Pharmacology of Selected Opioids.txt

  1. Pharmacology of Selected Opioids: classification
    • Agonist: strong, mild-to-moderate
    • Opioids with mixed actions: agonist-antagonist (Ag-Antag); partial agonist
    • Antagonist: .
  2. Strong agonists
    • Morphine
    • Heroin
    • Hydromorphone (Dilaudid)
    • Oxymorphone (Numorphan)
    • Methadone (Dolophine)
    • Meperidine (Demerol)
    • Fentanyl (Sublimaze)
    • Levorphanol (Levo-Dromoran)
  3. Metabolism of heroin
    • Heroin is biologically inactive
    • In the body it is converted to MAM (monoacetylmorphine) and then to morphine: MAM and morphine are responsible for the effects elicited upon injection of heroin
  4. Methadone (Dolophine)
    • Mu agonist
    • similar to morphine
    • prolonged use fives rise to tolerance
    • Oral efficacy!
  5. Methadone (Dolophine): Uses
    • relief of pain
    • treatment of opioid abstinence syndrome
    • treatment of opioid dependence
  6. Opioid withdrawal syndrome
    • within hours of missing first dose of morphine: sense of intense fear (can be alleviated by placebo)
    • 8-16 hrs: lactation, rhinorrhea (as in a severe head cold), yawning, sweating, mydriasis, anorexia, nervousness, irritability, tremors, increased anxiety and fear, restless sleep
    • within 36 hrs: skeletal muscle fasciculation and twitch, severe/painful cramps develop in legs and stomach
    • intense/uncontrolled vomiting, salivation, diarrhea, and urination
    • weakness, depression, chilliness/sweating, gooseflesh, muscle spasms, kicking movements
    • patient is unable to sleep: increased respiratory rate, increased blood pressure, increased temperature, increased blood sugar, increased basal metabolic rate
    • 48-72 hours: Reaches it's peak; subsides over net 10 days
    • Withdrawal reaction: is evidence for physical dependence
  7. Intensity of withdrawal reaction depends on
    • half-life of drug being used: for morphine, with a short half-life, symptoms of abstinence are intense but brief
    • for methadone, with a long-half-life, symptoms are less intense but more prolonged
    • degree of physical dependency: withdrawal syndrome of methadone and codeine qualitatively the same but less intense than for morphine
  8. Methadone
    • Why is it used in treatment of opioid dependence?
    • Methadone withdrawal is: *
    • slower in onset
    • longer in duration
    • much less intense
    • Why don't opioid addicts like it?
  9. Differences in response to heroin and methadone
    • methadone keeps plasma concentration in a narrow range
    • but methadone has a wide range, get highs and lows
  10. Meperidine (Demerol)
    • does what morphine does, but - has a problem
    • Mu-Agonist
    • In equianalgesic doses produces as much sedation, respiratory depression, and euphoria as does morphine
    • the rise in bile duct pressure - thought to be less than that caused by morphine
    • constipation, urinary retention: less common than with morphine
  11. Meperidine Toxicity
    • can use it for a day or 2 but NOT for a week or 2
    • Large, repeated doses can lead to an
    • excitatory syndrome: hallucinations; tremors; muscle twitches; dilated pupils; hyper-reflexia; convulsions
    • Due to the accumulation of normeperidine
    • half time 15-20 house (meperidine = 3 hours)
    • Not drug of choice for treatment of severe prolonged pain
  12. Fentanyl
    • Mu agonist
    • 80 times more potent than morphine: as an analgesic
  13. Uses of Fentanyl
    • For anesthesia and post-op analgesia
    • Duragesic: (transdermal patch) releases fentanyl over a period of 72 hours (for treatment of chronic pain; cancer pain)
    • Patient controlled anesthesia (Actiq) - lollypop
  14. Mild-to-moderate agonists
    • Codeine
    • Oxycodone (Oxycontin)
    • Hydrocodone (Vicodin)
  15. Propoxyphene - synthetic derivative, not very efficacious (Darvon)
    • metabolizes to norpropoxyphene: 1/2 life ~30 hrs; accumulates and causes cardiotoxicity
    • prolonged PR and QT intervals and widened QRS complex
  16. Codeine
    • high oral/parenteral ratio: partially protected from conjugation by the methyl group at C3
    • Has very low affinity for opioid receptors
    • Analgesic efficacy is due to its conversion to morphine: polymorphisms in cytochrome P450 isoform CYP2D6
    • Dispensed alone or in combination with aspirin or acetaminophen
  17. CYP3A4
    very important enzyme in metabolizing drugs in the liver
  18. Codeine and gene polymorphisms
    • Caucasians (7%) - poor metabolizers
    • Saudi Arabia, 20% , Ethiopia, 29% - Ultra-rapid metabolizers
  19. Independent mechanisms of analgesia
    • Hydrocodone: dispensed in combination with other drugs
    • Acetaminophen - norcet, vicodin, lortab
    • Ibuprofen - vicoprofen
    • Oxycodone: Oxycontin - dispensed alone or in combination with
    • Aspirin - percodan
    • Acetaminophen - percocet
    • Ibuprofen - combunox
  20. Ototoxicity
    • Rapid, progressive, and profound (> 83%) sensorineural hearing loss in patients taking Vicodin: successful rehabilitation with cochlear implants
    • Hearing loss reported with propoxyphene
    • Oxycodone (vicodin) gets concentrated in inner ear: when combine with other drugs, leads to hearing loss, tinnitus and 1st sigh of autotoxicity
  21. Opioids with mixed actions: agonist-antagonist opioids
    • substances that appear to be agonists at some receptors but antagonists at others: pentazocine; butorphanol
    • Partial agonists: buprenorphine
  22. Pentazocine
    • intrinsic Mu antagonistic activity is sufficient to afford advantages over morphine as analgesic
    • 20 mg -> decreased respiration = 10 mg morphine
    • increased doses do not cause proportionate depression of respiration
    • But high doses -> increased BP; increased HR
    • Increased cardiac work in patients with coronary artery disease
    • May precipitate withdrawal when given to Mu-opioid dependent individual
  23. Pentazocine
    • Talwin-NX (50mg Talwin + 0.5mg naloxone)
    • Oral pill laced with naloxone, to prevent abuse potential through injection
    • The added naloxone is degraded in liver
    • If oral pill is powdered for injection naloxone produces aversive effects in individuals dependent on opioids
  24. Ag-Antag Opioids
    • Butorphanol (Stadol)
    • More potent that morphine (on a per weight basis)
    • 2-3mg -> 10mg morphine
    • Onset, peak activity, duration ~ morphine
    • lowest abuse potential
    • Actions similar to pentazocine
    • increased pulmonary arterial BP -> increases work of heart
    • thus, less useful in patients with CHF or MI
  25. Buprenorphine (Buprenex)
    • on a per weight basis - better in longer duration of action: !
    • Highly lipophilic opioid derivative of thebaine
    • Partial Mu agonist; 25-50-fold more potent than morphine
    • Produces analgesia and other CNS effects ~ to those of morphine
    • Duration of analgesia is longer than that of morphine
  26. Opioid antagonists
    • Opioid antagonists produce few effects unless opioid agonists have been administered previously
    • Naloxone
    • Naltrexone
  27. Naloxone: Clinical Use
    In treatment of opioid toxicity, especially respiratory depression: In patients with respiratory depression small doses IM or IV promptly reverse effects of Mu opioid agonists in 1-2 minutes!
  28. In diagnosis of physical dependence on opioids: IM small doses of naloxone precipitate moderate-to-severe withdrawal syndrome within minutes and subside in about 2 hours!!
  29. Naltrexone
    • Efficacious by the oral route
    • Duration of action 24-48 hours
    • Used in long-term management of opioid addiction
    • the long duration of action serves as a safety valve after detoxification for patients with high motivation to remain opioid-free
    • if a pt injects themselves with morphine or opioid, blocks the high of the drug..
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Pharmacology of Selected Opioids.txt