Exam 2: L26 Flashcards
(50 cards)
1
Q
What are the components of the innate immune system?
A
- mechanical: skin/epidermis and mucus
- biochemical: antimicrobial peptides and proteins, complement; enzymes (lysozymes and acid hydrolases); interferons; acidic pH and ROS (H2O2, superoxide anion O2-)
- cellular: neutrophils, monocytes, macrophages, NK cells, natural killer T cells
2
Q
Distinguish between complement, opsonins, and chemoattractants
A
3
Q
What is Erythropoietin (EPO) and Thrombopoietin (TPO)?
A
- cytokines the promote RBC production (EPO) and platelet production (TPO)
4
Q
What are the characteristics of adaptive immune systems?
A
- responds to various antigens
- discriminates between foreign antigens
- T cell and B cells
- memory
- requires APC (dendritic cells, macrophages, and B lymphocytes)
5
Q
Name the 8 classes of immunosuppressive therapy
A
1) Glucocorticoids
2) Calcineurin inhibitors
3) Proliferation Signal Inhibitors (PSI)
4) Mycophenolate mofetil
5) Thalidomide derivatives
6) Cytotoxic agents
7) Immunosuppressive antibodies
8) Monoclonal antibodies (MABs)
6
Q
Goals of immunosuppressive therapy
A
- minimize the occurrence of impact of deleterious effects of exaggerated or inappropriate immune responses
- can increase susceptibility of other diseases
7
Q
Describe Glucocorticoids
A
- no toxic effects
- Mechanism: interferes with cell cycle activated lymphoid cells; toxic to certain types of T cells; modify cellular functions
- used for shirt term treatment; long term will cause diminished response (adaptation)
- first line immunosuppressive therapy for solid organs and hematopoietic stem cell transplant recipients
8
Q
Describe calcineurin inhibitors
A
- Key drugs: Cyclosporin and Tacrolimus
9
Q
Cylosporine A (CsA)
A
- used in human organ transplantation to help prevent organ rejection and to treat graft vs host disease and in the treatment of selected autoimmune disorders
- mechanism: CsA binds to cyclophilin (intracellular protein; member of immunophilins) and forms a complex. Complex inhibits cytoplasmic phosphatase calcineurin
- Cytoplasmic phosphatase calcineurin is necessary for activation of a T cell TF, NF-AT, which is involved in the synthesis of interleukin by activated T cells.
- metabolized by CYP3A in liver, so drug-drug interactions are possible
- potential toxicities: nephrotoxicity, hypertension, liver dysfunction, hyperkalemia, altered mental status, seizures, and hirsutism
10
Q
Tacrolimus
A
- immunosuppressive macrolide antibiotic produced by streptomyces tsukubaensis
- mechanism: binds to immunophilin FK binding protein; complex bind to cytoplasmic peptidylprolyl isomerase, inhibiting calcineurin
- Tacrolimus is 10-100 times more potent with same toxicities as CsA
- used for the same indications as CsA
- CYP3A substrate, so potential drug-drug interactions
- potential toxic effects: nephrotoxicity, neurotoxicity, hyperglycemia, hypertension, hyperkalemia, and GI problems
11
Q
Name Proliferation Sigal Inhibitors
A
- Sirolimus (rapamycin)
- everolimus
- tofacitinib (Xeljanz)
12
Q
Sirolimus and Everolimus
A
- long half lives
- CYP3A
- Bind circulating immunophilin FK506 binding protein 12, resulting in blocking mTor
- leading to inhibition of interleukin driven T cell production
- Toxicity: myelosuppression, hepatotoxicity, diarrhea, hypertriglyceridemia, pneumonitis, and headache
- may want to use this instead of CsA for patients with compromised renal functions
13
Q
Tofacitinib
A
- Inhibits Jak enzymes that stimulate hematopoiesis and immune cell function in response to cytokine or growth factor signaling
- reduces NK cells, serum immunoglobulin, and CRP
- approved for adults with moderate to severe RA; has box warning for serious infections and malignancies
14
Q
Mycophenolate Mofetil
A
- derivative of mycophenoic acid . from mld penicillium g
- prodrug taht is htdrolusr to mycophenolic acid
- some potential drug
15
Q
Thalidomide derivatives
A
- inhibits angiogenesis and has anti-inflammatory and immunomodulator effects
- mechanism: 1) inhibits TNF alpha 2) reduces phagocytosis by neutrophils 3) increase production of IL-10 4) alters adhesion molecule expression 5) enhances cell-mediated immunity via interactions with T cells
- extensive toxicity–> trying to find less toxic analogs like IMids (still have similar toxicity)
16
Q
Cytotoxic agents
A
- target rapidly growing cells
- used as anticancer, chemotherapeutic agents
17
Q
Azathioprine
A
- prodrug if mercaptopurine, functioning as an antimetabolite
- mechanism: interferes with purine metabolism at steps that are required fir lymphoid cell proliferation
- primary toxicity: bone marrow suppression
18
Q
Cyclophosphamide
A
- alkylating agent that is the most efficacious immunosuppressant
- as chemotherapeutic agent- used to treat lymphoma, multiple myeloma, leukemia ovarian cancer, breast cancer, small cell lung cancer, neuroblastoma, and sarcoma
- As immunosuppressant- used in the treatment of: nephrotic syndrome, granulomatosis with polyanglitis, and following organ transplant
- typically used in the early state of treatment and then switched for another treatment
- Side effects: bone marrow suppression, alopecia, lethargy, nausea, and vomiting, stomachache, hemorrhagic cystitis, diarrhea, etc.
- metabolized by several CYP
- mechanism of action due to its metabolite phosphoramide mustard
19
Q
Pyrimidine synthesus inhibitirs- Leflunomide (cytotoxic agent)
A
- prodrug of teriflunomide, which reversible inhibits mitochondrial enzyme dihydroorate dehydrogenase, which is involved in pyrimidine synthesis
- results in decreased lymphocyte activation
20
Q
Hydoxychloroquine
A
- used in the treatment of malaria
- immunosuppressant activities: suppress intracellular antigen presenting and loading of peptides onto MHC class II molecules by increasing the pH of lysosomal and endosomal compartments–> decreasing T cell activation
21
Q
Methotrexate
A
- anti folate
- in high doses- used as chemotherapy drug
- in low doses–> used in treatment of autoimmune disorders (especially first-line treatment of RA)
-Mechanism of action: inhibits dihydrofolate reductase with 1000x fold higher affinity than folate, resulting in inhibition of DNA synthesis
-
22
Q
Describe the mechanism of action of Methotrexate with rheumatoid arthritis
A
1) inhibition of enzymes involved in purine metabolism, leading to accumulation of adenosine
2) inhibition of T cell activation and suppression of intercellular adhesion molecule expression by T cells
3) selective down-regulation of B cells
4) increasing CD95 sensitivity of activated T cells
5) inhibition of methyltransferase activity, leading to deactivation of enzyme activities critical for immune system function
6) inhibition of the binding of IL-1beta to its cell surface receptor
23
Q
Immunosuppressive Antibodies
A
- antisera directed against lymphocytes
- Heterologous antilymphocyte globulin (ALG) and antithymocyte globulin (ATG) are used in transplant programs
- Mechanism: antibodies deplete circulating lymphocytes by directing cytotoxicity (complement and cell mediated) and block lymphocyte function by binding to cell surface molecules involved in regulating of cell function
- ATG contains cytotoxic antibodies that bind to CD2/3/4/8/11a
24
Q
Therapeutic monoclonal antibodies
A
- mab at the end
- suffices:
- antibodies that neutralize TNF alpha activities–>
- Mechanism: block activation of T cells by binding CD80, blocking the CD28 activation signal in T cells
25
What does abetaxept and belatacept do?
- recombinant fusion proteins composed of extracellular domain of CTLA-4 fused to the Fc domain oof human IgG
26
What is glucocorticoids mechanism of action?
glucocorticoid response elements in DNA --> regulated gene expression
27
What is cyclosporine mechanism of action?
calcineurin--> inhibits phosphatase activity
28
What is Tacrolimus mechanism of action?
Calcineurin --> inhibits phosphatase activity
29
What is Azathioprine mechanism of action?
DNA (false nucleotide incorporation)
30
What is Mycophenolate mofetil mechanism of action?
Inosine monophosphate dehydrogenase is inhibited
31
What is Sirolimus mechanism of action?
mTOR, protein kinase involved in cell-cycle progression is inhibited
32
What is Everolimus mechanism of action?
mTOR, protein kinase involved in cell-cycle progression is inhibited
33
What is Belatacept mechanism of action?
costimulatory ligands (DC80 and CD86) presented on APC are inhibited
34
What is Alemtuzumab mechanism of action?
CD52 protein, widely expressed on B cells, T cells, macrophages, NK cells (induces lysis)
35
What is Muromonab-CD3 mechanism of action?
T cell receptor complex that blocks antigen recognition
36
What is Daclizumab mechanism of action?
IL-2R ( blocks IL-2 mediated T cell activation)
37
Which agent is teh firstline for iodiopathic thrombocytopenic purpura, anutoimmune hemolytic anemia, and acute glomerulonephritis?
- prednisone
38
What agent us used often for organ transplantation of kidneys, heart, liver and bone marrow?
- cyclosporine
39
Which agent is used for the prevention of cell proliferation in coronary stents and neovascular macular degeneration?
- coronary stent: sirolimus
- Ranibizumab, bevacizumab
40
What is immunomodulation therapy?
- agents that modulate the immune response rather than suppress it (can increase or decrease immune response)
- advantages: patients with selective or generalized immunodeficiency can increase the immune responsiveness
- can use with immunodeficiency disorders, chronic infectious disease, cancer
- cytokines can be immunomodulating drugs
41
What are the types of cytokine immunomodulating drugs?
- interferons
- interleukins
- Tumor necrosis factor alpha and beta- Hematopoietic growth factors
42
What are the goals of therapy?
- no cure
- decrease disease symptoms, disease progression
- improve quality of life; impt becoase conditionofof disease being treated in chronic
43
What are drug selection considerations?
- drug target
- safety profile ( benefit or risk analysis)
- combination therapy to minimize the effects of a single agent
- combination therapy to have different targets
- delivery method-->depends of the disease is local of systemic
- frequency of administration; depends on the drug half life
- managed care and financial considerations
44
What are some common adverse effects of corticosteroids?
- can involved most organ systems
- used for many autoimmune diseases and auto reactive tissue disorders (MS, IBS, scleroderma, SLE, RA)
- when used fir anti-inflammatory and immunosuppressive properties, use systemic agents with the least mineralocorticoid activity
- short term effects and long term effects (adverse effects)
45
How should you go about withdrawing corticosteroids?
Withdrawal of corticosteroids should be done gradually
- abrupt withdrawal of high dose corticosteroid is very dangerous and can cause hypotension and shock
46
What are the common adverse effects of Methotrexate
- increase the risk of cytotoxicity
- at risk of diabetes, obesity, and renal disease ...increase the risk for hepatotoxicity
- contraindicated in alcoholic patients and those with pre-exisisting liver disease
- considered the most effective and least expensive first-line therapy
- typically patients are on it for 5-7 years, mprovement often occurs 6 months in
47
Hydroxychlororquine
- doesn't impact the kidney or bone
- used in anti-malaria, RC=A, and SLE
-
48
JAK inhibitors
- - "tinib"
- Precautions and warnings: GI perforation, birth defects and miscarriages, bone marrow suppression, hepatotoxicity, infections, lip abnormalities, increased risk of thrombosis (high doses)
48
TNF alph aantagonisy
- may use with methotrexate, glucocorticoids, or NSAIDS
- u=typicaly usedas montherapy with MTX or in combination
- adverse effects: new onset or worsening of CNS demyelination disorders, may decrease the efficacy if live vaccines, may reactivate Hep B , used with caution in patients with CHF or hematologic abnormalities
49
Anti- CD20 monoclonal antibody (Rituximab)
- chimeric MAb
- used for non-Hodgkin lymphoma, CLL, Wegener's granulomatosis, RA in combo with MTX
-common adverse effects: cough, fever, shivering, rash, pruritis, BP changes; monitor cytopenias
