1. Chapter 16
NSAIDs and
COX- 2- Selective Inhibitors
Je ffre y A. Ka tz , M. D .
R2 Le e S e un g Il

2. Me c ha n is m o f Ac tio n
P ro s ta g la n d in P h ys io lo g y
Cell membrane phospholipid
Cell membrane damage Phospholipase A2
Arachidonic acid
Cyclooxygenase 1 & 2 Lipooxygenase
Prostaglandin G2
Leukotriene B4,
Prostaglandin H2 LTC4, LTD4, LTF4
Tissue specific prostaglandins synthase
Thromboxan A2, Prostacyclin (PGI2), PGD2, PGE2, PGF2

3. Me c ha n is m o f Ac tio n
P ro s ta g la n d in s a n d P a in : P e rip he ra l
a c tio n s
 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

4. Mechanism of Action
Prostaglandins 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 

5. Me c ha n is m o f Ac tio n
P ro s ta g la n d in s a n d P a in : Ce n tra l
a c tio n s
 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-1β in the CNS
- IL-1β 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

6. Me c ha n is m o f Ac tio n
COX Is o fo rm s
 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

7. Me c ha n is m o f Ac tio n
COX Is o fo rm ratio
IC50 s
mean inhibitory concentration of drug
to inhibit COX-2 vs COX-1 by 50%
 Selectivity of various NSAIDs for COX-1 vs COX-2

8. Me c ha n is m o f Ac tio n
COX Is o fo rm s
 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 ?

9. Me c ha n is m o f Ac tio n
NS AID An a lg e s ic Ac tio n s
 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

10. Me c ha n is m o f Ac tio n
NS AID An a lg e s ic Ac tio n s
 NSAID 가 CNS 에서 작용한다는 간접적인 증거
- NSAID 는 BBB 를 통과한다
- COX-2 selective inhibitor 역시 BBB 를 통과한다
- NSAID 의 해열작용은 hypothalamus 에 대한 작용을
기초로 한다
 Interindividual variability in pharmacodynamic response
to NSAIDs
- 질병의 종류에 따라 진통 효과가 더 좋은 NSAID 가 있고
- 같은 질병에서도 환자마다 진통 효과가 더 좋은 NSAID 가 있
다
진통 작용의 기전이 상당히 다양하고
각 NSAID 의 화학적 구조에 차이가 있기 때문인 것으로

11. Me c ha n is m o f Ac tio n
COX- 2 S e le c tivity o f NS AIDs
 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

12. P ha rm a c o kin e tic s
 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 (> 90 %)
- in the elderly, serum albumin  & free fraction 
 efficacy  & toxicity 
- interaction with warfarin
 cause significant risk of bleeding

13. P ha rm a c o kin e tic s
 There are subclasses of the drug with unique features
 Salicylates
 Differences in efficacy between NSAIDs
(1) dose   half-life 
(1) pharmacodynamic variability
 time to achieve steady-state blood concentration 
예 ) 1.5 g/day  days
2
(2)3pharmacokinetic differences
g/day  more than 1 week
- wide differences in bioavailability and elimination
(2) displace other NSAIDs (naproxen and phenylbutazone)
between patients
from plasma binding sites
 free concentration  & risk of toxicity 

14. To xic ity
Ga s tro in te s tin a l to xic ity
 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

15. To xic ity : Ga s tro in te s tin a l to xic ity
S to m a c h
 NSAIDs affect
- mucus and bicarbonate secretion
- blood flow
- epithelial cell turnover and repair
- mucosal immunocyte function
 Hemorrhagic gastric erosion
- 발생 부위 : corpus
- 원인 : topical irritation
- NSAIDs 복용 기간이 지속되면 acidic irritation 에 위 점막
이
적응하여 topical irritation 의 정도가 약화된다고 함

16. To xic ity tin a l
To xic ity : Ga s tro in te s to xic ity
Ga s tro in te s tin a l toa c h ity - S to m a c h
S to m xic
  Gastric risk factors ulcer
Other / duodenal
- - 발생 첫 3 개월에 궤양 발생이 많다는 보고가 있으나
투여 부위 : antral and prepyloric lesion
- 원인 : 없다는 보고도 prostaglandin synthesis
상관 inhibition of 있음
- -silent ulceration is common
H. pylori 가 NSAIDs-related gastropathy 의 위험을 증가시키지도 않
:고
위내시경으로 진단 받은 NSAIDs-related ulcer 환자의 70% 에서 무
증상
NSAIDs 가 H.pylori infection 에 영향을 주지도 않음
 Risk factors of NSAIDs gastropathy
- 60 세 이상
- prior history of peptic ulcer disease
- steroid use
- alcohol use
- multiple NSAID use

17. To xic ity : Ga s tro in te s tin a l to xic ity
S m a ll in te s tin e a n d Co lo n
 Colitis 가 악화되었다는 보고가 있음
- 관련성이 확실히 밝혀진 것은 아님
 NSAID enteropathy
- NSAID 관련 소장 질환
- changes in permeability and protein wasting
- prevented by use of misoprostol, COX-2 inhibitor

18. To xic ity : Ga s tro in te s tin a l to xic ity
P re ve n tio n o f NS AID g a s tro p a thy
 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 이 효과가 좀 더 나음

19. To xic ity : Ga s tro in te s tin a l to xic ity
P re ve n tio n o f NS AID g a s tro p a thy
 Misoprostol
- synthetic analogue of prostaglandin E1
- preventive effect : successful
 placebo, sucralfate 와의 비교 연구에서 좀 더 좋은 효과를 보
임
- side effect : diarrhea & relatively expensive
 high risk group 환자에게 주로 투여
 Proton pump inhibitor (omeprazole)
- preventive effect : successful

20. To xic ity : Re n a l to xic ity
(1 ) Re d uc tio n in re n a l p e rfus io n
 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

21. To xic ity : Re n a l to xic ity
(1 ) Re d uc tio n in re n a l p e rfus io n
 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

22. To xic ity : Re n a l to xic ity
(2 ) Ac ute in te rs titia l n e p hritis
 Acute renal failure with tubular necrosis
 acute overdose
 Allergic nephritis
 There is no evidence that COX-2 selective inhibitors confer
- tubulointerstitial nephritis with proteinuria
any additional safety benefit in terms of renal toxicity
- treatment : steroid and dialysis
: COX-2 is constitutively expressed in the kidney
(3 ) Min im a l c ha n g e n e p hro tic s yn d ro m e
 Discontinuing the drug typically results in complete remission
in a few weeks

23. To xic ity : He m a to lo g ic to xic ity
(1 ) In hib itio n o f TXA2 fo rm a tio n
 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

24. To xic ity : He m a to lo g ic to xic ity
(2 ) In te ra c tio n w ith w a rfa rin
 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

25. To xic ity : He p a tic to xic ity
 Minor increase in hepatic enzymes
 Hepatocellular injury
 Mechanism is not clear
- seems to be immunologic or metabolic
- dose-related toxicity : aspirin and acetaminophen
To xic ity : Effe c ts o n b o n e h e a lin g
 NSAIDs inhibit bone healing?
- NSAIDs 가 fracture healing 에 영향을 준다는 보고와
관련이 없다는 상반되는 보고들이 함께 존재
- 관련이 있다는 보고 중 lumbar fusion fail 보고가 있
음
- COX-2 inhibitor 가 non-selective NSAIDs 보다

26. To xic ity
As p irin - in d uc e d As thm a
 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
- 이론상 bronchospasm 유발하지 않음
- 몇몇 연구가 이를 뒷받침하고 있음

27. S p e c ific Drug s
Cla s s ific a tio n b y c he m ic a l s truc ture
Salicylates
 Aspirin
- dose   elimination half life 
- peak blood levels a hour after an oral dose
- Reye’s syndrome : limited use in children
 Diflunisal
 Choline magnesium trisalicylate and salsalate

28. S p e c ific Drug s
Cla s s ific a tio n b y c he m ic a l s truc ture
Acetaminophen
 Analgesic and Antipyretic Ceiling effect
 Inhibition central prostaglandin synthesis 증가하다가
약물의 농도가 증가할수록 효과도
어느 순간부터 농도가 증가해도 효과는
(endogenous pyrogen)
그대로이거나 아주 조금만 증가하는 현상
 direct action 하지만 이 시점 이후에도 부작용은 계속 증가한다
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

29. S p e c ific Drug s
Cla s s ific a tio n b y c he m ic a l s truc ture
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 의 50 배 ), antipyretic (aspirin 의 20
배)
- for moderate postoperative pain treatment
: morphin 과 유사한 진통 효과를 보이면서 부작용은 적음
- potential alternative to fentanyl for intra-operative use
- oral ketorolac : GI toxicity 때문에 사용이 제한됨

30. S p e c ific Drug s
Cla s s ific a tio n b y c he m ic a l s truc ture
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

31. S p e c ific Drug s
Cla s s ific a tio n b y c he m ic a l s truc ture
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

32. S p e c ific Drug s
Cla s s ific a tio n b y c he m ic a l s truc ture
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

33. Hig hly S e le c tive COX- 2 In hib ito rs
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
Higher affinity to
Rofecoxib 0.93 11 hours COX-2 enzyme
Celecoxib 17 hoursOnce-daily single dose
Valdecoxib 0.83 8.11 hours

34. Hig hly S e le c tive COX- 2 In hib ito rs
Celecoxib, Rofecoxib, Valdecoxib, Etoricoxib, Lumericoxib
 Parecoxib
- the only parenteral COX-2-selective inhibitor
- 간에서 valdecoxib 으로 전환되어 작용함
- ketorolac 과 유사한 효과가 있으면서 부작용은 적음
 Rofecoxib
- nonfatal MI, hypertension, peripheral edema 등의
발병률이 증가한다는 보고들이 있음
- high dose 에서만 증가한다는 보고와 high dose & low
dose
상관없이 증가한다는 보고들이 함께 공존
- 기전은 아직 밝혀지지 않음
- 다른 COX-2 inhibitor 에서는 아직까지 MI 나 HTN 이
증가한다는 보고는 없었음

35. 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
- 진통 효과 과
- opioid 투여 용량을 감소시켜서 opioid 로 인한 부작용
용

36. 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
- 불충분한 용량 투여 시 진통 효과 onset time 이 훨씬 길어진
다
- sedation, nausea, respiratory depression 부작용이 없으므로
최대 용량을 투여해도 문제가 되지 않는다

37. Role in Acute Pain Management
Timing
 진통제를 수술 전에 주는가 후에 주는가 자체가
질병의 경과에 크게 중요한 것은 아니나
환자의 만족도를 고려한다면
통증 경험 전에 주는 것이 훨씬 좋다
 NSAIDs 는
sedation 이나 respiratory depression 의 부작용이 없기 때문
에
마취 전이나 마취 도중 또는 마취에서 깨어나기 바로 전에
주어도 괜찮으며
부분 마취 또는 국소 마취 중 어느 때에 투여해도 괜찮다

38. Role in Acute Pain Management
Toxicity
 Antiplatelet effect & bleeding
- 이러한 문제 때문에 수술 전 , 중 , 후에 NSAIDs 투여를
꺼려 할 수 있다
- 하지만 COX-2-selective inhibitor 를 투여함으로 해결 가능하
다
 Renal toxicity
- 마취로 인한 renal blood flow 감소 , 수술로 인한 출혈 ,
renal toxic agent (aminoglycoside, radiographic dyes 등 ) 의
투여는 NSAIDs renal toxicity 의 위험을 증가시킨다
- 신기능 부전 환자나 single kidney 환자에게는 NSAIDs 투여
를

39. 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

40. 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