1. Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Chapter 69 Immunosuppressants

2. 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

3. 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

4. Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.4 Fig. 69–1. Sites of action of immunosuppressant drugs.

5. 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

6. 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

7. Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.7 Cyclosporine (Sandimmune)  Drug and food interactions  Drugs that can decrease cyclosporine levels  Drugs that can increase cyclosporine levels  Nephrotoxic drugs  Grapefruit juice  Repaglinide

8. 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

9. 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

10. Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.10 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

11. 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

12. Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.12 Sirolimus (Rapamune)  Drug and food interactions  Drugs that inhibit or induce CYP3A4 (the 3A4 isozyme of cytochrome P450)  High-fat foods  Grapefruit juice

13. Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.13 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%)

14. 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

15. Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.15 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

16. Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.16 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 Neutropenia Thrombocytopenia Thrombocytopenia  GI disturbances  Reduced fertility  Alopecia

17. Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.17 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

18. Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.18 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

19. Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.19 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

20. 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

21. Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.21 Other Antibodies  Basiliximab  Monoclonal antibodies  Blocks activation of T cells by IL-2  Prophylaxis of acute organ rejection  Lymphocyte immune globulin (Atgam)  Antithymocyte (Equine)