**1. Introduction**

Immunosuppressive drugs are used to reduce the immune response in organ transplantation and autoimmune disease. In transplantation, the major classes of immunosuppressive drugs used today are: (1) glucocorticoids, (2) calcineurin inhibitors, (3) antiproliferative/antimeta‐ bolic agents, and (4) biologics (antibodies). These drugs have met with a high degree of clinical success in treating conditions such as acute immune rejection of organ transplants and severe autoimmune diseases. However, such therapies require lifelong use and nonspecifically suppress the entire immune system, exposing patients to considerably higher risks of adverse effects [1].

The pharmacokinetics of the immunosuppressive drugs is complex and unpredictable. A narrow therapeutic index unique to each patient, as well as variable absorption, distribution, and elimination, are characteristics of these drugs. Therapeutic drug monitoring plays a key role in helping clinicians maintain blood and plasma levels of immunosuppressive drugs within their respective therapeutic ranges. Variation in concentrations outside the narrow therapeutic ranges can result in adverse clinical outcomes. Therapeutic drug monitoring ensures that concentrations are not too high or too low, thereby reducing the risks of toxicity or rejection, respectively. This chapter briefly reviews some immunosuppressive drugs: cyclosporine, tacrolimus, mycophenolic acid, sirolimus, everolimus, azathioprine, daclizumab and basiliximab, alemtuzumab and glucocorticoids. A general discussion of mechanism of action and side effects of these immunosuppressive agents used more commonly today are described below, followed by an overview of general principles of therapeutic drug monitoring

© 2013 Piedras et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

and concluding with brief information about monitoring of individual immunosuppressive agents as well as a brief description of future trends in immunosuppression therapy.

mild to moderate hypertension may occur in approximately 50% of renal transplant patients and most cardiac transplant patients. In liver transplant patients (n=75), 27% experienced hypertension. Incidence: 13% to 53% [9]. Discontinuation of CsA therapy may be required for persistent blood pressure elevation despite adjustments in therapy. Antihypertensive agents such as calcium-channel blockers may be used, with isradipine and nifedipine most appro‐ priate since they do not interfere with CsA metabolism. Other calcium-channel blockers (eg, diltiazem and verapamil) may increase cyclosporine levels. Patients with preexisting hyper‐ tension controlled by beta-blockers may continue to receive the same therapy. Angiotensin converting enzyme inhibitors and diuretics are not recommended [10]. Probable mechanisms for cyclosporine induced hypertension involve increased prostaglandin synthesis, decreased free water excretion, and decreased sodium and potassium excretion [11]. CsA is nephrotoxic, the mechanism by which CsA causes nephrotoxicity is attributed to changes in vasomotor tone induced by activation of the sympathetic nervous system [12]. Tremor was reported to appear within a few days of initiating CsA therapy and was considered dose dependent. Incidence:

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**Immunosuppressive agent Site of Action**

Cyclosporine and tacrolimus Calcineurin (inhibits phosphatase

Sirolimus and everolimus Protein kinase involved in cellcycle

Azathioprine Deoxyribonucleic acid (false

Alemtuzumab Cell surface glycoprotein CD52 Glucocorticoids Glucocorticoid response elements

Administration of CsA adversely affects plasma lipoprotein and cholesterol levels causing hyperlipidemia [9]. In a study CsA increased total cholesterol by 21%, low-density lipoproteins by 31%, and apolipoproteins by 12% over 27 days [13]. Gingival hyperplasia was reported in 4% to 16% of patients treated with CsA [9]. Histologically, CsA-induced gingival overgrowth is characterized by cellular hyperplasia along with myxomatous changes and accumulation of collagen [14]. Reduction of the dose of CsA may result in complete resolution of gingival

Daclizumab and basiliximab IL-2 receptor (block IL-2–mediated

**Table 1.** Sites of action of immunosuppressive agents on T-cell activation [1]

Mycophenolic acid Inosine monophosphate dehydrogenase

activity)

(inhibits activity)

progression (mTOR) (inhibits activity)

nucleotide incorporation)

T-cell activation)

in DNA (regulate gene transcription)

12% to 55% [9].

hyperplasia [15,16].
