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Antiinflammatory and nsai ds


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Antiinflammatory and nsai ds

  1. 1. Antiinflammatory Agents and Nonsteroidal Antiinflammatory Drugs (NSAIDs)
  2. 2. NSAIDs <ul><li>Large and chemically diverse group of drugs with the following properties: </li></ul><ul><ul><li>Analgesic </li></ul></ul><ul><ul><li>Antiinflammatory </li></ul></ul><ul><ul><li>Antipyretic </li></ul></ul>
  3. 3. NSAIDs: Mechanism of Action <ul><li>Activation of the arachidonic acid pathway causes: </li></ul><ul><li>pain </li></ul><ul><li>headache </li></ul><ul><li>fever </li></ul><ul><li>inflammation </li></ul>
  4. 4. NSAIDs: Mechanism of Action <ul><li>Analgesia—treatment of headaches and pain </li></ul><ul><li>Block the undesirable effects of prostaglandins, which cause headaches </li></ul>
  5. 5. NSAIDs: Mechanism of Action <ul><li>Antipyretic: reduce fever </li></ul><ul><li>Inhibit prostaglandin E 2 within the area of the brain that controls temperature </li></ul>
  6. 6. NSAIDs: Mechanism of Action <ul><li>Relief of inflammation </li></ul><ul><li>Inhibit the leukotriene pathway, the prostaglandin pathway, or both </li></ul>
  7. 7. NSAIDs <ul><li>Six structurally related groups: </li></ul><ul><li>Acetic acids </li></ul><ul><li>Carboxylic acids </li></ul><ul><li>Propionic acids </li></ul><ul><li>Enolic acids </li></ul><ul><li>Fenamic acids </li></ul><ul><li>Nonacidic compounds </li></ul>
  8. 8. NSAIDs: Acetic Acid <ul><li>diclofenac sodium (Voltaren) </li></ul><ul><li>diclofenac potassium (Cataflam) </li></ul><ul><li>etodolac (Lodine) </li></ul><ul><li>indomethacin (Indocin) </li></ul><ul><li>sulindac (Clinoril) </li></ul><ul><li>tolmetin (Tolectin) </li></ul>
  9. 9. NSAIDs: Carboxylic Acids <ul><li>Acetylated </li></ul><ul><li>aspirin (ASA) </li></ul><ul><li>choline magnesium salicylate (Trilisate) </li></ul><ul><li>diflunisal (Dolobid) </li></ul><ul><li>Nonacetylated </li></ul><ul><li>salicylamide </li></ul><ul><li>salsalate (Disalcid) </li></ul><ul><li>sodium salicylate </li></ul>
  10. 10. NSAIDs: Propionic Acids <ul><li>fenoprofen (Nalfon) </li></ul><ul><li>flurbiprofen (Ansaid) </li></ul><ul><li>ibuprofen (Motrin, others) </li></ul><ul><li>ketoprofen (Orudis) </li></ul><ul><li>ketorolac (Toradol) </li></ul><ul><li>naproxen (Naprosyn) </li></ul><ul><li>oxaprozin (Daypro) </li></ul>
  11. 11. NSAIDs: Other Agents <ul><li>Enolic acids </li></ul><ul><li>phenylbutazone (Butazolidin) </li></ul><ul><li>piroxicam (Feldene) </li></ul><ul><li>Fenamic acids </li></ul><ul><li>meclofenamic acid (Meclomen) </li></ul><ul><li>mefenamic acid (Ponstel) </li></ul><ul><li>Nonacidic compounds </li></ul><ul><li>nabumetone (Relafen) </li></ul>
  12. 12. NSAIDs: Other Agents <ul><li>COX-2 Inhibitors </li></ul><ul><li>celecoxib (Celebrex) </li></ul><ul><li>rofecoxib (Vioxx) </li></ul>
  13. 13. NSAIDs: Drug Effects <ul><li>Analgesic (mild to moderate) </li></ul><ul><li>Antigout </li></ul><ul><li>Antiinflammatory </li></ul><ul><li>Antipyretic </li></ul><ul><li>Relief of vascular headaches </li></ul><ul><li>Platelet inhibition (ASA) </li></ul>
  14. 14. NSAIDs: Therapeutic Uses <ul><li>Relief of mild to moderate pain </li></ul><ul><li>Acute gout </li></ul><ul><li>Various bone, joint, and muscle pain </li></ul><ul><li>Osteoarthritis </li></ul><ul><li>Rheumatoid arthritis </li></ul><ul><li>Juvenile rheumatoid arthritis </li></ul><ul><li>Dysmenorrhea </li></ul><ul><li>Fever </li></ul>
  15. 15. NSAIDs: Specific Agents <ul><li>salicylates (aspirin) </li></ul><ul><li>More potent effect on platelet aggregation and thermal regulatory center in the brain </li></ul><ul><ul><li>analgesic </li></ul></ul><ul><ul><li>antipyretic </li></ul></ul><ul><ul><li>antiinflammatory </li></ul></ul><ul><li>Antithrombotic effect: used in the treatment of MI and other thromboembolic disorders </li></ul>
  16. 16. NSAIDs: Specific Agents <ul><li>phenylbutazone (Butazolidin) </li></ul><ul><li>Greater effects on uric acid production and excretion, in addition to antiinflammatory effects </li></ul><ul><li>More commonly used for treatment of gout </li></ul>
  17. 17. NSAIDs: Side Effects <ul><li>Gastrointestinal </li></ul><ul><li>dyspepsia, heartburn, epigastric distress, nausea </li></ul><ul><ul><li>**GI bleeding </li></ul></ul><ul><ul><li>**mucosal lesions (erosions or ulcerations) </li></ul></ul><ul><li>Misoprostol (Cytotec) can be used to reduce these dangerous effects. </li></ul>
  18. 18. NSAIDs: Side Effects <ul><li>Renal </li></ul><ul><li>reductions in creatinine clearance </li></ul><ul><li>acute tubular necrosis with renal failure </li></ul>
  19. 19. NSAIDs: Side Effects <ul><li>Cardiovascular </li></ul><ul><li>noncardiogenic pulmonary edema </li></ul>
  20. 20. NSAIDs: Salicylate Toxicity <ul><li>Adults: tinnitus and hearing loss </li></ul><ul><li>Children: hyperventilation and CNS effects </li></ul><ul><li>Effects arise when serum levels exceed 300  g/mL. </li></ul><ul><li>Metabolic acidosis and respiratory alkalosis may be present. </li></ul>
  21. 21. NSAIDs: Nursing Implications <ul><li>Before beginning therapy, assess for conditions that may be contraindications to therapy, especially: </li></ul><ul><ul><li>GI lesions or peptic ulcer disease </li></ul></ul><ul><ul><li>Bleeding disorders </li></ul></ul><ul><li>Assess also for conditions that require cautious use. </li></ul><ul><li>Perform lab studies as indicated (cardiac, renal, liver studies, CDC, platelet count). </li></ul>
  22. 22. NSAIDs: Nursing Implications <ul><li>Perform a medication history to assess for potential drug interactions. </li></ul><ul><li>Several serious drug interactions exist: </li></ul><ul><ul><li>alcohol </li></ul></ul><ul><ul><li>heparin </li></ul></ul><ul><ul><li>phenytoin </li></ul></ul><ul><ul><li>oral anticoagulants </li></ul></ul><ul><ul><li>steroids </li></ul></ul><ul><ul><li>sulfonamides </li></ul></ul>
  23. 23. NSAIDs: Nursing Implications <ul><li>Salicylates are NOT to be given to children under age 12 because of the risk of Reye’s syndrome. </li></ul><ul><li>Because these agents generally cause GI distress, they are often better tolerated if taken with food, milk or an antacid to avoid GI irritation. </li></ul><ul><li>Explain to patients that therapeutic effects may not be seen for 3 to 4 weeks. </li></ul>
  24. 24. NSAIDs: Nursing Implications <ul><li>Educate patients about the various side effects of NSAIDs, and to notify their physician if these effects become severe or if bleeding or GI pain occur. </li></ul><ul><li>Patients should watch closely for the occurrence of any unusual bleeding, such as in the stool. </li></ul><ul><li>Enteric-coated tablets should not be crushed or chewed. </li></ul>
  25. 25. NSAIDs: Nursing Implications <ul><li>Monitor for therapeutic effects, which vary according to the condition being treated: </li></ul><ul><ul><li>decrease in swelling, pain, stiffness, and tenderness of a joint or muscle area </li></ul></ul>
  26. 26. Nonsteroidal Anti-inflammatory Drugs (NSAIDs) <ul><li>Common therapeutic indications </li></ul><ul><li>Common adverse effects </li></ul><ul><li>Different pharmacokinetics and potency </li></ul><ul><li>Different chemical families </li></ul><ul><li>Common mechanism of action (cyclooxygenase inhibition) </li></ul><ul><li>Different selectivities to COX I and II </li></ul><ul><li>Similarities more striking than Differences </li></ul>
  27. 27.
  28. 28.
  29. 29. Common Pharmacological Effects <ul><li>Analgesic (CNS and peripheral effect) may involve non-PG related effects </li></ul><ul><li>Antipyretic (CNS effect) </li></ul><ul><li>Anti-inflammatory (except acetaminophen) due mainly to PG inhibition. </li></ul><ul><li>Some shown to inhibit activation, aggregation , adhesion of neutrophils & release of lysosomal enzymes </li></ul><ul><li>Some are Uricosuric </li></ul>
  30. 30. Common Adverse Effects <ul><li>Platelet Dysfunction </li></ul><ul><li>Gastritis and peptic ulceration with bleeding (inhibition of PG + other effects) </li></ul><ul><li>Acute Renal Failure in susceptible </li></ul><ul><li>Sodium+ water retention and edema </li></ul><ul><li>Analgesic nephropathy </li></ul><ul><li>Prolongation of gestation and inhibition of labor. </li></ul><ul><li>Hypersenstivity (not immunologic but due to PG inhibition) </li></ul>
  31. 31. NSAID ↑ Leukocyte-Endothelial Interactions Capillary Obstruction Ischemic Cell Injury Proteases + Oxygen Radicals Endo/Epithelial Cell Injury Mucosal Ulceration Loss of PGE 2 and PGI 2 mediated inhibition of acid secretion and cytoprotective effect Loss of PGI 2 induced inhibition of LTB 4 mediated endothelial adhesion and activation of neutrophils
  32. 32. The Salicylates - Aspirin <ul><li>Effect on Respiration: triphasic </li></ul><ul><li>Low doses: uncoupling phosphorylation -> ↑ CO 2 -> stimulates respiration. </li></ul><ul><li>Direct stimulation of respiratory center -> Hyperventilation -> resp. alkalosis -> renal compensation </li></ul><ul><li>Depression of respiratory center and cardiovascular center -> ↓ BP, respiratory acidosis, no compensation + metabolic acidosis also </li></ul>
  33. 33. <ul><li>GI system </li></ul><ul><li>Dose dependent hepatitis </li></ul><ul><li>Reye’s syndrome </li></ul><ul><li>Metabolic </li></ul><ul><li>Uncoupling of Oxid. Phosphorylation </li></ul><ul><li>Hyperglycemia and depletion of muscle and hepatic glycogen </li></ul><ul><li>Endocrine: corticosteroids, thyroid </li></ul>Aspirin
  34. 34. <ul><li>Antipyretic, analgesic </li></ul><ul><li>Anti-inflammatory: rheumatic fever, rheumatoid arthritis, other rheumatological diseases. High dose needed (5-8 g/day) </li></ul><ul><li>Prophylaxis of diseases due to platelet aggregation (CAD, post-op DVT) </li></ul><ul><li>Pre-eclampsia and hypertension of pregnancy (?excess TXA 2 ) </li></ul>Aspirin - Therapeutic Uses
  35. 35. Generation of Lipoxins by Aspirin
  36. 36. Role of Lipoxins in Anti-inflammatory effects of Aspirin
  37. 37. Effect of NSAID’s on Platelet-Endothelial Interactions
  38. 38. Use of Aspirin in Unstable Angina
  39. 39. Use of Aspirin in Unstable Angina
  40. 40. <ul><li>Headache - timmitus - dizziness – hearing impairment – dim vision </li></ul><ul><li>Confusion and drowziness </li></ul><ul><li>Sweating and hyperventilation </li></ul><ul><li>Nausea, vomiting </li></ul><ul><li>Marked acid-base disturbances </li></ul><ul><li>Hyperpyrexia </li></ul><ul><li>Dehydration </li></ul><ul><li>Cardiovascular and respiratory collapse, coma convulsions and death </li></ul>Aspirin Toxicity - Salicylism
  41. 41. <ul><li>Decrease absorption - activated charcoal, emetics, gastric lavage </li></ul><ul><li>Enhance excretion - alkalinize urine, forced diuresis, hemodialysis </li></ul><ul><li>Supportive measures - fluids, decrease temperature, bicarbonate, electrolytes, glucose, etc… </li></ul>Aspirin Toxicity - Treatment
  42. 42. Other NSAID’s <ul><li>Phenylbutazone: additional uricosuric effect. Aplastic anemia. </li></ul><ul><li>Indomethacin: Common ADR’s. CNS most common: halucinations, depression, seizures </li></ul><ul><li>Propionic acids: better tolerated. Differ in pharmacokinetics </li></ul><ul><li>Acetaminophen: differes in effects and ADR’s from rest. Main toxicity: hepatitis due to toxic intermediate which depletes glutathione. Treat with N-acetylcysteine. </li></ul>
  43. 43.
  44. 44. Attempts to Decrease Toxicity of NSAID’s – Nitroaspirins
  45. 45.
  46. 46. Selective COX-II Inhibitors <ul><li>Anti-inflammatory with less adverse effects, especially GI events. </li></ul><ul><li>Potential toxicities: kidney and platelets - ? increased risk of thrombotic events </li></ul><ul><li>Role in Cancer prevention </li></ul><ul><li>Role in Alzheimer’s disease </li></ul>
  47. 47. VIGOR - Summary of GI Endpoints † p < 0.001. * p = 0.005. 0 1 2 3 4 5 Confirmed Clinical Upper GI Events Confirmed Complicated Upper GI Events All Clinical GI Bleeding RR: 0.46 † (0.33, 0.64) RR: 0.43 * (0.24, 0.78) RR: 0.38 † (0.25, 0.57) Rates per 100 Patient-Years Rofecoxib Naproxen ( ) = 95% CI. Source: Bombardier, et al. N Engl J Med . 2000.
  48. 48. VIGOR - Confirmed Thrombotic Cardiovascular Events Patients with Events (Rates per 100 Patient-Years) Event Category Rofecoxib N=4047 Naproxen N=4029 Relative Risk (95% CI) Confirmed CV events 45 (1.7) 19 (0.7) 0.42 (0.25, 0.72) Cardiac events 28 (1.0) 10 (0.4) 0.36 (0.17, 0.74) Cerebrovascular events 11 (0.4) 8 (0.3) 0.73 (0.29, 1.80) Peripheral vascular events 6 (0.2) 1 (0.04) 0.17 (0.00, 1.37) Source: Data on file, MSD
  49. 49. Effect of Celecoxib & Rofecoxib on PGIM * p<0.05 vs. placebo. 0 40 80 120 160 200 Placebo N=7 Celecoxib 400 mg N=7 Ibuprofen 800 mg N=7 Urinary PGI-M (pg/mg creatinine) (Mean ± SE) ** * Placebo N=12 Rofecoxib 50 mg QD N=12 Indomethacin 50 mg TID N=10 ** ** Single Dose Rx † Two Weeks Rx †† 0 40 80 120 160 200 † Proc. Natl. Acad Sci. USA 1999;96:272-277. Urinary 2,3 dinor-6-keto-PGF 1  (PGIM) †† J. Pharmacol. Exp. Ther . 1999;289:735-741. **p<0.01 vs. placebo.
  50. 50. Investigator-Reported Thrombotic Cardiovascular Events in the VIGOR Study Compared with Phase IIb/III OA Study 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Months of Follow-up 0 2 4 6 8 10 12 14 Cumulative Incidence % Rofecoxib (OA) FDA files Ibuprofen, Diclofenac, Nabumetone (OA) Rofecoxib (VIGOR) Naproxen (VIGOR)
  51. 51. Treatment of Gout