Ns Sai Ds


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Ns Sai Ds

  1. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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