**2.8. Glucocorticoids**

The introduction of glucocorticoids as immunosuppressive drugs in the 1960s played a key role in making organ transplantation possible. Steroids are a cornerstone of immunosuppres‐ sive therapy in kidney transplantation despite their side effects and morbidity. More than 95% of transplant recipients are treated with steroids as a usual component of clinical immuno‐ suppressive regimens. Prednisone, prednisolone, and other glucocorticoids are used alone and in combination with other immunosuppressive agents for treatment of transplant rejection and autoimmune disorders [1,48]. Transplantation specialists are now moving toward protocols that reduce the incidence of infections and minimize adverse events. Most immunosuppressive regimens are currently based on the combination of calcineurin inhibitors (CsA, TRL) with antiproliferative agents (azathioprine, MMF) and steroids (prednisone) [49].

#### *2.8.1. Mechanism of action*

Glucocorticoids lyse (in some species) and induce the redistribution of lymphocytes, causing a rapid, transient decrease in peripheral blood lymphocyte counts. To effect longer-term responses, steroids bind to receptors inside cells; either these receptors, glucocorticoid-induced proteins, or interacting proteins regulate the transcription of numerous other genes. Addi‐ tionally, glucocorticoid-receptor complexes increase IκB expression, thereby curtailing activation of NF-κB, which increases apoptosis of activated cells. Of central importance, key proinflammatory cytokines such as IL-1 and IL-6 are down regulated. T cells are inhibited from making IL-2 and proliferating. The activation of cytotoxic T lymphocytes is inhibited. Neu‐ trophils and monocytes display poor chemotaxis and decreased lysosomal enzyme release. Therefore, glucocorticoids have broad anti-inflammatory effects on multiple components of cellular immunity [1].

an acceptable level of toxicity or efficacy, nor are there consistent procedures used to establish

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In general, a therapeutic range should never be considered in absolute terms, as it represents no more than a combination of probability charts. In other words, a therapeutic range is a range of drug concentrations within which the probability of the desired clinical response is relatively

Since the development of the range is probabilistic in nature, a concentration that is within the "therapeutic range" for a given drug does not exclude the possibility that signs and symptoms of toxicity experienced by an individual patient are related to the monitored drug. A concen‐ tration outside of the range also does not indicate that a patient will experience toxicity or reduced efficacy; however, the likelihood of either is certainly lower [51]. It is important to recognize that the therapeutic range is not necessarily valid outside of the population used to establish it. This is particularly critical for immunosuppressive drugs, as most patients that are treated with these drugs receive additional immunosuppressive agents. A change in dosing of one drug may have a profound impact on the pharmacodynamic relationship of another. The nature of the transplanted organ (e.g., cadaveric versus living-related donor kidneys), age, and co-morbid illness can all have important influences on the pharmacodynamic response.

The process of selecting the most appropriate dosage regimen to achieve concentrations in a relatively narrow range may be complicated by unpredictable intrapatient and interpatient variability in the drug's pharmacokinetics. A sophisticated application of pharmacokinetic principles, incorporating prior and subsequent measures of drug concentration and effects, can improve the quality of one's predictions. Although a single "best" approach to using drug concentrations does not exist for every drug, it is imperative to realize that without a systematic approach to therapeutic drug concentration monitoring, drug concentrations may be uninter‐ pretable, unhelpful and potentially harmful. It thus becomes essential to recognize the key elements of clinical pharmacokinetics and pharmacodynamics, and to develop strategies to

There are a number of advantages to therapeutic drug monitoring that provide the clinician with clinically useful information. Plasma drug concentrations in conjunction with a thorough assessment of the patient's clinical status and the therapeutic goals to be achieved provide a means of successfully and rapidly individualizing a patient's therapeutic regimen to assure optimal benefits con minimal risk. Therapeutic drug measuring is only one part of therapeutic drug monitoring that provides expert clinical interpretation of drug concentration as well as evaluation based on pharmacokinetic principles. Expert interpretation of a drug concentration measurement is essential to ensure full clinical benefit. Clinicians routinely monitor drug pharmacodynamics by directly measuring the physiological indices of therapeutic responses,

such as lipid concentrations, blood glucose, blood pressure, and clotting [53].

high and the probability of unacceptable toxicity is relatively low [52].

The importance of these factors should not be ignored [51].

**3.2. Interpretation of plasma drug concentration**

perform and use them most effectively [52].

a therapeutic range [51].

#### *2.8.2. Side effects*

Steroids are effective in reducing the incidence of acute rejection but are an important cause of morbidity and probably mortality. Moreover, they have adverse effects on cardiovascular risk factors such as hypertension, hyperglycemia, or hyperlipidemia, deleterious effects on bone metabolism, and may contribute to an increased risk of infection [1,48].
