NSAIDs Flashcards
What is inflammation?
characterized by pain, redness, heat, swelling, and tenderness
Describe the function of COX-1
-constitutively expressed, normal protective and maintenance physiologic functions (“housekeeping”)
-ubiquitous expression (increases during inflammation)
-pharmacologically inactivated by NSAIDs and low dose aspirin
Describe the function of COX-2
-inducible by inflammatory mediators TNF-a and IL-1 (due to stress or injury)
-expressed in inflamed tissue and during chronic inflammation
-pharmacological inactivated by NSAIDs
What are the classifications of NSAIDs?
aspirin, COX-2 selective inhibitors, non-selective COX inhibitors
What is the main use of aspirin?
anti-platlet effects
Describe the MOA of aspirin:
irreversible inhibition of COX-1 and COX-2, covalent acetylation of Serine in the active site through the lifetime of the platelet
What are the adverse effects of aspirin?
increased bleeding risk
What is the MOA of COX-2 selective inhibitors (celecoxib)?
greater selectivity for COX-2 inhibition
What are the adverse effects of COX-2 selective inhibitors?
increased risk of cardiovascular event
What drug products are nonselective COX inhibitors?
ibuprofen, naproxen, indomethacin, ketoralac
Describe T-cell activation:
-antigen presenting cells (macrophages and dendritic cell) display protein fragments or peptides (antigens) to their surface
-antigens presented by MHC II proteins are recognized by T-cells carrying CD4 that downstream releases cytokines
-costimulatory signals are required for T cell activation so in the cases of self-antigens there is no costimulatory signal so no T cell activation
Describe: Autoimmune Disease
immune system cannot distinguish between foreign antigen and self antigen leading to chronic inflammation
What are the characteristics of autoimmune disorders?
-tissue damage
-chronic disease
-could be organ specific or systemic
Describe rheumatoid arthritis
chronic, systemic, inflammatory disease that affects the joints
Describe the role of eicosanoids in rheumatoid arthritis
immune complexes deposited in joints so cells in the joints and synovial fluid produce elevated levels of COX products such as PGE2 and TXA2
What is the role of citrullination of proteins play in rheumatoid arthritis?
L-arginine is citrullinated by peptidyl arginine deaminase (PAD) which cause protein unfolding and degradation of the protein. citrullinated auto-antigen activates T-cells causing a release of cytokines and other immune cells
What are the diagnostic tests for rheumatoid arthritis?
-B-cells produce anti-cyclic citrullinated peptides (CCP2 test)
-activation of IgG/IgM-Rheumatoid Factor(RF test)
Why do patients with RA experience joint destruction?
chronic inflammation= abundant osteoclasts (damage bone)= synoviocytes (cartilage damage)
What are DMARDs?
Disease Modifying anti-Rheumatic Agents= halt/slow the disease process in the synovium improving the patients daily life by decreasing the disabling potential which can be seen in improved radiographic progression
-may take 2 weeks to 6 months to become clinically evident
What is the preferred DMARD?
conventional synthetic (csDMARDs), methotrexate
What is the MOA of methotrexate?
low-dose therapy gives the MOA for autoimmune disease
-> inhibits AICAR transformylase (ATIC) -> increased cAMP -> inhibits inflammation and suppresses immune function
high-dose gives rise to other MOA
What are the boxed warnings for methotrexate?
-experienced antimetabolite providers-closely monitor
-serious toxic reactions -> death
Describe Leflunomide
csDMARD
-MOA= inhibition of de novo pyrimidine synthesis -> decreases lymphocyte proliferation/ inhibits B-cell proliferation of activated cells (cytostatic= cell cycle arrest)
Describe Tofacitinib
csDMARD
-MOA= janus kinase (JAK) inhibitor which prevents inflammatory cytokine production
-BOX WARNING= risk of opportunistic infection and malignancy
What are the advantages of biologic DMARDs?
they are proteins (generally, monoclonal antibodies) directed against cytokines or other cell surface molecules and can begin working in 2-6 weeks (shorter than the synthetic DMARDs)
Describe Abatacept
recombinant fusion protein
-MOA: IgG like and blocks CD28-dependent co-stimulation by binding B7/CD80/CD86 co-stimulatory molecules on APCs -> no T-cell activation
Describe Tociluzumab
monoclonal antibody against IL-6R
-MOA= competitively antagonizes IL-6 receptors -> blocks signaling and activation of B-cells and T-cells
Describe Rituximab
a human/mouse chimeric IgG1 monoclonal antibody
-MOA= targets B-cell lymphocyte restricted surface antigen molecule CD20 _> rapid CD20 B-cell depletion
What are the biologic DMARDs that target TNF-a?
*binds TNF-a to prevent it from binding to its receptor target
-etanercept (protein)
-infliximab
-adalimumab
-certolizumab pegol
-golimumab
What can be used to treat asthma?
-relax smooth muscle contraction (many drugs to this)
-anti-inflammatory drugs
What is the role of leukotrienes in asthma?
using the LOX pathway, arachidonic acid -> leukotrienes -> receptors in lungs encouraging mucus secretion and bronchoconstriction
What drugs are leukotriene antagonists?
montelukast, pranlukast, zafirlukast
What is the MOA of zileutin?
LOX inhibitor
What is the MOA of montelukast?
inhibits leukotriene binding
