Chapter 183: Immunosuppressive and Antirejection Drugs

CONCEPTS OF IMMUNOSUPPRESSION

Patients who receive organ transplants from a donor who is genetically different must receive immunosuppressive drug therapy to prevent or treat rejection of the transplanted organ. These agents dampen the immune response triggered by the foreign antigen. Graft rejection reactions are classified according to the time course after transplantation: within the first 24 hours (hyperacute), in the first few weeks (acute), or months to years later (chronic).

Immunosuppressive therapy consists of three phases:

1. Induction: the set of drugs administered prior to transplantation

2. Maintenance: a combination of drugs for long-term efficacy

3. Antirejection: new drugs or higher dose agents to treat rejection

Immunosuppressive therapy is tailored to the patient. The first order of importance is the specific organ transplanted. Different organs have special pharmacological requirements. The characteristics of the recipient are also important. Patients who are presensitized or receive an organ incompatible with their blood group will require much more aggressive therapy. A number of immunosuppressant drugs are combined to maximize synergy while minimizing side effects and toxicity.

Unfortunately, no therapy currently exists that is completely effective in preventing rejection. While progress has been made in reducing the incidence of acute rejection, the rates of long-term organ survival are improving but at a slower pace. Furthermore, because these patients have to receive multiple nonspecific immunosuppressants, they are now predisposed to malignant and infectious complications. In fact, cancer now has assumed significant morbidity and mortality in this patient population.

In the perioperative period, patients should continue taking their immunosuppressive drugs. Since there is an increased risk of adverse drug interactions, all transplant patients should receive a detailed preoperative review of their medications with a focus on potential side effects and drug interactions. These immunosuppressive drugs can have significant implications for anesthetic management.

SPECIFIC IMMUNOSUPPRESSANTS

Inhibition of T-Cell Interaction

A. Steroids (Prednisolone)

With their broad anti-inflammatory effects, glucocorticoids are a major component of all phases of immunosuppressant therapy. They are particularly helpful, however, in the prevention and treatment of acute rejection. The specific mechanisms of action are somewhat unknown. Steroids suppress the proliferation and activation of T-lymphocytes by downregulating expression of cytokines (such as IL-1, IL-2, and IL-6) in macrophages. They also reduce plasma antibody levels, decrease capillary permeability, and promote a transient decrease in peripheral lymphocyte counts.

Oral prednisone, usually less than 5 mg per day, is the most common regimen. High doses of intravenous methylprednisolone are used to treat acute rejection. The chronic use of steroids can have serious side effects, including Cushing disease, poor wound healing, bone disease (avascular necrosis, osteopenia), glucose intolerance, cataracts, hypertension, hyperglycemia, and increased infection risk. The combination of glucocorticoids with other agents such as calcineurin inhibitors has enabled lower doses and therefore a decrease in morbidity.