Opioids lecture 08

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Opioids lecture 08

  1. 1. OPIOID ANALGESICS Dennis Paul, Ph.D. MEB 7154
  2. 3. Opioid Receptor Subtypes <ul><li>Mu receptors: </li></ul><ul><ul><li>Mu 1 and Mu 2 receptors </li></ul></ul><ul><li>Kappa receptors: </li></ul><ul><ul><li>Kappa 1 , and Kappa 3 receptors </li></ul></ul><ul><li>Delta receptors: </li></ul><ul><ul><li>Delta 1 and Delta 2 receptors </li></ul></ul>
  3. 4. Endogenous Opioids <ul><li>Pro-opiomelanocortin peptides: </li></ul><ul><ul><li> -endorphin </li></ul></ul><ul><li>Pro-enkephalin peptides: </li></ul><ul><ul><li>met-enkephalin and leu-enkephalin </li></ul></ul><ul><li>Prodynorphin peptides: </li></ul><ul><ul><li>Dyn-A, Dyn-B and  -neo-endorphin </li></ul></ul><ul><li>Endomorphins: </li></ul><ul><ul><li>Endomorphin-1 and Endomorphin-2 </li></ul></ul>
  4. 5. Opioid receptors, endogenous ligands and function: Mu receptors Mu 1 : B-endorphin, endomorphin enkephalin Mu 2 : B-endorphin, endomorphin Kappa receptors Kappa 1 : dynorphins Kappa 2 & 3 : dynorphins , unknown Delta receptors Delta 1 : enkephalins , dynorphins Delta 2 : enkephalins
  5. 6. Cloned Opioid Receptors <ul><li>MOR, DOR, KOR </li></ul><ul><li>7-transmembrane domains </li></ul><ul><li>G-protein linked (G i or G o ) to adenylyl cyclase or potassium channels </li></ul>
  6. 7. In vivo assays: <ul><li>1. Analgesic properties </li></ul><ul><li>2. Reinforcing properties </li></ul><ul><li>3. Stimulus properties </li></ul>
  7. 8. Analgesic Assays <ul><li>Thermal stimuli </li></ul><ul><li>Tactile stimuli </li></ul><ul><li>Inflammation </li></ul><ul><li>Neuropathy </li></ul>
  8. 9. Reinforcing Properties <ul><li>Self-administration </li></ul><ul><li>Conditioned Place Preference </li></ul>
  9. 10. Stimulus Properties <ul><li>Discrimination tasks </li></ul><ul><li>Addiction Research Center Inventory </li></ul>
  10. 11. II Opioid Agonists <ul><ul><li>A. Opium alkaloids and derivatives B. Synthetic compounds </li></ul></ul><ul><ul><li>III. Antagonists </li></ul></ul><ul><ul><li>IV. Mixed agonist-antagonists </li></ul></ul><ul><ul><li>V. Partial agonists </li></ul></ul>
  11. 12. Desirable properties of morphine as an analgesic <ul><li>Effective over a wide range of doses </li></ul><ul><li>Effect on mood </li></ul><ul><li>Sedation </li></ul>
  12. 13. Undesirable properties of morphine as an analgesic <ul><li>Sedation* </li></ul><ul><li>Mental Clouding </li></ul><ul><li>Dysphoria </li></ul><ul><li>Constipation* </li></ul><ul><li>Dizziness </li></ul><ul><li>Nausea and vomiting </li></ul><ul><li>Respiratory depression* </li></ul><ul><li>Cough reflex depression* (medulla) </li></ul><ul><li>Circulatory depression </li></ul><ul><li>Pinpoint pupils </li></ul><ul><li>Pruritis and rash </li></ul><ul><li>Biliary tract spasms </li></ul><ul><li>Ureter and vesical spasms </li></ul><ul><li>Urinary retention </li></ul><ul><li>Behavioral dependence </li></ul><ul><li>Physical dependence </li></ul><ul><li>Tolerance </li></ul>
  13. 14. Tolerance <ul><li>Associative or behavioral tolerance </li></ul><ul><li>Nonassociative or pharmacologic tolerance </li></ul><ul><li>Cross-tolerance </li></ul><ul><li>Intrinsic efficacy may affect development of tolerance and cross-tolerance </li></ul>
  14. 15. Multiple sites of action <ul><li>Dorsal horn of the spinal cord </li></ul><ul><li>Activate descending inhibitory system </li></ul><ul><li>Peripheral receptors </li></ul>
  15. 18. Multiple sites of action <ul><li>Dorsal horn of the spinal cord </li></ul><ul><li>Activate descending inhibitory system </li></ul><ul><li>Peripheral receptors </li></ul>
  16. 19. Metabolism of morphine <ul><li>Morphine-3ß-glucuronide (inactive) </li></ul><ul><li>Morphine-6ß-glucuronide (active) </li></ul><ul><li>Accumulate in patients with renal damage </li></ul>
  17. 20. Heroin <ul><li>Crosses blood-brain barrier more rapidly than morphine </li></ul><ul><li>2-4 X greater potency than morphine </li></ul><ul><li>Converted to morphine </li></ul>
  18. 21. Hydromorphone (Dilaudid) <ul><li>About 8-10X potency of morphine </li></ul><ul><li>Slightly shorter duration than morphine </li></ul><ul><li>available as suppository </li></ul>
  19. 22. Oxymorphone (Numorphan) <ul><li>Same as hydromorphone </li></ul>
  20. 23. Codeine <ul><li>About 1/10th the potency of morphine </li></ul><ul><li>lower efficacy than morphine </li></ul><ul><li>about 10% converted to morphine by CYP450 2D6 </li></ul><ul><li>10% of patients do not possess this enzyme </li></ul>
  21. 24. Oxycodone <ul><li>About 10X potency of codeine </li></ul><ul><li>Also metabolized by CYP450-2D6 </li></ul><ul><li>Controlled release formulation (OxyContin) </li></ul>
  22. 25. Hydrocodone and Dihydrocodeine <ul><li>Same as oxycodone </li></ul>
  23. 26. Mixtures containing Codeine <ul><li>Acetaminophen or NSAIDs </li></ul><ul><li>Logic: Additive or synergistic analgesia without concomitant increase in adverse effects. </li></ul>
  24. 27. Mixtures containing Codeine
  25. 28. Synthetic compounds <ul><li>Meperidine </li></ul><ul><li>Fentanyl, Sufentanyl, Alfentanyl Remifentanyl </li></ul><ul><li>Methadone </li></ul><ul><li>L- α-acetyl-methadol: LAAM </li></ul><ul><li>Propoxyphene </li></ul>
  26. 29. Meperidine <ul><li>About 1/8th potency of morphine </li></ul><ul><li>shorter duration </li></ul><ul><li>fewer smooth muscle spasms than morphine </li></ul><ul><li>No meiosis </li></ul><ul><li>biotransformed to a toxic metabolite that builds up and can cause seizures. </li></ul><ul><li>Synergistic with gila monster venom </li></ul>
  27. 30. Fentanyl <ul><li>80 - 100 x potency of morphine </li></ul><ul><li>fast onset, short duration </li></ul><ul><li>used i.v. for anesthesia </li></ul><ul><li>available as patch </li></ul><ul><li>available as oral slow release device. </li></ul>
  28. 31. Fentanyl derivatives <ul><li>Alfentanyl </li></ul><ul><li>Sufentanyl </li></ul><ul><li>Remifentanyl </li></ul>
  29. 32. Methadone <ul><li>Potency similar to morphine for i.v. administration, but 4 x more potent orally </li></ul><ul><li>long plasma half-life </li></ul><ul><li>used in treatment of narcotic dependence </li></ul><ul><li>Duration of action increases with repeated use </li></ul>
  30. 33. LAAM <ul><li>Extremely long plasma half-life (>72 hr) </li></ul><ul><li>Suppresses opiate withdrawal for 4-5 days </li></ul>
  31. 34. Propoxyphene <ul><li>Potency compared to codeine </li></ul><ul><li>Potency compared to placebo </li></ul><ul><li>Produces cardiotoxicity and pulmonary edema </li></ul><ul><li>Active metabolite produces convulsions </li></ul>
  32. 35. Opioid Antagonists <ul><li>Naloxone </li></ul><ul><li>Naltrexone </li></ul><ul><li>Nalmefene </li></ul>
  33. 36. Signs of Overdose <ul><li>Stuporous or in coma </li></ul><ul><li>Respiratory rate extremely low </li></ul><ul><li>pinpoint pupils </li></ul><ul><li>low body temperature </li></ul><ul><li>flacid skeletal muscles, jaw relaxed </li></ul>
  34. 37. Naloxone <ul><li>Short half-life </li></ul><ul><li>not effective orally </li></ul>
  35. 38. Naltrexone <ul><li>Long half-life </li></ul><ul><li>effective orally or injected </li></ul><ul><li>available in oral form only </li></ul><ul><li>used for treatment of dependence </li></ul>
  36. 39. Nalmefene <ul><li>Intermediate duration (4-6 hr) </li></ul><ul><li>orally active </li></ul><ul><li>no hepatotoxicity with long term use </li></ul>
  37. 40. Mixed agonist-antagonists <ul><li>Nalorphine and cyclazocine </li></ul><ul><li>Pentazocine: Talwin NX </li></ul><ul><li>Butorphanol </li></ul><ul><li>Nalbuphine </li></ul>
  38. 41. Nalorphine and Cyclazocine <ul><li>Kappa 3 receptor agonists </li></ul><ul><li>Mu receptor antagonists </li></ul><ul><li>produce psychotomimetic effects </li></ul><ul><li>produce dysphoria </li></ul>
  39. 42. Pentazocine <ul><li>Kappa and delta agonist </li></ul><ul><li>‘ Ts and blues’ </li></ul><ul><li>Talwin NX </li></ul>
  40. 43. Butorphanol <ul><li>Kappa receptor agonist </li></ul><ul><li>Mu receptor antagonist </li></ul><ul><li>Available as nasal spray </li></ul><ul><li>5 X more potent in women than men </li></ul>
  41. 44. Nalbuphine <ul><li>Kappa receptor agonist </li></ul><ul><li>Mu receptor antagonist </li></ul><ul><li>Little dysphoria compared to nalorphine </li></ul><ul><li>Less abuse potential than morphine </li></ul>
  42. 45. Partial agonist: Buprenorphine <ul><li>Partial agonist at mu receptors </li></ul><ul><li>Partial agonist at kappa 3 receptors </li></ul><ul><li>Antagonist at kappa 1 receptors </li></ul><ul><li>Lower efficacy analgesic than morphine </li></ul>
  43. 46. Tramadol <ul><li>Opioid receptor agonist (mu and delta) </li></ul><ul><li>NE and 5-HT reuptake blocker (antidepressant) </li></ul><ul><li>α-2 adrenoceptor agonist </li></ul><ul><li>These actions are synergistic for analgesia </li></ul>
  44. 47. Dependence and Withdrawal <ul><li>Dependence varies from mild craving to compulsion to take the drug </li></ul><ul><li>Degree depends upon dose and frequency </li></ul><ul><li>Withdrawal signs opposite in direction to the drug effects. </li></ul><ul><li>Will last about 72 hrs for morphine or heroin </li></ul><ul><li>Not life threatening </li></ul>
  45. 48. Other factors that influence the effectiveness of opioid treatment <ul><li>Progression of tissue-damaging disease </li></ul><ul><li>Sensitization of CNS neurons </li></ul><ul><li>Collateral transmission </li></ul>
  46. 50. Salvinorin A <ul><li>Active ingredient in Salvia Divinorum </li></ul><ul><li>Very selective kappa opioid agonist </li></ul><ul><li>Hallucinogen </li></ul>

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