EXAM #3 OPIOIDS REVIEW Flashcards
Pain is transmitted via a______That originates where?
three-neuron system that originates
at the periphery and ends at the cerebral cortex.
At periphery tissues, noxious stimuli are mainly received and transmitted by
A beta, A delta, and C fiber neurons.
These first-order neurons synapse with
second-order neurons in the dorsal horn of the spinal cord level.
Second-order neurons
travel up the spinal cord via the
dorsal column and spinothalamic tract and synapse with third-order neurons at the thalamus, which then transmit signals to the cerebral cortex, the site of pain perception.
Opioids exert their effects at
receptors at all three levels of this system.
The major receptors activated by opioids are
mu, delta, and kappa
Opioids receptors are
These are G-coupled receptors, which carry the
mediator-induced signal in conjunction with a second messenger such as cyclic adenosine monophosphate (cAMP).
Opioids receptors are
G-coupled receptors, which carry the mediator-induced signal in conjunction with a second messenger such as cyclic adenosine monophosphate (cAMP).
Where are opioids receptors located? They are located at the
periphery, the dorsal horn of the spinal
cord, and finally the brainstem, thalamus, and cortex.
At the opioid receptor locations, the three major mechanisms of action are:
- Inhibition of presynaptic Ca2+ influx, which depolarizes the cell and inhibits the release of neurotransmitters at the synaptic cleft.
- Increasing postsynaptic K+ efflux, which depolarizes and inhibits cellular signal transmission.
- Activation of the descending inhibitory pain pathway
via inhibition of GABAergic receptors found in the
brainstem.
Opioid analgesia is primarily achieved at the brain, spinal
cord, and peripheral tissues via
mu1 and mu2 receptors.
In the spinal cord, opioids target
mu2 receptors
Supraspinal sites are
periaqueductal gray matter
locus coeruleus
nucleus raphe mmagnus) effects are achieved at mu1 receptor
Supraspinal effects are achieved at
Mu 1 receptor
Morphine on respiratory system
Morphine and other mu1 agonists decrease CO2 responsivity in the medullary respiratory center.
Morphine on ventilatory response
There is a right shift and decrease in the slope of the ventilatory response to CO2 curve
Remifentanil is most notably known for its short
context-sensitive half-life
Morphine : It is primarily metabolized by
hepatic phase II conjugation (3- glucuronidation) to form morphine-3-glucoronide
Methadone protein binding and metabolism
Methadone is 90% protein bound and
undergoes N-demethylation in the liver
Fentanyl metabolism and % excretion
in the liver by N-dealkylation to norfentanyl and only 6% is excreted unchanged by the kidneys.
How does meperidine reduces shivering?
Through kappa-opioid receptors,
Whereas all opioids and propofol in a dose-dependent manner,
suppress motor evoked potentials (MEPs)
Remifentanil and MEPs
suppresses MEPs to a lesser extent.
The partial agonists and mixed agonist–antagonists are have clinical effects at mu and kappa receptors
nalbuphine, butorphanol, and buprenorphine
The partial agonists and mixed agonist–antagonists are have clinical effects at what receptors?
mu and kappa receptors
What happens with an agonists and a partial antagonists?
When combined with low doses of a full agonist compound, the effects of the partial agonist are additive up to the maximum, or “ceiling” effect of the partial agonist. With increasing doses of a full agonist, the partial
agonist will behave as an antagonist.
Can cause hypotension from histamine release, 2 opioids
morphine and meperidine,
Methadone can cause
Prolonged QT syndrome
Urinary system and opioids
Inhibition of urethral sphincter relaxation causes urinary retention, and can be seen after systemic and neuraxial morphine
administration
High-dose morphine or fentanyl can
reduce abdominal muscle and thoracic wall compliance via supraspinal mu receptors
Hydromorphone vs morphine
High-dose morphine or fentanyl can reduce abdominal muscle and thoracic wall compliance via supraspinal mu receptors
Hydromorphone active metabolites are
dihydromorphine and dihydroisomorphine.
The inactive metabolite of hydromorphone :
hydromorphone-3-glucuronide can accumulate in renal failure patients and cause neuroexcitation and cognitive impairment.
Opioids site of action ; nociceptive pain
the dorsal horn (layer 4 and 5 of the substantia gelatinosa) of the spinal cord, which inhibits the transmission of nociceptive information;
Meperidine active metabolites is_______: What can it cause
Normeperidine; Accumulation such as seen with renal patients can lead to seizures./
How does opioids causes nausea and vomiting?
Opioids stimulate the chemoreceptor trigger zone located in the area postrema of the brain stem, which can result in nausea and vomiting.
Postoperative shivering can be attenuated with
meperidine, which may
act through a k-receptor mechanism.
Dose of meperidine for shivering?
Only 12.5 to 25 mg of meperidine, administered intravenously as a slow push,
Dependence refers to the presence of
withdrawal symptoms if a drug is withheld and can be either physical or psychological.
Psychological dependence refers to
craving for a drug and is synonymous
with addiction.
Tolerance is the need to
increase the dose of an opioid over time to maintain the desired analgesic effect, reflecting the desensitization of the antinociceptive pathways to opiates and the upregulation of opioid binding receptors.
The apnea threshold, defined as the highest Paco2 without ventilatory effort with opiods
increased with the use of opioids.
Opioid- receptor activation inhibits the
presynaptic release and postsynaptic
response to excitatory neurotransmitters (glutamate, acetylcholine, and substance P)
Opioid administration decreases minute ventilation by
decreasing the respiratory rate (as opposed to decreasing the tidal volume).
OPIOIDS administration muscle rigidity can be prevented by
decreasing the rate of opioid administration or by concomitantly administering a neuromuscular blocking agent and controlling ventilation.
The fentanyl family is known to produce
chest wall rigidity
Which analgesic or labor is not associated with significant respiratory depression affecting the mother or fetus?
(A) Mor
Nalbuphine
Your patient has a history of asthma. Which opioid
will you avoid?
(B) Morphine
Which narcotic will you avoid in patients taking MAO inhibitors?
Meperidine ( Demerol)
Those medications lead to metabolites accumulate in patients with renal disease and increase the likelihood o respiratory depression and/or seizures.
Meperidine and Morphine
Which common anesthetic medications should be
avoided during the induction of a patient diagnosed
with acute intermittent porphyria?
Barbiturates and etomidate should be
avoided.
Which o the ollowing has mainly analgesic and anytipyretic properties?
A) Acetaminophen
Which opioid causes the greatest respiration depression in newborns?
Morphine
Rank opioids from most to least lipid-soluble.
Sufentanil Fentanyl Alfentanil Meperidine Remifentanil Morphine
Most of the clinically used opioids arerelatively selective for what receptor: mu, kappa or delta?
Mu receptors
Contrast spinal and supraspinal analgesia.
With spinal analgesia perception of pain is decreased. With supraspinal analgesia the patient’s response to pain is altered
On what receptors do spinal opioids work to produce spinal analgesia?
mu-1, mu-2, kappa, and delta receptors of the spinal cord and brain to produce spinal anesthesia
Spinal anesthesia is mediated primarily by
mu-2 receptors.
On what receptors do intravenous opioids work to produce supraspinal analgesia?
Opioids work on mu-1, kappa, and delta receptors to produce supraspinal analgesia.
Stimulation of what opioid receptor does not produce supraspinal analgesia?
Supraspinal analgesia is mediated primarily by mu -1
receptors.
In addition to spinal and supraspinal analgesia, stimulation of mu-1 receptors elicits what six responses? Does stimulation of mu-1 receptors have high or low
abuse potential?
Stimulation of mu-1 receptors produces:
(l) euphoria
(2) miosis
(3) bradycardia
(4) hypothermia
(5) urinary retention and
(6) pruritus.
Which receptors have low abuse potential?
Mu-1
Supraspinal analgesia is mediated primarily by
mu -1 receptors.
In addition to spinal analgesia, stimulation
of mu-2 receptors elicits what three responses?
Stimulation of mu-2 receptors produces: (1) depression of ventilation, (2) marked constipation, and (3) physical dependence.
Does stimulation of mu-2 receptors have high or low abuse potential?
Mu-2 receptors have high abuse potential because of the physical dependence.
What opioid receptor promotes respiratory
depression?
Mu-2 receptors
At what anatomic locations do opioids work to produce spinal analgesia?
Opioids work in the substantia gelatinosa of the spinal cord and at several supraspinal sites including the periaqueductal and periventricular gray matter.
In what two ways do epidural and intrathecal
opioids produce spinal analgesia?
Opioids administered epidurally or intrathecally diffuse into the substantia gelatinosa and: (I) combine with presynaptic opioid receptors and inhibit the release of substance P, and (2) combine with postsynaptic opioid receptors and decrease activity in neurons ascending in the lateral spinothalamic tracts
An important target for opioids in the brainstem is the
periventricular and periaqueductal gray matter
Does electrical stimulation of the periventricular/periaqueductal gray produce supraspinal or spinal analgesia?
Yes; “
Stimulation of midbrain periaqueductal gray in humans produces _____why?
widespread analgesia:’ This analgesia occurs because the periventricular/ periaqueductal gray sends impulses via the dorsolateral tract down to the spinal cord to inhibit transmission of pain impulses through the
substantia gelatinosa.
What spinal cord tract modulates pain? Explain.
The descending dorsolateral funiculus modulates pain. Action potentials in this tract activate the enkephalin-containing neurons of the substantia gelatinosa, which diminish the transmission of pain impulses through the
spinal cord
What brainstem areas send action potentials to the substantia gelatinosa via the dorsolateral funiculus?
The periaqueductal gray and the periventricular gray.
Spinal cord gray matter was divided by Rexed into how many laminae?
The gray matter of the spinal cord was divided by Rexed into IO lamina (I- X).
Opioids work in which of these lamina?What is
another name for this lamina?
. Lamina II is also known as the substantia gelatinosa. Note: Some sources indicate the substantia gelatinosa is formed by Rexed’s lamina II and III.
What are seven responses to mu -1
receptor stimulation?
(I) Supraspinal analgesia
2) urinary retention
(3) miosis
(4) decreased heart rate
(5) hypothermia
(6) pruritus
(7) euphoria.
Which opioid can block voltage-dependent
sodium channels, in other words, which opioid has local anesthetic properties?
Meperidine is an agonist of both μ- and K-receptor and has been shown to block voltage-dependent sodium channels
Mediate opioid-induced bradycardia.
Mu receptors
Which opioid receptor(s) mediate bradycardia?
mu receptors mediate opioid-induced bradycardia
Name the opioid that depresses myocardial contractility and increases heart rate.
Meperidine (Demerol) has a significant negative inotropic effect (it decreases myocardial contractility) and a positive chronotropic effect (it increases heart rate).
Regarding tricyclic antidepressants specifically meperidine, they interact with
meperidine to accentuate
meperidine’s respiratory depressant actions.
What seven adverse signs and symptoms might develop if a patient on an MAO inhibitor receives meperidine?
Meperidine (Demerol), but not synthetic opioids (e.g., fentanyl}, interacts with MAO inhibitors such that the patient may exhibit the following: ( l)hyperpyrexia (2) hypertension (3) hypotension (4) ventilatory depression, (5) skeletal muscle rigidity (6) seizures {7} coma
How do the opioids (except meperidine) produce bradycardia?
With the exception of meperidine, opioids stimulate the vagal nucleus in the medulla, which increases vagal impulses to the heart.
What affect do opioids have on the blood C02 dissociation curve?
If respiratory depression occurs, Pa02 decreases, and the C02 curve shifts.
List four ventilatory effects of opioids.
decrease breathing rate
decrease minute ventilation
decrease ventilatory response to carbon dioxide due to
brainstem depression, and
increase arterial carbon dioxide tension.
What is the major clinical implication of the opioid-induced decrease in gastrointestinal tone and motility?
The decreased gastrointestinal tone and motility delays gastric emptying and increases the risk of aspiration
What are the endocrine effects of opioids?
High dose opioids reduce or block the metabolic stress response to surgery.
Opioids also stimulate the release of what hormones?
prolactin and growth hormone and depress the release of antidiuretic hormone.
Does opioid-induced spasm of the sphincter of Oddi cause pain?
Yes, and it resembles the pain of angina pectoris.
What seven agents may relieve suspected spasms of the sphincter of Oddi?
Treatment of suspected spasm of the sphincter of Oddi (choledochoduodenalsphincter) is with glucagon ( 12 mg IV,
Do all opioids have the potential of producing rigidity of skeletal muscles, especially of the chest and abdomen?
yes
Under what conditions do opioids cause
truncal rigidity?
Opioids induce rigidity by large dose, rapid infusion, or concomitant use of nitrous oxide.
Stimulation of what opioid receptors causes skeletal muscle rigidity: mu, or kappa, or delta?
Stimulation of mu receptors causes skeletal muscle rigidity.
The incidence and severity of opioid-induced skeletal muscle rigidity may be increased by addition of what inhalational agent to the anesthetic?
Nitrous oxide.
What are seven possible side-effects of opioid premedication?
(l) Respiratory depression
(2) nausea and vomiting
(3) orthostatic hypotension,
(4) delayed gastric emptying
(5) pruritus,
(6) sphincter ofOddi spasm, and
(7) histamine release by morphine and meperidine
List four common side-effects associated with intrathecal (spinal) opioid administration, and state which of these is most common.
(a) pruritus (60%), (b) urinary retention (50%), (c)
nausea and vomiting {20-30%), and (4) respiratory depression (
Is the most common side effect of intrathecal opioids.
Pruritus
Which opioid should not be given with a neuraxial technique? Why?
Remifentanil should not be administered intrathecally or epidurally, as the safety of the buffering vehicle has not been determined. The buffering vehicle is glycine, which is an inhibitory neurotransmitter.
How do opioids produce vomiting?
Opioids stimulate the chemoreceptor trigger zone (located on the floor of the third ventricle). When stimulated, the chemoreceptor trigger zone
activates the vomiting center, which is located nearby in the brain stem.
Which opioid agonist has the smallest volume of distribution? What is the significance of this?
Alfentanil. Alfentanil is eliminated faster (has a shorter half-time of elimination) than all other opioids except remifentanil because of its small volume of distribution.
Rank the following opioids relative to elimination half-life (from shortest to longest)
.Remifentanil (shortest) «_space;alfentanil < morphine
S sufentanil < meperidine S fentanyl (longest). [
Single dose of fentanyl does have a shorter duration of action than
dose a single dose or morphine. However, with continuous infusion fentanyl has a longer duration of action than does morphine, owing to fentanyl’s
longer elimination half-life.
Except for remifentanil, how are opioids eliminated? What are the implications for a patient with liver disease receiving an opioid?
Except for remifentanil, opioids are eliminated by hepatic metabolism. In a patient with liver disease, the clearance of all opioids except remifentanil
will be delayed (slowed) and significant accumulation can occur
What is the main concern with administration
of morphine sulfate in post-partum patients?
Respiratory depression
Do opioids inhibit hypoxic pulmonary vasoconstriction (HPV)?
NO
Tramadol is an atypical opioid, specifically tramadol is a
synthetic 4-phenyl-piperidine analog of codeine with a dual mechanism of action.
Tramadol weakly stimulates the
μ-opioid receptor and, to a lesser extent, the delta- and K-opioid receptors.
Tramadol, like tricyclic antidepressants, produces analgesia by
activating spinal inhibition of pain by decreasing the
reuptake of norepinephrine and serotonin.
The opioid effects of tramadol are mediated by a
metabolite formed by 0-demethylation by CYP450 2D6,
in other words tramadol is a prod rug.
What is the maximum daily dose of tramadol?
The maximum dose of tramadol is 400 mg/day to 500 mg/day.
Tramadol may produce life-threatening serotonin-syndrome if given to patients taking what other agents?
Tramadol may cause life-threatening serotonin syndrome in patients taking monoamine oxidase inhibitors (MAO-I), serotonin/norepinephrine uptake inhibitors, selective serotonin uptake inhibitors (SSRI) and tricydic
antidepressants.
List four advantages tramadol provides over other opioids. State three common side effects of tramadol.
Tramadol is advantageous to other opioids owing to its lack of respiratory depression, organ toxicity, and depression of GI motility as well as its low potential for abuse.
The most common side effects of tramadol are
nausea, dizziness, and constipation
Identify five opioid agonist/antagonists.
Pentazocine (Talwin), butorphanol (Stadol), buprenorphine (Buprenex), • nalbuphine (Nubain), and dezocine (Dalgan).
Agonist-antagonist opioids work primarily Agonist-Antagonist opioids promote analgesia (the desired therapeutic
kappa receptors and also on delta receptors
Name the 3 antagonists
Naloxone, the longer-acting naltrexone (Trexate), and nalmefene (Incysnists
Context sensitive half time of opioids from more to least
FASR
Fentanyl
Alfentanil
Sufentanil
Remifentanil
Clinical effects of fentanyl are terminated mainly by
Redistribution
After 3 hour IV infusion , which opioid has the longest context sensitive half time?
Fentanyl
Which opioids has the longest duration of action after epidural injection?
Morphine
Which opioid is the most hydrophillic?
Morphine
Activation of opioid receptors leads to activation of which intracellular transduction mechanism?
G proteins
Which opioid must be converted from a prodrug to an active form?
Codeine
A patient with significant hepatic and renal impairment, to avoid dosage adjustments due to this impairment, which opioid should used?
Remifentanil
Opioid likely to produce the most hypotension?
Morphine
Factors increasing the risk of opioid related respiratory depression?
Medications GA Barbiturates OSA very young, very old
Opioid causes biliary spasm
Morphine
Behavior drug seeking that occurs despite negative social or physical outcomes
Addiction
Combination of MAOI, and opiate receptor agonist can lead to
Serotonin syndrome
OPIOID Best choice for patients taking a MAOI is
Morphine
Opioid causing prolonged QT is
Methadone
Which agent is administered to patients undergoing treatment for substance abuse to prevent the euphoric effect of opioids?
Naltrexone
Which opioid agent is used mainly for the treatment of opioid abstinence syndromes, heroin addiction, and chronic pain relief?
Methadone
Upon what receptors does nalbuphine act? (select two)
Mu
Kappa
Nalbuphine is an opioid derivative that acts as a partial agonist at
mu, kappa, and delta receptors.
Nalbuphine acts to antagonize
mu receptor activity, agonize delta receptors, and act as a partial agonist on kappa receptors.
What is the most common side effect of neuraxial opioids?
Pruritus
Neuraxial opioid pruritus is typically is concentrated on the
face, neck, and upper chest but can be distributed throughout the entire body.
Pruritus in OB, It is most common in obstetric patients, presumably from the
combined pruritic effect of estrogen.
Which opioid is most likely to cause histamine release?
Morphine
Morphine-6 glucuronide is a more
powerful CNS depressant than morphine
Morphine inactive metabolite
Morphine-3-glucuronide
Which of the following statements regarding fentanyl are true? (select two)
Intravenous fentanyl has an onset of 2-5 minutes
It undergoes significant first-pass metabolism when administered orally
Fentanyl IV onset
2-5 minutes
Fentanyl peak effect of and
3-5 minutes
Fentany: its effects are terminated principally by
redistribution away from the central nervous system.
Which agent should not be used in a neuraxial block? why?
Remifentanil. Glycine
Which opioid receptor produces diuresis when stimulated?
Kappa
Which agent has the ability to reverse opioid induced respiratory depression, yet maintain analgesia?
Nalbuphine
Effectively reverse opioid induced respiratory depression while maintaining analgesia.
Nalbuphine
Which of the following statements is true concerning the effect of opioids on the CO2 response curve?
They shift the curve to the right, which represents a decrease in responsiveness to CO2
Compared to nalbuphine, butorphanol exhibits (select two)
greater analgesic qualities
greater sedative effects
Butorphanol is similar to nalbuphine in that it is a kappa receptor agonist and a weak mu receptor antagonist, but it has greater
analgesic qualities than nalbuphine and produces more sedation when used clinically.
A patient is experiencing pruritus from the administration of an opioid for surgical pain. What is the most appropriate treatment for the itching?
nalbuphine
Select two opioids that cause the release of histamine from mast cells when administered in high doses.
Administration of high-doses of morphine, codeine, and meperidine can produce histamine release from mast cells.
Which opioid agonist agent is the least potent?
Sufentanil>fentanyl=remifentanil>alfentanil
Which organs are primarily responsible for excreting opioids and their metabolites?
Kidneys
Lipophilic opioids penetrate faster and achieve higher concentrations in the spinal cord than hydrophilic opioids.
Fentanyl and sufentanil are more lipophilic.
Select the two most lipophilic opioids.
Morphine and meperidine are more hydrophilic.
The use of meperidine requires caution in patients with renal failure because of the potential for
prolonged respiratory depression
What is the most common serious complication associated with opioid intrathecal and epidural administration?
Respiratory depression
Which intravenous opioid has the fastest onset?
Alfentanil
Alfentanil has a
small volume of distribution, and 90 percent of the drug is in the nonionized form at physiologic pH, leading to an increased amount of drug being available for binding.
Following administration of morphine for pain, a patient complains of pruritus. Which agent would be the most appropriate to alleviate the itching?
Nalbuphine
Which agent is a pure opioid antagonist that reverses opioid induced respiratory depression and analgesia?
Naloxone
Which narcotic is rapidly metabolized by blood and tissue esterases?
Remifentanil
In opioids with a high volume of distribution, the decrease in plasma concentration and termination of the analgesic effect is due primarily to .
redistribution of the drug away from the site of action
In opioids with a small volume of distribution, the termination of the analgesic effect is primarily due to
clearance of the drug.
Which opioid has the shortest half-life?
Remifentanil
Which piperidine opioid contains a methyl ester side chain and is metabolized by nonspecific blood and tissue esterases?
Remifentanil
The major metabolite of fentanyl is
the inactive compound norfentanyl
Fentanyl is _______ times more potent than morphine
100
It has a highly lipophilic structure which allows it to quickly cross the blood-brain barrier.
Fentanyl
Which area is responsible for producing opioid-induced, postoperative nausea and vomiting?
Chemoreceptor trigger zone
Which calcium channel blockers inhibit CYP450? (select two)
diltiazem and verapamil.
Remifentanil exhibits a _____ volume of distribution than fentanyl due to a(n) _____ clearance.
smaller, increased
Drugs such as fentanyl that are highly lipophilic and exhibit low protein-binding exhibit a
high volume of distribution
What is the context-sensitive half-life of remifentanil?
2-4 minutes
After intravenous administration of fentanyl, there is an initial rapid increase in plasma concentration of the drug followed by a rapid decline in plasma administration and a second, slower decrease in the plasma concentration. The second, slower decline is due primarily to
redistribution to adipose tissue
Nausea and vomiting from opioid administration occurs due to direct stimulation of
the chemoreceptor trigger zone
What is the drug of choice for use in cases of life-threatening, opioid-induced respiratory depression?
Narcan
Remifentanil is metabolized by
nonspecific esterases
After intravenous administration of fentanyl, there is an initial rapid increase in plasma concentration of the drug followed by a rapid decline in plasma administration. This initial, rapid decline is due primarily to
Redistribuation to highly perfused organs
After intravenous administration of fentanyl, there is an initial rapid increase in plasma concentration of the drug followed by a rapid decline in plasma administration. This initial, rapid decline is due primarily to
Redistribution to highly perfused organs
Endogenous opioids include the
enkephalins, dynorphins, and β-endorphins,
β-endorphins and enkephalins have the greatest affinity for
μ and δ receptors,
Dynorphins preferentially bind to the
κ receptors.
Mechanism of Opioid Analgesia
In the spinal cord, opioids inhibit the release of substance P from primary sensory neurons in the dorsal horn, attenuating the transmission of painful stimuli from peripheral nerves to the cerebral cortex.
In the brainstem, opioids act at
descending inhibitory pathways to attenuate painful stimuli.
Is the most potent opioid commercially available for human use;
Sufentanil
5 μg of intravenous sufentanil is the analgesic equivalent to
50 μg of fentanyl.
1 mg of morphine equivalent to : Methadone
1mg of Methadone
1 mg of morphine equivalent to Meperidine
10mg
1 mg of morphine equivalent to : Fentanyl
50 mcg
1 mg of morphine equivalent to : Hydromorphone
0.2 mg
1 mg of morphine equivalent to : Alfentanil
150 mcg
1 mg of morphine equivalent to : Sufentanil
5 mcg
1 mg of morphine equivalent to : Remifentanil
50 mcg
Factors that increase the risk of opioid-induced ventilatory depression include
high dose, natural sleep, old age, other CNS depressants, and decreased clearance due to hepatic or renal insufficiency.