NSAIDs and COX-2-Selective Inhibitors

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NSAIDs and COX-2-Selective Inhibitors

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History and Background

• NSAIDs
• Most often used nonopiod analgesics
• 70 million prescriptions were given in 1991
• 2.2 billion cost, worldwide over 6 billion per
  year
• First extracted from the bark of the willow
  tree(salix alba)
• Documented for use in fever since at least 1827
• Synthesized in 1899 by Felix Hoffman
• In 1971, discovered aspirin acts an inhibitor of
  COX, preventing of PG

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• Contains compounds that are chemically unrelated
• Grouped based on their therapeutic actions
• Have analgesic, anti-inflammatory, antipyretic
  properties
• Do not demonstrate tolerance, often more
  effective at controlling certain pain with fewer
  side effects than opioid
• usually supplementating rather than replacing
  the role of opioid

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Must be cautious

• Majority of studies with patients are rheumatic
  or other arthritic conditions
• lack of association between analgesia and
  anti-inflammatory effect
• Dosage requirement is different
• defference in the pain model used
• Most studies performed in elderly patients
• concomitant medical conditions
• NSAIDs are actually not analgesics
• antihyperalgesics

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Mechanism of Action

• Prostaglandin Physiology
• NSAIDs provide analgesia primarily through
  actions outside the CNS
• traditional concept
• by inhibiting the formation of PG
• Arachidonic acid
• broken down by lipooxygenase system or COX
  enzyme system
• PGG2 or LT pathway

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Prostaglandins and Pain Peripheral Actions

• Prostaglandin
• not important mediators of pain transmission
• contribute to hyperalgesia peripherally by
  sensitizing nociceptive sensory n. endings to
  other mediators and by sensitizing nociceptors to
  respond to non-nociceptive stimuli
• elevation of resting mem. potential and
  reduction in the firing threshold

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Prostaglandins and Pain Central Actions

• direct actions at the level of the spinal cord
  to enhance nociception at the terminals of
  sensory neurons in the dorsal horn
• inc. release of neurotransmitters
• inc. the sensitivity of second-order neurons
• inh. the release of descending inhibitory
  neurotransmitters

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• Upregulation
• direct neural input
• humoral factors
• IL-6 trigger the IL-1b in the CNS, inc.
  production of COX-2 and PGE2

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COX Isoforms

• The two isoforms
• about 60 identical in molecular structure
• significant difference in expression and
  functions
• Type I COX
• present in variable amounts in most cells
• platelet, kidney, stomach, vascular smooth m.
• protecting gastric mucosa, ensuring proper
  platelet function, maintaining renal function
• Type II COX
• almost undetectable in most tissue under normal
  physiologic conditions
• inc. during inflammation 10 to 80 folds
• key in the production of hyperalgesia following
  injury
• responsible for forming PG in the periphery and
  CNS
• COX-3
• genetic modification of the COX-1 enzyme
• play a role in CNS pain processing

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NSAIDs Analgesic Actions

• Preventing sensitization of peripheral
  nociceptors by diminishing PG formation
• Inhibiting the release of inflammatory mediators
  from neutrophils and macrophages
• Reversing the inhibition by PGs of the descending
  opioid-mediated noradrenergic pathways inv. in
  pain inhibition

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COX-2 Selectivity of NSAIDs

• Aspirin irreversible inhibition of both COX-1
  and COX-2
• Ibuprofen reversible competitive inhibition of
  both
• Flurbiprofen and indomethacin slower,
  time-dependent inhibition
• Celecoxib, rofecoxib, valdecoxib, etoricoxib,
  parecoxib largely COX-2 selective

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Enantiomer Activity

• Most of the COX inhibitory activity lies with the
  S form
• Peripheral analgesia is only mediated by the S
  form
• R and S form both mediate central analgesia

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Pharmacokinetics

• Have similar pharmacokinetic characteristics
• rapidly and extensively absorbed after oral
  administration
• tissue distribution is very limited
• metabolized extensively in the liver with little
  dependence on renal elimination
• have low clearances
• Toxicity may be related to their plasma
  half-lives
• difference in efficacy is more related relative
  dose than property of medications

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Toxicity

• GI side effects added 45 to the cost of treating
  arthritis pts.
• 72 is epigastric discomfort
• Greater with inc. age
• M/c reactions GI, dermatological,
  neuropsychiatric
• M/s reactions GI, renal, hematologic, hepatic
  organ sys.

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Gastrointestinal Toxicity

• Gastric distress alone and actual damage with
  ulceration
• Dyspepsia, GI bleeding, perforation, topical
  irritation
• Alteration in GI function
• mucus and bicarbonate secretion
• blood flow
• epithelial cell turnover and repair
• mucosal immunocyte function
• By topical irritation and result of inhibition of
  PG synthesis

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• Risk factors
• age over 60yrs
• prior history
• steroid use
• alcohol use
• multiple NSAIDs use
• first 3months of use
• Sucralfate
• Basic aluminium salt
• Mechanisms
• forming a complex with proteins at an ulcer base
• stimulating PG synthesis in gastric mucosa
• promoting gastric mucus secretion by
  PG-independent mechanism
• Misoprostol
• Synthetic analogue of PGE1
• H/Na ATPase inhibitors
• R enantiomers og NSAIDs
• Nitric oxide

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Renal Toxicity

• 18 of pts., 6 ARF
• Reduction in renal perfusion, acute interstitial
  nephritis, nephrotic syndrome, allergic nephritis
• PGI2 and PGE2
• vasodilators
• attenuate the effect of angiotensin II, renal
  sympathetic nerve activity, catecholamines
• PGH2 and TXA2
• potent renal vasoconstrictors
• Renal response to an NSAIDs contingent on the
  relative amounts of these compounds

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• Renal prostaglandin-dependent state(RPDS)
• volume depletion
• low cardiac output
• hepatic cirrhosis
• renal ischemia
• aminoglicoside toxicity
• unilat. or subtotal nephrectomy
• HTN and DM
• Sulindac
• Theoretical advantages in pt. at risk for renal
  toxicity
• COX-2-selective inhibitors
• No evidence of additional safety benefit in terms
  of renal toxicity

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Hematologic Toxicity

• TXA2 as a platelet activator and vasoconstrictor
• PGI2 as a platelet inhibitor and vasodilator
• Aspirin takes 7-10days for platelet to recover
• Nonaspirin NSAIDs resolve drug is mostly
  eliminated
• Most NSAIDs potentiate the anticoagulant activity
  of warfarin
• by displacing the protein-bound drug
• by inhibiting metabolism by hepatic microsomal
  enzyme
• COX-2-selective inhibitors
• No effects on plaetlet function even in
  supratherapeutic doses d/t lack of COX-2 in
  plaetlet

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Hepatic Toxicity

• 3 of pts.
• Seems to be immunologic or metabolic
• Sulindac and diclofenac
• high risk of producing hepatic damage

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Effects on Bone Healing

• Both play a role in bone healing following Fx.
• Reduce the rate of successful fusion
• Nonselective NSAIDs have a greater effect on
  inhibiting bone healing than do the
  COX-2-selective inhibitors

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Asthma

• Aspirin-induced asthma(AIA)
• present in 10 of asthmatics
• not a true allergy
• diversion of arachidonic acid breakdown from COX
  pathway to lipooxygenase pathway
• Cox-2-selective inhibitors - not trigger this
  reaction

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Specific Drugs
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Highly Selective COX-2 Inhibitors

• Celecoxib, rofecoxib, valdecoxib, etoricoxib,
  lumericoxib
• Reduced GI morbidity and complete lack of effect
  on platelet function
• Renal effects may be the same as nonselective
  NSAIDs
• Rofecoxib
• unique cardiovascular and renal toxicity profile
  inc. in coagulability

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Combination Drugs

• Ibuprofen containing hydrocodone
• Diclofenac with misoprostol
• Ibuprofen with caffeine

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Role in Acute Pain Management

• Providing critical synergy to opioid analgesia
• 3 areas is important dosing, timing, toxicity
• Demonstrating a ceiling effect in efficacy but
  remain a dose-response relationship up to ceiling
• Doesn't matter whether analgesia is given before
  or after surgical insult
• Toxicity issues relevant to the postsurgical pt.
  often limit their use

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Future Trends

• Improved understanding of the role of PG in
  nociception and normal physiology
• Developing NSAIDs to effect isolated to the CNS
  with complete lack of the peripheral toxic
  effects
• Development of nitric oxide NSAID and COX-3