Lecture 14: Narcotic Analgesics Flashcards
Which opioid agonist is used for pulmonary edema?
Morphine
Which 2 opioid agonists are used for severe pain and as an adjunct in anesthesia?
- Fentanyl
- Morphine
What is the MOA on both the presynaptic μ-receptor and post-synaptic μ-receptor by opioids?
- Presynaptic μ-receptor activation INHIBITS Ca2+ influx into sensory neurons, which decreases NT release
- Post-synaptic μ-receptor activation INCREASES K+ efflux, which decreases postsynaptic response to excitatory neurotransmission
What are the 3 opioids which are strong μ-receptor agonists?
- Morphine
- Fentanyl
- Methodone
What are the pharmacokinetics of the strong opioid agoinsts?
Exception?
- First pass effect
- Duration 1-4 hours
- Except methadone = 4-6 hours
What’s the MOA of Codeine and Hydrocodone, as compared to the strong opioid agonists?
- Less efficaious than morphine, partial μ-receptor agonists
- Can antagonize strong agonist
What are the clinical applications of Codeine and Hydrocodone?
- Mild-moderate pain
- Cough (codeine)
What are the 2 opioids belonging to the class of mixed opioid agonist-antagonist?
- Buprenorphine
- Nalbuphine
What are effects of the opioids, Buprenorphine and Nalbuphine?
- Like strong agonists, but can antagonize their effects
- Also reduces craving for alcohol
What is Buprenorphine used for clinically?
- Moderate pain
- Some maintenane rehabilitation programs
What is the duration of action for Buprenorphine and Nalbuphine and associated toxicity?
- Long duration of action: 4-8 hours
- May precipitate abstinence syndrome
What is the clinical application for the use of the opioid, Nalbuphine?
Moderate pain
What is the effect of Dextromethorphan?
- Reduces cough reflex
- Not an analgesic
What is Dextromethorphan used for?
Acute debilitating cough
*This is Nyquil or Robitussin = Antitussives
What is the MOA of Naloxone?
Strong antagonist of μ, δ, and k receptors
What is clinical application for Naloxone?
Opioid overdose
What is a potential toxicity associated with Naloxone?
Precipitates abstinence (withdrawl) syndrome in dependent users
What is the MOA of the analgesic, Tapentadol?
- Moderate μ agonist
- Strong NET inhibitor
What is Tapentadol used for clinically?
Moderate pain
What are some of the toxicities/consequences associated with Tapentadol?
- Headache; nausea and vomiting
- Possible dependence
What is the MOA of the analgesic, Tramadol?
- Weak μ agonist
- Moderate SERT inhibitor
- Weak NET inhibitor
*Mixed effects
What is the clinical application of Tramadol?
- Moderate pain
- Adjunct to opioids in chronic pain syndromes
What are some of the potential toxicities associated with Tramadol?
- Seizures
- Risk of serotonin syndrome
What is the MOA of Naltrexone and Nalmefene; how are they different from Naloxone?
- Strong antagonist of μ, δ and k receptors (just like Naloxone)
- Longer duration of action (10 hours!)
What are some of the clinical applications of Naltrexone?
- Maintenance programs and can block heroin effects for up to 48 h
- Used for alcohol and nicotine dependence
*When combined with bupropion may be effective in weight-loss programs
What are the functions/downstream effects caused by activation of the μ-receptor?
- Supraspinal and spinal analgesia
- Sedation
- Inhibition of respiration
- Slowed GI transit
- Modulation of hormone and NT release
What are the functions/downstream effects caused by activation of the δ-receptor?
- Supraspinal and spinal analgesias
- Modulation of hormone and NT release
What are the functions/downstream effects caused by activation of the k-receptor?
- Supraspinal and spinal analgesias
- Psychotomimetic effects
- Slowed GI transit
What is the endogenous opioid peptide affinity for μ, δ, and k-receptor (endorphins, dynorphins, and enkephalins?
- μ-receptor: Endorphins > enkephalins > dynorphins
- δ-receptor: Enkephalins > endorphins and dynorphins
- k-receptor: Dynorphins >> endorphins and enkephalins
What is the MOA of Nalbuphine?
- k-receptor agonist
- μ-receptor antagonist
*Mixed opioid agonist-antagonist
What is the MOA of Buprenorphine?
- Partial/weak μ-receptor agonist
- k-receptor antagonist
*Mixed opioid agonist-antagonist
Which 5 opioids are partial or weak agonists of μ-receptors?
- Hydrocodone
- Codeine
- Pentazocine
- Buprenorphine
- Butorphanol
Which opioid is a strong k-receptor agonist and partial/weak agonist of μ-receptors; and can only be given parenterally?
Butorphanol
What are some of the adverse effects associated w/ acute use of opioids?
- Respiratory depression
- Nausea/vomiting
- Pruritus/Uticaria
- Constipation and Urinary retention
- Delirium – Sedation
- Myoclonus
- Seizures
What are some of the adverse effects associated w/ chronic use of opioids?
- Hypogonadism
- Immunosuppression
- Increased feeding
- Increased GH secretion
- Withdrawl effects
- Tolerance, dependence –> Abuse, addiction
- Hyperalgesia (increased sensitivity to pain)
- Imapirment while driving
What are the relative contraindications for morphine?
- Acute respiratory depression
- Renal failure (due to accumulation of the metabolites morphine-3-glucuronide and morphine-6-glucuronide)
- Chemical toxicity (potentially lethal in low tolerance patients)
- Raised ICP, including head injury (risk of worsening respiratory depression)
- Biliary colic
How does the physiological state of obesity play a role in the pharmacokinetic variance in use of narcotic analgesics?
- Overdosage
- Central Vd is not reflected by ABW
- Increased adipose tissue causes and increase in total Vd —> prolongs elimination half-life
What are 2 pharmacokinetic variances in the elderly that must be accounted for when administering narcotic analgesics?
1) Decreased neuronal mass and decreased central Vd —> Increased sensitivity to opioids
2) Decreased LBM w/ increased adipose tissue causes increase in total Vd + Decreased Hepatic Blood Flow (by 40-50% age 75) –> Prolongs effect of infusion
What pharmacokinetic variances in infants need to be accounted for when administering narcotic analgesics?
Decreased conjugation capacity and immature renal function —> Prolonged effect
By what mechanism may renal failure lead to morphine toxicity?
- Accumulation of Morphine-6-Glucuronide (M6G)
- Possible hydrolysis of glucuronides back to parent compound
- Uraemia potentiates CNS depression and increased BBB permeability
Renal failure may lead to Pethidine toxicity due to the accumulation of __________
Norpethidine
What is the mechanism by which severe liver failure may lead to increase sensitivity to opioids?
There may be synergism when?
Which drugs will have an increased elimination half-life?
- Synergism if encephalopathic
- Altered integrity of BBB
- Increased elimination half-life for pethidine and tramadol
Which 3 genes related to opioid receptors and signal transduction have been implicated as genetic factors in the Pharmacodynamics of Opioids?
- OPRM1
- COMT
- MC1R
Which genes related to metabolizing enzymes and transporters have been implicated in the variation of the Pharmacokinetic profile of Opioids?
- CYP2D6 and UGT2B7 —> Metabolizing enzymes
- ABCB1 —> Transporter
