copyright © 2013, 2010 by saunders, an imprint of elsevier inc. chapter 69 immunosuppressants

Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

Chapter 69

Immunosuppressants

Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 2

Immunosuppressants

Inhibit immune response Uses

Prevention of organ rejection Treatment of autoimmune diseases

Toxicity Increased risk of infection Increased risk of neoplasms


Calcineurin Inhibitors Principal use is for prevention of organ rejection in

transplant recipients Cyclosporine and tacrolimus—most effective

immunosuppressants available Differ in structure, but share the same mechanism

Inhibition of calcineurin suppresses production of interleukin (IL)-2

IL-2 needed for T-cell proliferation Cyclosporine developed first and used more than

tacrolimus


Fig. 69–1. Sites of action of immunosuppressant drugs.


Cyclosporine (Sandimmune)

Mechanism Suppresses the production of interleukin-2,

interferon gamma, and other cytokines Therapeutic uses

Drug of choice for organ rejection (kidney, liver, and heart) of an allogenic transplant

Some autoimmune diseases Pharmacokinetics



Adverse effects Nephrotoxicity Infection Hepatotoxicity Lymphoma Hypertension Tremor Hirsutism Leukopenia, gingival hyperplasia, gynecomastia,

sinusitis, hyperkalemia Anaphylactic reactions



Drug and food interactions Drugs that can decrease cyclosporine levels Drugs that can increase cyclosporine levels Nephrotoxic drugs Grapefruit juice Repaglinide


Tacrolimus (Prograf)

An alternative to cyclosporine Somewhat more effective—but also more toxic Concurrent use with glucocorticoids Therapeutic use

Prophylaxis of organ rejection (liver, kidney, or heart) Mechanism of action Adverse effects

Nephrotoxicity is the major concern Neurotoxicity GI effects Hypertension Hyperkalemia


Tacrolimus (Prograf)

Adverse effects (cont’d) Hyperglycemia Hirsutism Gum hyperplasia Anaphylaxis with IV administration

Drug and food interactions Agents that inhibit CYP3A (an isozyme of

cytochrome P450) Grapefruit juice NSAIDs should be avoided


mTOR Inhibitors

Enzyme known as mammalian target of rapamycin (mTOR) Protein kinase that helps regulate cell growth,

proliferation, and survival Structurally similar to tacrolimus Somewhat different mechanism Does not involve inhibition of calcineurin


Sirolimus (Rapamune)

Actions and therapeutic use Only for prevention of renal transplant rejection Used in conjunction with cyclosporine and

glucocorticoids Adverse effects

Increased risk of infection Raises levels of cholesterol and triglycerides Risk of renal injury Severe complications in the liver and lung Rash, acne, anemia, thrombocytopenia, joint pain,

diarrhea, hypokalemia


Sirolimus (Rapamune)

Drug and food interactions Drugs that inhibit or induce CYP3A4 (the 3A4

isozyme of cytochrome P450) High-fat foods Grapefruit juice


Everolimus (Zortress)

Therapeutic use Mechanism of action Adverse effects

Peripheral edema (45%) Constipation (38%) Hypertension (30%) Nausea (29%) Anemia (26%) Urinary tract infection (22%) Hyperlipidemia (21%)


Everolimus (Zortress)

Effects in pregnancy and lactation Drug and food interactions

Drugs that inhibit or induce CYP3A4 (the 3A4 isozyme of cytochrome P450)

High-fat foods Grapefruit juice


Glucocorticoids

Used to widely suppress immune response Suppression of allograft rejection, treatment of

asthma, rheumatoid arthritis, systemic lupus erythematosus (SLE), and multiple sclerosis

Large doses used to prevent rejection Increased risk of infection, thinning of skin, bone

dissolution with fracture, impaired growth in children, and suppression of hypothalamic-pituitary-adrenal axis


Cytotoxic Drugs

Suppress immune response by killing B and T lymphocytes undergoing proliferation

Nonspecific—toxic to all proliferating cells Adverse effects

Bone marrow suppression• Neutropenia• Thrombocytopenia

GI disturbances Reduced fertility Alopecia


Cytotoxic Drugs

Azathioprine (Imuran) Suppresses cell-mediated and humoral immune

responses Therapeutic uses

Adjuvant treatment with transplants Autoimmune disorders

Adverse effects Neutropenia Thrombocytopenia Mutagenic and teratogenic Neoplasms


Other Cytotoxic Drugs

Cyclophosphamide (Cytoxan, Neosar) Anticancer drug

Methotrexate (Rheumatrex, Trexall) Anticancer agent Autoimmune disorders Suppression of B and T lymphocytes

Mitoxantrone (Novantrone) Anticancer agent Reduction of neurologic disability and clinical relapse for

multiple sclerosis (MS) patients Dangerous drug reserved for patients who are not

responsive to safer drugs


Other Cytotoxic Drugs

Mycophenolate mofetil (CellCept, Myfortic) Approved for prophylaxis of organ rejection Acts on B and T lymphocytes to inhibit inosine

monophosphate dehydrogenase Selective inhibition of B- and T-lymphocyte

proliferation


Antibodies

Muromonab-CD3 (Orthoclone OKT3) Monoclonal antibody

Actions and uses Blocks all T-cell function Prevents acute rejection of transplants Depletes T cells before bone marrow transplant

Adverse effects Fever Chills Dyspnea Chest pain Nausea and vomiting


Other Antibodies

Basiliximab Monoclonal antibodies Blocks activation of T cells by IL-2 Prophylaxis of acute organ rejection

Lymphocyte immune globulin (Atgam) Antithymocyte (Equine)

copyright © 2013, 2010 by saunders, an imprint of elsevier inc. chapter 69 immunosuppressants

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