Post Pancreas Transplant Manual of Therapeutics

Immunosuppression

We utilize induction therapy, which is inclusive of an antilymphocyte globulin, during the first few days following the transplant. The patients are then quickly converted to an IL-2 inhibitive immunosuppressive agent, such as FK506 or Cyclosporine. We use a multi-drug therapy to take advantage of the synergy that occurs between these drugs resulting in an overall state of immunosuppression with less toxicity. These medications include mycophenolic acid (CellCept®) or azathioprine (Imuran®) which are inhibitors of purine synthesis. Additionally the patient is placed on prednisone tapering to a maintenance of 0.3 mg/kg. The medications are adjusted according to their measured blood levels or their toxicities. The most common time course for the development of acute rejection is during the first six months. Therefore, the immunosuppression is lowered after approximately six months and then again at a year to a stable lifelong immunosuppression dosing.

FK506 (Prograf®) and Cyclosporine (Neoral®) work very similarly in their ability to inhibit the lymphocyte growth factor IL-2. They also share many similar side effects and toxicities. These include the negative impact upon renal function. However, with appropriate dosing the renal toxicity can commonly be negated. Both tend to elevate blood pressure and both unfortunately suppress insulin secretion. Cyclosporine produces more cosmetic side effects, such as hirsutism, while FK506 produces more gastrointestinal side effects.

Mycophenolate has recently been approved by the FDA for use for immunosuppression. Mycophenolate, trade name CellCept®, is a purine inhibitor like azathioprine. Mycophenolate is specific for the de novo pathway of purine synthesis where azathioprine works on both de novo and scavenger pathways. Lymphocytes do not possess the scavenger pathway of purine synthesis, therefore, mycophenolate becomes more lymphocyte specific.

Azathioprine is also a purine inhibitor but works via both the de novo and scavenger pathways and is therefore not lymphocyte specific. The side effects from azathioprine are well known. The most common side effects are leukopenia as well as a rare incidence of hepatic toxicity. Mycophenolate seems to have less of the side effect of leukopenia, but much more associated diarrhea with some nausea and vomiting. Mycophenolate's side effects are usually dose responsive and the patient symptoms seem to accommodate over a period of weeks.

Prednisone is not a new drug, but with the addition of these other immunosuppressive agents, there has been an attempt to lower steroid doses. However, complete elimination of the steroids has not routinely been achieved. Steroids have the problems of associated weight gain, production of insulin resistance and alteration of body image.

Cyclosporine and FK506 are metabolized initially through the liver's P-450 enzyme system. Therefore drugs that alter P-450 metabolism, alter the elimination of these drugs resulting in increased toxicity or inadequate immunosuppression. Erythromycin, diltiazem, verapamil, estrogen supplementation, and some anti fungal medications are all know to decrease P-450 metabolism, resulting in significantly elevated plasma levels of FK506 and Cyclosporine. Medications that increase P-450 metabolism include Phenytoin, barbiturates Rifampin, and Carbamazepine. With increased P-450 metabolism, blood levels of the immunosuppressive agents are lowered resulting in inadequate immunosuppression which could precipitate an acute rejection event. Immunosuppression medications decrease the body's cellular immune response, thus making the patient more susceptible to fungal and viral infections. The nephrotoxic side effect of these drugs is enhanced by concomitant use of other nephrotoxic drugs such as sulfas, amphotericin, aminoglycosides and non-steroidals. In summary, the metabolism and toxicities of the immunosuppressive medications requires consideration when choosing an antibiotic therapy, antihypertensive therapy or other therapies.