Opioids Flashcards
Naturally occurring opioids
phenanthrenes (morphine and codeine)
benzylisoquinolines (papaverine)
Thebaine
Semisynthetic opioids
Heroin
Dihydromorphone, morphinone
Thebaine derivatives (e.g., etorphine, buprenorphine)
Synthetic opioids
Morphinan derivatives (e.g., levorphanol, butorphanol)
Diphenylpropylamine derivatives (e.g., methadone)
Benzomorphan derivatives (e.g., pentazocine)
Phenylpiperidine derivatives (e.g., meperidine, fentanyl, sufentanil,
alfentanil, remifentanil)
Morphine binds to the μ-opioid receptor protein to form an active complex with signaling proteins, including …
The … signaling pathway is thought to mediate analgesic action of morphine, whereas … signaling results in unwanted side effects including euphoria, which can lead to addiction, respiratory depression, and gastrointestinal effects
Gi/o and β-arrestin
Gi/o
β-arrestin
OBS.: TRV130, a “G protein-biased” μ-opioid ligand with G-protein–coupling efficacy similar to that of morphine, but markedly reduced receptor phosphorylation, recruitment of β-arrestin 2, and internalization, was tested in a randomized, double-blind, placebo-controlled crossover study in healthy volunteers. TRV130 produced greater analgesia than morphine, but less respiratory depression and
less severe nausea
Mechanism of opioid analgesia in the brain
The analgesic effects of opioids arise from their ability to inhibit directly the ascending transmission of nociceptive information from the spinal cord dorsal horn and to activate pain control circuits that descend from the midbrain, through the rostral ventromedial medulla (RVM), to the spinal cord dorsal horn.
Petrovic and colleagues used an experimental pain model and positron emission tomography (PET) to study mechanisms of action of the short-acting μ-opioid agonist remifentanil and found drug-induced activation of the rostral anterior cingulate cortex, insula, orbitofrontal cortex, and brainstem areas. The activated brainstem regions overlapped with brain areas that have been implicated in pain modulation, such as the periaqueductal gray (PAG).
The μ receptor produces analgesia within descending pain control circuits, at least in part, by the removal of γ-aminobutyric acidergic inhibition of RVM-projecting neurons in the PAG and spinally projecting neurons in the RVM
Mechanism of opioid analgesia in the spinal cord
Local spinal mechanisms, in addition to descending inhibition, underlie the analgesic action of opioids.
In the spinal cord, opioids act at synapses either presynaptically or postsynaptically.
Opioid receptors are abundantly expressed in the substantia gelatinosa, where glutamate and substance P release from the primary sensory neuron is inhibited by opioids.
Histamine receptors are known to participate in spinal cord nociceptive transmission, and previous studies have suggested that histaminergic receptors are also involved in the analgesic effects of morphine. An H1 antagonist and H3 agonist were found to potentiate the analgesic and antiedematogenic effects of morphine, suggesting that histaminergic and opioid spinal systems may be explored for means of improving analgesia, as well as peripheral antiinflammatory effects.
Methadone is clinically used as a racemic mixture of the l and d isomers. The opioid-like activity of the racemate seems to be almost entirely the result of …, whereas … acts as an …
l-methadone
d-methadone
NMDA antagonist
The serotonin type 3A (5-HT3A) receptor, which is directly and indirectly linked to … , is competitively inhibited by morphine and hydromorphone, as well as naloxone; however, fentanyl-like opioids did not significantly affect activity of the 5-HT3A receptor
gastrointestinal motility, visceral pain, nausea, and vomiting
The mechanism for tramadol analgesia is complex and appears
to be composed of two actions that include …
reuptake inhibition of the noradrenergic serotonergic system and activation of the μ-opioid receptor
Describe a possible neurochemical basis of opioid-induced change in consciousness
Cortical acetylcholine originates in the basal forebrain and is essential for maintaining normal cognition and arousal. Injection of morphine to the substantia innominata or intravenous morphine administration significantly decreased acetylcholine release within the prefrontal cortex in the rat, and this effect may be the neurochemical basis of opioid-induced change in consciousness
Many hypotheses have been advanced to explain the etiology of opioid-induced hallucinations. One common feature of these hypotheses involves opioid-induced …
Overactivation of the … is thought to result in auditory and visual hallucinations
dopamine dysregulation
dopaminergic pathways
Opioids effectes on the electroencephalography
Small doses of fentanyl (2-5 μg/kg) produce minimal EEG changes, whereas higher doses (30-70 μg/kg) result in high-voltage slow (δ) waves suggesting a state consistent with anesthesia.
In a study, At 1 minute with 37.5 μg of sufentanil, the EEG showed loss of β activity and the presence of primarily α waves (8-13 Hz).
At 3.5 minutes and 65.6 μg of sufentanil, the EEG consisted of mixed θ (4-7 Hz) and δ (<4 Hz) waves, and at 4.0 min and 75 μg of sufentanil, it consisted of δ waves of high amplitude
How do opioids affect evoked responses?
- Opioids do not appreciably alter sensory-evoked potentials elicited at the posterior tibial or median nerve;
- Remifentanil produced dose-dependent reduction in auditory-evoked potentials, but it was also reported that remifentanil infusion (target plasma concentrations of 1, 2, and 3 ng/mL) did not affect evoked potential amplitudes and latencies;
- In healthy human volunteers receiving 3 μg/kg fentanyl, amplitude and latency of motor-evoked responses to transcranial stimulation were not significantly affected;
How do opioids affect the CNS perfusion?
Opioids, in general, do not significantly effect measures of CBF.
Opioids are generally thought to affect ICP minimally under
conditions of controlled ventilation.
Explain the muscle rigidity and the difficult ventilation tha may occur after opioid administration
Opioid-induced rigidity is characterized by increased muscle tone that sometimes progresses to severe stiffness and associated clinical challenges.
Clinically significant opioid-induced rigidity usually begins just as, or after, a patient loses consciousness. Mild manifestations of rigidity, such as hoarseness, can occur in conscious patients.
Vocal cord closure is primarily responsible for the difficult ventilation with bag and mask that follows the administration of opioids
The precise mechanism by which opioids cause muscle
rigidity is not clearly understood.
The nucleus raphe pontis within the reticular formation and the caudate nucleus within the basal ganglia have been implicated mechanistically.
Pharmacologic investigation using selective agonists and antagonists suggests that systemic opioid-induced muscle rigidity is primarily caused by the activation of central μ-receptors, whereas supraspinal δ1 and κ1 receptors may attenuate this effect
Opiods do not produce EEG seizure activity.
T or F
F
Focal neuroexcitation on the EEG (e.g., sharp and spike wave activity) occasionally occurs in humans after large doses of fentanyl, sufentanil, and alfentanil
How do opioids affect the pupile size?
Morphine and most μ− and κ−agonists cause constriction of the pupil by an excitatory action on the parasympathetic nerve innervating the pupil.
Light induces excitation of the Edinger-Westphal nucleus leading to pupillary constriction, which is inhibited by hypercarbia, hypoxia, and nociception. Opioids release the effect of inhibitory neurons on the
Edinger-Westphal nucleus, resulting in papillary constriction
Opioid-based anesthesia probably reduces thermoregulatory thresholds to a degree similar to that of the potent inhaled anesthetics. However, … is unique among opioids in its ability to effectively terminate or attenuate shivering. The antishivering effect of … is primarily related to a reduction in the shivering threshold
meperidine
meperidine
A quantitative systematic review of randomized controlled trials found that meperidine … mg and … 35 to 220 mg were more effective than control for parenteral pharmacologic interventions for the prevention of postoperative shivering
12.5 to 35
tramadol
Name an opioid associated with an increase in postanesthetic shivering. Explain the probable mechanism.
Remifentanil is associated with an increased incidence of postanesthetic shivering, which is not related with intraoperative hypothermia.
The higher incidence of postanesthetic shivering with higher doses of remifentanil probably reflects acute opioid tolerance and stimulation of the NMDA receptors
Opioids activating the … receptor cause dose-dependent depression of respiration, primarily through a direct action on …
μ
brainstem respiratory centers
High doses of opioids usually eliminate spontaneous respirations without necessarily producing unconsciousness. Patients receiving high doses of opioids may still be responsive to verbal command and
often breathe when they are directed to do so
T or F
T
Factors Increasing the Magnitude and/or Duration of Opioid-Induced
Respiratory Depression
- High dose
- Sleep
- Old age
- Central nervous system depressant (Inhaled anesthetics, alcohol, barbiturates, benzodiazepines)
- Renal insufficiency
- Hyperventilation, hypocapnia
- Respiratory acidosis
- Decreased clearance
- Reduction of hepatic blood flow
- Secondary peaks in plasma opioid levels
- Reuptake of opioids from muscle, lung, fat, and intestine
- Pain
How do opioids modulate the autonomic nervous system? How does this influence the cardiovascular system?
Most opioids reduce sympathetic and enhance vagal and parasympathetic tone. Patients who are volume depleted, or individuals depending on high sympathetic
tone or exogenous catecholamines to maintain cardiovascular function, are predisposed to hypotension after opioid administration.
The predominant and usual effect of opioids on heart rate is bradycardia resulting from stimulation of the central vagal nucleus. Blockade of sympathetic actions may
also play a role in opioid-induced bradycardia
Which opioid is most associated with tachycardia?
Meperidine, in contrast to other opioids, rarely results in bradycardia, but it can cause tachycardia. Tachycardia after meperidine may be related to its structural similarity to atropine, to normeperidine, its principal metabolite, or to early manifestations
of its toxic CNS effects
The oculocardiac reflex, which is caused by traction of extraocular muscles during strabismus surgery, was significantly … by fentanyl, sufentanil, and remifentanil
augmented
How do opioids affect Myocardial Ischemia?
Opioids can mimic ischemic preconditioning. Opioid receptor stimulation results in a reduction in infarct size similar to that produced by ischemic preconditioning. Although the preconditioning effect of opioids is mediated mainly by the cardiac κ- and δ-opioid receptors, part of the protective effect of remifentanil may be produced by μ-agonist activity outside the heart.
Whether the experimental results showing protective effects of opioid against myocardial ischemia will translate into reductions in morbidity and mortality in patients with coronary artery disease has yet to be established by clinical trials. Clinically, high doses of opioids can maintain myocardial perfusion and the O2
supply-demand ratio as well or better than can inhalation based techniques
It is well known that morphine causes histamine release and sympathoadrenal activation.
… are examples of other opioids that can induce mast cell activation with the release of histamine, probably by a mechanism other than the μ-opioid receptors.
Unlike morphine, the opioids … do not produce increases in plasma histamine,
subsequently hypotension is less frequent with their administration
Codeine and meperidine
fentanyl, alfentanil, sufentanil, and remifentanil
In humans endocrine system, opioids generally increase … , and decrease …
The effects of opioids on … are conflicting.
The primary endocrine disorder that results from opioid misuse is …
growth hormone, thyroid stimulating hormone, and prolactin
luteinizing hormone, testosterone, estradiol, and oxytocin
arginine vasopressin and ACTH
hypogonadism, particularly in males
The main components of the neuroendocrine stress response are …
and …
Morphine modifies hormonal responses to surgical trauma in a dose-related fashion through …
the corticotropin-releasing hormone brain centers (e.g., paraventricular hypothalamic nucleus)
the locus ceruleus-norepinephrine/autonomic nervous system
blockade of ACTH release, suppression of surgically induced increases
in plasma cortisol, and attenuation of the pituitary-adrenal response to surgical stress
