Opioid Pharmacology : New Insight and Clinical Relevance

1
Opioid Pharmacology New Insight and Clinical
Relevance

• R4 Yi Seong-Min

2

• 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

3
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

4
Opioid Receptors ( II )
5
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

6
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

7
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

8
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

9
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

10
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

11
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

12
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

13
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

14
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

15
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

16
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

17
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

18
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

19
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 tramadols 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

20
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

21
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

22
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