NSAIDS Flashcards
What are the properties of NSAIDs?
Analgesic, anti-inflammatory, anti-pyretic
What are NSAIDs used to treat?
Pain and inflammation
What are some specific conditions NSAIDs are used for?
Surgical procedures, inflammatory diseases, osteoarthritis, rheumatoid arthritis, migraine, dysmenorrhea, myalgia, dental pain
What are NSAIDs originally derived from?
from natural sources such as the bark of the willow tree, Salix alba.
What compounds do these plants contain?
These plants contain derivatives of salicylic acid and were used to treat pain and fever.
When were these “alkaloids” (used to make NSAIDS) first chemically synthesized and with commercial production?
These alkaloids were first chemically synthesized in 1860, commercial production began in 1874
When were claims of curing rheumatic disorders first published?
Claims of being able to ‘cure’ rheumatic disorders were first published in 1876.
What is the mechanism of action of NSAIDs?
The mechanism of action was first described in 1971 as the inhibition of the enzyme cyclo-oxygenase (COX), thus preventing the synthesis of prostaglandins.
What are the two isoforms of cyclooxygenase identified in the late 1980s and early 1990s?
The two isoforms are COX-1 and COX-2.
What induces COX-2?
COX-2 is induced by cellular cytokines in localized areas of injury and in the spinal cord in response to tissue damage.
Where is COX-1 expressed?
COX-1 is expressed in low levels in many tissues, including lung, liver, spleen, kidney, and stomach.
What is the role of COX-1?
COX-1 is responsible for maintaining homeostasis.
What are conventional NSAIDs?
Conventional NSAIDs are non-specific inhibitors of both COX-1 and COX-2 isoforms. They provide:
analgesia
anti-inflammatory action
affect platelet function and protection of the gastric mucosa.
What is the advantage of newer COX-2 inhibitors?
Newer COX-2 inhibitors are thought to have a more favorable side effect profile since they spare the COX-1 isoform.
What is nociception?
Nociception is the detection of
extremes of temperature,
painful mechanical stimuli
noxious chemical stimuli by the distal ends of primary afferent neurons.
Where do primary afferent neurons terminate?
They terminate in the dorsal horn of the spinal cord, with their cell bodies located within the dorsal root ganglia.
What triggers the production of prostaglandins?
The inflammatory process triggers COX to produce prostaglandins.
What is the effect of prostaglandins on nociceptive neurons?
Prostaglandins increase the sensitivity of nociceptive neurons to bradykinin, histamine, serotonin, and other mechanical, chemical, and thermal stimuli.
What is released from membrane phospholipids in response to stimuli?
Arachidonate is released from membrane phospholipids in response to a variety of stimuli.
What does COX oxidize arachidonate to?
COX oxidizes arachidonate to PGG2, which is then further oxidized to PGH2.
What are produced from PGH2?
Prostaglandins and Thromboxanes
What does the platelet produce
Platelet produces TxA2.
What does vascular tissue produce
Vascular tissues produce PGI2 (prostacyclin).
What do mast cells produce
Mast cells produce PGD2.
What does inflamed tissue produce
Inflamed tissue produces PGE2.
biochemical pathway involved in the production of prostaglandins and thromboxanes:
Stimuli → Membrane Phospholipids → (Phospholipase A₂) → Arachidonic Acid
(COX enzyme: COX-1 & COX-2) oxidizes Arachidonic Acid → PGG₂→ further oxydize to → PGH₂
PGH₂then converted into “Tissue-specific enzymes” called prostaglandins and Thromboxanes, which are: (Extra):
Thromboxane A₂ (TxA₂) → Produced by platelets, promotes clotting (platelet aggregation) and vasoconstriction.
Prostacyclin (PGI₂) → Produced by vascular endothelial cells, has anti-clotting effects (inhibits platelet aggregation) and causes vasodilation.
Prostaglandin D₂ (PGD₂) → Produced by mast cells, plays a role in allergic reactions and sleep regulation.
Prostaglandin E₂ (PGE₂) → Produced by inflamed tissues, contributes to pain, fever, and inflammation.
What is the distribution of COX-1?
COX-1 is distributed in the GI tract, platelets, kidneys, and most other tissues.
What is the distribution of COX-2?
COX-2 is distributed in inflammatory cells, the female reproductive tract, the brain, kidneys, and cancer cells.
What inflammatory cells respond to?
Inflammatory cells respond to cytokines such as interleukin-1 and tumor necrosis factor-alpha.
What are NSAIDs?
Nonsteroidal anti-inflammatory drugs (NSAIDs) are competitive, reversible inhibitors.
What type of inhibitor is Ibuprofen?
is a competitive, reversible inhibitor.
What type of inhibitor is Indomethacin?
is a time-dependent inhibitor.
What type of inhibitor is Naproxen?
is a mixed kinetic inhibitor (slow weakly binding).
What type of inhibitor is Aspirin?
is an irreversible inhibitor.
What is the absorption characteristic of NSAIDs?
NSAIDs are rapidly and well absorbed from the GI tract.
How are NSAIDs distributed in the body?
NSAIDs are highly protein bound and found within most tissues, including synovial fluid and CSF.
What is the metabolism of NSAIDs like?
The metabolism of NSAIDs varies greatly, from non-specific esterases to complex hepatic pathways.
How are NSAIDs primarily excreted?
Excretion of NSAIDs is primarily renal.
What are some examples of COX-2 inhibitors?
Examples include Celebrex (celecoxib), Vioxx (rofecoxib), and Bextra (valdecoxib).
How do COX-2 inhibitors differ from other NSAIDs?
COX-2 inhibitors are highly lipophilic, neutral, nonacidic molecules with limited aqueous solubility.
What is unique about parecoxib?
Parecoxib (Cox 2 inhibitor) is a water soluble pro-drug of valdecoxib and may be available soon for IV or IM administration.
What are the risks associated with NSAIDs when coadministered with anticoagulants?
Increased bleeding risks, including prolonged postoperative bleeding and upper GI bleeding. Care should be exercised when coadministered with other anticoagulants (e.g., coumadin).
COX-2 inhibitors have much less interaction with anticoagulants.
What is the risk of renal injury associated with NSAIDs?
Increased risk of renal injury secondary to blockade of renal protectant prostaglandins.
COX-2 inhibitors have a reduced risk for renal insufficiency, but the risk is still present.
What cardiovascular effects can NSAIDs have?
They can cause hypertension and edema, which are related to decreased renal function in most cases.
Overall cardiac safety of COX-2 inhibitors is ??????????? (per Dave)
How do NSAIDs affect patients with hepatic and renal disease?
Patients with hepatic and renal disease may have difficulty in metabolizing and excreting these agents.
What role do NSAIDs play in postoperative regimens?
NSAIDs are an important element in balanced multimodal postoperative regimens, often combined with opioids, and may serve as an alternative to opiates in minor surgical procedures.
What makes Ketorolac a notable NSAID?
Ketorolac is one of the more potent NSAIDs and has been shown to be a more effective analgesic in surgical models compared to other NSAIDs. Its parenteral availability also makes it more practical.
What are the benefits of preoperative administration of NSAIDs?
Preoperative administration may have benefits compared to postoperative administration.
However, pre-emptive dosing may increase the risk of bleeding complications.
What is the effect of adding NSAIDs to a post-operative regimen?
It prolongs relief duration and reduces post-op nausea and vomiting.
How do NSAIDs compare to opioid in post-op pain management?
NSAIDs reduce sedation,
respiratory impairment,
sleep disturbances,
ileus/constipation,
and urinary retention.
What is the IM dosing of Ketorolac?
60 mg IM.
What is the IV/IM dosing of Ketorolac for patients <65 years?
30 mg IV/IM q6h.
What is the IV/IM dosing of Ketorolac for patients ≥65 years?
15 mg IV/IM q6h.
What is the 24-hour maximum dose for Ketorolac in patients <65 years?
120 mg/24 hours.
What is the 24-hour maximum dose for Ketorolac in patients ≥65 years?
60 mg/24 hours.
What is the maximum oral dose of Ketorolac?
40 mg/day (10 mg po q6h).
Why is the use of Ketorolac limited to 5 days?
Increased risk of GI ulceration and major bleeding episodes.
How is patient response to specific NSAIDs?
Highly patient-specific.
What is the analgesic/anti-inflammatory dose of Aspirin?
3 grams per day.
What is the cardioprotective dose of Aspirin?
81-325 mg per day (162 mg is a new common dose).
What is the dosing range for Diclofenac?
75-150 mg/day in divided doses.
What is the analgesic dose of Ibuprofen?
200-400 mg po q4-6h.
What is the anti-inflammatory dose of Ibuprofen?
400-800 mg po q6h.
What is the dosing for Naproxen?
250-375 mg twice daily (up to 375-750 mg twice daily).
What is the dosing for Celecoxib?
100-200 mg twice daily (higher doses for RA).
What is the dosing for Rofecoxib?
12.5-25 mg daily (higher dose of 50 mg can be used short-term for acute pain).
What is the dosing for Valdecoxib?
10-20 mg daily (40 mg for acute pain only, short-term use).
What are the contraindications for NSAIDs?
- History of hypersensitivity to NSAIDs
- bleeding complications
- GI disease, elderly patients
- children
- congestive heart failure
- hepatic impairment,
- renal impairment
- hypertension
- drug interactions with multiple NSAIDs, probenecid, pentoxifylline, lithium, or anticoagulant therapy.
What are the properties of Acetaminophen?
Effective analgesic and antipyretic but lacks anti-inflammatory properties.
What is the synergistic effect of Acetaminophen?
Acts synergistically with opioids and may decrease the required opioid dose.
What is the maximum daily dose of Acetaminophen? And why?
No more than 4 grams per day to prevent hepatotoxicity due to glutathione depletion.
What caution should be taken with Acetaminophen in hepatic disease?
Lower dose threshold in patients with hepatitis, alcoholism, or active liver disease.
What is the dosing for Acetaminophen IV (Ofirmev)?
1000 mg given as a 15-minute infusion.
What is the dosing for Ibuprofen IV (Caldolor)?
400-800 mg over 30 minutes every 6 hours (max 3200 mg/24 hours).
Contraindication: Not for peri-operative pain management in coronary artery bypass graft (CABG) surgery patients.
What is the dosing for Diclofenac IV (Dyloject)?
37.5 mg over 15 seconds every 6 hours (max 150 mg/24 hours).
Contraindication: Not for CABG patients.
