NSAIDs

Question 1

What is inflammation?

Answer 1

characterized by pain, redness, heat, swelling, and tenderness

Question 2

Describe the function of COX-1

Answer 2

-constitutively expressed, normal protective and maintenance physiologic functions (“housekeeping”)
-ubiquitous expression (increases during inflammation)
-pharmacologically inactivated by NSAIDs and low dose aspirin

Question 3

Describe the function of COX-2

Answer 3

-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

Question 4

What are the classifications of NSAIDs?

Answer 4

aspirin, COX-2 selective inhibitors, non-selective COX inhibitors

Question 5

What is the main use of aspirin?

Answer 5

anti-platlet effects

Question 6

Describe the MOA of aspirin:

Answer 6

irreversible inhibition of COX-1 and COX-2, covalent acetylation of Serine in the active site through the lifetime of the platelet

Question 7

What are the adverse effects of aspirin?

Answer 7

increased bleeding risk

Question 8

What is the MOA of COX-2 selective inhibitors (celecoxib)?

Answer 8

greater selectivity for COX-2 inhibition

Question 9

What are the adverse effects of COX-2 selective inhibitors?

Answer 9

increased risk of cardiovascular event

Question 10

What drug products are nonselective COX inhibitors?

Answer 10

ibuprofen, naproxen, indomethacin, ketoralac

Question 11

Describe T-cell activation:

Answer 11

-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

Question 12

Describe: Autoimmune Disease

Answer 12

immune system cannot distinguish between foreign antigen and self antigen leading to chronic inflammation

Question 13

What are the characteristics of autoimmune disorders?

Answer 13

-tissue damage
-chronic disease
-could be organ specific or systemic

Question 14

Describe rheumatoid arthritis

Answer 14

chronic, systemic, inflammatory disease that affects the joints

Question 15

Describe the role of eicosanoids in rheumatoid arthritis

Answer 15

immune complexes deposited in joints so cells in the joints and synovial fluid produce elevated levels of COX products such as PGE2 and TXA2

Question 16

What is the role of citrullination of proteins play in rheumatoid arthritis?

Answer 16

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

Question 17

What are the diagnostic tests for rheumatoid arthritis?

Answer 17

-B-cells produce anti-cyclic citrullinated peptides (CCP2 test)
-activation of IgG/IgM-Rheumatoid Factor(RF test)

Question 18

Why do patients with RA experience joint destruction?

Answer 18

chronic inflammation= abundant osteoclasts (damage bone)= synoviocytes (cartilage damage)

Question 19

What are DMARDs?

Answer 19

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

Question 20

What is the preferred DMARD?

Answer 20

conventional synthetic (csDMARDs), methotrexate

Question 21

What is the MOA of methotrexate?

Answer 21

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

Question 22

What are the boxed warnings for methotrexate?

Answer 22

-experienced antimetabolite providers-closely monitor
-serious toxic reactions -> death

Question 23

Describe Leflunomide

Answer 23

csDMARD
-MOA= inhibition of de novo pyrimidine synthesis -> decreases lymphocyte proliferation/ inhibits B-cell proliferation of activated cells (cytostatic= cell cycle arrest)

Question 24

Describe Tofacitinib

Answer 24

csDMARD
-MOA= janus kinase (JAK) inhibitor which prevents inflammatory cytokine production
-BOX WARNING= risk of opportunistic infection and malignancy

Question 25

What are the advantages of biologic DMARDs?

Answer 25

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)

Question 26

Describe Abatacept

Answer 26

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

Question 27

Describe Tociluzumab

Answer 27

monoclonal antibody against IL-6R
-MOA= competitively antagonizes IL-6 receptors -> blocks signaling and activation of B-cells and T-cells

Question 28

Describe Rituximab

Answer 28

a human/mouse chimeric IgG1 monoclonal antibody
-MOA= targets B-cell lymphocyte restricted surface antigen molecule CD20 _> rapid CD20 B-cell depletion

Question 29

What are the biologic DMARDs that target TNF-a?

Answer 29

*binds TNF-a to prevent it from binding to its receptor target
-etanercept (protein)
-infliximab
-adalimumab
-certolizumab pegol
-golimumab

Question 30

What can be used to treat asthma?

Answer 30

-relax smooth muscle contraction (many drugs to this)
-anti-inflammatory drugs

Question 31

What is the role of leukotrienes in asthma?

Answer 31

using the LOX pathway, arachidonic acid -> leukotrienes -> receptors in lungs encouraging mucus secretion and bronchoconstriction

Question 32

What drugs are leukotriene antagonists?

Answer 32

montelukast, pranlukast, zafirlukast

Question 32

What is the MOA of zileutin?

Answer 32

LOX inhibitor

Question 33

What is the MOA of montelukast?

Answer 33

inhibits leukotriene binding