Immunosuppressive agents week 5 Flashcards
What is calcineurin? What is its signaling pathway?
Calcineurine is a Ca2+ dependent serine/threonine phosphatase that activates T-cells.
Once a T cell receptor becomes activated via an antigen presenting cell (like macrophage) there is an increase in cytoplasmic calcium concentrations. High calcium concentrations activate calcineurin, which has activity at the genomic level. Calcineurin activates the cytoplasmic domain of nuclear factor of activated T cell (NFAT-c), an important transcription factor, by dephosphorylating it. Once this transcription factor is activated, the IL-2 gene (among others) leading to activation of genes that encode pro-inflammatory cytokines. This is the mechanism by which APCs like macrophages induce T cells to produce pro-inflammatory cytokines.
Cyclosporine
MOA
Uses
Toxicities
Drug-drug interactions
Cyclosporine blocks T cell antigen receptor-mediated activation and proliferationby binding to cyclophilin. The newly formed complex inhibits the activity of calcineurin which keeps NFAT inactive. Therefore, no new pro-inflammatory genes are turned on-Prevents IL-2 transcription.
- Peptide made from fungus, Beauveria nivea
- Oral or IV administration
- Combined with other agents
- Variable absorption though as dependent on bile
- Different preparations/formulations are available to address PK problems
- Different preparations not bioequivalent, dosing considerations needed
Uses: Transplant rejection prophylaxis, psoriasis, rheumatoid arthritis
Main adverse reactions: Nephrotoxicity, gingival hyperplasia, hypertension, tremor, hyperlipidemia, hirsutism.
A major and well-known drug interaction exists with cyclosporin due to CYP3A4, P glycoprotein, and coadministration of sirolimus.
When drugs are combined with CYP3A4 inducers they lose their effectivness. When drugs are combined with CYP3A4 inhibitors, they have enhanced effectivess to the point of being toxic marked by high serum levels.
Tacrolimus
MOA
Uses
Toxicities
Drug-drug interactions
Tacrolimus
MOA: similar mechanism of action to cyclosporine, but a different molecular target. Tacrolimus binds to FKBP (FK- binding protein) another negative regulator of calcineurin rendering it inactive. Prevents IL-2 transcription.
Clinical use: Transplant rejection prophylaxis. Around 70-80% of transplant patients get Tacrolimus.
Chemically, a macrolide antibiotic from Streptomyces tsukubaensis
Extensive hepatic CYP3A biotransformation
Toxicities: Similar to cyclosporine: Nephrotoxicity, hyperlipidemia, hypertension. Increased risk of diabetes and neurotoxcity (temor); no gingival hyperplasia or hirsutism
Both tacrolimus and cyclosporine cause nephrotoxicity via afferent arteriole constriction.
Belatacept
MOA
Belatacept: a selective, co-stimulatory blocker for CD80 and CD86 (B 7.1) on antigen presenting cells preventing binding to CD28 on T cells. This is another mechanism to block T cell activation by inhibiting the APC contribution to the process.
Sirolimus/Rapamycin
MOA
Clinical uses
Toxicities
What drug is synergistic with sirolimus?
metabolism
Sirolimus aka Rapamycin
Sirolimus (also known as rapamycin) is another drug that targets the T cell but in a different mechanism (which is why it is here). Sirolimus binds to FKBP like Tacrolimus, but this mechanism is independent of calcineurin blockade and downstream of gene activation by NFAT. This pathway is the m-TOR pathway (mammalian target of rapamycin). This protein kinase is a key enzyme in cell cycle progression and when inhibited, the cell cycle is halted. FA: prevents response to IL-2-blocks resposne of proliferative genes.
Notes: Cell cycle phase stopped in the G1 to S phase
Clinical uses: Kidney transplant rejection prophylaxis, drug eluting stents to decrease inflammation.
Toxicities: Anemia, thrombocytopenia, leukopenia, insulin resistance, hyperlipidemia. NOT NEPHROTOXIC. Kidney “sir-vives with sirolimus”.
Synergistic with cyclosporine but increases cyclosporine associated with nephrotoxicity.
CYP3A4 biotransformation
Everolimus
MOA
metabolism
toxicities
Everolimus
- Another m-TOR inhibitor
- Cell cycle phase stopped in the G1 to S phase
- Binds to FKBP
- CYP3A4 biotransformation
- Known as a proliferation signal inhibitor, like its cousin, Sirolimus
- Adverse effects associated with dose-dependent myelo-suppression
Fingolimod
MOA
toxicities
Fingolimod: an S1P1 (EDG-1, sphingosine 1 receptor-1) partial agonist. InducesT cell sequestering to the secondary lymph structures to prevent their peripheral activity.
- Specifically, a unique class of drugs that affects T cell homing
- Clinical trials for relapsing MS currently approved.
- Side effects include lymphopenia which is reversible with dose discontinuation and bradycardia (there are S1P1 receptors on the heart).
- Bradycardia occurs with first dose then returns to baseline after ~2 days.
Azathioprine
MOA
Clinical use
Toxicities
Drug-drug interaction
Anti-metabolic agents
Azathioprine is a purine antimetabolite and blocks T and B cell proliferation.
- Converted to 6-mercaptopurine (6MP)
- 6MP then gets converted into 6-thioinosinic acid via hypoxanthine guanine phosphoribosyl transferase (HGPRT)
- 6-Thioinosinic acid inhibits purine synthesis required for DNA replication.
- Adverse effects seen in rapidly growing cells: leukocytes, thrombocytes, GI epithelium. Also, higher risk for infection, and hepatotoxicity.
- Requires dose adjustment (reduction) with allopurinol and febuxostat.
- Renal physiology has minimal impact on efficacy or toxicity.
Mycophenolate mofetil (MMF)
MOA
Clinical use
Toxicities
Drug-drug interaction
Mycophenolate mofetil (MMF) is a prodrug that rapidly hydrolyzed into MPA which inhibits de novo purine synthesis via inhibition of the inosine monophosphate dehydrogenase; but not the purine salvage pathway
- More selective for T and B cells (which rely less on the purine salvage pathway, anyway).
- T 1⁄2 is 16 hours
- Lymphocyte functions affected include lymphocyte proliferation, adhesion, migration, and antibody formation.
- Useful as prophylaxis in organ transplant for rejection reactions
- May be used with calcineurin inhibitors and glucocorticoids
- Adverse effects similar to azathioprine, seen in rapidly growing cells: leukocytes, thrombocytes, GI epithelium. Also, higher risk for infection, and hepatotoxicity.
Muromonab
MOA
Toxicities
Better alternatives to this drug for transplant pts
Muromonab: Antagonist of CD3 at the ε chain. CD3 is a marker for T cells and upon binding; this antibody causes internalization of the T cell receptor (TCR) which prevents antigen recognition. The TCR complex has roles in antigen recognition, cell signaling, and proliferation. Administration of this antibody leads to rapid reduction of T cells in the bloodstream and in the secondary lymphoid structures.
Associated with a cytokine release syndrome
Better alternatives for the transplant patient: (ATG and Alemtuzumab)
Alemtuzumab
MOA
Clinical use
Alemtuzumab: binds to CD52, a glycoprotein found on lymphocytes, monocytes, macrophages, and NK cells.
- Drug induces apoptosis of these cells which means their removal from blood, bone marrow and organs = complete lymphocyte depletion
- A special class of drugs known as “depleting antibodies”
- Humanized monoclonal antibody for CLL (chronic lymphocytic leukemia) which is a B cell diseases
- Also efficacious against T cells – maybe in solid-organ transplant in future
- Since 2012 not commercially available, needs manufacturer distribution
Anti-thymocyte globulin (ATG)
MOA
Use
Anti-thymocyte globulin (ATG): Cytotoxic antibodies to human CD2, CD3, CD4, CD8, CD11a,CD18, CD25, CD44, CD45 as well as HLA class I and II.
- Made by injecting human serum (thymocytes) into a rabbit.
- Antibodies deplete circulating lymphocytes via direct cytotoxicity (complement and cell mediated)
- Antibodies also block lymphocyte function by binding to cell surface molecules involved in the regulation of their function.
- Used for induction of immune suppression.
- Another example of a special class of drugs known as “depleting antibodies”
Basiliximab
MOA
Clinical use
Toxicities
Basiliximab:
- A non-depleting antibody
- This is a humanized mouse antibody is ~ 70% human and 25% mouse in its structure.
- IL-2 receptor antagonist, also known as Anti CD25 antibodies. Why? CD25 (ligand) binds to the IL-2 receptor.
- Currently available in US
- Approved for use in renal transplant with cyclosporine and corticosteroids
- Not many side or adverse effects. Some hypersensitivity reactions. FA: edema, HTN, tremor
Infliximab, Adalimumab
MOA
Clinical use
toxicities
MOA: Bind to TNFα and inhibit binding to receptors
IV use for rheumatoid arthritis, IBD, ankylosiing spondylitis, psoriasis
All TNF-α inhibitors predispose to infection, including reactivation of latent TB, since TNF is important in granuloma formation and stabilization.
Etanercept
MOA
clinical use
Toxicities
MOA: Etanercept is a TNF decoy receptor.
Clinical use: Rheumatoid arthritis, psoriasis, ankylosingspondylitis
All TNF-α inhibitors predispose to infection, including reactivation of latent TB, since TNF is important in granuloma formation and stabilization.
