9. NSAIDS.pptxNSAIDS inhibit the enzyme cyclooxygenase (COX) types 1 and 2, which convert arachidonic acid to prostaglandins �Effects of NSAIDS

Renal
Renally produced prostaglandins (PGE2 and PGI2) are essential
in maintaining adequate renal perfusion when the level of circulating vasoconstrictors Platelets
Impaired platelet function (reduced aggregation).
as a result of decreased thromboxane A2 (TXA2) production.
TXA2 is present in large amounts in activated platelets and acts locally as a chemo-attractant for other platelets, leads to the formation of a platelet plug and induces localized vasoconstric

1. Non-steroidal anti-inflammatory drugs [ Cyclooxygenase Inhibitors ]

2. Introduction The NSAIDs are among the most commonly used drugs because of their anti-inflammatory, analgesic, and antipyretic effects. They are used widely to treat mild to moderate perioperative pain. They also reduce opioid consumption in the perioperative period. In addition, they are opioid-sparing and can significantly decrease the incidence of opioid-related side effects such as postoperative nausea and vomiting and sedation

3. Cont.… Inflammatory Process A normal, beneficial process that begins immediately after injury to facilitate repair and return the tissue to normal function. Initiated by stimulus including physical trauma, radiation, chemicals, heat, infection, and hypersensitivity  c auses the release of chemical mediators

4. cont….. Chemical mediators Definition: are compounds released by one cell type that attach to the receptor of a second cell type to affect the response by that second cell Contained in mast cells and basophils. Histamine- increases vascular permeability, increases blood flow to injured area prostaglandins- pain response and vascular permeability. Phagocytes- neutrophils and macrophages remove debris Serotonin- increases capillary blood flow and vascular permeability

5. Cont.… Peripherally, prostaglandins do not directly mediate pain; rather, they contribute to hyperalgesia by sensitizing nociceptors to other mediators of pain sensation such as histamine and bradykinin. Centrally, prostaglandins enhance pain transmission at the level of the dorsal horn by (1) increasing the release of substance P and glutamate from first-order pain neurons, (2) increasing the sensitivity of second-order pain neurons, and by inhibiting the release of neurotransmitters from the descending pain-modulating pathways.

6. Mechanism of action of NSAIDS NSAIDS inhibit the enzyme cyclooxygenase (COX) types 1 and 2, which convert arachidonic acid to prostaglandins thereby preventing the production of both prostaglandins (including prostacyclin) and thromboxanes from membrane phospholipids.

7. Cont… Arachidonic acid is an unsaturated fatty acid that is the substrate for the production of compounds (metabolites) that contribute to the inflammatory response. Arachidonic acid contributes to symptoms of inflammation, including redness, swelling, and pain.

8. Cont… COX-1- produced in most tissues at a stable rate. COX-1 receptors are widely distributed throughout the body, including the gut and platelets. It has general "house-keeping" functions such as gastric protection and hemostasis. COX-2 is produced in response to pain, inflammation, fever, and carcinogenesis Thus, NSAIDs primarily inhibit COX-2 rather than both isoforms. Non-selective NSAIDs inhibits both COX-1 & COX-2 reversibly. Agents that inhibit COX non-selectively (e.g., aspirin) will control fever, inflammation, pain, and thrombosis. Selective NSAIDs inhibits only COX-2 reversibly. The COX pathway leads to the production of TX, PG.

9. Cont…

10. 10 Cell Membrane Phospholipids Arachidonic Acid Prostaglandin H2 Thromboxane Prostaglandins Prostacyclin Toxic Oxygen Radicals Cyclooxygenase (COX) or prostaglandin H2 [PGH2] synthetases) Phospholipase A2 Tissue Trauma

11. Effects of NSAIDS Gastrointestinal tract Gastric irritation Prostaglandins have a ‘gastro-protective effect’ in that they decrease gastric acid production,  production of the protective gastric mucosal barrier and  local gastric mucosal blood flow . Thus, NSAIDS by decreasing prostaglandin production therefore, results in damage to the gastric mucosa.

12. Cont… Intestinal erosions not limited to the stomach are commonly encountered during prolonged administration of NSAIDs. COX-2 selective NSAIDs have been shown to be associated with a lower incidence of upper GI side effects.

13. Cont… Renal Renally produced prostaglandins (PGE2 and PGI2) are essential in maintaining adequate renal perfusion when the level of circulating vasoconstrictors (rennin, angiotensin, noradrenaline) is high. In patients with heart failure, chronic renal failure and/or hypovolemia, renal blood flow is much more dependent on prostaglandin-induced vasodilatation than it would be in a healthy person. As a result of this, NSAID induced reduction in prostaglandin levels can precipitate acute renal failure.

14. Cont… The inhibition of the prostaglandins normally inhibiting anti-diuretic hormone production leads to increased sodium and water retention with the risk of oedema and/or hypertension. Aspirin and other NSAIDs may alter this delicate balance by inhibiting prostaglandins production, reducing renal perfusion and potentially leading to acute renal failure. Consequently, all NSAIDs are contraindicated in patients with heart failure.

15. Cont… Platelets Impaired platelet function (reduced aggregation). as a result of decreased thromboxane A2 (TXA2) production. TXA2 is present in large amounts in activated platelets and acts locally as a chemo-attractant for other platelets, leads to the formation of a platelet plug and induces localized vasoconstriction. The reduced production of thromboxanes A2 prevents platelet aggregation and vasoconstriction and, therefore, inhibits the haemostatic process.

16. Cont… While altered platelet function may be advantageous in certain circumstances acute myocardial infarction and prevention of stroke, during the peri-operative period it may cause increased blood loss.

17. Cont… The effects of aspirin on platelets last for the life span of the platelet for two reasons: platelets are unable to generate new cyclooxygenase and the enzyme inhibition is irreversible. Up to 14 days are required to generate new platelets. It is for this reason that aspirin must be discontinued for a week prior to elective surgery. COX-2 inhibition has no effect on platelet function even at high doses.

18. Cont… Cardiovascular system COX inhibitors do not act directly on the cardiovascular system. Any cardiovascular effects result from the actions of these agents on coagulation. Prostaglandins maintain the patency of the ductus arteriosus, thus, prostaglandin inhibitors have been administered to neonates to promote closure of a persistently patent ductus arteriosus Respiratory At appropriate clinical doses, none of the COX inhibitors have effects on respiration or lung function.

19. Cont… Obstetrics Prostaglandins are important for initiating labour. Thus, NSAID usage can lead to prolonged labour and a NSAID (commonly rectal indomethacin) is sometimes used as a tocolytic in premature labour . Foetal oliguria, and premature closure of the ductus arteriosus. Normally patency of the ductus arteriosus is maintained by PGE2 and NSAID-induced closure in utero can lead to pulmonary hypertension and myocardial infarction .

20. Cont… Hepatotoxicity This is normally observed following prolonged or excessive use of NSAIDs. Up to 15% of patients may experience a rise in serum transaminase levels, even following short courses .

21. Cont.. Potential adverse effect produced by NSAIDs Inhibition of platelet aggregation Asthma exacerbation Gastric ulceration Allergic reaction Renal dysfunction Tinnitus Hepatocelular injury

22. Classification of NSAIDs Group Class Drug Non-specific COX inhibitors Relatively selective COX-2 inhibitors salicylates Acetic acid derivatives Proprionic acids Para- aminophenols Aspirin Diclofenac ketorolac Indomethacin Ibuprofen Naproxen Acetaminophen (Paracetamol)

23. Cont… Preferential COX-2 inhibitors Oxicams Meloxicam Specific COX-2 inhibitors * pyrazole - methylsulphone * phenylacetic acid Derivative * Parecoxib , * Celecoxib , * Rofecoxib - Etoricoxib * lumaricoxib

24. Non-specific COX inhibitors Salicylates Aspirin (acetylsalicylic acid) It is used for its analgesic, antiplatelet and anti-inflammatory effects. It is also used for its effects on platelet function in acute myocardial infarction and the prevention of stroke. Now it is used exclusively for prevention of thrombosis in susceptible individuals or for treatment of acute myocardial infarction.

25. Cont… Mechanism of action At low dose, aspirin selectively inhibits platelet cyclo-oxygenase while preserving vessel wall cyclooxygenase. This has the effect of reducing TXA2-induced vasoconstriction and platelet aggregation while leaving vessel wall synthesis of prostaglandins unaltered and, therefore, dilated. Aspirin is unique in that it irreversibly inhibits COX-1 by acetylating a serine residue in the enzyme. The irreversible nature of its inhibition underlies the nearly 1-week duration of its clinical effects (e.g., return of platelet aggregation to normal) after drug discontinuation.

26. Cont.. Adult dosing Tab 81 mg, 325 mg, 500mg, 1000 mg For pain/fever: 500-1000 mg q4-6h; maximum daily dose (MDD)= 4g/day in healthy adults. MI prevention. 81-325 mg po qd N.B Because of the risk of Reye's syndrome, avoid the use of aspirin in children <12 years old.

27. Cont… Aspirin induced asthma Occurs in 8-20% all asthmatic adults Bronchoconstriction is associated with derangement of arachidonic acid metabolism.

28. Cont… Acetaminophen (paracetamol) It is relatively selective COX-2 agent. Acetaminophen is available in an intravenous form for perioperative use Route: PO, PR (rectal) and IV Presentation and uses Paracetamol is presented as 500 mg tablets alone and in combination with weak opioids. Suppositories contain 125 mg and 1 gm. The pediatrics elixir contains 120 mg in 5 ml. The adult dose is 4 gm/day in divided doses every 6 hrs.

29. Cont.… Dosage 500-1000 mg q4-6hr; MDD in healthy adults =4 gram The initial pediatric & under 50kg dose PO/IV-------- 15–30 mg/kg which is then reduced to 10–15 mg/kg every 4 hours with a maximum dose of 75 mg/ kg./day PR: 25-40mg/kg loading I t is also available as 1 g/100 ml infusion that does not require reconstitution and can be infused IV over 15 minutes.

30. Acetaminophen… Intravenous dosing guidelines for Acetaminophen Adult >50 kg: 1 gm q4-6hr not to exceed 4 gm/day Adult <50 kg: 15 mg/kg q4-6hr not to exceed 3 gm/day Pedi >33 kg: 15 mg/kg q4-6hr not to exceed 3 gm/day Pedi 10-33 kg: 15 mg/kg q4-6hr not to exceed 2 gm/day

31. Cont… Pharmacokinetics Paracetamol is well absorbed from the small bowel and has an oral bioavailability of 80%. Unlike the other NSAIDs it does not cause gastric irritation, is less protein bound (10%) and has a larger volume of distribution. Paracetamol is metabolized by the liver. These are actively excreted in the urine, only a small fraction being excreted unchanged.

32. Acetic acid derivatives Diclofenac It is non-specific (nonselective) COX inhibitor. Routes of Administration: PO, Rectal, IM, IV Dosing: Single doses of 1-2 mg/kg for IV/IM 0.5 mg/kg for suppositories, and 1 mg/kg PO every 8-12 hours It is also available in combination with misoprostil, which provides prophylaxis against gastric and duodenal ulceration. Benefits : Generally more effective than ibuprofen The maximum adult dose is 150 mg/day in divided doses.

33. Cont… The pediatric dose of Diclofenac is 1 mg/kg for pain associated with minor surgery (tonsillectomy, inguinal herniotomy). Owing to its effects on cyclo-oxygenase, it may also precipitate gastric irritation, acute renal impairment and reduced platelet function, which often prevents it from being used in major surgery. Pharmacokinetics It undergoes hepatic hydroxylation and conjugation to inactive metabolites that are excreted in the urine (60%) and bile (40%).

34. Cont… Ketorolac It is a parenteral NSAID that provides analgesia by inhibiting prostaglandin synthesis potent analgesic potent antipyretic. but limited anti-inflammatory activity or it is devoid of any anti-inflammatory effects. . It may be given orally or parenterally. It has a duration of action of up to 6 hours. It shares the side-effect profile common to all NSAIDs.

35. Cont.… Daily dose Ketorolac 40 mg. Ketorolac 30 mg IM produces analgesia that equivalent to 10 mg of morphine or 100mg of meperidine. Drug useful when patient have spasm of the biliary tract. A standard dose of ketorolac provides analgesia equivalent to 6–12 mg of morphine administered by the same route. Its time to onset is also similar to morphine, but ketorolac has a longer duration of action (6–8 h).

36. Cont.… Dosage of Ketorolac Loading dose: 60 mg IM or 30 mg IV; followed by a maintenance dose of :15–30 mg every 6-8 hr. not to exceed 5 day. MDD: 120 mg. Elderly patients (>65 years of age) clear ketorolac more slowly and should receive reduced doses. In addition, reduce the dose in renal failure.

37. Cont.… Drug Interactions Aspirin decreases the protein binding of ketorolac, increasing the amount of active unbound drug. Ketorolac does not affect MAC of IAA, and its administration does not alter the hemodynamics of anesthetized patients. It decreases the postoperative requirement for opioid analgesics .

38. Proprionic acids Ibuprofen Ibuprofen is prepared as 200–600 mg tablets and as a pediatric elixir containing 20 mg/ml. Routes of Administration: Oral and IV Dosing : 10 mg/kg every 8 hours It is not recommended for children below 1 year of age. The pediatric dose is 20 mg/kg/day in divided doses.

39. Cont.… Benefits : Decreases narcotic requirement by 20%, non-sedating. It has mild anti-inflammatory and analgesic effects But it has the lowest incidence of side effects of the most commonly used NSAIDs. IV ibuprofen: Infuse over 30 minute to avoid phlebitis Limit adult dose to 3200 mg/day.

40. Specific COX-2 inhibitors Further COX-2 inhibitors will have been withdrawn from the market due to concerns about myocardial infarction (MI) and stroke. It is currently unclear if these concerns revolve around individual drugs or the entire class of COX-2 inhibitors. Initially, large studies suggested that there was a significantly reduced incidence of GI side effects associated with COX-2 inhibitors compared with standard NSAIDs.

41. Cont… However, the Food and Drug Administration (FDA) later presented further data that exposed the increased MI and stroke rates but also a gastrointestinal side-effect rate equal to standard NSAIDs after 12 months therapy as well as a number of other side-effects hypertension, heart failure, Hepatotoxicity and edema.

42. Drug Route Half-life (h) Dose Acetaminophen Po and IV 2 500-1000 mg q4-6 Hrs. Maximum daily dose(MDD) 4gm / 24 hrs. Ibuprofen Po and IV 2 400 mg q4-6/8hrs. Ketorolac IV 6 30 mg initially followed by 15-30 mg q6-8 hr. not to exceed 5 days. MDD=120 mg Diclofenac PO, IV, IM 2 PO 50mg q8 hr. 1-2 mg/kg for IV/IM 0.5 mg/kg for suppositories. MDD=150 mg 42

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