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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
    • Mu receptors:
      • Mu 1 and Mu 2 receptors
    • Kappa receptors:
      • Kappa 1 , and Kappa 3 receptors
    • Delta receptors:
      • Delta 1 and Delta 2 receptors
  • 4. Endogenous Opioids
    • Pro-opiomelanocortin peptides:
      •  -endorphin
    • Pro-enkephalin peptides:
      • met-enkephalin and leu-enkephalin
    • Prodynorphin peptides:
      • Dyn-A, Dyn-B and  -neo-endorphin
    • Endomorphins:
      • Endomorphin-1 and Endomorphin-2
  • 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
    • MOR, DOR, KOR
    • 7-transmembrane domains
    • G-protein linked (G i or G o ) to adenylyl cyclase or potassium channels
  • 7. In vivo assays:
    • 1. Analgesic properties
    • 2. Reinforcing properties
    • 3. Stimulus properties
  • 8. Analgesic Assays
    • Thermal stimuli
    • Tactile stimuli
    • Inflammation
    • Neuropathy
  • 9. Reinforcing Properties
    • Self-administration
    • Conditioned Place Preference
  • 10. Stimulus Properties
    • Discrimination tasks
    • Addiction Research Center Inventory
  • 11. II Opioid Agonists
      • A. Opium alkaloids and derivatives B. Synthetic compounds
      • III. Antagonists
      • IV. Mixed agonist-antagonists
      • V. Partial agonists
  • 12. Desirable properties of morphine as an analgesic
    • Effective over a wide range of doses
    • Effect on mood
    • Sedation
  • 13. Undesirable properties of morphine as an analgesic
    • Sedation*
    • Mental Clouding
    • Dysphoria
    • Constipation*
    • Dizziness
    • Nausea and vomiting
    • Respiratory depression*
    • Cough reflex depression* (medulla)
    • Circulatory depression
    • Pinpoint pupils
    • Pruritis and rash
    • Biliary tract spasms
    • Ureter and vesical spasms
    • Urinary retention
    • Behavioral dependence
    • Physical dependence
    • Tolerance
  • 14. Tolerance
    • Associative or behavioral tolerance
    • Nonassociative or pharmacologic tolerance
    • Cross-tolerance
    • Intrinsic efficacy may affect development of tolerance and cross-tolerance
  • 15. Multiple sites of action
    • Dorsal horn of the spinal cord
    • Activate descending inhibitory system
    • Peripheral receptors
  • 16.  
  • 17.  
  • 18. Multiple sites of action
    • Dorsal horn of the spinal cord
    • Activate descending inhibitory system
    • Peripheral receptors
  • 19. Metabolism of morphine
    • Morphine-3ß-glucuronide (inactive)
    • Morphine-6ß-glucuronide (active)
    • Accumulate in patients with renal damage
  • 20. Heroin
    • Crosses blood-brain barrier more rapidly than morphine
    • 2-4 X greater potency than morphine
    • Converted to morphine
  • 21. Hydromorphone (Dilaudid)
    • About 8-10X potency of morphine
    • Slightly shorter duration than morphine
    • available as suppository
  • 22. Oxymorphone (Numorphan)
    • Same as hydromorphone
  • 23. Codeine
    • About 1/10th the potency of morphine
    • lower efficacy than morphine
    • about 10% converted to morphine by CYP450 2D6
    • 10% of patients do not possess this enzyme
  • 24. Oxycodone
    • About 10X potency of codeine
    • Also metabolized by CYP450-2D6
    • Controlled release formulation (OxyContin)
  • 25. Hydrocodone and Dihydrocodeine
    • Same as oxycodone
  • 26. Mixtures containing Codeine
    • Acetaminophen or NSAIDs
    • Logic: Additive or synergistic analgesia without concomitant increase in adverse effects.
  • 27. Mixtures containing Codeine
  • 28. Synthetic compounds
    • Meperidine
    • Fentanyl, Sufentanyl, Alfentanyl Remifentanyl
    • Methadone
    • L- α-acetyl-methadol: LAAM
    • Propoxyphene
  • 29. Meperidine
    • About 1/8th potency of morphine
    • shorter duration
    • fewer smooth muscle spasms than morphine
    • No meiosis
    • biotransformed to a toxic metabolite that builds up and can cause seizures.
    • Synergistic with gila monster venom
  • 30. Fentanyl
    • 80 - 100 x potency of morphine
    • fast onset, short duration
    • used i.v. for anesthesia
    • available as patch
    • available as oral slow release device.
  • 31. Fentanyl derivatives
    • Alfentanyl
    • Sufentanyl
    • Remifentanyl
  • 32. Methadone
    • Potency similar to morphine for i.v. administration, but 4 x more potent orally
    • long plasma half-life
    • used in treatment of narcotic dependence
    • Duration of action increases with repeated use
  • 33. LAAM
    • Extremely long plasma half-life (>72 hr)
    • Suppresses opiate withdrawal for 4-5 days
  • 34. Propoxyphene
    • Potency compared to codeine
    • Potency compared to placebo
    • Produces cardiotoxicity and pulmonary edema
    • Active metabolite produces convulsions
  • 35. Opioid Antagonists
    • Naloxone
    • Naltrexone
    • Nalmefene
  • 36. Signs of Overdose
    • Stuporous or in coma
    • Respiratory rate extremely low
    • pinpoint pupils
    • low body temperature
    • flacid skeletal muscles, jaw relaxed
  • 37. Naloxone
    • Short half-life
    • not effective orally
  • 38. Naltrexone
    • Long half-life
    • effective orally or injected
    • available in oral form only
    • used for treatment of dependence
  • 39. Nalmefene
    • Intermediate duration (4-6 hr)
    • orally active
    • no hepatotoxicity with long term use
  • 40. Mixed agonist-antagonists
    • Nalorphine and cyclazocine
    • Pentazocine: Talwin NX
    • Butorphanol
    • Nalbuphine
  • 41. Nalorphine and Cyclazocine
    • Kappa 3 receptor agonists
    • Mu receptor antagonists
    • produce psychotomimetic effects
    • produce dysphoria
  • 42. Pentazocine
    • Kappa and delta agonist
    • ‘ Ts and blues’
    • Talwin NX
  • 43. Butorphanol
    • Kappa receptor agonist
    • Mu receptor antagonist
    • Available as nasal spray
    • 5 X more potent in women than men
  • 44. Nalbuphine
    • Kappa receptor agonist
    • Mu receptor antagonist
    • Little dysphoria compared to nalorphine
    • Less abuse potential than morphine
  • 45. Partial agonist: Buprenorphine
    • Partial agonist at mu receptors
    • Partial agonist at kappa 3 receptors
    • Antagonist at kappa 1 receptors
    • Lower efficacy analgesic than morphine
  • 46. Tramadol
    • Opioid receptor agonist (mu and delta)
    • NE and 5-HT reuptake blocker (antidepressant)
    • α-2 adrenoceptor agonist
    • These actions are synergistic for analgesia
  • 47. Dependence and Withdrawal
    • Dependence varies from mild craving to compulsion to take the drug
    • Degree depends upon dose and frequency
    • Withdrawal signs opposite in direction to the drug effects.
    • Will last about 72 hrs for morphine or heroin
    • Not life threatening
  • 48. Other factors that influence the effectiveness of opioid treatment
    • Progression of tissue-damaging disease
    • Sensitization of CNS neurons
    • Collateral transmission
  • 49.  
  • 50. Salvinorin A
    • Active ingredient in Salvia Divinorum
    • Very selective kappa opioid agonist
    • Hallucinogen