NSAIDs and DMARDs Flashcards
How do prostaglandins potentiate pain?
They potentiate the stimulation of nerve endings produced by histamine or bradykinin (these cause pain)
What does pyrogen do?
Stimulate prostaglandin production in the hypothalamus, which increases body temperature (fever)
What are the GI side effects of NSAIDs?
Dyspepsia N/V blood loss ulcer GI hemorrhage
How can you decrease GI side effects of NSAIDs?
Administer w/food
What causes GI side effects?
- NSAIDs are acidic
- NSAIDs inhibit PGE2, which is cytoprotective in the gastric mucosa
- NSAIDs inhibit platelet aggregation –> bleeding
What can be used to decrease hypersensitivity from NSAIDs?
Lipoxygenase inhibitors–hyposensitivity caused by leukotrienes
What disease state is more likely to have hypersensitivity to NSAIDs?
Asthma
What is Reye’s syndrome?
A rare, acute, life-threatening condition characterized by vomiting, delirium, and coma
Who is at risk for Reye’s syndrome?
Children (<12) who have flu or chicken pox
What class of NSAIDs causes Reye’s Syndrome?
Salicylates
What are the CNS side effects of NSAIDs?
Tinnitus
Dizziness
Headache
Who is at risk for renal failure from use of NSAIDs?
Patients with cardiovascular, hepatic, and renal diseases
Order of side effect frequency of aspirin, indomethacin, naproxen, and sulindac?
Aspirin = indomethacin > naproxen > sulindac
What two drugs are used to prevent GI side effects with NSAIDs?
PPIs and misoprostol
What is misoprostol?
PGE1 analog–mucus protectant
Why is naproxen used in combination products?
It has fewer side effects than other NSAIDs
What causes the drug interactions associated with NSAIDs?
NSAIDs are highly bound to albumin
What class of drugs commonly interacts with NSAIDs?
anticoagulants
What should be done to anticoagulant dosing when administered with NSAIDs?
Decrease (NSAIDs compete for albumin, which causes more free anticoagulant in the blood PLUS NSAIDs are already antithrombotic)
What functional group do most NSAIDs have?
Carboxylic acid
Where is the acidic group located in salicylates?
Directly off of the carbon ring
Where is the acidic group located in arylacetic acids and arylpropionic acids?
1 carbon between the acid and the ring
What is the structural difference between arylpropionic acids and arylacetic acids?
Arylpropionic acids have an alpha methyl group on the carbon next to the COOH
What does a methyl group on the carbon atom separating the acidic group from the aromatic ring due to activity levels?
Increases
What does a second area of lipophilicity that is noncoplanar with the aromatic ring due to activity levels?
Enhances
What was the first salicylate derived from?
Willow and poplar bark
What form are salicylates absorbed in?
Ionic in small intestine mainly, also unionized in stomach
What enzyme do salicylates inhibit?
COX-1 and COX-2
What are the three salicylates?
Aspirin
Salsalate
Diflunisal
How does aspirin irreversibly inhibit COX?
Acetylates a serine residue in the active site
What is aspirin hydrolyzed into?
Salicylate
How does aspirin reduce the risk of MI?
It blocks TXA2–which causes platelet aggregation?
Is aspirin found in solution form?
No–not stable
What is the structure of salsalate?
Dimer of salicylic acid?
Does salsalate cause GI bleeding?
No–not active in the stomach b/c it needs to be cleaved
Where is salsalate get hydroylzed?
small intestine
Is diflunisal a more potent alangesic than aspirin?
Yes
Is diflunisal a more potent antipyretic than aspirin?
No
Does diflunisal have fewer side effects than aspirin?
yes
Does diflunisal have a longer half-life than aspirin?
Yes (3-4 times)
What are the arylacetic acids?
Indomethacin
Sulindac
Etodalc
Diclofenac
Which arylacetic acids are somewhat selective for COX-2?
Etodalc and Diclofenac
Which arylacetic acid inhibits both COX and lipoxygenase pathways?
Diclofenac
Which arylacetic acid is a prodrug?
Sulindac–sulfoxide group reduced
What is the least potent arylacetic acid?
Sulindac
Which arylacetic acids can be used for long-term use?
Sulindac, etodalc
Which arylacetic acids have lesss GI side effects?
Sulindac (prodrug)
Etodalc (COX-2 selective)
Which aryacetic acid is not stable in solution due to hydrolysis of the amide bond?
Indomethacin
Which arylacetic acid has high incidents of side effects?
Indomethacin
What is the most commonly used NSAID?
Diclofenac
What is etodalc used for?
Osteoarthritis
What is sulindac used for?
Chronic inflammation
What are the arylpropionic acids?
ibuprofen, naproxen, ketoralc
Which of the arylpropionic acids is a racemic mixture?
Ibuprofen
How does ibuprofens potency compare to aspirin and indomethacin?
In between them
Is naproxen or ibuprofen more potent?
Naproxen
What is naproxen used for?
Rheumatoid arthritis and osteoarthritis
What is the structure of ketorolac?
Cyclized heteroarylpropionic acid derivative
What is ketorolac used for?
Short term management of severe pain (as strong as an opioid)
What are the non-carboxylate NSAIDs?
Nabumetone
Meloxicam
What is the active form of nabumetone?
6-MNA
What is nabumetone good at?
Anti-inflammation (weak analgesic activity)
Does nabumetone have many gastric side effects?
Nope (prodrug)
Which NSAID is longest acting?
Meloxicam
How does meloxicam’s potency compare to aspirin and indomethacin?
About as potent as indomethacin
Which of the non-carboxylates is selective for COX-2
Meloxicam
What are the most potent anti-inflammatory NSAIDs?
Meloxicam
Indomethacin
Diclofenac
Sulindac
what are the safest and most potent NSAIDs?
Meloxicam
Diclofenac
What is the least potent NSAID?
Aspirin
What is the difference between the COX-1 and COX-2 active site?
COX-2 has a valine instead of isoleucine–makes it a larger active site
How are COX-2 selective inhibitors structurally different from non-selective?
They have larger and more rigid functional groups (b/c COX-2 has bigger binding site)
What are the 3 FDA classified COX-2 Inhibitors?
Celecoxib
Rofecoxib
Valdecoxib
What is the only selective COX-2 inhibitor still in market?
Celecoxib (Celebrex)
How do selective COX-2 inhibitors increase the risk of cardiovascular events?
They inhibit PGI2 (inhibiting platelet aggregation) but not TXA2 (which causes platelet aggregation)–> increased risk of clots (strokes, MIs, etc)
What drug is celebrex’s potency similar to?
Naproxen
What is celecoxib used for?
Rheumatoid arthritis
Osteoarthritis
Pain/inflammation/fever
What does acetaminophen do?
Reduce pain and fever (not inflammation)
How does acetaminophen work?
It scavenges peroxynitrite which is required for PGHS (COX)–only works with low levels of peroxynitrite, not during inflammation when levels are high
What is the major caution with acetaminophen?
Hepatotoxicity
What causes hepatotoxicity from acetaminophen?
It is made into N-acetylmidoquinone by CYP450, which is reduced by glutathione, Too much APAP means more is made, which means more glutathione is used. Glutathione is needed for cells, so this causes cell damage in the liver
What can make acetaminophen toxicity worse? How?
Alcohol–induces CYP450 enzyme so more N-acetylmidoquinone is made form APAP more quickly
How long do DMARDs take to act?
1 to 6 months
What is the common mechanism of action of DMARDs?
Immunosuppression
What are the 3 uses for DMARDs?
Rheumatoid arthritis
Inflammatory bowel disease
Reduce rejection in organ transplant
WHat is the first line treatment of RA?
Methotrexate
What is the MOA of methotrexate?
Inhibits ribonucleotide transformylase and thymidylate synthetase to decrease purine and pyrimidine synthesis
What are side effects of methotrexate?
Gi symptoms, stomatitis, rash, hair loss
Myelosuppression (decreased bone marrow activity)
Hepatotoxicity
Pulmonary toxicity
When is methotrexate contraindicated?
Pregnancy
What is the MOA of leflunomide?
Pyrimidine synthesis inhibitor and T cell proliferation inhibitor
What are the side effects of leflunomide?
Heptotoxicity, diarrhea, hair loss, rash
What should you monitor when taking leflunomide?
Hepatotoxicity
When is leflunomide contraindicated?
Any women of childbearing age
Is leflunomide a prodrug?
Yep
What is hydroxychloroquine?
Protein secretion inhibitor–in lysosomes
What should be monitored when taking hydroxychloroquine?
Opthalmologic monitoring for reversible retinal toxicity
What does sulfasalazine do?
Suppress release of cytokines from macrophages
How long does sulfasalazine take to work?
Several months
What needs to be monitored with sulfasalazine use?
myelosuppression
What are the active components of sulfasalazine?
sulfapyridine and 5-aminosalicylic acid
What is infliximab?
TNF blocker–chimeric
How is infliximab given?
IV every 8 weeks
What is adalimumab?
Human antibody to TNF-alpha
How is adalimumab given?
Subcutaneously every 2 weeks
What is etanercept?
TNF-alpha receptor antibody (competitively inhibits TNF-alpha)
What is the IL-1 receptor antagonist?
Anakinra
Can anakinra be used with TNF blockers?
No
What is rituximab?
Monoclonal antibody against CD20–induces apoptosis of B cells
Blocks activation of T cells
When is rituximab used?
With methotrexate if TNF-alpha blockers don’t work
What is the risk with rituximab?
Serious infection (antibody production decreases)
What is abatacept?
Fusion protein of cytotoxic T-lymphosyte associated protein 4 (CTLA4) and FC region of human antibody
How does abatacept work?
It mimics CTLA4 to bind to CD80 on APCs, thereby preventing activation of T cells
Can abatecept be combined with TNF-alpha blockers?
no
What are the side effects of abatacept?
Risk of serious infection
Risk of lymphomas
