individual agents to minimize their toxicity.
- Calcineurin inhibitors (CNIs), such as cyclosporine and tacrolimus, which inhibit interleukin (IL)-2 and thus block T-cell activation are the backbone of immunosuppressive regimens. However, they are associated with significant adverse effects, namely, nephrotoxicity and neurotoxicity.
- CNI-induced nephrotoxicity is one of the most common side effects observed in transplant recipients and is the leading cause of renal dysfunction in nonrenal transplant patients. Therapeutic drug monitoring is used in an attempt to optimize the use of CNIs.
- Corticosteroids are a key component of immunosuppressive regimens because they block the initial steps in allograft rejection. However, the adverse effects associated with their long-term use have prompted the investigation of corticosteroid-free immunosuppressive protocols. Corticosteroids remain the cornerstone of the treatment of allograft rejection.
- Antimetabolites agents such as azathioprine and mycophenolate inhibit T-cell proliferation by altering purine synthesis to prevent acute rejection. Bone marrow suppression is the most significant adverse effect associated with these agents.
- The proliferation signal inhibitors (PSI) sirolimus and everolimus exert their activity by inhibiting the mammalian target of rapamycin (mTOR) receptor, which alters T-cell response to IL-2. The adverse effects associated with sirolimus include thrombocytopenia, anemia, and hyperlipidemia.
- Antibody preparations that target specific receptors on T cells are classified as depleting or nondepleting. Most lymphocyte-depleting antibodies are associated with significant infusion-related reactions.
- Long-term allograft and patient survival is limited by chronic rejection, cardiovascular disease, and long-term immunosuppressive complications such as malignancy.
On completion of the chapter, the reader will be able to:
Identify major indications for the various types of solid-organ transplants.
Describe the physiologic consequences associated with kidney, liver, and heart transplantation.
Describe the changes in drug metabolism following liver transplantation.
Compare and contrast the pharmacology of cardiovascular medications in patients before and following heart transplantation.
Explain the mechanisms and risk factors associated with the different types of allograft rejection.
Discuss the goals of immunosuppression and the various immunosuppressive strategies utilized.
Compare and contrast the mechanism of the different immunosuppressants.
Describe the pharmacokinetics of the immunosuppressants.
Identify the side effects associated with the different immunosuppressants.
Develop a monitoring plan for transplant recipients receiving immunosuppressants.
Discuss the differences in renal allograft rejection and calcineurin inhibitor toxicity.
Explain the rationale of the major drug interactions with immunosuppressants.
List the factors that limit long-term patient and allograft survival following transplantation.
Describe the most common complications associated with immunosuppression.
Recommend patient-specific drug therapy to reduce morbidity associated with immunosuppression-related complications.
Solid-organ transplantation provides a lifesaving treatment for patients with end-stage cardiac, kidney, liver, lung, and intestinal disease. Over 300 U.S. hospitals offer transplant services, and pharmacists are often an integral part of the transplant team. The Centers for Medicare and Medicaid Services regulations require that transplant programs have a multidisciplinary team including individuals with experience in pharmacology. While ...