Transcript Opioid Pharmacology : new insight and clinical relevance

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, agonistsantagonists
– 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