McPhail Exam 4 Flashcards
Mechanism of methotrexate
inhibits dihydrofolate reductase, which is involved in the de novo synthesis of thymine. Also causes the release of adenosine into the bloodstream and tissues, which has anti-inflammatory effects
Methotrexate interaction
NSAIDs increase the blood concentrations of methotrexate
What is the active metabolite of leflunomide
A77 1726
A77 1726 mechanism
inhibits dihydro-orotate dehydrogenase, which is required for pyrimidine biosynthesis. It also inhibits tyrosine kinase, which would interfere with T and B cell proliferation. The cells become non-responsive to cytokines and inflammatory signals.
Thalidomide mechanism
reported to decrease circulating TNF-a in patients with erythema nodosum leprosum but increase it in patients who are HIV seropositive
Methotrexate indication
Rheumatoid arthritis
Leflunomide indication
Rheumatoid arthritis
Thalidomide indication
erythema nodosum
Echinacea mechanism
has no direct antibacterial activity, but stimulates the innate immune system by increasing phagocytosis and the release of TNFs and interferons from macrophages and T cells
Levamisole class
Immunorestorative agents/immunostimulants
Levamisole mechanism
Mimics thymic hormone thymopoietin, which is probably why it’s effective. Restores depressed immune function of B cells, T cells, monocytes, and macrophages caused by chemotherapy.
Imiquimod mechanism
toll like receptor 7 agonist that stimulates the immune system to produce interferon-α and other cytokines (IL-1,6,8,10,12, TNF-α) and activates macrophages, NK cells, TH¬1 cells, and B cells
Vaccine definition
suspensions of attenuated or dead microorganisms administered for prevention amelioration, or treatment of infectious diseases
What type of T cells do vaccines stimulate
TH2
Killed (inactivated) pathogens
denaturing disinfectant kills pathogen, allows recovery of the surface antigens, but this risks losing antigenicity
Live/attenuated pathogens
pass the pathogen through many generations of host animals to yield low virulent strain. Some viruses are too dangerous even at low virulence and they can regain virulence.
Live/attenuated related strain
cowpox virus used in place of smallpox virus
Cellular antigen from a pathogen
isolate the surface antigen from the pathogen, purify it and reconstitute into a vaccine preparation
Genetically engineered pathogens
clone a piece of DNA encoding the surface antigen from the pathogen and over produce the antigen. This way you don’t have to expose workers to the pathogen and lower risk.
Simple vaccine
contains only one kind of antigen or strain
Multivalent vaccine
contains two or more kinds of antigens or strains that cause the same disease
Polyvalent vaccine
contains two or more kinds of antigens or strains that cause different diseases
Single-dose vaccine
needed only once during lifetime
Multiple-dosing regimen
several doses needed to get full protection
Booster dose
needed to bolster/reinforce protection after some time
Co-administered vaccine
only if they don’t interfere with each other
Viral vaccines examples
smallpox, influenza, polio, chickenpox, rubella, hepatitis, measles, rotavirus, mumps, HPV
Bacterial vaccines examples
pertussis, tuberculosis, meningococcal, cholera, haemophilus influenza type B, pneumococcal
Toxoids
denatured pathogens the bacteria would produce
What are the two subtypes of antibodies?
immunoglobulins (polyclonal) and monoclonal antibodies
What are the two major uses for antibodies in the treatment of human disease?
to neutralize and eliminate toxic molecules or to eliminate target cells
What are the four ways antibodies can eliminate target cells?
antibody-mediated cell growth control (bound antibodies block binding of growth factors)
antibody-mediated reticuloendothelial clearance aka macrophage system (antibody-costed target cells can be engulfed by phagocytes)
complement-mediated cytotoxicity aka CMC (IgG and IgM binding to cells elicits complement, leading to the formation of a membrane attack complex)
antibody-dependent cell-mediated cytotoxicity aka ADCC (large cells can be killed by cytotoxic substances released by macrophages and killer cells)
human immunoglobulin examples
rabies, tetanus, hepatitis B, rho
Digibind origin
Fab fragment of the IgG isolated from sheep immunized against digoxin
Digibind mechanism
It tightly binds digoxin, shifting the equilibrium away from drug receptor complex formation
What are the two types of anti-thymocyte globulin and what is the difference?
Thymoglobulin is from rabbits
Atgam is from horses
Indication for anti-thymocyte globulin
Rejection of transplanted kidney, aplastic anemia in patients who are not suitable for bone marrow transplant, interim treatment until bone marrow transplant
anti-thymocyte globulin mechanism
depletes circulating T-lymphocytes by direct killing, blocks lymphocyte function by binding to cell surface molecules involved in the regulation of cell function, which suppresses the cascade of immune cells.
monoclonal antibody definition
an antibody synthesized from a single clone of B-lymphocytes or plasma cells
polyclonal antibody definition
multiple immunoglobulins responding to different epitopes on an antigen molecule
chimeric antibody
66% human
constant region from human, antigen-binding region from mouse
humanized antibody
> 90% human
only specific antigen binding sites (sugar fragments) from mice
How do we make chimeric/humanized/fully human antibodies?
recombinant genetic engineering
amab
rat
emab
hamster
imab
primate
omab
mouse
umab
human
ximab
chimerized
zumab
humanized
Indication for MAbs that attach to a T cell receptor
used to stop rejection of transplanted organs
What compounds did we cover that attach to a T cell receptor
muromonab-CD3 (OKT3), basiliximab, belatacept
OKT3 generic
muromonab-CD3
OKT3 mechanism of action
Interacts with the CD3 marker of human T cells and flags them for destruction. Decreases T cell numbers in the blood within minutes
Basiliximab mechanism of action
binds to the IL-2 receptor of activated T cells as a competitive antagonist
Mechanism of action for belatacept
cytotoxic T lymphocyte associated antigen 4 (CTLA4) interrupts CD28 costimulation of T cell, resulting in an attenuation of interleukin 2 and interleukin 2 receptor (T cell anergy) and arrest of T cells at the G1 phase of the cell cycle (T cell apoptosis). Belatacept is a soluble recombinant fusion protein that mimics CTLA4
What MAbs did we cover for lymphomas?
rituximab, alemtuzumab, brentuximab vedotin, tositumomab I-131, and Y-90-labeled ibritumomab tiuxetan
Indications for rituximab
cancer, follicular lymphoma, Wegener’s granulomatosis, and microscopic polyangiitis
Rituximab mechanism of action
binds to CD20, which is distributed on more than 90% of B cell non-Hodgkin’s lymphomas but also present on normal B cells. However, since the cancer results in an overproduction of B cells, more of them are wiped out than the normal B cells.
Indication and target for alemtuzumab
indication: B-cell chronic lymphocytic leukemia
target: CD52
Bentuximab vedotin indication
Hodgkin’s lymphoma and systemic anaplastic large cell lymphoma
Three components of bentuximab vedotin
The chimerized IgG1 antibody cAC10, specific for human CD30
The microtubule disrupting agent MMAE
A protease-cleavable linker that covalently attaches MMAE to cAC10
Bentuximab vedotin mechanism of action
CD30 is prevalent in HL and sALCL but has limited expression in healthy cells. Binding of brentuximab to CD30 on the cell surface initiates internalization of the ADC-CD30 complex. Inside the cell, MMAE is released via proteolytic cleavage. Binding of released MMAE to tubulin disrupts the microtubule network, which interferes with cell division, inducing apoptotic cell death.
Tositumomab I-131 target
CD20
Tositumomab mechanism of action
induces normal immunological reactions and radioimmunoconjugates deliver cytotoxic ionization radiation. High energy beta particles emitted by I-131 are cytotoxic over distances of about 1-2mm, therefore also kills cells that are inaccessible to the antibody.
Y-90-labeled ibritumomab tiexetan target
CD20
HER2
an oncogene in breast cancer that stimulates cell division
Anti-HER2 MAbs
Tratuzumab, Ado-tratuzumab emtansine
Trastuzumab mechanism of action
Anti-HER2 antibodies inhibit HER2-mediated signaling in cancer cells by blocking the extracellular receptor of HER2/neu, ultimately upregulating the levels and activity of p27 (Kip1) protein (an important cell dependent kinase (Cdk) inhibitor), which leads to cell cycle G1 arrest and growth inhibition.
At least six signaling targets and pathways are modulated by trastuzumab
mechanism of emtansine/DM1
a maytansinoid that disrupts microtubule function
MAbs that bind to epidermal growth factor receptor
Cetuximab, panitumumab
Indication for cetuximab and panitumumab
EGFR expressing metastatic colorectal cancer (after disease progression following all available chemotherapy regimens).
cetuximab and panitumumab mechanism of action
prevents ligand binding at the epidermal growth factor receptor, which inhibits cancer cell growth
MAbs for rheumatoid arthritis and Crohn’s disease
infliximab, adalimumab, tocilizumab, etanercept
Infliximab mechanism of action
binds to both free and membrane bound TNF-α. Blocking TNF-α slows the progression of the disease
infliximab indications
rheumatoid arthritis, Crohn’s disease, and ankylosing spondylitis
adalimumab target
TNF-alpha
tocilizumab target
IL-6 receptor
etanercept mechanism of action
binds TNF-α, slowing down/stopping joint damage by preventing it from binding to immune cells
MAbs for asthma and allergic rhinitis
omalizumab, mepolizumab
omalizumab mechanism of action
selectively binds to circulating IgE, so prevents binding of IgE to mast cells and other effector cells. Without surface-bound IgE, these cells are unable to recognize allergens, so prevents cellular activation by antigens and the subsequent allergic reactions
mepolizumab target
IL-5 receptor on eosinophils
efalizumab indication
psoriasis
efalizumab mechanism of action
Inhibits the interaction of CD11a (LFA-1) with various ICAM molecules. Because ICAM-1 (CD54) is expressed on activated endothelial cells and antigen presenting cells (APCs), the antibody inhibits both the APC-T cell interaction and the T cell adhesion to endothelial cells, preventing trans-endothelial migration so immune cells can’t get into the tissues
Interferon alpha 2b indications
Hairy cell leukemia, malignant melanoma, follicular lymphoma, Kaposi’s sarcoma, chronic hepatitis B, Roferin-A also has the indication of Chronic Granulomatous Disease
Interferon beta-1a indications
neurological exacerbations in relapsing-remitting multiple sclerosis
Interferon beta-1b indications
neurological exacerbations in relapsing-remitting MS
How does commercial IL-2 differ from natural IL-2
commercial IL-2 differs from native IL-2 in that it’s not glycosylated, has no terminal alanine, and a serine is substituted for cysteine-125 (serine has an OH and cysteine has an SH)
IL-2 indications
cancer, especially metastatic renal cell carcinoma
IL-11 indications
following myelosupressive chemotherapy in patients with nonmyeloid malignancies
Effects on anakinra
When given alone or in combination with methotrexate it improves clinical signs and symptoms, decreases radiographic progression, improves patient function, decreases pain and fatigue, and slows bone erosion and degradation of the joint.
Target for anakinra
blocks the binding of IL-1
growth factor definition
control the expansion, proliferation, and differentiation of myeloid cells
G-CSF
granulocyte colony stimulating factor
M-CSF
macrophage colony stimulating factor
GM-CSF
granulocyte macrophage colony stimulating factor
Multi-CSF
multi-lineage colony stimulating factor
EPO
erythropoietin
TPO
thrombopoietin
What produces/secretes CSFs
activated T cells or macrophages
What produces/secretes erythropoietin
endothelial cells and fibroblasts
What is the difference between filgrastim and pegfilgrastim?
pegfilgrastim has polyethylene glycol attached
mechanism of action of the G-CSF analogs
stimulates the bone marrow to produce more white blood cells
G-CSF analog examples
filgrastim, pegfilgrastim
G-CSF analog indication
neutropenia due to non-myeloid cancer chemotherapy or severe chronic neutropenia or after bone marrow transplant
G-CSF risk
could promote growth of malignant myeloid cells in blood cancers
GM-CSF examples
sargramostim, erythopoietin
sargramostim indication
autologous bone marrow replacement
sargramostim mechanism
hastens myeloid reconstitution
epoetin alfa indications
kidney dialysis, chemotherapy in non-myeloid malignancies
Difference between epoetin alfa and darbepoetin alfa
Darbepoetin alfa differs from epoetin alfa by having two extra carbohydrate chains, which gives it greater metabolic stability – it has a three-fold longer half-life
Indications for darbepoetin alfa
anemia associated with chronic renal failure, cancer chemotherapy
induction of immunosuppression
Medications given immediately after transplantation in intensified doses for the purpose of preventing acute rejection (up to 30 days)
Not used for long-term for immunosuppressive maintenance
Includes methylprednisolone, atgam, thymoglobulin, OKT3, and basiliximab
maintenance of immunosuppression
Medications given before, during or after transplant with the intention to maintain them long-term
Maintenance immunosuppression does not include any immunosuppressive medications given to treat rejection episodes or for induction of immunosuppression
Includes prednisone, cyclosporine, tacrolimus, mycophenolate mofetil, azathioprine, or rapamycin
anti-rejection immunosuppression
Medications given for the purpose of treating an acute rejection episode during the initial post-transplant period or during a specific follow up period, usually up to 30 days after the diagnosis of acute rejection
Includes methylprednisolone, atgam, OKT3, thymoglobulin, and basiliximab
role of analgesics in treating RA
relieve pain
role of NSAIDs in treating RA
relieve pain and reduce inflammation
*only stops the prostaglandin inflammation process, the other pathways keep going
role of steroids in treating RA
relieve pain and reduce inflammation
role of DMARDs in treating RA
reduce pain, swelling, and tenderness as well as slow joint damage
role of biologic medicines in treating RA
targeted treatment to relieve pain and swelling and slow joint damage
old treatment for RA
used to relieve symptoms until it got too bad then address the disease
new treatment for RA
treat to stop it from progressing as far as the patient gets older
RA pathophysiology
Activated T cells stimulate macrophages and fibroblast-like synoviocytes. These generate proinflammatory mediators and proteases, which induces a synovial inflammatory response and destroys the cartilage and bone. Proinflammatory cytokines released by synovial macrophages include TNF-α, IL-1, 6, 12, 15, 18, and 23.
Biologic agents whose main indication is RA
infliximab, adalimumab, ankinra, rituximab, tocilizumab, etanercept
nonpharmacological treatments for RA
exercise, diet (less animal products and more leaves), stress reduction, physical therapy, and surgery
Medication based therapies for RA
NSAIDs, nonbiologic and biologic DMARDs, immunosuppressants, and corticosteroids
Comparison of DMARDs and biologics in regards to deliver method
DMARDs are usually oral, and methotrexate is usually given just once a week. Biologics are usually injected under the skin or given IV, and administration ranges from daily to monthly
Comparison of DMARDs and biologics in regards to drug target
DMARDs target the entire immune system, while biologics work by targeting specific steps in the inflammatory process.
Comparison of DMARDs and biologics in regards to response time
it can take months before it is known whether a DMARD is working. With biologics, results are likely seen within 4-6 weeks, after just a few treatments. In the meantime, an NSAID or a steroid medication may relieve pain and swelling.
Comparison of DMARDs and biologics in regards to risks
both DMARDs and biologics can increase risk for infections. Serious infections, such as pneumonia, are the biggest risk of taking a biologic.
