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Opioids lecture 08
Opioids lecture 08
Opioids lecture 08
Opioids lecture 08
Opioids lecture 08
Opioids lecture 08
Opioids lecture 08
Opioids lecture 08
Opioids lecture 08
Opioids lecture 08
Opioids lecture 08
Opioids lecture 08
Opioids lecture 08
Opioids lecture 08
Opioids lecture 08
Opioids lecture 08
Opioids lecture 08
Opioids lecture 08
Opioids lecture 08
Opioids lecture 08
Opioids lecture 08
Opioids lecture 08
Opioids lecture 08
Opioids lecture 08
Opioids lecture 08
Opioids lecture 08
Opioids lecture 08
Opioids lecture 08
Opioids lecture 08
Opioids lecture 08
Opioids lecture 08
Opioids lecture 08
Opioids lecture 08
Opioids lecture 08
Opioids lecture 08
Opioids lecture 08
Opioids lecture 08
Opioids lecture 08
Opioids lecture 08
Opioids lecture 08
Opioids lecture 08
Opioids lecture 08
Opioids lecture 08
Opioids lecture 08
Opioids lecture 08
Opioids lecture 08
Opioids lecture 08
Opioids lecture 08
Opioids lecture 08
Opioids lecture 08
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Opioids lecture 08

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  • 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>
  • 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>
  • 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
  • 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>
  • 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>
  • 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>
  • 9. Reinforcing Properties <ul><li>Self-administration </li></ul><ul><li>Conditioned Place Preference </li></ul>
  • 10. Stimulus Properties <ul><li>Discrimination tasks </li></ul><ul><li>Addiction Research Center Inventory </li></ul>
  • 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>
  • 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>
  • 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>
  • 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>
  • 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>
  • 16.  
  • 17.  
  • 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>
  • 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>
  • 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>
  • 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>
  • 22. Oxymorphone (Numorphan) <ul><li>Same as hydromorphone </li></ul>
  • 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>
  • 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>
  • 25. Hydrocodone and Dihydrocodeine <ul><li>Same as oxycodone </li></ul>
  • 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>
  • 27. Mixtures containing Codeine
  • 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>
  • 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>
  • 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>
  • 31. Fentanyl derivatives <ul><li>Alfentanyl </li></ul><ul><li>Sufentanyl </li></ul><ul><li>Remifentanyl </li></ul>
  • 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>
  • 33. LAAM <ul><li>Extremely long plasma half-life (>72 hr) </li></ul><ul><li>Suppresses opiate withdrawal for 4-5 days </li></ul>
  • 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>
  • 35. Opioid Antagonists <ul><li>Naloxone </li></ul><ul><li>Naltrexone </li></ul><ul><li>Nalmefene </li></ul>
  • 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>
  • 37. Naloxone <ul><li>Short half-life </li></ul><ul><li>not effective orally </li></ul>
  • 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>
  • 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>
  • 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>
  • 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>
  • 42. Pentazocine <ul><li>Kappa and delta agonist </li></ul><ul><li>‘ Ts and blues’ </li></ul><ul><li>Talwin NX </li></ul>
  • 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>
  • 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>
  • 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>
  • 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>
  • 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>
  • 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>
  • 49.  
  • 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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