Term
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Definition
Cyclosporin Tacrolimus Sirolimus |
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Term
| T Cell Blockers: Cyclosporine |
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Definition
- cyclic polypeptide derived from a fungus that acts to inhibit lymphocytic proliferation. Cyclosporin binds to cyclophilin and the cyclosporine-cyclophilin complex inhibits calcineurin.
- available either intrevenously or orally.
- also cyclosporine eye drops which are designed to restore tear production.
- extensively metabolized in the gut and the live by cytochrome p450; there are significant drug interactions with cyclosporine and other drugs that either inhibit or induce cytochrome p450
- Toxicity - high levels of cyclosporine induce hypertension and renal toxicity
- Therapeutic uses
- cyclosporine is used in kidney, heart, and liver transplants as well as in the treatment of rheumatoid arthiritis and psoriasis
- both oral forms are administered in two daily doses and neoral form is administered on a concistent schedule with regard to time of day and in relation to meals
- nephrotoxic - need to monitor levels in transplant patients
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Term
| T Cell Blockers: Tacrolimus |
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Definition
- macrolide antibiotic that bins to the FK506 binding protein, and the Tacrolimus-FK506 complex acts to inhibit calcineurin (Tacrolimus is FK506)
- calcineurin inhibition works by preventing the dephosphorylation of nuclear factor of activated T cells (NFAT) which in turn inhibits the T cell receptor activated induction of IL-2 (T cell growth factor), IL-3, IL-4, and the TNF-alpha gene.
- tacrolimus is available either intravenously or orally and is thought to be either 10-100 times more potent in its ability to inhibit IL-2
- metabolized my cytochrome p450 (potential for drug interactions) and is extensively distributed into tissues
- toxicity - high levels of tacrolimus can manifest in nephrotoxicity, neurotoxicity, diarrhea, hypertension, hyperglycemia and infections
- therapeutic uses - hepatic transplantation, kidney transplantation, therapeutic monitoring of drug through concentrations, and plasma concentrations of this agent are also monitored because of the toxic effects.
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Term
T Cell Blockers: Sirolimus |
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Definition
- antifungal agenst formerly known as rapamycin, and is similar to cyclosporine and tacrolimus, but does not act to inhibit calcineurin.
- it inhibits the intracellular signaling pathway from the IL-2 receptor to DNA synthesis. This is a less effective inhibitor of cytokine synthesis than cyclosporine, but is just as potent in preventing the proliferation of T cells.
- Sirolimus also prevents the proliferation of B cells.
- drug metabolism is mediated by the Cytochrome P450 system, and there is again the potential for drug interactions with other drugs that affect Cytochrome P450
- Therapeutic Use - indicated for use in acute renal rejection in combination with cyclosporine and steroids
- Toxicities include leukopenia, thrombocytopenia, headache, nausea, dizziness, and high triglycerides.
- There is less renal toxicity compared to cyclosporine and tacrolimus, possible de to the lack of calcineurin inhibition. KNOWN THE DIFFERENCE BETWEEN ALL THREE OF THESE DRUGS!
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Term
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Definition
- throught to reduce circulation of lymphocytes, inhibit antibody formation and binding to target cells, and prevent B and T cell proliferation.
- also has antinflammatory properties
- these agents typically have a pretty short half-life
- takes 4-5 half lives to elminate a drug fromt he system; takes 4-5 half lives of a drug to achieve steady state
- most corticosteroids do not require frequent dosing because their capacity to inhibit lymphokine production persists for 24 hours.
- therapeutic uses - used in combination with other immunosuppressive agents in organ transplantation and autoimmune diseases, and dosing depends ont he product used. The dose of one steroid is not equivalent to the dose of another steroid.
- ton of toxicities - increased infections, impaired growth, bone disease, diabetes, obesity, hypertension and many more
- important to taper patient off of steroids to prevent acute adrenal insufficiency
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Term
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Definition
- Azathioprine
- Mycophenolate
- Cyclophosphamide
- Leflunomide
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Term
| Cytotoxic Drugs: Azathioprine (AZA) |
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Definition
- prodrug metabolized to 6-mercaptopurine (6-MP)
- antagonist to purine metabolism which prevents DNA synthesis and T-cell proliferation
- short half-life but DNA inhibition lasts for days
- patients with hepatic dysfunction insufficient in converting from prodrug to 6-MP
- patients with renal insufficiency have accumulation of Azathioprine metabolites, which can cause pancytopenia, so important to decrease dose in these patients
- therapeutic uses - prevention of acute renal rejection, but it is not used for treatment. also been used in rheumatoid arthritis
- toxicities - bone marrow suppression, increased risk of neoplasia and irreversible liver damage
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Term
Cytotoxic Drugs: Mycophenolate
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Definition
- prodrug of mycophenolic acid (MPA) - inhibits inosine monophosphate dehydrogenase leading to depletion of endogenous purine nucleotide pools, which causes inhibition of de novo purine synthesis.
- T and B cells dependent on de novo synthesis of purines for their proliferation.
- Also potent cytostatic effect on T and B cell growth and suppression of antibody formation by B cells
- Mycophenolate is rapidly hydrolyzed to MPA in the liver after GI absorption. MPA then undergoes glucouronidation in the liver, and goes through enterohepatic circulation, which converts it back to the active MPA
- Therapeutic uses - renal and cardiac transplantation in conjunction with corticosteroids and cyclosporine
- Drug Interactions - mycophenolate and tacrolimus can interact, causing higher mycophenolate concentrations when both drugs are administered together. also interacts with antacids, cholestyramine and colestipol which decrease mycophenolate absorption. Ganciclover and SMZ-TMP, an antibiotic which can increase the incidence of bone marrow suppression.
- Toxicities - GI effects (anorexia, nausea, vomiting, diarrhea), hematologic effects (leukopenia, thrombocytopenia, anemia), and an increased risk of infections.
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Term
| Cytotoxic Drugs: Cyclophosphamide |
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Definition
- alkylation agent that is a nitrogen mustard derivative which interferes with DNA replication and RNA transcription, which disrupts nucleic acid function.
- therapeutic uses - rejection following renal, liver, heart, and bone marrow transplants. it is possibly as effective as Azathioprine for maintenance of renal transplants and better for liver transplants.
- Toxicities include bone marrow suppression, GI nausea and vomiting, cardiotoxicity, increased incidence of neoplasm, and increased bladder cancer due to acrolein (metabolite of phosphamide, they are hydrated and receive a drug called mesna which binds the acrolein to hopefully prevent hemorrhagic cystitis)
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Term
| Cytotoxic Drugs: Leflunomide (LEF) |
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Definition
- pyrimidine synthesis inhibitor that modulates the immune system by inhibiting dihydroorotate dehydrogenase, which is involved in de novo pyrimidine synthesis.
- antiproliferative activity
- following oral admin, active metabolite levels peak between, 6-12 hours after dosing. specific site of metabolism is unknown, but it is thought to be metabolized in the GI wall and liver. it is renally eliminated.
- Therapeutic uses - LEF is used in the treatment of active rheumatoid arthritis and also has been shown to retard structural damage of erosions and joint space narrowing
- toxicities - include liver enzymes, nausea, diarrhea, alopecia and rash.
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Term
What are two categories of antibody reagents? |
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Definition
- polyclonal antibodies
- monoclonal antibodies
These are antibodies against human lymphocytes and can have significant immunosuppressant action. |
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Term
Antibody Reagents: Polyclonal Antibodies
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Definition
- bind to proteins on the surface of the lymphocyte that is triggering the complement response and leads to lysis of the lymphocyte. It basically targets all T-cells which results in broad immunosuppression and can lead to infection.
- 2 agents used:
- Antilymphocyte immunoglobulin (thymoglobulin) - derived from rabbits
- Antithymocyte immunoglobulin (ATGAM) - derived from horses
- both agents given IV and bind to circulating lymphocytes, bone marrow cells and visceral tissues
- since these are derived from animals, efficacy differs from batch to batch and there is a significant risk of allergic reaction.
- therapeutic uses - treatment of renal transplant acute rejection with concomitant immunosuppression, bone marrow transplant, and anemia. The duration of therapy is usually 7-14 days.
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Term
Antibody Reagents: Monoclonal Antibodies What are three major drugs in this category? |
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Definition
- Muromonab-CD3 (OKT3)
- Daclizumab (Zenapax)
- Basiliximab (Simulect)
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Term
| Antibody Reagents: Monoclonal Antibodies |
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Definition
- are the process by which large quantities of antibodies targeted against a particular antigen can be produced.
- Muromonab-CD3 (OKT3) - derived from only one type of cell and is an anti-CD3 monoclonal antibody.
- Diclizumab and Basiliximab - anti CD25 monoclonal antibodies
- CD25 is the high affinity IL-2 receptor, which mediates early steps in the T cell activation. CD25 is expressed only on activated T cells.
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Term
| Antibody Reagents: Monoclonal Antibodies: Muromonab-CD3 (OKT3) |
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Definition
- IgG2A immunoglobulin derived from mice.
- binds to the CD3 antien of human T cells and reverses graft rejection, probably by blocking the function of all T cells, which play a major role in acute rejection.
- IV administration
- Toxicities
- cytokine release syndrome, which is characterized by common flu-like symptoms that appear early o, with later, less common onset of CNS symptoms (headaches, seizures, photophobia, confusion).
- acute reversible renal dysfunction: higher probability occurs after first and second doses
- Therapeutic uses - induction therapy (prophylaxis), which is reversal of acute graft rejection in renal, cardiac and hepatic transplant patients. Effective in 70-80% of liver transplant patients who have corticosteroid-resistant rejection, and it is strongly recommended to administer IV methylprednisolone to reduce the incidence and severity of reactions to the first dose.
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Term
| Antibody Reagents: Monoclonal Antibodies: Daclizumab |
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Definition
- monoclonal antibody from recombinant DNA technology and contains 90% human and 10% murine antibody sequences.
- binds to alpha-subunit of the IL-2 receptor (CD25) which is expressed only on the surface of activated lymphocytes.
- IL-2 receptor antagonist that inhibits IL-2 binding, which is critical for the activation of T cells in the acute rejection process.
- Daclizumab is available in IV administration only and has a half-life of 11-38 days. It saturates the IL-2 receptors for about 120 days. A serum concentration of 5-10 microgram/ml is required to saturate the Tac subunit (alpha subunit of CD25)
- Therapeutic uses - prophylaxis of acute organ rejection in renal transplant recipients in conjuction with cyclosporine and corticosteroids
- Toxicities - include GI, headache, dizziness, but otherwise it is relatively well tolerated.
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Term
| Antibody Reagents: Monoclonal Antibodies: Basiliximab (Simulect) |
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Definition
- has the same mechanism of action as Daclizumab (binds to the IL-2 receptor aka CD25) but contains a higher concentration of murine.
- administrated IV
- has HL of 4-14 days, and only saturates the receptors for about 36 days
- therapeutic uses - prophylaxis of acute organ rejection in renal transplant recipients in conjunction with cyclosporine and corticosteroids
- toxicities - include common hypersensitivity reactions
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Term
| Cytokine Inhibitors (specifically two that inhibit TNF-alpha) |
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Definition
- Etanercept (Enbrel)
- Infliximab (Remicade)
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Term
| Cytokine Inhibitors: The following inhibit TNF-alpha, a cytokine secreted by macrophages and activated helper T cells, which stimulates macrophages to produce cytotoxic metabolites. TNF-alpha also produces pyrogenic effects and stimulates the production of acute phase proteins. |
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Definition
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Term
| Cytokine Inhibitors: Etanercept (Enbrel) |
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Definition
- is a monoclonal antibody, which binds to TNF-alpha and TNF-beta, preventing TNF from binding with its receptors. TNF-alpha is thought to induce pro-inflammatory cytokines, enhance leukocyte migration, and activate neutrophils and eosinophils
- administered twice weekly via SC injection
- Therapeutic uses - include treatment of rheumatoid arthritis and Crohn's disease
- Toxicities - infusion reactions, upper resp. infections, and lupus-like syndromes
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Term
| Cytokine Inhibitors: Infliximab (Remicade) |
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Definition
- monoclonal antibody, which binds to TNF-alpha ONLY! (Etanercept binds both alpha and beta), preventing TN-alpha form binding to its receptors.
- Elevated levels of TNF-alpha have been found in the synovial fluid of patients with rheumatoid arthritis and in the stool of Crohn's disease patients, and thus correlate with increaseed disease activity.
- IV infusion, but you must also administer methotrexate to prevent the formation of antibodies
- Toxicities include infusion reactions, upper resp. infections and lupus-like syndromes
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Term
| Immunostimulants: designed to stimulate cellular and/or humoral immunity, which should benefit people with immune deficiencies. The complication is that the degree of stimulation is relatively small and the effect is generalized throughout the immune system. However, there are potential clinical roles in treatment of AIDS, cancers and chronic infectious diseases |
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Definition
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Term
What are three ways to immunostimulate? |
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Definition
- Intravenous Immune Globulins (IVIG)
- Cytokines
- Synthetic Agents (Levamisole)
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Term
| Immunostimulants: Intravenous Immune Globulins (IVIG) |
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Definition
- pooled plasma from donors which contain passively provided antibodies
- these agents are administered IM or by IV and have fairly long half lives (3 weeks)
- they are used in replacement therapy in primary immune deficiency diseases
- specific preparations are also available for diseases such as Hep B, botulism, diphtheria, tetanus and rabies. sometimes anaphylaxis presents with the use of IVIG.
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Term
| Immunostimulants: Cytokines |
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Definition
- INF-gamma-1-b which prevents infection in chronic granulomatous disease
- INF-alpha 2a/b is used in hepatitis, HPV and Kaposi's sarcoma
- INF-beta may reduce the severity of multiple sclerosis attacks
- IL-2 stimulates T helper and T cytotoxic cells, and is primarily used to treat metastatic melanoma and renal cell carcinoma. It is highly toxic and can lead to severe hypotension with life-threatening cardiotoxicity, pulmonary edema, renal and hematologic toxicity.
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Term
| Immunostimulants: Synthetic Agents (Levamisole) |
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Definition
- increases delayed hypersensitivity and/or T-cell mediated immunity.
- it is thought to cause macrophages to secrete IL-1 and other factors that suppress tumor growth, and is used in Hodkin's disease, rheumatoid arthritis, and colorectal cancer.
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