Narcotic Analgesics Flashcards
What are the 3 opioid receptors and their distribution?
μ = primary and peripheral sensory neurons, periaqueductal grey matter, nucleus raphe magnus, rostral ventral medulla, thalamus, cortex
κ = hypothalamus, nociception areas
δ = olfactory bulb, cerebral cortex, presynaptic on primary afferent neurons, motor integration areas, and nociception areas
[Note that all 3 major receptors are present in high concentrations in the dorsal horn of the SC. Receptors are present both on SC pain transmission neurons and on the primary afferents that relay the pain message to them. Although opioid agonists directly inhibit dorsal horn pain transmission neurons, they also inhibit the release of excitatory transmitters from the primary afferents. Importantly, the μ receptor is associated with TRPV1 and substance-P-expressing nociceptors, whereas δ-receptor expression predominates in the nonpeptidergic population of nociceptors, including many primary afferents with myelinated axons]
Opioids classified as strong agonists
Fentanyl (+sufentanil, alfentanil,remifentanil) Hydromorphone Meperidine Morphine Methadone Oxymorphone Levorphenol
Fentanyl, hydromorphine, meperidine, morphine, methadone, and oxymorphone are considered strong opioid agonists. What is their MOA (receptors) and clinical application?
MOA: strong μ receptor agonists; variable κ and δ agonists
Clinical: severe pain, anesthesia adjuncts, dependence maintenance (methadone)
Which opioids are considered partial agonists (bind same receptors as strong agonists but with lower affinity)?
What are their clinical applications?
Codeine
Hydrocodone
Clinically: mild-to-moderate pain; cough (codeine), analgesic combinations with NSAIDs or acetaminophen
Which opioids are classified as mixed agonist-antagonists?
Buprenorphine
Nalbuphine
Pentazocine
Butorphanol
MOA and clinical application of Buprenorphine
Partial μ agonist and κ antagonist
Moderate to severe pain; dependence maintenance — reduces craving for alcohol
Of the mixed agonist-antagonists, ______ has a long duration of action, while _______ is parenteral only
Buprenorphine; nalbuphine
MOA and clinical application of Nalbuphine
κ agonist and μ antagonist
Clinically: moderate-to-severe pain
What are some opioid antagonists and what is their primary clinical application?
Naloxone
Naltrexone
Nalmefene
Used to reverse opioid overdose [naltrexone can be used for dependence maintenance]
Of the opioid antagonists, ______ has a duration of about 2 hours, while _____ and ____ last >10 hrs
Naloxone; naltrexone and nalmefene
Which opioid is utilized as an antitussive? What is its MOA?
Codeine, dextromethorphan
Full mechanism uncertain; weak μ agonist, inhibits NE and 5-HT transporters
______ is a weak μ agonist and blocks serotonin reuptake. It is used in cases of moderate pain, often as an adjunctive to opioids in chronic pain states. It causes seizures at toxic levels
Tramadol
What effects might the following physiological states have on opioid metabolism: obesity, elderly, infant, renal failure, or hepatic failure
Obesity: increased risk of overdose (central Vd not reflected by actual body weight)
Elderly: increased sensitivity to opioid, prolonged effect of infusion
Infant: prolonged effect
Renal failure: morphine or pethidine toxicity
Hepatic failure: increased sensitivity to opioids (in severe liver failure only)
General MOA of μ receptor agonists (presynaptic and postsynaptic)
All are linked to G-protein (GPCRs)
Presynaptic μ-receptor activation inhibits calcium influx into sensory neurons, which decreases NT release
Postsynaptic μ-receptor activation increases K+ efflux, which decreases postsynaptic response to excitatory neurotransmission
Which opioid is used for pulmonary edema?
Morphine
T/F: hydromorphine and oxymorphone are like morphine in efficacy but lower potency
False; hydromorphine and oxymorphone are like morphine in efficacy but HIGHER potency
Which of the opioid agonists is considered a strong agonist with anticholinergic effects?
Meperidine
T/F: sufentanil, alfentanil, remifentanil are like fentanyl but with shorter durations of action
True
Opioid antagonist used in maintenance programs and can block heroin effects for up to 48 hrs; also used for alcohol and nicotine dependence and, when combined with buproprion, may be effective in weight-loss programs
Naltrexone
Potent μ-receptor antagonists with poor entry into the CNS; can be used to treat severe opioid-induced constipation without precipitating an abstinence syndrome
Alvimopan
Methylnaltrexone bromide
Moderate μ-receptor agonist and strong NET inhibitor used to promote analgesia in cases of moderate pain; at toxic levels may cause headache, nausea, vomiting, and possible dependence
Tapentadol
Endogenous opioid peptide affinity of each of the opioid receptor subtypes
μ = endorphins > enkephalins > dynorphins
δ = enkephalins > endorphins and dynorphins
κ = dynorphins»_space; endorphins and enkephalins
Adverse effects with acute use of opioid analgesics
Respiratory depression Nausea/vomiting Pruritis Urticaria Constipation Urinary retention Delirium Sedation Myoclonus Seizures Truncal rigidity Hyper or hypothermia
Adverse effects with chronic use of opioid analgesics
Hypogonadism Immunosuppression Increased feeding Increased growth hormone secretion Withdrawal effects Tolerance, dependence Abuse, addiction Hyperalgesia Impairment while driving
Contraindications to opioid analgesic use (e.g., morphine)
Acute respiratory depression
Renal failure (d/t accumulation of metabolites morphine-3-glucuronide and morphine-6-glucuronide)
Chemical toxicity (potentially lethal in low-tolerance individuals)
Raised intracranial pressure, including head injury (risk of worsening respiratory depression)
Biliary colic
Pregnancy
Endocrine disease
Why are oral doses of narcotics typically higher than parenteral doses?
First-pass effect
However, certain analgesics like codeine and oxycodone are effective orally because they have reduced first-pass metabolism; can also get around this by fiving nasally, oral mucosa (lozenges), or transdermal
General metabolism of opioids
Many opioids undergo hepatic P450 degradation then are converted in large part to polar metabolites (mostly glucuronides), which are then readily excreted by the kidneys.
Examples: Fentanyl (CYP3A4), Codeine/oxycodone/hydrocodone (CYP2D6), methadone (CYP2B6)
Note that esters such as heroin and remefentanil undergo plasma esterase metabolism
Effect of opioids on the uterus
Prolonged labor
Effect of opioids on endocrine system
Stimulate release of ADH, prolactin, and somatotropin
Inhibit release of LH
With chronic therapy: low testosterone (men), dysmenorrhea or amenorrhea (women)
