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MECHANISM OF ACTION
A. OPIOID PEPTIDES
n Unclear if they function as NTAs
n Appear to modulate transmission in the
brain, spinal cord and in primary afferents
A. Also found in the adrenal medulla and gut
n IONIC MECHANISM
B. At the postsynaptic level
A. Open K+ ion channels to cause membrane hyperpolarization (IPSP)
C. At the presynaptic level
A. Close voltage-gated Ca+2 ion channels to inhibit NTA release
n Ach, NE, serotonin, glutamate, and substance P
ACUTE EFFECTS
A. ANALGESIA
A. Most powerful drugs for the relief of pain
B. Attenuate both emotional and sensory aspects of pain experience
n Strong agonists
n Highest analgesic efficacy
n Full agonists
n Morphine Meperidine
n Methadone Fentanyl
n Levorphanol Heroin
n Partial agonists
n Mild to moderate analgesic efficacy
n Codeine
n Hydrocodone
n Oxycodone
n Weak agonist
¡ Propoxyphene
B. SEDATION AND EUPHORIA
n Occur at doses below those required for maximum analgesia
n Additive with other CNS depressants
¡ With little amnesia
n At higher doses
¡ Mental clouding, stupor, or coma
C. RESPIRATORY DEPRESSION
n Inhibition of the respiratory center
n Decrease response to CO2 challenge
n With full agonist
¡ Maybe seen at conventional doses
D. RESPIRATORY DEPRESSION
n Increase PCO2
¡ Cause cerebrovascular dilation
n Increased blood flow
n Increased ICP
E. ANTITUSSIVE ACTIONS
n Suppression of the cough reflex
n Unknown mechanism
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F. NAUSEA AND VOMITING
n Activation of chemoreceptor trigger zone
n Increased by ambulation
G. GIT EFFECTS
n Constipation
n Decreased intestinal peristalsis mediated by opioid receptors in the enteric
nervous system
n Basis for use as antidiarrheal drugs
H. SMOOTH MUSCLES
Contraction of biliary tract smooth muscle
n Biliary colic or spasm
n Increased ureteral and bladder sphincteric tone
Reduction in uterine tone which may contribute to prolongation of labor
I. MIOSIS
n Causes pupillary constriction
n Except meperidine
n Blocked by opioid antagonist
n Naloxone
n Atropine
CHRONIC EFFECTS
A. TOLERANCE
n Marked tolerance can develop
n Except for miosis and constipation
n Mechanism may involve receptor
“uncoupling”
n Ketamine
n Antagonist of glutamate NMDA receptor
n Blocks opioid tolerance
¡ “Opioid rotation”
n Analgesia is maintained (e.g., in cancer patients) by changing from one drug to
another
n Cross-tolerance exists between different opioid agonists, but is not complete
B. DEPENDENCE
n Physiologic response to chronic therapy
n Strong agonists
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Abrupt discontinuance
Symptoms
n Rhinorrhea Lacrimation
n Gooseflesh Muscle aches
n Diarrhea Yawning
n Anxiety Hostility
Precipitated withdrawal
n More intense state results
n Opioid antagonist is administered
to physically dependent individual
CLINICAL USES
A. ANALGESIA
n Treatment of moderate to severe pain
¡ Acute setting
n Strong agonist
n Given IV
n Prolonged analgesia
n Reduction in adverse effects
n Epidural administration of strong agonists
Fentanyl
n Transdermal route for analgesia
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Morphine
n For less severe pain and in the chronic setting
n Moderate agonists
n Oral
B. COUGH SUPPRESSION
n Oral antitussive drugs
n Codeine
n Dextrometrophan
C. TREATMENT OF DIARRHEA
n Selective antidiarrheal opioids
¡ Diphenoxylate
¡ Loperamide
¡ Oral
D. MANAGEMENT OF ACUTE PULMONARY EDEMA
n IV morphine
n Hemodynamic effects and calming effects
n Relief of pulmonary symptoms
E. ANESTHESIA
n Preoperative medications and intraoperative adjuncts in balanced anesthesia
n High-dose IV opioids
n Morphine and fentanyl
n Used for cardiac surgery
F. OPIOID DEPENDENCE
Methadone
Long-acting opioid
Management of opioid withdrawal states
Maintenance programs for addicts
n Buprenorphine
Longer duration of action
Maybe used for withdrawal states
TOXICITY
A. ADRs
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B. OVERDOSE
n Triad
n Pupillary constriction
n Comatose state
n Respiratory depression
n IV administration of naloxone
n Results to prompt signs of recovery
n Ventilatory support and other therapeutic measures
C. DRUG INTERACTIONS
n Additive CNS depression
n Ethanol
n Sedative-hypnotics
n Anesthetics
n Antipsychotic drugs
n TCAs
n Antihistamines
AGONIST-ANTAGONIST DRUGS
ANALGESIC ACTIVITY
n Analgesic activity varies with individual drugs
n Less than the strong agonists
RECEPTORS
Nalbuphine and pentazocine
k- receptor agonist with weak m receptor antagonist activity
Buprenorphine
m-receptor agonist with weak antagonist effects at k and d receptors
Lead to unpredictable results if used together with pure agonists
EFFECTS
Sedation at analgesic doses
Dizziness, sweating and nausea
Adverse effects
Anxiety, hallucinations, and nightmares
Respiratory depression is less intense
Not predictably reversed by naloxone
Less tolerance develops
Minimal cross-tolerance
Physical dependence may occur but abuse liability is less
OPIOID ANTAGONISTS
Naloxone
Nalmefene
Naltrexone
Greater affinity to the m receptors
Clinical use for management of acute opioid overdose
Naloxone
Given IV
Shorter duration of action
Requires multiple doses
Nalmefene
8-12 h
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Given IV
Naltrexone
Long elimination half-life (24 h)
Blocks the action of strong agonist
Heroin
Decreases craving for alcohol
Adjunctive drug for alcohol dependency program
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