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Pharmacology of NSAIDs (Non-Steroidal Anti-Inflammatory Drugs (Dr. Sohail Ahmad)

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Pharmacology of NSAIDs (Non-Steroidal Anti-Inflammatory Drugs)
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Dr. Sohail Ahmad

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Pharmacology of NSAIDs (Non-Steroidal Anti-Inflammatory Drugs (Dr. Sohail Ahmad)

  1. 1. NSAIDs Non steroidal Anti- inflammatory drugs Dr. Sohail Ahmad 1
  2. 2. 2
  3. 3. Inflammation It is a non-specific manifestation of many diseases. Acute Chronic Anti-inflammatory drugs are extensively used. 3
  4. 4. Non steroidal Anti- inflammatory drugs (NSAIDs) mainly produce their effects by inhibiting the biosynthesis of Prostanoids Prostaglandins , Thromboxane A2 & Prostacyclin. 4
  5. 5. Membrane phospholipids Arachidonic acid 5
  6. 6. Membrane phospholipids Arachidonic acid Leukotrienes Prostaglandins Thromboxane Prostacyclin Prostanoids 6
  7. 7. Membrane phospholipids Arachidonic acid Leukotienes Prostaglandins Thromboxane Prostacyclin Prostanoids COXLipoxygenase Phospholipase 7
  8. 8. Membrane phospholipids Arachidonic acid Leukotienes Prostaglandins Thromboxane Prostacyclin Prostanoids COXLipoxygenase Phospholipase NSAIDS Cosrticosteroids 8
  9. 9. Arachidonic acid is the primary precursor of prostanoids Prostanoids are also called ‘Eicosanoids’ Arachidonic acid is a component of the phospholipids of cell membrane. Free Arachidonic acid is released by cell damage mainly by the action of Phospholipase A2 enzyme. Arachidonic acid undergoes 2 pathways, by the enzymes Cyclooxygenase & Lipooxygenase, Biosynthesis of Prostanoids: 9
  10. 10. Membrane phospholipids Arachidonic acid Leukotienes Prostaglandins Thromboxane Prostacyclin COXLipoxygenase NSAIDS Phospholipase Cosrticosteroids Prostanoids 10
  11. 11. Inhibition of cyclooxygenase enzyme & reduced biosynthesis of Prostanoids (Prostaglandins Prostacyclin ,Thromboxane A2) Aspirin & older non-selective NSAIDs reduce biosynthesis of Prostanoids by inhibiting both isoforms of the Cyclooxygenase (COX) enzyme (COX-1& COX-2) MOA of ASPIRIN / NSAIDs 11
  12. 12. COX-1 It is responsible for the Physiologic production of prostanoids. It is “House keeping “enzyme that regulates the normal cellular processes (via production of PGs) such as  Gastric cytoprotection  Vascular homeostasis  Platelet aggregation  Kidney function. 12
  13. 13. COX-2 It is constitutively expressed only in brain, kidney & bone Its expression at other sites is increased in inflammation. It is responsible for the elevated production of prostanoids in inflammation & disease. The selective COX-2 inhibitors have been synthesized. Its expression is inhibited by Glucocorticoids COX-3 more effects in CNS 13
  14. 14.  Aspirin is unique, it acetylates , & irreversibly inhibits the enzymes, all other drugs produce reversible inhibition  There is ↓ PGs & Thromboxane synthesis throughout the body.  Release of PGs for inflammation as well as for homeostatic function is disrupted (specially cytoprotection in gastric mucosa & auto regulation of renal function)  Newer drugs, coxibs are COX2 selective inhibitors . 14
  15. 15. PGG2 PGH2 Scheme for prostaglandin Biosynthesis Stimulus Disturbance of cell membrane Phospholipids Corticosteroids inhibit Phospholipase – A2 Arachidonic Acid Aspirin & NSAIDs inhibit Cyclooxygenase Lipoxygenase Endoperoxides Prostacycline Hydroperxides TXA2PGD2PGF2αPGE2Leukotrienes X 15
  16. 16. 16
  17. 17. Classification of NSAIDs A: Non-Selective COX Inhibitors.(Inhibitors of COX I & II) 1. Drugs with Analgesic & Marked Anti-inflammatory Effects: a. Salicylic Acid Derivatives  Aspirin (Acetylsalicylic acid)  Diflunisal  Sodium Salicylate  Magnesium Choline salicylate b. Pyrazolon Derivatives Apazone, Phenylbutazone , Oxyphenbutazone c. Acetic Acid Derivatives Diclofenac , Tolmetin , ketorolac Indomethacin , Etodolac , Sulindac d. Oxicams ( Enolic acids): Piroxicam , Tenoxicam e. Naphthylacetic Acid Prodrug: Nabumetone 17
  18. 18. 2. Drugs with Analgesic & Moderate Anti-inflammatory Effect: a. Propionic acid derivatives Ibuprofen, Fenoprofen, Flurbiprofen , Ketoprofen , Naproxen, oxaprozin , carprofen , Tiaprofen b. Fenamates: Mefenamic , Meclofenamic & Flufenamic acid 3. Drug with Analgesic & no Anti-inflammatory Effect: Para aminophenol Derivative : Acetaminophen B: Selective COX Inhibitors.(Inhibitors of COX II only) Celecoxib , Etoribcoxib , Meloxicam ,Nimesulide. 18
  19. 19. ASPIRIN Prototype Drug The oldest member used. 19
  20. 20. ASPIRIN Chemistry: Aspirin is Acetyl salicylic Acid. Pharmacokinetics of Aspirin: Absorption: Well from stomach & upper small intestine Distribution: wide , crosses placental barrier PPL: In 1-2hrs. t1/2: 15 min. Metabolism: Rapid hydrolysis by Esterases in blood & tissues in to Salicylate & Acetic Acid. Salicylate is 80-90-% PPB 20
  21. 21. Salicylate is metabolized in liver into: 1.Salicyluric acid (glycine conjugate) 2.Glucuronide conjugate 3. Gentisic acid 21
  22. 22. 22
  23. 23. MOA of ASPIRIN / NSAIDs As Anti-inflammatory: Aspirin irreversibly acetylates both isoforms of cyclooxygenase enzyme , COX-1 & COX-2 & inactivates them. So it inhibits biosynthesis of PGs which, primarily modulates those aspects of inflammation in which PGs act as mediators. Aspirin inhibits inflammation in Rheumatoid Arthritis but it neither arrests the progress of disease nor it induces remission. Other NSAIDs reversibly inhibit cyclooxygenase enzyme . 23
  24. 24. As Analgesic: 1. Aspirin & Other NSAIDs inhibit cyclo-oxygenase enzyme , reduce production of PGs in injured tissue. PGE2 is thought to sensitize the nerve ending (pain receptors)to action of bradykinin , Histamine & other mediators released by the inflammatory process. So due to reduced production of PGE2 , they repress the sensation of pain. 2. Inhibit pain stimuli at subcortical sites --Thalamus & Hypothalamus. 24
  25. 25. As Antipyretic: Aspirin lowers raised body temperature , no effect on normal temperature Fever occurs when the set point of the thermoregulatory center in anterior hypothalamus is elevated. This may be due to PGE2 synthesis , stimulated by pyrogen such as cytokine. Cytokine is released from WBCs, activated by infection, malignancy or inflammation.  Because of inhibition of PGE2 synthesis , the thermostat is reset towards normal. & rapidly lowers body temperature by increasing heat dissipation due to peripheral vasodilation & sweating. 25
  26. 26. AS Antiplatelet: TXA2 normally promotes platelet aggregation. prostacyclin –PGI 2 normally inhibit platelet aggregation. In low doses Inhibit Platelet Aggregation due to irreversible acetylation of COX-1 enzyme in platelets.  Low doses 81-100mg/ d inhibit TXA2 synthesis in platelets , higher doses inhibit prostacyclin –PGI2 also.  Platelet aggregations is the first step in coagulation so it prevents coagulation & prolongs bleeding time .  The action lasts for 3-8 days -- life span of platelets, because they lack nuclei & can’t synthesize new enzyme.  Aspirin should be stopped 7-10 prior to operations, to avoid risk of bleeding. 26
  27. 27. Therapeutics Uses of Aspirin/ NSAIDS 1. Analgesic : a. used alone in pain like. : Headache, Myalgia, Arthralgia, Neuralgia osteomyelitis, osteoarthritis. Toothache, Dysmenorhoea b. With opioids – synergistic action In pain of cancer metastases in bone Post operative pain-  requirement of opioids. 27
  28. 28. 2. Anti pyretic :↓ body temp in fever Not effective in raised body temp. due to heat stroke or malignancy. Does not lower normal body temp . 3. Acute rheumatic fever :Both for antipyretic & anti-inflammatory effects. 4. Rheumatoid Arthritis, Osteoarthritis: To control symptoms. No effect on progression of disease. Does not induce remission. 28
  29. 29. 5. Anti Platelet : Aspirin is used prophylactically : For primary & secondary prevention (In Post myocardial infarction & post stroke patients) of : Transient ischemic attacks & stroke. Unstable angina Coronary artery thrombosis & Myocardial infarction. To prevent Thrombosis after coronary artery bypass grafting. 29
  30. 30. 6. In Bartter’s syndrome: There is defect in tubular transport of K---Hypokalemia----PG synthesis stimulated---Increased Renin--- Hyperaldosteronism. Aspirin prevents this secondary Hyperaldosteronism due to inhibition of PG synthesis . 30
  31. 31. 7.Chemoprophylaxis of cancer of colon .50% decrease with frequent use of aspirin 8.Closure of PDA . As PGs keep patency of Ductus arteriosus. 9. Diarrhea after Radiation & Cholera in which PGs are implicated. 10.Prophylaxis of Cataract: some studies indicate decrease in incidence of cataract with frequent use of aspirin. 11. With Niacin to improve compliance because Aspirin ↓ flushing, which is an A/E of Niacin due to PGs. 31
  32. 32. Dosage of Aspirin: 3 therapeutic dose ranges: 1. Low range<300mg/d(81, 100mg) as single dose --to↓ Platelet Aggregation 2. Intermediate dose :300-2400mg/d as 3 divided doses) Analgesic, Antipyretic. 3. High dose : 2400- 4000mg/d– as 3 divided doses --for Anti- Inflammatory effect. 32
  33. 33. Adverse Effects of Aspirin At therapeutic doses 1. Gastric Intolerance: The most common & serious is gastritis, Gastric ulceration or Exacerbation of Peptic ulcer symptoms.  Dyspepsia & Heart burn , Abdominal Pain .  Nausea & Vomiting, Hematemesis  Fecal blood loss  Iron deficiency Anemia 33
  34. 34. To decrease gastric intolerance: Aspirin may be given with Misoprostol. Addition of Proton pump inhibitors with Aspirin.  H2 Blockers, if aspirin has been stopped Use of Special Prep. Of Aspirin: only marginally effective  Aloxiprin (Enteric coated aspirin)  Buffered Aspirin 34
  35. 35. 2. Impaired hemostasis: ↓ Platelet Aggregation & Hypoprothrobinaemia: 3. Allergic / Hyper sensitivity Reactions: Skin rashes, Rhinitis, Bronchial asthma 4. Hyperuricemia: Retention of uric acid at low doses<2.5 g/d , (although at high doses> 3.6/d –increases uric acid excretion). 35
  36. 36. 5. Decreased renal function: Normally PGE2 & PGI2are responsible for maintaining renal flow specially in presence of circulating vasoconstrictors. Inhibition of PGs synthesis may produce: Retention of Sodium & water Edema Hyperkalemia. Interstitial nephritis with other NSAIDs , but not Aspirin 36
  37. 37. 37
  38. 38. 6.Effects on Respiration: In high doses– stimulation of Respiratory Center—hyperventilation– respiratory alkalosis—compensated by kidney------ compensated respiratory alkalosis In toxic doses respiratory depression & a combination of uncompensated respiratory & metabolic acidosis . 38
  39. 39. 7. Effects on CNS: In large doses: Salicylism--- Vomiting ,tinnitus, ↓ hearing ,vertigo. In Toxic Doses :Stimulation of CNS including convulsions ,followed by depression.  Repiratory depression  Cardiotoxicity  Hyperpyrexia because salicylates uncouple the oxidative phosphorylation. The energy normally used for production of ATP is dissipated as heat . 39
  40. 40. 8. ↑ Risk of Reye’s syndrome: Aspirin & other salicylates given in viral infection in young children have been associated with an ↑ incidence of Reye’s syndrome. In Reye’s syndrome there is fulminating hepatitis ,with cerebral edema which may be fatal. So Acetaminophen or Ibuprofen should be used instead of Aspirin. 40
  41. 41. In pregnancy & during lactation: Avoid in pregnancy & lactation  Aspirin & salicylates cross placental barrier & are secreted in breast milk. 41
  42. 42. 10. Drug Interactions: Corticosteroids ,other NSAIDs: ↑ GIT A/E. With ACE inhibitors. ↓ Antihypertensive effect With Warfarin or Heparin : ↑ GIT bleed. With Probenecid & sufinpyrazone: Aspirin antagonizes uricosuric action of Probenecid & sufinpyrazone , as it inhibits tubular secretion of uric acid (in low doses—< 2g/d). So C/I in Gout in low doses. 42
  43. 43. Displacement of PPB drugs: As aspirin is 90-95 % PPB Aspirin can displace many drugs from PPB sites , ie Warfarin , Phenytoin , Valproic acid , Sulfonylureas, Methotrexate , Indomathacin , Naproxen , Ketoprofen, Fenoprofen & Bilirubin ----Increased level of free drugs/ Bilirubin– toxicity. Aspirin ↓ diuretic action of Fursemide, Thiazides, Spironolactone. Aspirin blocks the active transport of Penicillin from CSF to blood. 43
  44. 44. Contraindications / Precautions:  Peptic ulcer.  Hemophilia.  Aspirin hypersensitivity  Children with a viral illness.  Chronic liver disease.  Aspirin should be stopped one week before elective surgery.  Avoid high doses in G-6-PD deficient.  Avoid in pregnancy & lactation  Consider drug interactions. 44
  45. 45. Management of Aspirin/Salicylate Overdose toxicity/Poisoning  Aspirin/Salicylate poisoning is a medical emergency, & death may result.  There is no antidote.  Management begins with rapid assessment, followed by  A(airway),B(breathing), C(circulation), D(decontamination) approach.  Gastric Lavage , Activated Charcoal to prevent further absorption, specially if enteric coated tablets have been used  Measurement of serum salicylate level & pH  Correct fluid, electrolyte & acid base balance.  Maintain high urine out put.  Keep airway patent.  Lower body temperature by cold sponging. 45
  46. 46.  Vit. K I/V to correct hypopthrombinemia.  Diazepam I/V for convulsions.  Promote excretion by NaHCO3 I/V to alkalinize urine, maintain pH at 8.o.  Hemodialysis /Peritoneal dialysis in severe acidosis & coma.  Ventilatory assistance in severe cases. 46
  47. 47. Topically used salicylates: Methyl salicylate: As counter irritant Salicylic acid :Topically on skin for corns ,warts Salfasalazine , Mesalamine --- suppository & rectal suspension enema in Inflammatory bowel disease. 47
  48. 48. 48
  49. 49. Therapeutic uses: 1. Mild to moderate pain like Aspirin 2. Antipyretic Preferred to Aspirin  In children with viral infections  In pt. with Peptic ulcer, Hemophilia  Pt. allergic to Aspirin.  Concomitantly with Probenecid & sulfinpyrazone in patients of gout. 49
  50. 50. Pharmacokinetics of Acetoaminophen  Rapid absorption from GIT.  Significant First pass metabolism in gut wall & liver.  When given in doses up to 0.5-4g/d:  90-95% metabolized to inactive glucuronide & sulphate conjugates which are excreted in urine.  5-10 % hydroxylated to form N- Acetyl=p benzoquinoneimine 50
  51. 51.  N- Acetyl-p benzoquinoneimine is a highly reactive metabolite which reacts with sulhydral groups.  Normally it reacts with sulhydral group Of Glutathion & forms a non-toxic substance. At doses above 4g/d Glutathion reserves are depleted & it can produce toxicity– Hepatic necrosis & Renal tubular necrosis. 51
  52. 52. Toxicity: At therapeutic doses  Rash & Allergic reactions.  Drug fever.  Mild increase in hepatic enzymes. With over dosage:  Doses above 4g may be toxic.  15g may be fatal due to metabolite N-Acetylbenzoiminoquinone which produces:  Hepatic necrosis--- potentially fatal  Renal tubular necrosis---may occur  Hypoglycemic coma --may occur 52
  53. 53. 53
  54. 54. Management of Acetoaminophen toxicity:  It constitutes a medical emergency, early diagnosis & treatment is required.  Activated Charcoal to prevent further absorption.  Correct fluid, electrolyte & acid base balance  Antidote--N-Acetylsysteine by I/V infusion.  It provide SH-groups to neutralize the toxic metabolite.  It is life saving if given within 10 hrs of overdose.  Avoid in severe hepatic impairment. 54
  55. 55. Prevention of toxicity: Base line & periodic estimation of hepatic enzymes should be undertaken in patients on high dose acetoaminophen. 55
  56. 56. B: Selective COX-2 Inhibitors (Coxibs) Prototype—Celecoxib : A Sulfonamide MOA: Celecoxib is 10-20 times more selective in inhibiting COX-2 than COX- 1. COX-2  It is constitutively expressed only in brain, kidney & bone .  Its expression at other sites is increased in inflammation.  It is responsible for the elevated production of prostanoids in inflammation & disease.  It has larger & more flexible substrate channel than COX-I . & a large space where the Celecoxib binds..  Its expression is inhibited by Glucocorticoids 56
  57. 57. MOA of Celecoxib--- conti  Arachidonic acid is the primary precursor of Prostaglandins, is a component of the phospholipids of cell membrane.  Free Arachidonic acid is released by cell damage mainly by the action of Phospholipase A2 enzyme.  Arachidonic acid is converted to prostaglandins at site of inflammation by Cyclo-oxygenase-2 (COX 2) enzyme.  It reduces PG synthesis by selectively inhibiting COX-2 enzyme induced at sites of inflammation without affecting the actions of COX-1--- gastric cytoprotection & platelet aggregation  Inhibition of COX-2 enzyme is time dependent & reversible. 57
  58. 58. 58
  59. 59. PGG2 PGH2 Scheme for prostaglandin Biosynthesis Stimulus Disturbance of cell membrane Phospholipids Corticosteroids inhibit Phospholipase – A2 Arachidonic Acid Lipoxygenase Cyclooxygenase Aspirin & NSAIDs inhibit Endoperoxides Prostacycline Hydroperxides TXA2PGD2PGF2αPGE2Leukotrienes X 59
  60. 60. Pharmacologic Effects :  Analgesic  Antipyretic  Anti-inflammatory effects No inhibition of platelet aggregation. Does not prolong bleeding time. No inhibition of protective gastric PGs--- No gastric irritation. 60
  61. 61. PhK:  Long half life: 11 hrs– Once or twice daily dose.  Metabolized by CYP2C9.  Excreted in feces & urine.  Can inhibit CYP2D6  Dose adjustment in hepatic dysfunction 61
  62. 62. Therapeutic uses:  Specially useful in osteoarithritis & Rheumatoid Arthritis.  Useful in Dysmenorrhea, acute gouty arthritis, acute musculoskeletal pain & ankylosing spondylitis  Also used in Primary familial adenomatus polyposis.  Useful in patients undergoing bone repair / operation. 62
  63. 63. A/E:  Potential for increasing thrombotic events– --------Myocardial infarction & stroke, specially in cases of Rheumatoid Arthritis Who are at risk of myocardial infarction.  Selective COX-2 inhibitors depress PGI2 formation by endothelial cells, without concomitant inhibition of platelets TXA2. PGI2 restrains the effects of TXA2 on CVS, so selective COX-2 inhibitors increase the risk of thrombosis.  Renal toxicities similar to non selective NSAIDs: depressed renal function, edema , Hypertension.  Less GIT A/E (mediated by inhibition of COX-1)  Skin rash---because it is a Sulfonamide 63
  64. 64. D/I:  Inhibitors of CYP2C9-- Fluconazole , Fluvastatin ,& Zafirlukast may increase the serum levels of Celecoxib  Celecoxib can inhibit CYP2D6--- may increase the serum levels of Beta blockers , Antidepressants & Antipsychotic drugs 64
  65. 65. C/I:  Sulfonamide allergy  Anaphylactoid reaction with Aspirin.  Hepatic dysfunction.  Severe renal insufficiency  Severe heart disease  Volume depletion 65
  66. 66. Meloxicam: Related to Piroxicam. Preferentially selective COX-2 inhibitor. Etoricoxib: Resembles diclofenac  Monitoring of hepatic functions required.  Long half life: 22 hrs Nimesulide: new compound less gastric irritation. Valdecoxib & Rofecoxib Withdrawn due to. higher risk of incidence of Cardiovascular thrombotic events----Myocardial Infarction & stroke. 66
  67. 67. Pyrazolone Derivatives  Phenylbutazone: Obsolete --- Agranulocytosis  Apazone / Azopropazone: less risk of agranulocytosis These are now rarely used. 67
  68. 68. Acetic Acid Derivatives Phenylacetic acid derivative: Diclofenac , Tolmetin , ketorolac Indomethacin , Etodolac , Sulnidac Diclofenac: Very commonly used NSAID. MOA: Non-selective COX inhibitor. Good anti- inflammatory. More potent than Indomethacin & Naproxen. Accumulates in synovial fluid . Drug & its metabolites are eliminated via kidney. t1/2 --- 1.1 hrs A/E: Nephrotoxic– Impaired renal blood flow & GF, fluid retention and edema  Less Gastric irritation  ↑ Liver enzymes 68
  69. 69. Uses & dosage forms  Diclofenac is used for long term use in Rheumatoid arthritis ,Osteoarthritis , & Ankylosing spondylitis.  Also for short term treatment of Dysmenorhea, post operative pain, acute musculoskeletal disorders. Oral tablets , capsules, intramuscular Injection Also available in combination with misoprostol & omeprazole.  Prevention of postoperative ophthalmic inflammation after intraocular lens implantation & strabismus surgery: 1% Eye drops  Solar keratoses: 3% gel  Choice for analgesia with nausea -- rectal suppository.  Oral mouthwash. 69
  70. 70. Etodolac:  10 times more selective Cox-2 inhibitor.  Good for post-operative relief after coronary artery bypass operation.  Less gastric intolerance. 70
  71. 71. Indomethacin: Indole derivative.  Potent non selective COX inhibitor.  May also inhibit Phospholipase- A2 & C.  ↓ neutrophils migration also ↓ T & B cell proliferation. Th. Uses:  Gout, ankylosing spondylitis, PDA.  Conjunctival & gingival inflammation.  Postlaminectomy syndrome-- epidural inj. 71
  72. 72. A/E of Indomethacin:  More GIT A/E & Pancrentitis  Headache, Dizziness confusion & Depression. Rare: Thrombocytopenia , Aplstic anemia.  Psychosis with hallucination  Hepatic abnormalities.  Renal papillary necrosis. Tolmetin: Ineffective in gout A/E: Thrombocytopenia. 72
  73. 73. Ketorolac:  Mainly Analgesic.Not anti-inflammatory  Can replace Morphine in post surgical pain .  More Nephrotoxic on chronic use Sulnidac: Sulfoxide prodrug, undergoes, EHC.  DOA: 12-16 hrs.  Suppresses familial polyposis, ↓ incidence of cancer colon , breast & prostate.  A/E: Serious  Stevens Johnsons syndrome  Nephrotic syndrome  Agranulocytosis  Hepatic toxicity. 73
  74. 74. Oxicams ( Enolic acids) : Piroxicam ,Tenoxicam Piroxicam (Feldene): Oxicam derivative. MOA: Non-selective Cox inhibitors  Inhibition of chemotaxis  migration of polys & macrophages , Inhibits lymphocyte function.  ↓ O2 radical production.  Long t ½ - once daily dosage.  Metabolized in liver-  A/E: peptic ulcer & bleeding (at higher dose > 20 mg/d ) 9.5 times higher than other NSAIDs. 74
  75. 75. Naphthylacetic Acid Prodrug: Nabumetone : Non-acid NSAID. Active metabolite has t ½ > 24hrs--- once daily A/E: Pseudoporphyria & photosensitivity. 75
  76. 76. Drugs with Analgesic & mild to moderate anti-inflammatory effect Propionic acid derivatives: Ibuprofen – prototype MOA: Like Aspirin– Non-selective COX inhibitor & also inhibits leukocyte migration.  Good anti- inflammatory.  2400 mg = 4 g of aspirin. t ½ : 2 hrs  More effective in closure of PDA 76
  77. 77. Preparations & Uses Oral tablet, liquid , I/V : For Anti-rheumatoid effects For closure of PDA in pre-term infants.  Topical cream for Osteoarthritis , liquid gel for post surgical dental pain. A/E: Like other NSAIDs  Less Gastric irritation  Nephrotoxic —Ac. renal failure , Interstitial nephritis. Nephrotic syndrome.  Aseptic meningitis in SLE patients  Interaction with anticoagulant uncommon.  Rare agranulocytosis & aplastic anaemia 77
  78. 78.  Flurbiprofen: Non-selective COX inhibitors & also inhibits TNF-α& Nitric oxide synthesis. Given orally. Other preparation also available Topical ophthalmic prep.– for inhibition of intraoperative miosis. I/V for periopretive analgesia. Lozenges for sore throat. Additional A/E: cogwheel rigidity , ataxia , tremor & myoclonus.  Fenoprofen: A/E--interstitial nephritis  Ketoprofen: Also inhibits lipo-oxygenase, not superior to other NSAIDs. 78
  79. 79.  Naproxen: More Toxic, rare allergic pneumonitis, vasculitis, pseudoporphyria.  Oxaprozin: t ½: 50-60hrs. Has uricosuric effect b. Fenamates Mefenamic, Meclofenamic & Flufenamic acid: Inhibit both COX & Phospholipase A2. Have no advantages over other NSAIDs. A/E: Severe diarrhea , inflammation of bowel , Hemolytic anemia. 79
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