Immunosuppressants Flashcards
What are the three types of immunosuppressive regimens?
Induction (at time of transplantation; relatively intense). Maintenance (lower potency; tolerable in chronic use, but not without side effects). Rescue (intense, effective, but chronically intolerable and applied in response to rejection episode).
What are the three types of drugs typically given in maintenance therapy? Why use a combo therapy?
Calcineurin inhibitor, anti-proliferative, steroid. Most patients remain on these drugs for the rest of their lives. Combo therapy allows relatively low doses of each drug, avoiding toxicity associated with higher doses - each drug has a different spectrum of toxicity because they all have a different mechanism of action.
Which immunosuppressant works by inhibiting cell cycling in T lymphocytes?
Azathioprine
What drug is contraindicated in transplant recipients who are Epstein-Barr virus (EBV) seronegative or with unknown EBV serostatus? Why?
Belatacept (an antibody drug). Risk of PTLD (Post-transplant Lymphoproliferative Disorder) or PML (Progressive Multifocal Leukoencephalopathy), both of which can cause death.
What are the 3 antibody drugs? Are they lymphocyte depleting? What are their cell targets? How are they administered and for what regimen?
Basiliximab: no, IL-2 receptor (CD25)
Rabbit ATG: yes, multiple
Belatacept: yes, CD80/86
Basiliximab prevents activation of IL-2 receptor. These are all administered IV as induction agents.
What are the two calcineurin inhibitors, and what is their mechanism of action? How are they administered?
Basics: IL-2 blockade; inhibition of T-lymphocyte activation and proliferation.
Details: cyclosporine (via cyclophilin) and Tacrolimus (via FKBP12). Inhibit first phase of T-cell activation. Compared to cyclosporine, tacrolimus is about 100x more potent in inhibiting T-cell proliferative responses. Non-specific target with wide tissue expression. When antigen presenting cell interacts with T-cell receptor, there is an increase in cytoplasmic calcium, activating calcineurin, by binding a regulatory subunit and activating calmodulin binding. Calcineurin, a protein phosphatase, activates the transcription factor NFAT by dephosphorylating it, permitting it to enter the nucleus. Calcineurin induces different transcription factors (NFATs) that are important in the transcription of IL-2 genes. As shown, the two drugs, cyclosporine A and Tacrolimus each associates with a different specific protein (cyclophilin or FK binding protein 12) that is essential to the functioning of calcineurin .
Administered IV/PO variable.
What is the major problem with calcineurin inhibitors (CNIs)?
Renal toxicity - dose/duration dependent (renal vasoconstriction - thromboxane, PGs, angiotensin II, PAF). Differentiating drug nephrotoxicity from graft rejection difficult (up to 20% of patients may have both).
What are the “other” CNI toxicities?
TWO IMPORTANT: hirsutism/hypertrichosis (abnormal hair growth) and gingival hyperplasia (both with cyclosporine) Additional: mild-moderate HTN, neurotoxicity with tacrolimus, various types of infection, and secondary malignancies
What is the mechanism of action of the corticosteroids? How are they administered?
Basics: anti-inflammatory; inhibition of IL-2 production.
Details: nuclear drug target- administered IV/PO. Transcriptional coactivators, such as CREB-binding protein (CBP), have intrinsic histone acetyltransferase (HAT) activity. They acetylate core histones, increasing expression of genes encoding multiple inflammatory proteins. Cytosolic glucocorticoid receptors (GR) bind corticosteroids; the receptor-ligand complexes translocate to the nucleus and bind to coactivators to inhibit HAT activity in two ways: directly and, more importantly, by recruiting histone deacetylase-2 (HDAC2), which reverses histone acetylation, leading to suppression of activated inflammatory genes.
What are the other immune system effects of corticosteroids?
Corticosteroids lead to a # of effects on immune system, including neutrophilia, eosinopenia, and monocytopenia.
What are the AE’s of corticosteroids?
Protein metabolism dysfunction (myopathy, impaired wound healing and skin atrophy, osteoporosis, etc.)
Increased susceptibility to infections
Hypercorticism (Cushing’s syndrome), menstrual irregularity, hyperglycemia
Hypercholesterolemia, atherosclerosis, thrombosis
Neurologic effects: insomnia, depression, anxiety (mediated by cell-surface receptors in addition to the cytoplasmic receptors)
What is the name of the mTOR inhibitor we need to know? What is its MOA? How is it administered?
Basics: Sirolimus inhibits IL-2 driven cell-cycle progression.
Details: mTOR (mammalian target of Rapamycin) is downstream from activation of the IL-2 receptor. Like tacrolimus, it binds to FKBP12, but inhibition of this protein prevents the action of mTOR, and the initiation of cell cycle-driven clonal expansion (G1 arrest). The drug target is also expressed in non-immune cells (affects proliferation of cells outside immune system, i.e., fibroblasts, smooth muscle cells, hepatocytes, etc.), which can lead to adverse drug effects elsewhere in the body. PO only.
Is synergistic with cyclosporine. Prevents B-cell differentiation into antibody-producing cells, decreasing levels of IgM, IgG, and IgA.
What are the adverse effects of sicrolimus?
Dose-related hyperlipidemia, thromboembolism, anemia, leukopenia, fever, diarrhea, hypokalemia, hypertension, HEPATOTOXICITY (may be fatal), renal toxicity, infections, and tumors.
Temsirolimus is a pro-drug for sirolimus.
What is the MOA of mycophenolate mofetil? How is it administered?
Basics: purine biosynthesis inhibitor.
Details: This drug is a cell-cycle disruptor, which inhibits inosine monophosphate dehydrogenase, interrupting DNA synthesis. This affects primarily T- and B-lymphocytes, which cannot synthesize GMP sufficiently through salvage pathway - inhibits activated T-cell proliferation.
Administered IV/PO.
What are some potential advantages of mycophenolate mofetil?
It blocks the secondary antibody responses mediated by memory B cells. It has a selective effect on lymphocyte proliferation, unlike azathioprine or methotrexate. No chromosomal breaks.
