Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Chapter 69 Immunosuppressants.
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Transcript of 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
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 3
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
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 4
Fig. 69–1. Sites of action of immunosuppressant drugs.
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 5
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
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 6
Cyclosporine (Sandimmune)
Adverse effects Nephrotoxicity Infection Hepatotoxicity Lymphoma Hypertension Tremor Hirsutism Leukopenia, gingival hyperplasia, gynecomastia,
sinusitis, hyperkalemia Anaphylactic reactions
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Cyclosporine (Sandimmune)
Drug and food interactions Drugs that can decrease cyclosporine levels Drugs that can increase cyclosporine levels Nephrotoxic drugs Grapefruit juice Repaglinide
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 8
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
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 9
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
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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
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 11
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
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Sirolimus (Rapamune)
Drug and food interactions Drugs that inhibit or induce CYP3A4 (the 3A4
isozyme of cytochrome P450) High-fat foods Grapefruit juice
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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%)
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 14
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
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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
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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
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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
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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
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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
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 20
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