1. What are the 3 major pathways involved in Arachidonic Acid metabolism and what do they generate?
    • 5-LOX (lipoxygenases) --> leuokotrienes
    • COX  --> prostanoids
    • CYP450  --> epoxyeicosatrienoic acid
  2. What is released from membrane phospholipids by the hydrolyzing action of phospholipases?
    Arachidonic acid
  3. What are the two ultimate products of archidonic acid metabolism into prostanoids after being metabolized by COX?
    • Prostaglandins
    • Thromboxane
  4. Where do you find COX-1 and what happens when it is inhibited?
    • Found in most tissues
    • Inhibition leads to GI, renal, and other toxicities
  5. Where do you find COX-2?
    Neurons, kidney, bones, reproductive tissues, and some cancers
  6. Which COX (1 or 2) is inhibited by inflammatory cytokines?
    • COX-2 is highly induced (10-10,000 fold by IL-1 and TNF)
    • COX-1 shows no induction
  7. Why don't we care about COX-3?
    No "functional" COX-3 in humans; in dogs, yes
  8. Which of the pathways in AA metabolism is inhibited by inflammation?
    Only COX (cyclooxygenase)
  9. What are the first two products of COX metabolism of AA?
    • Prostaglandin G2 
    • Prostaglandin H2
  10. What stimulates COX-1 to syntehsize prostaglandins?
    Circulating hormones; normal renal function, homeostasis, gastric mucosa integrity

    Inflammatory cytokines
  11. Salicylates, APAP, and NSAIDs are responsible for what percentage of adverse drug events?
  12. Salicylates, APAP, and NSAIDs are minor analgesics that are good in relieving pain from _____ and _____?
    Injury or inflammation

  13. Antiinflammatory drugs inhibit _____ at the site of _____

    Analgesia - inhibits _____ production that sensitizes pain receptors

    Antipyretics inhibit _____ production in the _____ as a response to bacterial pyrogens and IL-1
    Prostaglandin; inflmmation


    Prostanoid; CNS (hypothalamus)
  14. _____ induces neurotransmitters, such as cAMP, to reset the body's temperature set point in response to bacterial pyrogens. This causes _____, _____, and _____.
    • PGE2
    • Fever; somnolence, lethargy
  15. Where are NSAIDs normally absorbed?
    Upper small intestine
  16. What percentage of NSAIDs are bound to albumin plasma proteins?
  17. What are the main enzymes that metabolize NSAIDs in the liver?
    UGT and SULT
  18. How are NSAIDs excreted?
    • Renally - filtration and active transport
    • SOME hepatic elimination
  19. What is the most common effect of NSAID toxicity?
    • Gastric or intestinal ulceration
    • (PGE2 actively promotes protective gastric juices, which are inhibited by taking NSAIDs)
  20. H2 blockers (ranitidine) are not effective at preventing gastric ulceration, but PPIs can be effective prophylactically or as treatment.

    Another treatment is _____, which is a PGE2 analog
    Misoprostol (Cytotec)
  21. Renally, what can happen because of NSAID toxicity?
    • Decreased blood flow
    • Increased hypertension
    • Increased retention of water, Na+, K+
  22. NSAIDs can inhibit TxA2, which can be a problem.  Why?
    Causes problems with platelet aggregation, bleeding
  23. What is the COX-2 hypothesis?
    Selective COX-2 inhibitors should cause less GI ulcerations than non-selective COX inhibitors
  24. Historically, where do salicylates originate?
    • Willow Bark
    • Oil of Wintergreen
  25. Salicylic acid inhibits _____ in vivo, but doesn't inhibit _____ in vitro.
    • Prostaglandin
    • COX enzymes
  26. Aspirin inhibits TxA2 production, which results in what?
    Irreversible decreased platelet aggregation, bleeding
  27. What is unique about aspirin's half-life?
    Dose dependent
  28. What is a unique, non-dose-dependent AE occasionally seen in aspirin?
  29. What is Reye's Syndrome and when might it occur?
    Sudden loss of consciousness, cerebral edema, fatty liver and renal tubules, brain damage upon recovery

    Salicylates in conjunction with chickenpox or flu
  30. What might happen in pregnant women taking aspirin?
    Premature closure of ductus arteriosus
  31. APAP has very little _____
    Antiinflammatory properties
  32. What enzyme metabolizes APAP after it has saturated the UGT and SULT pathways?
    CYP 2E1
  33. What are 2 ways to induce CYP 2E1?
    • Alcohol
    • Fasting
  34. What are 2 treatments for APAP hepatotoxicity?
    • Activated charcoal
    • N-acetylcysteine
  35. APAP is not an effective antiinflammatory, but has antipyretic and analgesic properties.  It primarily acts where?
    In the CNS
  36. NSAIDs function as competitive inhibitors of what?
    Arachidonate (AA) binding sites
  37. NSAIDs reversibly/irreversibly inhibit platelet aggregation.
  38. NSAID drug of choice due to low toxicity - metabolized by CYP 2C9 (which it also inhibits)
  39. NSAID of choice due to low toxicity profile - LONG t1/2
  40. Drug of choice for gout - frequent adverse effects (35-50%)
  41. Available with misoprostol (Arthrotec) to decrease GI toxicity
  42. The only NSAIDs that appear that appear to be effective for the regression of colorectal polyps
    Sulindac and celecoxib
  43. Only for analgesic purposes, but too toxic for extended use
    Mefenamic Acid
  44. Can be as effective as opiates for pain, high GI toxicity
  45. Name the 2 Class I salicylates.
    • Aspirin
    • Diflunisal
  46. Name the Class II para-aminophenol.
  47. Name 5 Class III traditional NSAIDs.
    • Diclofenac
    • Ibuprofen
    • Naproxen
    • Indomethacin
    • Ketorolac
    • Meloxicam
    • Nabumetone
    • Naproxen
    • Piroxicam
    • Sulindac
  48. Name the Class IV (COX-2 selective inhibitor)
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