PTN - Immunomodulators (Dolloff) Flashcards
What are the two possible mechanisms by which immunosuppresion leads to malignant neoplasms?
- Loss of immunosurveillance
- Stimulation of rapid proliferation of stem cells in an attempt to restore immune system
What are the 3 primary indications for treating with an immunomodulatory drug?
- Autoimmune and inflammatory diseases
- Transplants and GVHD
- Oncology
What is the main difference between autoimmune and autoinflammatory processes?
Autoimmune processes are characterized by hyperactivity of the adaptive immune system.
Autoinflammatory processes are characterized by hyperactivity of the innate immune system.
What are the 3 main side effects of cyclosporin?
- Renal toxicity - dose-dependent and usually reversible
- Hypertension
- Neurologic toxicity - tremors and seizures
What is the function and mechanism of action of azathioprine?
- Function: inhibits purine synthesis
- MoA:
- Azathioprine converted into 6-mercaptopurine
- 6-MP incorporated into replicating DNA and halts DNA replication –> cell cycle arrest
Infliximab can be used to treat what 2 conditions?
Crohn’s Disease and Rheumatoid Arthritis
Infliximab is a monoclonal antibody against TNF-alpha. This will lead to a decrease in inflammation, which will limit autoimmune destruction of GI tract and joints.
True or False: Pegfilgrastim has a longer half-life than Filgrastim.
True
This allows for more sustained duration of action and less frequent dosing
6-mercaptopurine is an active metabolite of what pro-drug?
Azathioprine
What is the mechanism of action of Filgrastim?
Filgrastim is a recombinant human Granulocyte-colony stimulating factor (G-CSF) and is used to increase production of neutrophils
What two immunosuppressants have severe hepatotoxic effects?
Leflunomide and methotrexate
What is the mechanism of action of methotrexate?
Inhibits dihydrofolate reductase, which blocks synthesis of TMP and purines
What is the mechanism of cyclosporin and tacrolimus (FK506)? What enzyme is targeted by each?
Both involved in inhibition of transcription of IL-2 to prevent T-cell proliferation
Enzyme: calcineurin
Cyclosporin targets cyclophilin or FKBP
Tacrolimus targets FKBP
What is the mechanism of action of etanercept?
Ligand-binding portion of human TNF-alpha receptor fused to Fc portion of human IgG1
Acts as a decoy receptor that binds TNF-alpha and prevents it form binding to its receptor
Cyclosporine and azathioprine should be given in conjunction with what other drug, as a prophylactic for preventing rejection?
Glucocorticoids to inhibit inflammation
What drug blocks dihydroorotate dehydrogenase? This prevents what?
Leflunomide
Prevents dihydroorotate dehydrogenase from forming pyrimidines
True or false: Rapamycin (sirolimus) and cyclosporin can be used together without interaction.
False
Rapamycin interacts with cyclosporin –> increased concentration of both drugs in blood
Cyclosporin toxicity –> renal dysfunction
Rapamycin toxicity –> hyperlipidemia
What is the structural analog of tacrolimus (FK506)?
Rapamycin (sirolimus)
Rituximab is currently used for what condition?
Rheumatoid arthritis
Acts as a monoclonal antibody against CD20 (B-cell marker) - depletes all B-cells except plasma cells
What is the drug which acts a soluble Fc receptor to IgG1, preventing the binding to TNF to cell membrane receptors?
Etanercept
What drug targets mTOR?
Rapamycin (sirolimus)
What immune response is more easily treated, primary or secondary?
Primary
Primary immune responses lack presence of memory cells, which can be difficult to erradicate. They also tend to work better prior to exposure.
What is the mechanism of action of mycophenolate mofetil?
Inhibits IMP dehydrogenase, which decreases de novo purine synthesis (specifically of guanine)
What is the mechanism of action of rituximab?
Binds to CD-20 on B-cells and kills B-cells
What is Lenalidomide used to treat and what is its mechanism of action?
Lenalidomide (a derivative of thalidomide) is used to treat multiple myeloma
MoA: Inhibits cereblon, an E3 uqiquitin ligase
What is the main side effect of Lenalidomide?
Teratogenicity
True or False: Lenalidomide should be administered with an anticoagulant because it increases risk of developing clots.
True
What does the drug Pembrolizumab target? What does it treat?
Pembrolizumab targets PD-1 and inhibits it from binding to T-cells, promoting an anti-tumor immune response.
Tumor cells upregulate PD-1 to prevent T-cells from attacking them.
Used to treat: melanoma, non-small cell lung cancer
What is the difference between Sargramostim and Filgrastim?
Sargramostim is a granulocyte-macrophate-colony stimulating factor (GM-CSF), which upregulates production of neutrophils and monocytes form hematopoietic stem cells.
Filgrastim is a granulocyte-colony stimulating factor (G-CSF) and only stimulates production of neutrophils
Drugs like Sargramostim and Filgrastim are used to treat what?
Neutropenia in patients with AIDS, who have just received chemotherapy, or who have just received an auto-stem cell transplant
What is the mechanism of action of Ipilimumab? What is it primarily used to treat?
Ipilimumab binds to CTLA-4 on tumor cells and prevents it from binding to T-cells, decreasing tolerance and activating an immune response against the tumor cells.
Used to treat: melanoma
