Exam 3: Opioids Flashcards
1
Q
What is meperidine?
A
Synthetic opioid introduced in 1939.
2
Q
What is the mechanism of action of methadone ?
A
Introduced in 1946; known for prolonged QT interval, long duration, and blocking NMDA receptors.
3
Q
What is nalorphine?
A
Introduced in 1942; counteracts the effects of morphine and produces limited analgesia.
4
Q
What are opiates? Examples?
A
Opiates are derived from opium, including morphine, codeine, and a variety of related alkaloids.
5
Q
What is an opioid?
A
An opioid includes all agonists and antagonists with alkaloid structures, as well as naturally occurring and synthetic peptides that bind to opioid receptors.
6
Q
What is a narcotic?
A
A narcotic is any drug that induces sleep; it was originally used to describe strong opiate analgesics and now refers to a wide variety of opioid and non-opioid abused substances.
**Footnote
Controlled Substances are better to call
7
Q
What are the types of opioid binding sites in the CNS?
A
Mu, kappa, delta
8
Q
What are opioid receptors coupled to?
A
Opioid receptors are coupled to G proteins.
9
Q
What do opioid receptors inhibit?
A
Opioid receptors inhibit adenylyl cyclases.
10
Q
What effect do opioid receptors have on Ca channels?
A
Opioid receptors decrease conduction of Ca channels.
11
Q
What is inhibited by opioid receptors in sensory neurons?
A
Opioid receptors inhibit the release of substance P from primary afferent sensory neurons in the spinal cord and peripheral terminals.
12
Q
What channels do opioid receptors open?
A
Opioid receptors open K channels.
13
Q
What is the result of K channel opening by opioid receptors?
A
It leads to hyperpolarization, preventing excitation or propagation of action potentials.
14
Q
How do mu receptors interact with NMDA receptors?
A
Mu receptors appear to block NMDA receptors.
15
Q
What is desensitization in the context of opioids?
A
Desensitization refers to prolonged activation leading to reduced sensitivity.
16
Q
What is internalization regarding opioid receptors?
A
Internalization is the removal of receptors from the cell membrane without a reduction in the total number of receptors.
17
Q
What is downregulation in opioid receptors?
A
Downregulation is the reduction in the total number of receptors.
18
Q
What is tolerance in the context of opioids?
A
Tolerance is the loss of effectiveness due to reduced receptor synthesis and altered drug metabolism.
19
Q
What are endogenous opioid ligands?
A
20 peptides from the brain, pituitary, adrenal, and immune cells.
20
Q
What are the types of endogenous opioid ligands?
A
Methionine-enkephalin and leucine-enkephalin (delta receptors), B-endorphin, Dynorphin-A (kappa receptors), Endomorphines (mu receptors).
21
Q
What are the effects of mu receptors?
A
Two sub-types: mu1 (analgesia) and mu2 (side effects).
22
Q
What are the effects of delta receptors?
A
Analgesia, respiratory depression, constipation, and urinary retention.
23
Q
What are the effects of kappa receptors?
A
Analgesia, dysphoria, aversion, diuresis, miosis, low abuse.
24
Q
Where are opioid receptor sites located?
A
CNS: spinal cord, dorsal root ganglia, brain stem, midbrain, cortex (specifically PAG, Locus ceruleus, and RMS).
25
Where else are opioid receptors found?
Peripheral nervous system: primary afferent neurons (increased in inflammation with limited tolerance), neuroendocrine, immune, and ectodermal tissues.
26
What is the eye effect of Demerol?
Dilates pupils.
27
What does dilated pupils indicate?
Too late/hypoxemia.
28
What are the receptor sites for opioids in the CNS?
Spinal cord, dorsal root ganglia, brain stem, midbrain, cortex (specifically Periaqueductal gray (PAG), Locus ceruleus, and Rostral ventral medulla (RMS))
FOOTNOTE**
Vagaltonic!!!! Putting into rest & digest
29
What are the receptor sites for opioids in the peripheral nervous system?
Primary afferent neurons (increased in inflammation with limited tolerance), neuroendocrine, immune, and ectodermal tissues
30
What are the short-term clinical effects of opioids?
Analgesia, Respiratory depression, Sedation, Euphoria, Vasodilation, Bradycardia, Cough suppression, Miosis, Nausea/vomiting, Skeletal muscle hypertonus, Constipation, Urinary retention, Biliary spasm
31
What are the long-term clinical effects of opioids?
Tolerance to effects, Physical and psychological dependence
32
What are the properties of clinically useful opioids?
Most clinically useful opioids are relatively selective for mu receptors; they provide similar analgesia and respiratory depression but differ in histamine release, presence of active metabolites, onset, and duration of action.
33
What effect does a selective kappa receptor agonist have?
A selective kappa receptor agonist (arylacetamide) caused significant dysphoria.
34
For what types of pain are opioids most effective? Less effective?
Opioids are most effective for visceral or burning pain; they are less effective for sharp pain (incision) and least effective for neuropathic pain.
35
What is the effect of opioids on nociception?
Opioid effect is selective for nociception leading to a change in the effective response to pain; pain is still present, but there is dissociation from pain and mood elevation (abuse potential).
36
How do opioids affect acute pain?
There is a dose and concentration dependent reduction in intensity of acute pain.
37
What is necessary for optimal effect of opioids?
Opioids need to be titrated for optimal effect.
38
What is a useful surrogate marker for intraoperative opioid use?
Intraoperative use of surrogate markers such as blood pressure, heart rate, and movement is very useful.
39
What factors can affect opioid efficacy?
Location and intensity of pain, psychological factors, drug interactions, age, pathologic disease, sex, and genetic differences.
40
How do drug interactions influence opioid analgesia? Good vs bad
Coadministration of NSAIDs, alpha2 agonists, or certain sedatives may enhance analgesia; others like alcohol, benzodiazepines, and barbiturates may increase toxicity.
41
How does age affect opioid sensitivity?
Elderly patients are more sensitive to opioids, but some may require higher doses.
42
What pathologic diseases can increase opioid sensitivity?
Hypothyroidism, pre-existing CNS disease, asthma, COPD, hepatic or renal disease.
43
How do genetic differences affect opioid metabolism?
Poor metabolizers at CYP2D6 cannot convert codeine to morphine, affecting 10% of whites and most Chinese.
44
Which population is more sensitive to morphine's respiratory effects?
Colombian Indians are more sensitive than white or Latino patients to the respiratory depressive effects of morphine.
45
How are opioids absorbed after oral administration?
Opioids are rapidly absorbed but undergo significant first pass effect.
46
What is becoming more popular to circumvent the short duration of opioids?
Delayed release formulations are becoming more popular.
47
How does fentanyl differ from morphine in terms of lipophilicity?
Fentanyl is much more lipophilic than morphine, allowing for forms like lollipops and patches.
48
What is the bioavailability of aerosolized morphine?
Aerosolized morphine can achieve 60% bioavailability.
49
What happens to opioids like fentanyl in the CNS?
Opioids move quickly into the CNS, and effects are terminated by redistribution.
50
What is the distribution characteristic of opioids?
Opioids are rapidly and extensively distributed throughout the body.
51
What influences the difference in onset and duration of opioids?
The difference is related to lipophilicity.
52
What happens after neuraxial administration of lipophilic opioids ((fentanyl) ?
move quickly into CNS and effects are terminated by redistribution (rapid onset of highly segmental block, rapid redistribution and offset of effect).
53
How long does it take for CSF to circulate from lumbar cistern to brain for water soluble opioids?
It takes 6 or more hours for CSF to circulate.
54
What can rostral spread of opioids lead to?
Rostral spread can lead to delayed respiratory depression or thoracic analgesia after lumbar epidural.
55
How are opioids metabolized and excreted?
Opioids undergo extensive hepatic metabolism to polar metabolites that are excreted in urine.
Remifentanil is uniquely hydrolyzed by esterases in plasma and peripheral tissues
– Morphine is metabolized to morphine-3- and -6-glucuronide
(active metabolites with prolonged effects especially in renal pts)
– Meperidine and fentanyl undergo oxidation by CYP450
56
What is unique about remifentanil's metabolism?
Remifentanil is uniquely hydrolyzed by esterases in plasma and peripheral tissues.
57
How is morphine metabolized?
Morphine is metabolized to morphine-3- and -6-glucuronide, which are active metabolites with prolonged effects, especially in renal patients.
58
How do meperidine and fentanyl undergo metabolism?
Meperidine and fentanyl undergo oxidation by CYP450.
59
What happens to meperidine during metabolism?
Meperidine is n-demethylated to normeperidine, which has analgesic properties but also convulsive properties, requiring caution in renal patients or the elderly.
60
What are the CNS clinical effects of opioids?
Sedation and sleep often accompany pain relief, but opioids are poor hypnotics. Agitation and dysphoria can occur. Convulsant effects are generally only with high doses. Increased intracranial pressure can occur due to hypercarbia. There is modest direct cerebral vasodilation.
61
What is the ventilatory response to opioids?
Opioids cause dose-dependent depression of ventilatory response to hypercapnia and hypoxia, initially decreasing ventilatory rate while increasing tidal volume, which decreases over time and can progress to apnea.
62
What are the principles of ventilatory depressive effects of opioids?
Equianalgesic doses of all opioids produce similar effects on ventilation. Reversal of ventilatory depression also causes reversal of analgesia. Tolerance develops to analgesia and ventilatory depression equally.
63
What is the risk associated with fentanyl, sufentanil, and alfentanil?
These opioids have caused 'recurrent' ventilatory depression, leading to dangerous postoperative depression of breathing in patients who previously seemed to be breathing well.
64
What is the effect of opioids on cough suppression?
Opioids suppress cough through their action on medullary cough centers, with codeine, heroin, and dextromethorphan being examples.
65
What are the effects of opioids on nausea and vomiting?
Opioids can cause nausea and vomiting through a direct effect at the chemoreceptor trigger zone in the area postrema, exacerbated by labyrinthic input.
66
What is the effect of opioids on pupils?
Opioids typically cause miosis (pinpoint pupils) due to a direct effect on the autonomic nucleus of the oculomotor nerve, with little or no tolerance to this effect. Meperidine may cause mydriasis (dilation) due to an atropine-like effect.
67
What is skeletal muscle rigidity in the context of opioids?
Skeletal muscle rigidity, or 'truncal or chest wall rigidity,' is generalized hypertonus of striated muscles throughout the body, most pronounced with potent opioids like fentanyl when given rapidly.
## Footnote
This condition makes patient ventilation difficult due to pharyngeal and laryngeal hypertonus.
68
What is the mechanism behind skeletal muscle rigidity caused by opioids?
The mechanism is thought to be inhibition of GABA with enhancement of dopaminergic tone.
69
How can skeletal muscle rigidity be treated?
It can be treated with muscle relaxants or reversed with naloxone.
70
What is bradycardia in relation to opioids?
Bradycardia is a direct effect on the vagus nerve, which can be prevented by atropine, pancuronium, or other vagolytic drugs.
## Footnote
Less likely with meperidine due to its weakly anticholinergic properties.
71
What causes vasodilation when using opioids?
Vasodilation is caused by vasomotor depression in the medulla and decreased sympathetic tone, leading to mild orthostatic hypotension responsive to fluids and recumbency.
72
What are the cardiovascular effects of opioids?
Opiate-based anesthesia is a good choice for critically ill patients with decreased cardiac reserve, as it does not cause myocardial depression, predispose to arrhythmias, blunt baroreceptor reflexes, or impair cardiac response to circulating catecholamines.
73
What is the incidence of true allergy to opioids?
True allergy to opioids is extremely rare; hives and itching are more likely due to histamine release from mast cells.
74
Which opioids do not release histamine?
Fentanyl and its congeners do not release histamine.
75
What are the effects of histamine release from opioids?
Histamine release leads to decreased systemic vascular resistance, hypotension, and tachycardia, which may be prevented by pre-treating with H1 or H2 blockers.
## Footnote
Itching and warmth over the neck and face are common, and epidural opioids are notorious for causing generalized itching.
76
What are the clinical effects of opioids on smooth muscle?
Opioids cause smooth muscle spasm, stimulating tonic contraction while reducing normal propulsive activity in the enteric nervous system.
## Footnote
This affects the plexus of the bowel, sacral plexus, biliary tree, ureters, and bladder.
77
What is the consequence of decreased peristalsis due to opioids?
Decreased peristalsis leads to constipation.
## Footnote
This can also lead to increased intrabiliary pressure and biliary colic or false positive cholangiograms, which can be reversed by naloxone, atropine, or nitroglycerin.
78
What tolerance develops with opioid use regarding smooth muscle effects?
Little if any tolerance develops to the smooth muscle spasm effects of opioids.
79
What is the effect of opioids on gastric emptying?
Opioids cause delayed gastric emptying and post-operative ileus.
80
What medication can reverse or prevent the peripheral effects of opioids?
Methylnaltrexone can reverse or prevent the peripheral component since it is permanently ionically charged.
81
How do opioids affect the gall bladder and cystic duct?
Opioids stimulate contraction of the sphincter of Oddi in the gall bladder and cystic duct.
82
What urinary effects are associated with opioid use?
Opioids can cause urinary retention due to decreased tone of the bladder detrusor muscle and increased tone of the urinary sphincter.
83
What are the effects of opioids on bladder awareness?
Opioids decrease awareness of bladder distension and inhibit the urge to void.
84
In which administration method are urinary effects of opioids most likely?
Urinary effects are most likely in epidural or intrathecal administration.
85
What is acute drug tolerance in opioids?
Acute drug tolerance, also known as tachyphylaxis, occurs within hours usually after a single high dose or rapid infusion. It may involve NMDA activation and production of nitric oxide, leading to effects such as constipation and miosis.
86
What are the characteristics of chronic drug tolerance in opioids?
Chronic drug tolerance is characterized by a decrease in duration and intensity of effect. Tolerance develops most rapidly to analgesic and ventilatory depression.
87
What is physical dependence in opioids?
Physical dependence is associated with opioid withdrawal syndrome, which includes symptoms such as restlessness, mydriasis, goose flesh, runny nose, diarrhea, shaking chills, and drug-seeking behavior.
88
What triggers the onset of opioid withdrawal symptoms?
The onset of symptoms is related to the elimination of the opioid from the body.
89
What can cause immediate severe withdrawal in opioid users?
The use of an opioid antagonist or a mixed agonist/antagonist can cause immediate severe withdrawal.
90
What is the methadone taper approach?
The methadone taper approach involves slow dosage reduction, which can lead to a protracted withdrawal syndrome.
91
What is the difference between physical and psychological dependence in opioids?
There is a separation between physical and psychological dependence (addiction), where long-acting opioids result in a longer period to withdrawal, while acute opioids lead to faster withdrawal.
92
What receptors do opioids trigger?
Opioids trigger all opioid receptors: mu, kappa (cough), delta
93
Name some opioid agonists.
Opioid agonists include Morphine, Meperidine, Sufentanil, Fentanyl, Alfentanil, Remifentanil, Codeine, Dextromethorphan, Hydromorphone, Oxymorphone, Methadone, and Heroin.
94
What are Opioid Agonist/Antagonists?
Opioid Agonist/Antagonists may trigger certain receptor family. Examples include: Pentazocine, Butorphanol, Nalbuphine, Buprenorphine, Nalorphine, Bremazocine, and Dezocine.
95
What are some examples of Opioid Agonist/Antagonists used in obstetrics?
Butorphanol and Nalbuphine are used in obstetrics.
96
What are Opioid antagonists?
Opioid antagonists attach to receptors and prevent them from turning on or being stimulated. Examples include: Naloxone, Naltrexone, Nalmefene, and Methylnaltrexone.
97
What are the two distinct chemical classes of alkaloids of opium?
Phenanthrenes and Benzylisoquinolines
98
What are the characteristics of Phenanthrenes?
They have 3 rings with 14 carbon atoms, are tertiary amines which are highly ionized and water soluble at physiologic pH, and levorotatory isomers tend to be most active.
99
Name three examples of Phenanthrenes.
Morphine, Codeine, and Thebaine
## Footnote
Thebaine has insignificant analgesic activity but is a precursor for etorphine, which is >1000 times more potent than morphine.
100
What are examples of Benzylisoquinolines?
Papaverine and Noscapine
## Footnote
Benzylisoquinolines lack opioid activity. Papaverine = Opiate, derived from opium; not opioid bc it doesn’t activate mu/kappa/delta receptors
101
What are some examples of synthetic opioids?
Levorphanol, Methadone derivatives, Benzomorphan derivatives (pentazocine), and Phenylpiperdine derivatives (meperidine and fentanyl)
## Footnote
Triggering nausea/vomiting is common with synthetic opioids.
102
What are the side effects of neuraxial opioids?
Pruritis, nausea/vomiting.
103
What is pruritis associated with neuraxial opioids?
Generalized; most pronounced in face, neck, and upper thorax.
## Footnote
More pronounced in obstetrical patients due to interaction of estrogen with opioid receptors.
104
What is the mechanism behind pruritis in neuraxial opioids?
Not histamine mediated; most likely mechanism is opioid receptors in trigeminal nucleus.
## Footnote
Giving Benadryl won't work.
105
How can pruritis be treated in patients receiving neuraxial opioids?
Naloxone is effective in treating pruritis; effect of antihistamines is secondary to sedative effects.
## Footnote
Use a small dose of naloxone for itch but save some for pain.
106
What causes nausea/vomiting with neuraxial opioids?
Activation of chemoreceptor trigger zone; depression of vomiting center.
107
What is the recommended treatment sequence for nausea/vomiting due to neuraxial opioids?
Try Nubain (Nalbuphine) -> zofran -> Benadryl.
108
What type of agents respond well to nausea/vomiting caused by neuraxial opioids?
Anti-dopamine agents (metoclopramide/promethazine).
## Footnote
No serotonergic = no zofran.
109
What is the drug of choice for opioid-induced nausea/vomiting?
Promethazine.
110
What is the placement of neuraxial opioids like fentanyl in the lumbar cistern?
They accumulate in fat around the cord, leading to a high degree of motor effects.
111
How long does morphine take to rise with CNS effects?
It may take 6-10 hours, and up to 12 hours to reach the brain, which can lead to respiratory depression.
112
What is a side effect of morphine related to urinary function?
Urinary retention occurs due to activation of opioid receptors in the sacral spinal cord, reducing parasympathetic outflow.
113
What are the risk factors for ventilatory depression with morphine?
High opioid dose, low lipid solubility, concomitant parenteral opioids or sedatives, lack of opioid tolerance, advanced age, patient position, and increased intrathoracic pressure.
114
When can delayed respiratory depression occur after morphine administration?
It can occur 6-12 hours after administration, but has never been described more than 24 hours after neuraxial administration.
115
What is the risk of respiratory depression in obstetric patients?
Obstetric patients have a lowered risk due to ventilatory stimulation by progesterone.
116
What may develop despite a normal breathing rate during opioid administration?
Arterial hypoxemia and hypercarbia may develop; monitoring with pulse oximetry is essential.
117
What is the best indicator of impending ventilatory depression?
A decreased level of consciousness may be the best indicator.
118
What is a common side effect of neuraxial opioids?
Sedation is a common side effect, dose dependent but occurs most frequently with sufentanil. Always think ventilatory depression first when there is decreased level of consciousness.
119
What can cause Central Nervous System Excitation with opioids?
Large doses of IV opioids can cause Central Nervous System Excitation, such as seizure activity; this is rarely seen with neuraxial opioids.
## Footnote
It is due to cephalad spread with blockade of glycine and GABA.
120
What is a potential viral reactivation associated with neuraxial opioids?
Herpes reactivation has been seen, especially in obstetrical patients.
## Footnote
This is caused by cephalad spread with interaction at the trigeminal nucleus.
121
What is a concern regarding neonatal morbidity with neuraxial opioids?
Clinically important ventilatory depression in the newborn has been observed as the placenta has no real barrier to the transfer of opioids.
122
How do the effects of morphine compare to meperidine?
The effects of morphine are much more pronounced when compared with meperidine.
