Docstoc

Opioid Pharmacology new insight and clinical relevance

Document Sample
Opioid Pharmacology new insight and clinical relevance Powered By Docstoc
					     Opioid Pharmacology :
New Insight and Clinical Relevance


                 R4 Yi Seong-Min
• Opioid
   – Compound with morphine-like activity
• Opiate
   – Substance extracted from opium
   – Exudate of seed pod of Papaver somniferum
   – True opiate – morphine, codeine
• Mordern definition of opioid
   – Molecule that interact with opioid receptor
• Opioid compound
   – Opioid receptor agoninsts, antagonists, agonists-
     antagonists
   – Natural products, synthetic and semisynthetic
     compounds, peptides synthesized by neurone and other
     cell
         Opioid Receptors ( I )

• Five classes of opioid receptor
  – , , , ,  receptor
• Subtype of , ,  receptor
• Structural characteristics
  – Typical G-protein-coupled receptor
     •   Seven hydrophobic region
     •   Three intracellular loops
     •   Three extracellular loops
     •   Intracellular carboxy-terminal tail
     •   Extracellular amino-terminal tail
Opioid Receptors ( II )
      Opioid Receptors ( III )
• Most of available opioid analgesics
  – Act at -opioid receptor
• Activation of -opioid receptor
   → analgesia, euphoria, respiratory depress,
    nausea, vomiting, decreased gastrointestinal
    motility, tolerance, dependence
• -, -opioid receptor agonist
  – Produce analgesia
  – Not cause respiratory depression or to decease
    GI motility
     → Analgesia without -opioid side effect
      Opioid Receptors ( IV )
• -opioid receptor agonist
  – Produce dysphoria and hallucination
  – Focus
     • Not cross BBB, act only at pph -opioid receptor
• Morphine
  – , ,  receptor activation
• Fentanyl, sufentanyl
  – More selective -receptor agonist
  – High effective analgesia
 Endogenous Opioid Peptides

• Pain modulation in brain
  – Endogenous Opioid Peptide : opioid-like
    pharmacologic activity
     • Cleaved from three primary precursor protein
       ( proopiomelanocortin, proenkephalin,
        prodynorphine)
     • Methionine-enkephalin and leucine-enkephalin
   Cellular Action of opioid
• Opioid action on neuron
  – Presynaptic nerve terminal
    • Inhibit voltage-sensitive calcium channel
       → inhibit release neurotransmitter
          ( substance P and glutamate)
  – Postsynaptic neuron
    • Opening potassium channel
      → hyperpolarize
   Anatomic Site of Opioid
        Actions ( I )
• Opioid receptor
  – In ascending pain pathway
    • pph. nerve terminal, dorsal horn of spinal
      cord, thalamus
    ※ dorsal horn of spina cord
      opioid agonist
       – 1. inhibit release of excitatory neurotransmitter
             from primary afferent neuron
         2. Directly inhibit second-order pain transmission
              neuron
     Anatomic Site of Opioid
          Actions ( II )
• Opioid receptor
  – In descending pain-modulating pathway
     • Midbrain periaqueductal gray area, rostral
        ventromedial medulla, locus ceruleus
     • Opioid
       : activate descending pathway by inhibiting
        inhibitory interneurons
          →inhibit spinal pain transmisssion
         Clincal Use of Opioid
• Adjunct to general anesthesia
   – Reduce hemodynamic response to intubation and
     surgical stimuli, amount of general anesthetic agent,
     coughing on emergence
   – Analgesia during early postoperative period
• High risk case
   – High dose opioid anesthesia
     ∵ not decrease myocardial contractility
• Opioid as analgegics
   – Systemically, epidurally, intrathecally apply
   – Moderate to severe acute pain, chronic cancer pain
   – Not recommended for chronic benign pain
     ∵ tolerance and dependence
        Opioid Side Effect ( I )
• Respiratory depression
   – Most dangerous opioid side effect
   – Brain stem respiratory control mechanism : inhibited
   – Increased in arterial carbon dioxide pressure
      • Caused by decreased respiratory rate, decreased tidal
        volume
• Nausea and vomiting
          Opioid Side Effect ( II )

• Constipation
   – Direct action on local enteric nerve system and effect on
     central nerve system
     in large intestine
      → resting tone increase, and propulsive peristaltic wave
       decrease
      → increase absorption of water from feces
      → constipation
• Other side effect
   – Euphoria, sedation, miosis, truncal rigidity, biliary spasm,
     urinary retention, tolerance, dependence
  Tolerance and Dependence ( I )

• Opioid dependence
   – 1. Tolerance to analgesic or side effect of opioid
     2. Specific withdrawal or abstinence syndrome resulting
     from physiologic dependence
     3. Craving for drug from psychological dependence
• Interaction between pain and opioid tolerance
   – Not develop tolerance for active, ongoing pain
   – Tolerant to analgesic effect for new pain, such as
     postoperative pain
  Tolerance and Dependence ( II )

• Repeated administration
   → lead to physiologic dependence
   → result in withdrawal or abstinence syndrome
   – Management
      • Careful tapering of drug with mild symptom
      ※ administration opioid antagonist undergeneral anesthesia
          – Controversial method

• Addiction
   – For painful medical condition
     → very low iatrogenic addiction risk
  New Routes of Administration of
           Opioid ( I )
• Oral, IM, SC, IV, epidural, intrathecal, transdermal,
  transmucosal route
• Intranasal route
   –   Dry power or dissolved in water or saline
   –   Preoperative sedation in children
   –   Well tolerated, not irritating
   –   Intranasal diamorphine
        • More acceptable than IM morphine
        • Time to maximum plasma concentration : less than 5
          minutes
   – Meperidine
        • Bitter burning taste in 20% of patients
    New Routes of Administration of
             Opioid ( II )
• Iontophoresis
  – Alternative to transdermal administration
  – In past, limitation
     • Hydrolysis of water, generation of hydrogen ions
       →decrease drug delivery rate, tissue acidosis and
       burn, electrode dissolution
  – Advantage over transdermal administration
     • Overcome prolonged time required for activity
       ( 120 minutes vs. 14 hours )
     • Rapid offset of opioid action
     • Delivery rate : adjusted
     • Allow delivery of drug that cannot be absorbed
       transdermally : morphine
  Newer Opioid Analgesics ( I )
• Remifentanil
   – -opioid receptor agonist
   – Ester side chain
      • Necessary for opioid activity
      • Hydrolysis by esterases
   – Short elimination half-life : 9.5 minutes
   – Rapid equilibrate between central compartment and
     action site
   – Terminated by metabolism
   – Blood concentration
      • Related linearly to infusion rate
      • Unrelated to duration of infusion
   – Pharmacokinetics
      • Not altered by liver dis., renal dis., pseudocholinesterase
        deficiency
 Newer Opioid Analgesics ( II )

• Tramadol
  – Analgesic action mechanism
     • Not fully understood
     • Weak affinity for -opioid receptor
     • Inhibition of norepinephrine reuptake
       → 2-adrenoreceptor activation
       → act synergistically with tramadol’s opioid receptor
       activation
       → analgesia
  – Advantage
     • Less respiratory depression, nausea, vomiting, constipation
     • Rapid psychomotor recovery
  – Moderate pain treatment : as effective as morphine
  – Severe pain treatment : less effective than morphine
       Peripherally Acting Opioid

• Opioid receptor – outside central nerve system
   – Peripherally acting opioid agonist
     → analgesia without CNS side effect
• Loperamide
   –   -opioid receptor agonist
   –   Not cross blood-brain barrier
   –   Treatment : inflammation-induced hyperalgesia
   –   Relieve diarrhea
• Peripherally acting opioid antagonist
     ( methylnaltrexone )
   – Systemically administered opioid agonist
     → reverse pph. side effect
   Opioid Interactions with Other
             Analgesics
• Goal of using analgesics in combination
  – Achieve superior analgesia
  – Reduce dose of each drug
  – Minimizing side effect
• NSAID
  – Synergistical action with systemic opioid to
    produce analgesia
• Local anesthetics and opioid
  – Synergistical pain relief when intrathecal or
    epidural administration
  Opioid and Neuropathic Pain
• Neuropathic pain
  – Less responsive to opioid than other pain
  – Opioid resistance of neuropathic pain
     • Mechanism : not completely clear
  – Cholecystokinin and dysnorphine
     • Antiopioid activity
     • Increase in spinal cord or dorsal root ganglion
     • Ch. benign pain patient
        – Cholecystokinin antagonist proglumide
          → enhance analgesic activity of opioid

				
DOCUMENT INFO