Download Chapter 16 Cholinesterase Inhibitors

Chapter 69
Immunosuppressants
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Immunosuppressants
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Inhibit immune response
Uses
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Prevention of organ rejection
Treatment of autoimmune diseases
Toxicity
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Increased risk of infection
Increased risk of neoplasms
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
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Calcineurin Inhibitors
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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
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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.
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Fig. 69–1. Sites of action of immunosuppressant drugs.
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
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Cyclosporine (Sandimmune)
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Mechanism
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Therapeutic uses
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Suppresses the production of interleukin-2,
interferon gamma, and other cytokines
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.
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Cyclosporine (Sandimmune)
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Adverse effects
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Nephrotoxicity
Infection
Hepatotoxicity
Lymphoma
Hypertension
Tremor
Hirsutism
Leukopenia, gingival hyperplasia, gynecomastia,
sinusitis, hyperkalemia
Anaphylactic reactions
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Cyclosporine (Sandimmune)
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Drug and food interactions
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Drugs that can decrease cyclosporine levels
Drugs that can increase cyclosporine levels
Nephrotoxic drugs
Grapefruit juice
Repaglinide
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Tacrolimus (Prograf)
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An alternative to cyclosporine
Somewhat more effective—but also more toxic
Concurrent use with glucocorticoids
Therapeutic use
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Prophylaxis of organ rejection (liver, kidney, or heart)
Mechanism of action
Adverse effects
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Nephrotoxicity is the major concern
Neurotoxicity
GI effects
Hypertension
Hyperkalemia
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
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Tacrolimus (Prograf)
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Adverse effects (cont’d)
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Hyperglycemia
Hirsutism
Gum hyperplasia
Anaphylaxis with IV administration
Drug and food interactions
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Agents that inhibit CYP3A (an isozyme of
cytochrome P450)
Grapefruit juice
NSAIDs should be avoided
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
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mTOR Inhibitors
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Enzyme known as mammalian target of
rapamycin (mTOR)
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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.
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Sirolimus (Rapamune)
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Actions and therapeutic use
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Only for prevention of renal transplant rejection
Used in conjunction with cyclosporine and
glucocorticoids
Adverse effects
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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)
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Drug and food interactions
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Drugs that inhibit or induce CYP3A4 (the 3A4
isozyme of cytochrome P450)
High-fat foods
Grapefruit juice
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
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Everolimus (Zortress)
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Therapeutic use
Mechanism of action
Adverse effects
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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.
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Everolimus (Zortress)
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Effects in pregnancy and lactation
Drug and food interactions
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Drugs that inhibit or induce CYP3A4 (the 3A4
isozyme of cytochrome P450)
High-fat foods
Grapefruit juice
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
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Glucocorticoids
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Used to widely suppress immune response
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Suppression of allograft rejection, treatment of
asthma, rheumatoid arthritis, systemic lupus
erythematosus (SLE), and multiple sclerosis
Large doses used to prevent rejection
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Increased risk of infection, thinning of skin, bone
dissolution with fracture, impaired growth in
children, and suppression of hypothalamicpituitary-adrenal axis
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Cytotoxic Drugs
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Suppress immune response by killing B and
T lymphocytes undergoing proliferation
Nonspecific—toxic to all proliferating cells
Adverse effects
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Bone marrow suppression
• Neutropenia
• Thrombocytopenia
GI disturbances
Reduced fertility
Alopecia
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
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Cytotoxic Drugs
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Azathioprine (Imuran)
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Therapeutic uses
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Suppresses cell-mediated and humoral immune
responses
Adjuvant treatment with transplants
Autoimmune disorders
Adverse effects
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Neutropenia
Thrombocytopenia
Mutagenic and teratogenic
Neoplasms
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Other Cytotoxic Drugs
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Cyclophosphamide (Cytoxan, Neosar)
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Methotrexate (Rheumatrex, Trexall)
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Anticancer drug
Anticancer agent
Autoimmune disorders
Suppression of B and T lymphocytes
Mitoxantrone (Novantrone)
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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
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Mycophenolate mofetil (CellCept, Myfortic)
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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
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Antibodies
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Muromonab-CD3 (Orthoclone OKT3)
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Actions and uses
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Monoclonal antibody
Blocks all T-cell function
Prevents acute rejection of transplants
Depletes T cells before bone marrow transplant
Adverse effects
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Fever
Chills
Dyspnea
Chest pain
Nausea and vomiting
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
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Other Antibodies
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Basiliximab
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Monoclonal antibodies
Blocks activation of T cells by IL-2
Prophylaxis of acute organ rejection
Lymphocyte immune globulin (Atgam)
Antithymocyte (Equine)
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