The use of new immunosuppressive agents has substantially reduced the incidence of acute rejection episodes (ARE) and has further improved 1-year graft survival rates. Today’s drugs require insight into the therapeutic index, drug monitoring, efficacy and adverse effects of each agent. Each therapeutic graft maintenance agent has three windows around the dose-response curves.
- Immunosuppressive effect (ISE): reduction of the incidence of ARE providing long term efficacy
- Non-immune toxicity (NIT): e.g. nephrotoxicity and anemia
- Immunodeficiency (ID): immunosuppression to the extent that opportunistic infections and induction of tumors occurs.
The dose limiting toxicity for the maintenance of immunosuppressants agents is the NIT. Therefore, combinations of immunosuppressants with different mechanisms of action are used in lower individual dosages to increase the efficacy (ISE), while not decreasing the NIT. However, increased ISE is associated with increased ID.
Other important considerations include therapeutic index (TI), availability of an oral formulation, and the half-life of a maintenance agent. The TI is an indication of how selective a drug is in producing the desired effect. TI is the preferred pharmacological key with respect to an immunosuppressive agent. E.g. tacrolimus is 10 to 100 times more potent than cyclosporine on molecular basis but may well have a very similar TI. Availability of a reliable oral formulation is almost as important as the immunological characteristics of a maintenance agent. For the drug to be both safe and effective, the half-life should probably be short.
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Bone marrow suppression is a major adverse effect of which of the following immunosuprressive drugs