Chapter 11 - Opiates

• Opiate


  Drug with properties similar to opium
• Papaver somniferum


  • Primary source of opium
  • Plant makes opium on only 10 days of its life cycle
  • Seed pods are scratched so that sap leaks out
  • Opium sap is scraped off; compressed into cakes
• Active ingredients in opium


  • Morphine (10% of weight)
  • Codeine (0.5%)
  • Thebaine (0.3%)
• Opiates


  • Opium
  • Morphine
  • Codeine
  • Thebaine
• Opiate derivatives


  • Hydromorphone
  • Oxycodone
  • Heroin
  • Etorphine
• Synthetic opiates


  • Methadone
  • Meperidine
  • LAAM
  • Fentanyl
• Morphine


  Named after "Morpheus" (Greek God of Dreams)
• Heroin


  Diacetylmorphine; lipid solubility is 10 times greater than morphine; gets into brain faster and in higher concentration
• Codeine


  Less potent as analgesic than morphine, produces antitussive effects at doses that do not cause analgesia; produces less euphoria
• Oxycodone


  From thebaine; sold as Percocet when combined with acetaminophen, or Percodan when combined with aspirin
• Meperidine (Demerol)


  Well-absorbed orally; often given parenterally; analgesia for severe pain; does not cause pinpoint pupils, dilates pupils (opposite effect compared to other opiates)
• Fentanyl (Sublimaze)


  100 times more potent than morphine as analgesic; high lipophilic, rapid onset and short duration of action (15-30 min); used as epidural during labor, anaesthesia, and in transdermal patch (absorbed readily through the skin)
• Methadone


  Longer acting, well absorbed orally, maintenance drug for heroin addicts (prevents them from going through withdrawal)
• Desomorphine


  Synthesized from codeine, street name krokodil due to rough, scaly green skin that occurs with repeated use (contaminants); users develop gangrenous wounds and deep abscesses, rotting ears, nose, lips, gums, necrosis of parts of limbs
• Morphine


  Base (pKa = 8.2)
• Oral administration of morphine

  Only ~15-40% available for absorption; first pass metabolism by enzymes in digestive system and liver
• Heroin/morphine administration


  Commonly administered parenterally; IV administration produces intense and immediate effects
• Methadone administration


  Well-absorbed orally; 70-80% available, equal to morphine in potency as an analgesic
• Opiates distribution


  • Most concentrate in lungs, liver, and spleen; 80-96% is bound to blood proteins
• Morphine distribution


  Readily crosses placental barrier, but slow to cross blood-brain barrier (low lipid solubility)
• Heroin distribution


  Highly lipid soluble; readily crosses blood-brain barrier
• Morphine metabolism and excretion

  Half-life = ~2-2.5 hours; 90% eliminated in less than 24 hours; Duration of effects lasts 4-5 hours
• Meperidine (Demerol) metabolism and excretion


  Half-life = ~3 hours; Faster acting, shorter duration of action (2 hours)
• Methadone metabolism and excretion

  Half-life = ~25-40 hours (extensively bound to blood proteins and not available for metabolism)
• Naloxone metabolism and excretion

  Half-life = 1.5 hours; Metabolized by the liver
• In 1973, opiate receptors were discovered in rat brain
• Endogenous opioids


  Chains of amino acids; Enkephalins: chains of 5 amino acids, concentrated in spinal cord; Endorphins: chains of 30 amino acids, produced in pituitary gland and hypothalamus, 100 times more potent than morphine as an analgesic
• Opiate receptors


  • Mu
  • Kappa
  • Delta
  • ORL1
• Opiate receptors


  • All G-protein coupled receptors, release 2nd messengers
  • Activate K+ channels, cause inhibition (hyperpolarization) at postsynaptic receptors
  • Inhibits voltage gated Ca++ channels
  • Inhibits release of neurotransmitters from presynaptic neurons
• Endogenous opiates


  Acts as neurotransmitters (stored in vesicles); neuromodulators (interferes with the release of other neurotransmitters)
• Mu and kappa receptors

  • Overlap in mesolimbic and mesocortical areas, kappa receptors regulate DA by opposing mu receptor action
  • Both mu and kappa receptors occur in ventral tegmental area (VTA), nucleus accumbens (NAc), prefrontal cortex (PFC), anterior cingulate cortex, and amygdala
  • Regulate motivational, effective, and rewarding aspects of opioids
• Mu receptor


  The primary target of nearly all opioids; Responsible for analgesic, drowsiness, respiratory depression, decrease in GI motility (constipation), pinpoint pupils, and decrease in body temperature effects
• Partial agonists


  Effects inversely related to degree of attraction to a receptor; Morphine – weak attachment to mu receptor, but produces strong effect; Nalorphine – strong attachment to mu receptor, but weak effect
• Nalorphine


  Displaces morphine [competitive antagonism], produces mild morphine-like effect
• Mixed agonists-antagonists


  Pentazocine (Talwin) produces analgesia (1/4 as potent as morphine) and respiratory depression at kappa receptor; blocks morphine at mu receptor while producing weak effect
• Naloxone (Narcan)


  Short duration; Reverses coma and respiratory depression from opiate overdose within 30 seconds with IV administration; Displaces other opiates from mu receptor; No pharmacological effect in normal individuals, but precipitates withdrawal in opiate users
• Naltrexone (ReVia)


  Longer duration of action (single oral dose blocks effect of injected heroin for up to 48 hours); Beneficial in treating chronic alcoholism; Naltrexone hepatotoxic at high doses (300 mg)
• Analgesia


  • Raises pain threshold at spinal cord level and alters perception of pain at cortical level; Patients aware of presence of pain (sensory), but sensation is not unpleasant (emotional aspect)
• Respiration


  • Respiratory depression and decrease in sensitivity to CO2 levels (increases in CO2 elicits faster and deeper breathing); Breath slow / shallow at high doses (2-4 breaths/min); Cessation of breathing is cause of death in overdose (coma, pinpoint pupils, low respiratory rate = diagnostic features)
• Pinpoint pupils


  Enhances parasympathetic stimulation to eye; Pinpoint pupils different than other sources of coma/respiratory depression that dilate pupils