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Pharmacology- NSAIDs

Terms in this set (79)

What is a positive immune response?
Invading organism is neutralized
Which isoform of COX is homeostatic in function?
COX-1
Memorize this diagram bc it's perfect
What are the 2 primary treatment goals for analgesic-antipyretic agents?
1) Relief of symptoms and maintenance of function 2) Slowing or arrest of the tissue-damaging process
Which treatment goal can be achieved with use of NSAIDs?
1) Relief of symptoms and maintenance of function
T/F: NSAIDs are appropriate for acute and chronic inflammatory conditions
True
NSAIDs suppress signs and symptoms of inflammation, but also exhibit ____ and ____ effects
Antipyretic and analgesic
Most of the NSAIDs are racemic mixtures which one is provided as a single enantiomer?
Naproxen
All of the NSAIDs are weak organic acids except which one?
Nabumetone (ketone prodrug metabolized to active acetic acid derivative in vivo)
What is the ADME of NSAIDs?
Acidic functional group slide
How long does aspirin irreversibly acetylate and block platelet COX for?
8-10 days (life span of a platelet)
What are the only 2 selective COX-2 inhibitors on the market?
Celecoxib and meloxicam
Which 2 classes of NSAIDs do not inhibit platelet aggregation?
COX-2 inhibitors and nonacetylated salicylates
COX-2 inhibitors have block box warnings concerning which type of risk?
CV
NSAIDs decrease the sensitivity of vessels to ____ and _____
Bradykinin and histamine
All NSAIDs are gastric irritants that can cause GI ulcers and bleeds, what other two types of toxicity can occur with NSAID use?
Nephrotoxicity and hepatotoxicity
Although NSAIDs inhibit inflammation they do NOT alter the course of any ______ disorder
Arthritic
Several NSAIDs (including aspirin) appear to reduce the incidence of which type of cancer when taken chronically with a 50% reduction in relative risk after 5 years?
Colon cancer
General AEs for all NSAIDs
NSAID Dual-Insult Mechanism
What phenomenon occurs during the primary insult in the dual-insult mechanism?
Ion trapping, COO- is trapped in the GI tract which leads to gastric damage
SA is a simply organic acid with a pKa of 3, what is the pKa of ASA?
3.5
Salicylates are rapidly absorbed from the ____ and _____ yielding a peak plasma in 1-2 hours
Stomach and upper small intestine
ASA is rapidly hydrolyzed to acetic acid and SA by which enzymes?
Esterases
What are examples of nonacetylated salicylates?
Mg choline salicylate, Na salicylate, Salicyl salicylate
Nonacetylated salicylates are less effective than aspirin, in which condition could they be preferred over COX inhibitors?
Asthma
IC50 ratios for COX-1/COX-2 displayed in class
COX-2 selective inhibitors were developed to inhibit PG synthesis induced at the site of inflammation without affecting the "housekeeping" COX-1 isoenzyme found where?
GI, kidneys, and platelets
T/F: COX-2 inhibitors have analgesic, antipyretic, and anti-inflammatory effects
True
COX-2 inhibitors do NOT inhibit synthesis of which PG in the vascular endothelium?
Prostacyclin (PGI2)
Celecoxib causes fewer ulcers than other NSAIDs but may cause _____ due to a functional group
Rashes due to sulfonamide
Celecoxib has a DI with warfarin because it is metabolized by which enzyme?
2C9
Which NSAID "preferentially" inhibits COX-2 over COX-1 and is an enol carboxamide related to piroxicam?
Meloxicam
Meloxicam is used for the treatment of most rheumatic diseases and is approved for the treatment of ______ in the USA
Osteoarthritis
Which drug is associated with less GI upset: Meloxicam or Piroxicam?
Meloxicam
Which nonselective NSAID is a phenylacetic acid derivative available in an ophthalmic preparation, topical gel, and suppository?
Diclofenac
Diclofenac is known to cause impairment of ____ and ____
Renal blood flow and GFR
What is the major metabolite of diclofenac that is responsible for 30-40% of activity
4'-hydroxy (metabolized by 3A4)
Which nonselective COX inhibitor is derived from SA but is not metabolized to SA or salicylate?
Diflunisal
Diflunisal undergoes what type of metabolism?
Enterohepatic cycle with reabsorption of its glucuronide metabolite followed by cleavage of the glucuronide to release the active moiety
Diflunisal is effective for the treatment of?
Cancer pain with bone metastases, pain control in dental surgery, and oral lesions
What is diflunisal clearance dependent on?
Renal and hepatic function so dose should be limited with impairment of either
Which nonselective COX inhibitor is a propionic acid derivative available as a topical ophthalmic, IV, and lozenge?
Flurbiprofen
What is the MoA of flurbiprofen which could be the most complex MoA of the NSAIDs?
(S)(-) enantiomer inhibits COX non-selectively but may also interact with TNF-α and NO synthesis
Why is the metabolism of flurbiprofen considered "extensive"?
(R)(+) and (S)(-) enantiomers have different pathways with no chiral conversion
T/F: Flurbiprofen undergoes enterohepatic circulation
True
Ibuprofen is a derivative of ________
Phenylpropionic acid
What are the equipotent doses of ibuprofen and aspirin for anti-inflammatory effects?
2400mg Ibuprofen=4000mg Aspirin
Oral ibuprofen has analgesic but no anti-inflammatory effects at what daily dose?
<2400mg
Ibuprofen is contraindicated for individuals who have ____ and ______
Angioedema and bronchospastic reactivity to aspirin
Concomitant administration of ibuprofen and aspirin antagonizes the _____ effect
Platelet inhibition (may also decrease total anti-inflammatory effect)
Which nonselective COX inhibitor at higher doses causes 1/3 of patients to experience HA (dizziness, confusion, depression), psychosis (rare) and ultimately discontinue use?
Indomethacin
Indomethacin is an _____ derivative
Indole
In addition to COX, what else may indomethacin inhibit?
PLA, PLC, reduce neutrophil migration, decrease T and B cell proliferation
Which nonselective COX inhibitor is a propionic acid derivative that also inhibits LOX?
Ketoprofen
T/F: In spite of dual effects on PGs and LTs, ketoprofen is not superior to other NSAIDs in clinical efficacy
True
Where do the major adverse effects from ketoprofen occur?
GI and CNS
Ketorolac is promoted for use as an analgesic and has been used to replace which opioid for mild to moderate postsurgical pain?
Morphine (may also decrease opioid requirement by 25-50%)
What is the most frequent route of administration of ketorolac?
IM or IV
Which toxicity is associated with chronic use of ketorolac?
Renal toxicity
Which drug is the ONLY non-acid NSAID currently used?
Nabumetone (resembles naproxen in structure)
Nabumetone has similar properties to other NSAIDs and may be less damaging to the stomach, but what is a downfall of using nabumetone?
High doses are often needed and it is very expensive
What is the active metabolite of nabumetone
6MNA
Naproxen is a ______ derivative
Naphthylpropionic acid
Naproxen's free fraction is significantly higher in which gender?
Women (but half life is similar to men)
Incidence of GI bleeding is low with OTC naproxen but is 2x that of which OTC NSAID?
Ibuprofen
Which NSAID has the greatest risk (9.5x) of peptic ulcers and bleeding?
Piroxicam
What are additional MoAs of Piroxicam at high concentrations?
Inhibits polymorphonuclear leukocyte (PMNs) migration and lymphocyte function, and decreases oxygen radical production
What can the acidic properties of piroxicam be attributed to?
Stabilization of negative charges in resonance forms impart acidic properties
Piroxicam is metabolized by which CYP?
Which NSAID is a sulfoxide prodrug?
Sulindac
How is sulindac metabolized?
Reversibly metabolized to active sulfide metabolite, which is excreted in the bile and reabsorbed from the intestine thus prolonging the duration of action
In addition to rheumatic disease, sulindac may inhibit the development of which types of cancer?
Colon, breast, and prostate cancer in humans and GI cancer in rats
Which NSAID has a short half life of 1-2 hours, is not often used, and is ineffective in the treatment of gout (so what is it good for exactly?)
Tolmetin
In general, all NSAIDs are about equally efficacious but choice is based on a balance of?
Efficacy, cost-effectiveness, safety, and personal factors (compliance, insurance, other drug/medical issues)
For patients with renal insufficiency, which NSAIDs are best?
Nonacetylated salicylates
Which NSAID is probably the safest for patients at high risk for GI bleeding?
Celecoxib (may be combined with omeprazole)
Some surveys suggest (Family Feud or nah?) that which 2 NSAIDs have the greatest toxicity?
Indomethacin and tolmetin
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