Chapter 16 NSAIDs and COX-2-Selective Inhibitors

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Chapter 16NSAIDs and COX-2-Selective Inhibitors

• Jeffrey A. Katz, M.D.
• R2 Lee Seung Il

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Mechanism of ActionProstaglandin Physiology
Cell membrane phospholipid
Phospholipase A2
Cell membrane damage
Arachidonic acid
Cyclooxygenase 1 2
Lipooxygenase
Prostaglandin G2
Leukotriene B4, LTC4, LTD4, LTF4
Prostaglandin H2
Tissue specific prostaglandins synthase
Thromboxan A2, Prostacyclin (PGI2), PGD2, PGE2,
PGF2
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Mechanism of ActionProstaglandins and Pain
Peripheral actions

• Hyperalgesia ?
• (1) sensitize nociceptive sensory nerve endings
• to other mediators (ex. histamine,
  bradykinin)
• (2) sensitize nociceptors to respond
• to non-nociceptive stimuli (ex. touch)
• PGE2 bind to receptors on nociceptive nerve
  ending
• ? phosphokinase action ?
• ? sodium channel permeability ? intracellular
  Na ?
• ? reduction in the firing threshold
• ? low-intensity stimuli cause pain

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Mechanism of ActionProstaglandins and Pain
Central actions

• Direct actions at the level of the spinal cord
• - enhance nociception
• - notably at terminals of sensory neurons in
  dorsal horn
• Enhance pain transmission
• (1) release of neurotransmitter (ex. substance
  P, glutamate)
• from primary nociceptive afferents ?
• (2) sensitivity of second-order neurons
• responsible for nociceptive transmission
  ?
• (3) release of descending inhibitory
  neurotransmitters ?

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Mechanism of ActionProstaglandins and Pain
Central actions

• Both COX-1 and COX-2 are present in CNS
• Intrathecal injection of selective inhibitors
• ? Inhibition of COX-2 and not COX-1 reduce
  hyperalgesia
• Inflammatory injury ? COX-2 in CNS ?
• - IL-6 triggers formation of IL-1? in the CNS
• - IL-1? causes increased production of COX-2
  and PGE2
• ? hyperalgesia
• humoral response
• not only in segment of spinal cord of injured
  area
• but throughout CNS including thalamus
  cerebral cortex

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Mechanism of ActionCOX Isoforms

• Type I COX (COX-1)
• constitutive form
• - GI cytoprotection (prostacyclin)
• - platelet aggregation (thromboxan A2)
• - maintaining of renal blood flow
  (prostaglandin E2)
• Type II COX (COX-2)
• inducible form during inflammation
• - inflammation ? fever, pain, headache
• - constitutive in brain and renal cortex
• - carcinogenesis
• both in the periphery and CNS

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Mechanism of ActionCOX Isoforms
IC50 ratio mean inhibitory concentration of drug
to inhibit COX-2 vs COX-1 by 50

• Selectivity of various NSAIDs for COX-1 vs COX-2

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Mechanism of ActionCOX Isoforms

• Type III COX (COX-3)
• - genetic modification of COX-1 enzyme
• - present in the brain of dogs and rats
• - may play a role in CNS pain processing ?

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Mechanism of ActionNSAID Analgesic Actions

• Inhibit COX
• Inhibit the release of inflammatory mediators
• from neutrophils and macrophages
• Potential action sites in the CNS (in animals)
• (1) reduce hyperalgia evoked by spinal action
• of substance P and NMDA
• (2) reverse the inhibition by prostaglandin
• of descending opioid-mediated pathway
• involved in pain inhibition
• (3) central opioid mechanism
• (4) serotonin and nitric oxide

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Mechanism of ActionNSAID Analgesic Actions

• NSAID? CNS?? ????? ???? ??
• - NSAID? BBB? ????
• - COX-2 selective inhibitor ?? BBB? ????
• - NSAID? ????? hypothalamus? ?? ???
• ??? ??
• Interindividual variability in pharmacodynamic
  response
• to NSAIDs
• - ??? ??? ?? ?? ??? ? ?? NSAID? ??
• - ?? ????? ???? ?? ??? ? ?? NSAID? ??
• ? ?? ??? ??? ??? ????
• ? NSAID? ??? ??? ??? ?? ??? ???
• ??? ? ??

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Mechanism of ActionCOX-2 Selectivity of NSAIDs

• Classification of NSAIDs based on COX selectivity
• (1) irreversible inhibition of COX-1 and COX-2
• - aspirin
• (2) reversible competitive inhibition of COX-1
  and COX-2
• - ibuprofen
• (3) slower, time-dependent inhibition of COX-1
  and COX-2
• - flubiprofen, indomethacin
• (4) selective inhibition of COX-2
• - celecoxib, rofecoxib, valdecoxib,
  etoricoxib, lumericoxib

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Pharmacokinetics

• Similar pharmacokinetic characteristics
• - rapidly and extensively absorbed after oral
  administration
• - high protein binding ? very limited tissue
  distribution
• - metabolized extensively in liver
• - little dependence on renal elimination
• - low clearance
• High protein binding (gt 90 )
• - in the elderly, serum albumin ? free
  fraction ?
• ? efficacy ? toxicity ?
• - interaction with warfarin
• ? cause significant risk of bleeding

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Pharmacokinetics

• There are subclasses of the drug with unique
  features
• Salicylates
• (1) dose ? ? half-life ?
• ? time to achieve steady-state blood
  concentration ?
• ?) 1.5 g/day ? 2 days
• 3 g/day ? more than 1 week
• (2) displace other NSAIDs (naproxen and
  phenylbutazone)
• from plasma binding sites
• ? free concentration ? risk of toxicity ?

• Differences in efficacy between NSAIDs
• (1) pharmacodynamic variability
• ?
• (2) pharmacokinetic differences
• - wide differences in bioavailability and
  elimination
• between patients

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Toxicity Gastrointestinal toxicity

• Dyspepsia
• - upper abdominal pain
• in the absence of documented gastric mucosal
  damage
• - annual prevalence 15
• - 12 weeks use 2-5 stopped NSAID use
• because of
  dyspepsia
• GI bleeding and perforation
• - the most frequently reported significant
  complication
• - 7,000 deaths and 70,000 hospitalizations /
  year
• in the USA

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Toxicity Gastrointestinal toxicity Stomach

• NSAIDs affect
• - mucus and bicarbonate secretion
• - blood flow
• - epithelial cell turnover and repair
• - mucosal immunocyte function
• Hemorrhagic gastric erosion
• - ?? ?? corpus
• - ?? topical irritation
• - NSAIDs ?? ??? ???? acidic irritation? ? ???
• ???? topical irritation? ??? ????? ?

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Toxicity Gastrointestinal toxicity - Stomach
Toxicity Gastrointestinal toxicity Stomach

• Gastric / duodenal ulcer
• - ?? ?? antral and prepyloric lesion
• - ?? inhibition of prostaglandin synthesis
• - silent ulceration is common
• ?????? ?? ?? NSAIDs-related ulcer ??? 70??
  ???
• Risk factors of NSAIDs gastropathy
• - 60? ??
• - prior history of peptic ulcer disease
• - steroid use
• - alcohol use
• - multiple NSAID use

• Other risk factors
• - ?? ? 3??? ?? ??? ??? ??? ???
• ?? ??? ??? ??
• - H. pylori? NSAIDs-related gastropathy? ???
  ?????? ??
• NSAIDs? H.pylori infection? ??? ??? ??

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Toxicity Gastrointestinal toxicity Small
intestine and Colon

• Colitis? ?????? ??? ??
• - ???? ??? ??? ?? ??
• NSAID enteropathy
• - NSAID ?? ?? ??
• - changes in permeability and protein wasting
• - prevented by use of misoprostol, COX-2
  inhibitor

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Toxicity Gastrointestinal toxicity Prevention
of NSAID gastropathy

• Antacids enteric coated NSAIDs
• - limited success
• Cimetidine and ranitidine
• - effective in treatment, bur not effective in
  prevention
• Sucralfate
• - basic aluminum salt of sucrose octasulfate
• ? forming a complex with proteins at an ulcer
  base
• ? stimulating prostaglandin synthesis in
  gastric mucosa
• ? promoting gastric mucus secretion
• by a prostaglandin-independent mechanism
• - side effect low
• - preventive effect gel formulation? ??? ? ?
  ??

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Toxicity Gastrointestinal toxicity Prevention
of NSAID gastropathy

• Misoprostol
• - synthetic analogue of prostaglandin E1
• - preventive effect successful
• ? placebo, sucralfate ?? ?? ???? ? ? ?? ???
  ??
• - side effect diarrhea relatively expensive
• ? high risk group ???? ?? ??
• Proton pump inhibitor (omeprazole)
• - preventive effect successful

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Toxicity Renal toxicity (1) Reduction in renal
perfusion

• PGE2 in the cortex
• PGI2 in the tubules medullary interstitial
  cells
• - act as direct vasodilators
• - attenuate vasoconstrictive effects of
  angiotensin II,
• renal sympathetic activity, catecholamines
• Prostaglandin regulation of renal blood flow
• - clinically significant in susceptible
  individuals,
• but not in normal patients
• PGH2 TXA2 potential renal vasoconstrictors
• - renal response depend on relative amount of
  PGE2, PGI2,
• PGH2 and TXA2

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Toxicity Renal toxicity (1) Reduction in renal
perfusion

• Susceptible individual
• renal prostaglandin-dependent state (RPDS)
• - elevated renal sympathetic nerve and/or
  angiotensin II activity
• volume depletion, low cardiac output,
  hepatic cirrhosis
• renal ischemia, aminoglycoside toxicity
• unilateral or subtotal nephrectomy,
  hypertension, diabetes
• Renal blood flow ?
• ? glomerular filtration rate ?
• ? water and electrolyte reabsorption in
  proximal tubule ?
• ? antagonize anti-hypertensive therapy
• exacerbate congestive heart failure

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Toxicity Renal toxicity (2) Acute interstitial
nephritis

• Acute renal failure with tubular necrosis
• ? acute overdose
• Allergic nephritis
• - tubulointerstitial nephritis with proteinuria
• - treatment steroid and dialysis

• There is no evidence that COX-2 selective
  inhibitors confer
• any additional safety benefit in terms of
  renal toxicity
• COX-2 is constitutively expressed in the
  kidney

(3) Minimal change nephrotic syndrome

• Discontinuing the drug typically results in
  complete remission
• in a few weeks

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Toxicity Hematologic toxicity (1) Inhibition of
TXA2 formation

• PGH2 ? TXA2 in platelet platelet activator,
  vasoconstrictor
• PGH2 ? PGI2 in vascular endothelium
• platelet inhibitor, vasodilator
• When NSAIDs inhibit COX
• - platelet have no nucleus ? unable to form
  additional COX
• - vascular endothelium ? able to create more
  COX
• Irreversible inhibition aspirin
• - takes 7 to 10 days for platelet to recover
• - BT tend to normalize sooner uninhibited
  platelet from BM
• Reversible inhibition non-aspirin NSAIDs
• - resolve when the drug is mostly eliminated
• - single dose of ibuprofen 24 hours

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Toxicity Hematologic toxicity (2) Interaction
with warfarin

• NSAIDs potentiate anticoagulant activity of
  warfarin
• ? displace the protein-bound drug ? free from ?
• ? inhibit metabolism by hepatic microsomal
  enzyme
• - they should used with caution, especially in
  the elderly

• COX-2 selective inhibitors have no effect on
  platelet function
• even in supra-therapeutic doses
• lack of COX-2 in platelet

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Toxicity Hepatic toxicity

• Minor increase in hepatic enzymes
• Hepatocellular injury
• Mechanism is not clear
• - seems to be immunologic or metabolic
• - dose-related toxicity aspirin and
  acetaminophen

Toxicity Effects on bone healing

• NSAIDs inhibit bone healing?
• - NSAIDs? fracture healing? ??? ??? ???
• ??? ??? ???? ???? ?? ??
• - ??? ??? ?? ? lumbar fusion fail ??? ??
• - COX-2 inhibitor? non-selective NSAIDs ??
• bone healing ??? ?? ????? ??? ??

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Toxicity Aspirin-induced Asthma

• About 10 of asthmatics
• Not a true allergy, skin test negative
• Blocking of COX pathway
• ? lipooxygenase pathway ?
• ? leukotriene C4 and other leukotriene ?
• ? severe bronchospasm
• COX-2 selective inhibitor
• - ??? bronchospasm ???? ??
• - ?? ??? ?? ????? ??

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Specific Drugs Classification by chemical
structure
Salicylates

• Aspirin
• - dose ? ? elimination half life ?
• - peak blood levels a hour after an oral dose
• - Reyes syndrome limited use in children
• Diflunisal
• Choline magnesium trisalicylate and salsalate

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Specific Drugs Classification by chemical
structure
Acetaminophen

• Analgesic and Antipyretic
• Inhibition central prostaglandin synthesis
• (endogenous pyrogen)
• ? direct action on hypothalamic heat-regulating
  centers
• No significant peripheral prostaglandin synthesis
  
• Little additional benefit is seen at dose above
  650 mg
• Almost entirely metabolized in the liver
• Minor metabolites are responsible for
  hepatotoxicity
• seen in overdose

Ceiling effect ??? ??? ????? ??? ????? ?? ????
??? ???? ??? ?????? ?? ??? ???? ?? ??? ? ?? ????
???? ?? ????
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Specific Drugs Classification by chemical
structure
Acetic Acid Derivatives (1)

• Indomethacin side effects ?, clinical use is
  limited
• Sulindac relatively lower GI toxicity
• Etodolac fewer side effects, notable COX-2
  selectivity
• Ketorolac the only parenteral NSAID in USA
• - anti-inflammatory
• - analgesic (naproxen? 50?), antipyretic
  (aspirin? 20?)
• - for moderate postoperative pain treatment
• morphin? ??? ?? ??? ???? ???? ??
• - potential alternative to fentanyl for
  intra-operative use
• - oral ketorolac GI toxicity ??? ??? ???

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Specific Drugs Classification by chemical
structure
Acetic Acid Derivatives (2)

• Diclofenac parenteral use in Europe
• - high first-pass effect ? low oral
  bioavailability
• - higher incidence of hepatotoxicity

Propionic Acid Derivatives

• Ibuprofen, fenoprofen, ketoprofen, flubiprofen,
  naproxen

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Specific Drugs Classification by chemical
structure
Oxicam Derivatives

• Piroxicam
• - time to peak concentration ? time to achieve
  steady-state ?
• - elimination half-life ?
• - ? allow once-daily dosing
• Meroxicam

Pyrazolone Derivatives

• Phenylbutazone
• - very effective antiinflammatory and analgesic
• - aplastic anemia and agranulocytosis

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Specific Drugs Classification by chemical
structure
Anthranilic Acid Derivatives

• Mefenamic acid severe pancytopenia
• Meclofenamate a high incidence of GI toxicity

Naphthyalkanones

• Nabumetone
• - relative COX-2 selectivity
• - non-acidic chemical structure
• minimal topical injury to the gastric mucosa

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Highly Selective COX-2 Inhibitors Celecoxib,
Rofecoxib, Valdecoxib, Etoricoxib, Lumericoxib

• Do not inhibit COX-1 in supra-therapeutic
  concentrations
• GI morbidity ? Effects on platelet function ?
• Effects on Bone healing ??
• Renal effects the same as nonselective NSAIDs
• Antiinflammatory, analgesic, antipyretic
• Lower dose for chronic pain higher dose for
  acute pain

Bioavailability Half-life
Rofecoxib 0.93 11 hours
Celecoxib 17 hours
Valdecoxib 0.83 8.11 hours
Higher affinity to COX-2 enzyme Once-daily
single dose
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Highly Selective COX-2 Inhibitors Celecoxib,
Rofecoxib, Valdecoxib, Etoricoxib, Lumericoxib

• Parecoxib
• - the only parenteral COX-2-selective inhibitor
• - ??? valdecoxib?? ???? ???
• - ketorolac? ??? ??? ???? ???? ??
• Rofecoxib
• - nonfatal MI, hypertension, peripheral edema
  ??
• ???? ????? ???? ??
• - high dose ??? ????? ??? high dose low dose
• ???? ????? ???? ?? ??
• - ??? ?? ???? ??
• - ?? COX-2 inhibitor??? ???? MI? HTN?
• ????? ??? ???

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Combination Drugs

• In an effort to enhance the efficacy and safety
• Ibuprofen hydrocodone
• Diclofenac misoprostol
• Caffeine aspirin / acetaminophen / ibuprofen

Role in Acute Pain Management

• NSAIDs play a key role in acute pain management
• Synergy to opioid analgesia
• - ?? ?? ?
• - opioid ?? ??? ????? opioid? ?? ??? ?

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Role in Acute Pain Management
Dosing

• Dose-response relationship up to ceiling effect
• in terms of analgesic efficacy
• For chronic use ? the lowest effective dose
• When attempting to decrease postoperative opioid
  use
• and prevent severe pain ? the maximum dose
• - ???? ?? ?? ? ?? ?? onset time? ?? ????
• - sedation, nausea, respiratory depression ????
  ????
• ?? ??? ???? ??? ?? ???

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Role in Acute Pain Management
Timing

• ???? ?? ?? ??? ?? ??? ???
• ??? ??? ?? ??? ?? ???
• ??? ???? ?????
• ?? ?? ?? ?? ?? ?? ??
• NSAIDs?
• sedation?? respiratory depression? ???? ??
  ???
• ?? ??? ?? ?? ?? ???? ???? ?? ??
• ??? ????
• ?? ?? ?? ?? ?? ? ?? ?? ???? ???

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Role in Acute Pain Management
Toxicity

• Antiplatelet effect bleeding
• - ??? ?? ??? ?? ?, ?, ?? NSAIDs ???
• ?? ? ? ??
• - ??? COX-2-selective inhibitor? ????? ?? ????
• Renal toxicity
• - ??? ?? renal blood flow ??, ??? ?? ??,
• renal toxic agent (aminoglycoside,
  radiographic dyes ?)?
• ??? NSAIDs renal toxicity? ??? ?????
• - ??? ?? ??? single kidney ????? NSAIDs ???
• ???? ??

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KEY POINTS

• NSAIDs are antihyperalgesic and analgesic
  compounds
• - cyclooxygenase inhibition ? prostaglandin
  synthesis ?
• - largely based on actions in the CNS
• - peripheral mechanism synergistic
• - analgesic benefits are not necessarily
  related to
• their anti-inflammatory capabilities
• COX-1 constitutive
• - protecting GI mucosa, facilitating platelet
  aggregation
• COX-2 inducible
• - involved in pain and inflammation

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KEY POINTS

• Nonselective NSAID toxicity
• - NSAIDs gastropathy and gastroduodenal ulcers
• - reduced platelet aggregation
• - aspirin-induced asthma
• Both nonselective NSAID and selective COX-2
  toxicity
• - reduced renal function
• - reduced bone healing
• - rare hepatic toxicity
• NSAIDs are extremely effective
• in enhancing opioid analgesia
  postoperatively
• - reducing opioid requirement
• - providing better pain control