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  1. 1. Analgesics and Anti-inflammatories Pharmacology 49.222 Bill Diehl-Jones RN, PhD Faculty of Nursing and Department of Zoology
  2. 2. Major Drug Classifications
  3. 3. Agenda <ul><li>A Zen Review </li></ul><ul><li>Analgesia in general </li></ul><ul><ul><li>Mediators of pain, pain pathways </li></ul></ul><ul><ul><li>Arachidonic Acid metabolites </li></ul></ul><ul><li>Narcotics and Non-Narcotics </li></ul><ul><li>NSAIDS </li></ul>
  4. 4. Drugs Used to Alleviate Pain and Inflammation <ul><li>Analgesics </li></ul><ul><li>Opioid Analgesics </li></ul><ul><li>Co-Analgesics </li></ul><ul><li>NSAIDS </li></ul>
  5. 5. Analgesics (Drugs to Treat Pain) <ul><li>What is pain? </li></ul><ul><ul><li>Sensory stimuli comes from release of prostaglandins, NO, bradykinins, histamine from damaged tissue </li></ul></ul><ul><ul><li>Substance P released from sensory nerves, causes spread of pain </li></ul></ul><ul><ul><li>Stimuli carried by sensory fibres to Thalamus & Cerebrum </li></ul></ul>Sensory Cortex Thalamus Spinothalamic Nerve Tract
  6. 6. A Few Word About Prostglandins Arachidonic Acid Prostaglandins Leukotrienes Lipoxygenase Cyclooxygenase Phospholipase A2 Cell Membrane (What’s the significance? We’ll talk later …)
  7. 7. So How do Non-Narcotic Analgesics Work? <ul><li>Acetaminophen </li></ul><ul><ul><li>inhibits PG synthesis in CNS </li></ul></ul><ul><ul><li>good substitute for aspirin </li></ul></ul><ul><ul><ul><li>why? </li></ul></ul></ul><ul><ul><li>Good stuff! </li></ul></ul><ul><ul><ul><li>Relatively few side effects </li></ul></ul></ul><ul><ul><ul><li>LARGE doses can damage liver </li></ul></ul></ul><ul><li>Phenacetin </li></ul><ul><ul><li>more toxic </li></ul></ul>
  8. 8. How About Narcotic Analgesics? <ul><li>Mainly, affect opioid receptors, </li></ul><ul><ul><li>opiate agonists </li></ul></ul><ul><ul><li>mixed agonists/antagonists </li></ul></ul><ul><ul><li>antagonists </li></ul></ul><ul><li>Important opium receptors: </li></ul><ul><ul><li>mu (  ), kappa (  ), delta (  ) </li></ul></ul><ul><ul><li>each is specific for different drugs </li></ul></ul>Excitatory Neurotransmitters (Eg: Substance P) Opioid Receptors
  9. 9. Examples of Opiate Agonists: Morphine <ul><li>Acts at mu receptors in spinal cord </li></ul><ul><li>inhibits substance P release (and others) </li></ul><ul><li>Clinical effects: </li></ul><ul><ul><li>Raises pain threshold in spinal cord </li></ul></ul><ul><ul><li>produces euphoria </li></ul></ul><ul><ul><li>DECREASES RESPIRATORY DRIVE, cough </li></ul></ul><ul><ul><li>pupillary constriction, CV depression </li></ul></ul><ul><li>What are some other effects? Why? </li></ul>
  10. 10. Examples of Opiate Agonists: Meperidine <ul><li>Synthetic, not related to morphine </li></ul><ul><li>binds to kappa receptors </li></ul><ul><li>causes respiratory depression, pupillary dilation, impedes GI motility </li></ul>
  11. 11. Two More Opioid Narcotics: <ul><li>Methadone </li></ul><ul><ul><li>works on mu receptors </li></ul></ul><ul><ul><li>synthetic, produces less euphoria </li></ul></ul><ul><ul><li>What is it a substitute for? </li></ul></ul><ul><li>Fentanyl </li></ul><ul><ul><li>works like meperidine </li></ul></ul><ul><ul><li>where used? </li></ul></ul>
  12. 12. Morphine, Meperidine, Methadone and Fentanyl are STRONG Opioid Agonists What does that mean?
  13. 13. Moderate Opioid Agonist: Codeine <ul><li>Produces less euphoria </li></ul><ul><li>Antitussive </li></ul><ul><li>But …. Also has antimotility effects </li></ul>
  14. 14. Mixed Agonist-Antagonist: Pentazocine <ul><li>Agonist for kappa receptors </li></ul><ul><li>Antagonist for mu, delta receptors </li></ul><ul><li>for moderate pain </li></ul><ul><li>produces less euphoria </li></ul>
  15. 15. Opioid Antagonist: Naloxone (Narcan) <ul><li>Used to reverse opioid overdose </li></ul><ul><li>displaces receptor-bound opioids </li></ul><ul><li>Good for overcoming respiratory/CV depression </li></ul>Opioid Receptor Naloxone Morphine Just beat it!
  16. 16. Clinical Pearls on Narcotics
  17. 17. Morphine <ul><li>Brand Names : </li></ul><ul><ul><li>Astramorph, Epimorph, MS Cantin, Roxanol </li></ul></ul><ul><li>Uses: </li></ul><ul><ul><li>Acute or chronic pain relief; relieves dyspnea of L. ventricular failure </li></ul></ul><ul><li>Watch: </li></ul><ul><ul><li>Caution with respiratory depression, increased intracranial pressures, acute asthma </li></ul></ul><ul><ul><li>Look for “morphine eyes” (pin-point pupils, glazed) </li></ul></ul><ul><ul><li>ALWAYS KEEP NARCAN ON HAND. Works in 2 minutes </li></ul></ul><ul><ul><li>Antidiarrheic, antitussive </li></ul></ul>
  18. 18. Meperidine <ul><li>Brand Names : </li></ul><ul><ul><li>Demerol, Pethadol, Pethidine </li></ul></ul><ul><li>Uses: </li></ul><ul><ul><li>Similar to morphine; controls moderate to severe pain </li></ul></ul><ul><ul><li>Often used for obstetric analgesia </li></ul></ul><ul><li>Watch: </li></ul><ul><ul><li>No miosis at usual dose (but will with overdose) </li></ul></ul><ul><ul><li>Little or no antidiarhheic or antitussive effect </li></ul></ul><ul><ul><li>Patients using St. John’s Wort may have increased sedation </li></ul></ul>
  19. 19. Codeine <ul><li>Brand Names : </li></ul><ul><ul><li>Paveral </li></ul></ul><ul><li>Uses: </li></ul><ul><ul><li>Similar to morphine; less potent (about one sixth) </li></ul></ul><ul><li>Watch </li></ul><ul><ul><li>Can cause more histamine effects than morphine </li></ul></ul><ul><ul><li>Less antitussive effect than morphine </li></ul></ul><ul><ul><li>Check older men – prostatic hypertrophy </li></ul></ul><ul><ul><li>Less risk of abuse than morphine </li></ul></ul><ul><ul><li>Give with milk if possible </li></ul></ul>
  20. 20. And Now, NSAIDs ….
  21. 21. How Do They Work? <ul><li>Inhibit prostaglandin synthesis </li></ul><ul><li>Aspirin is the prototype </li></ul><ul><li>These differ from acetaminophen: </li></ul>Anti-inflammatory Analgesic Antipyretic Analgesic Antipyretic N S A I D s A C E T A M I N O P H E N
  22. 22. Where do NSAIDs Work? Arachidonic Acid Prostaglandins Leukotrienes Lipoxygenase Cyclooxygenase Phospholipase A2 Cell Membrane Steroids works here: NSAIDs
  23. 23. NSAIDs We Know And Love: <ul><li>Salicylates </li></ul><ul><ul><li>Aspirin </li></ul></ul><ul><li>Propionic Acid Derivatives </li></ul><ul><ul><li>Ibuprofen, naproxen </li></ul></ul><ul><li>Indolacetic Acids </li></ul><ul><ul><li>Indomethacin </li></ul></ul>
  24. 24. Clinical Pearls on NSAIDS
  25. 25. Aspirin <ul><li>Brand Names : </li></ul><ul><ul><li>A.S.A., Alka-Seltzer, Entrophen, Novasen </li></ul></ul><ul><li>Uses: </li></ul><ul><ul><li>Low to moderate pain, RA and osteoarthritis, reduce risk of TIA and MI </li></ul></ul><ul><li>Watch: </li></ul><ul><ul><li>Not for use in children with chickenpox or influenza due to Reye’s syndrome </li></ul></ul><ul><ul><li>Risk of GI bleed </li></ul></ul><ul><ul><li>Take with lots of water </li></ul></ul>
  26. 27. Ibuprofen <ul><li>Brand Names : </li></ul><ul><ul><li>Advil, Motrin, Ibuprin, Medipren </li></ul></ul><ul><li>Uses: </li></ul><ul><ul><li>Chronic RA, gout </li></ul></ul><ul><li>Watch: </li></ul><ul><ul><li>Caution with bleeding abnormalities, renal failure </li></ul></ul><ul><ul><li>Can cause hyponatremia </li></ul></ul><ul><ul><li>A larger loading dose is often used (400-600 mg in adults), followed by 200 mg </li></ul></ul>
  27. 28. Indomethacin <ul><li>Brand Names : </li></ul><ul><ul><li>Indameth, Indocid, Indocin </li></ul></ul><ul><li>Uses: </li></ul><ul><ul><li>Also used with rheumatoid, gouty arthrits </li></ul></ul><ul><ul><li>Closes PDAs in premature infants </li></ul></ul><ul><li>Clinical Pearls: </li></ul><ul><ul><li>Dizziness, hallucinations not uncommon </li></ul></ul>
  28. 29. Naproxen <ul><li>Brand Names : </li></ul><ul><ul><li>Apo-Naproxen, Naprosyn, Naxen, Walprox </li></ul></ul><ul><li>Uses: </li></ul><ul><ul><li>Also used with rheumatoid, gouty arthrits </li></ul></ul><ul><li>Clinical Pearls: </li></ul><ul><ul><li>An OTC drug in Canada, can be purchased without a script in the US </li></ul></ul><ul><ul><li>More sustained duration of action than ibuprofen </li></ul></ul>
  29. 30. And now, a word about VIOXX
  30. 31. Vioxx <ul><li>A new type of analgesic that is used in the treatment of pain from osteoarthritis, rheumatoid arthritis, dysmenorrhea, and other sources of acute pain. </li></ul><ul><li>Other examples of COX-2 inhibitors include Celebrex and Bextra. </li></ul>
  31. 32. So, what happened …? <ul><li>Vioxx, was voluntarily withdrawn on September 30, 2004 due to mounting evidence linking it to increased risk of cardiovascular problems. </li></ul><ul><li>Following a three-year study involving the drug, researchers concluded that withdrawing Vioxx from the market would be in the best interest of the patients. </li></ul><ul><li>The drug has also been connected with higher incidences of respiratory and liver and kidney dysfunction. </li></ul>
  32. 33. Some Clinical Pointers on NSAIDS <ul><li>New evidence suggests that Ibuprofen may interfere with anticoagulatory effects of aspirin </li></ul>