Exam 3 Opioids Flashcards
What year was meperidine introduced?
1939
What year was methadone introduced?
1946
What year was nalorphine introduced?
1942
Nalorphine countered the effects of morphine and produced limited analgesia.
What are opiates?
Opiates are derived from opium, including morphine, codeine, and a variety of related alkaloids.
What is the definition of opioids?
Opioids include all agonists and antagonists with alkaloid structures, as well as naturally occurring and synthetic peptides that bind to opioid receptors.
What is a narcotic?
A narcotic is any drug that induces sleep; it was initially used to describe strong opiate analgesics and now refers to a wide variety of opioid and non-opioid abused substances.
What are the types of opioid binding sites in the CNS?
Mu, kappa, delta
What are opioid receptors coupled to?
G proteins
What do opioid receptors inhibit?
Adenylyl cyclases
What effect do opioid receptors have on Ca channels?
Decrease conduction of Ca channels
What is inhibited from primary afferent sensory neurons in the spinal cord and peripheral terminals
Substance P release
What channels do opioids open?
K channels
What is the result of K channel opening?
Hyperpolarization (prevents excitation or propagation of action potentials)
How do mu receptors interact with NMDA receptors?
Mu receptors appear to block NMDA receptors
What is desensitization?
Prolonged activation can lead to reduced sensitivity.
What is internalization?
Removal of receptors from cell membrane without reduction in total number of receptors.
What is recycled/downregulation?
Reduction in total number of receptors.
What is tolerance?
Loss of effectiveness due to reduced receptor synthesis and altered drug metabolism.
What are endogenous opioid ligands?
20 peptides from the brain, pituitary, adrenal, and immune cells.
What are the types of endogenous opioid ligands?
Methionine-enkephalin, leucine-enkephalin, B-endorphin, dynorphin-A, and endomorphines.
Which receptors do methionine-enkephalin and leucine-enkephalin act on?
Delta receptors.
Which receptors does dynorphin-A act on?
Kappa receptors.
Which receptors do endomorphines act on?
Mu receptors.
What are the effects of mu receptors?
Analgesia, respiratory depression, sedation, reward, euphoria, physical dependence, constipation, bradycardia, hypothermia, urinary retention.
What are the sub-types of mu receptors?
Mu1 (analgesia) and mu2 (side effects).
What are the effects of kappa receptors?
Analgesia, dysphoria, aversion, diuresis, miosis, low abuse potential.
What are the effects of delta receptors?
Analgesia, respiratory depression, constipation, and urinary retention.
What are the receptor sites in the CNS?
Spinal cord, dorsal root ganglia, brain stem, midbrain, cortex (specifically Periaqueductal gray (PAG), Locus ceruleus, and Rostral ventral medulla (RMS))
What are the receptor sites in the peripheral nervous system?
Primary afferent neurons (increased in inflammation with limited tolerance), neuroendocrine, immune, and ectodermal tissues
What are the short-term clinical effects of certain substances?
Analgesia, Respiratory depression, Sedation, Euphoria, Vasodilation, Bradycardia, Cough suppression, Miosis, Nausea/vomiting, Skeletal muscle hypertonus, Constipation, Urinary retention, Biliary spasm
What are the long-term clinical effects of certain substances?
Tolerance to effects, Physical and psychological dependence
What receptors are most clinically useful opioids selective for?
Most clinically useful opioids are relatively selective for mu receptors.
How do opioids differ despite similar analgesia and respiratory depression?
Opioids differ in histamine release, presence of active metabolites, onset, and duration of action.
What effect does a selective kappa receptor agonist have?
A selective kappa receptor agonist (arylacetamide) caused significant dysphoria.
What type of pain are opioids most effective for?
Opioids are most effective for visceral or burning pain.
How effective are opioids for sharp and neuropathic pain?
Opioids are less effective for sharp pain (incision) and least effective for neuropathic pain.
What is the opioid effect on nociception?
Opioid effect is selective for nociception leading to a change in the effective response to pain.
What is the result of opioid use on pain perception?
Pain is still present, but there is a dissociation from pain and mood elevation (abuse potential).
What is the relationship between opioid dose and pain intensity?
There is a dose and concentration dependent reduction in intensity of acute pain.
What is necessary for optimal effect of opioids?
Opioids need to be titrated for optimal effect.
What surrogate markers are useful during intraoperative use of opioids?
Blood pressure, heart rate, and movement are very useful surrogate markers.
What variable factors affect opioid efficacy?
Location and intensity of pain, psychological factors, drug interactions, and age.
How do psychological factors influence opioid response?
Previous positive or negative experiences can affect the response to opioids.
What is the effect of coadministering NSAIDs or alpha2 agonists with opioids?
Coadministration may enhance analgesia.
What substances may increase toxicity when coadministered with opioids?
Alcohol, benzodiazepines, and barbiturates may increase toxicity.
How does age affect opioid sensitivity?
Elderly patients are more sensitive, but some may require higher doses.
What can cause increased sensitivity in patients?
Pathologic disease, such as hypothyroidism or pre-existing CNS disease.
Who may be more at risk of toxicity from certain medications?
Asthmatics and patients with a history of COPD due to increased secretions and bronchospasm.
What are some variable factors affecting medication sensitivity?
Hepatic or renal disease, sex (not fully understood), and genetic differences.
What is the impact of genetic differences on codeine metabolism?
Poor metabolizers at CYP2D6 have an inability to convert codeine to morphine, affecting 10% of whites and most Chinese.
Which population is more sensitive to the respiratory depressive effects of morphine?
Colombian Indians are more sensitive than white or Latino patients.
What is the absorption characteristic of opioids after oral administration?
Rapidly absorbed after oral administration, but undergo significant first pass effect.
What is a popular method to circumvent short duration of opioids?
Delayed release formulations are becoming more popular to circumvent short duration via slower onset.
How does the lipophilicity of fentanyl compare to morphine?
Fentanyl is much more lipophilic than morphine.
What is the bioavailability of aerosolized morphine?
Morphine can be aerosolized and achieve 60% bioavailability.
What is the distribution characteristic of opioids in the body?
Rapid and extensive throughout the body.
What factors influence the onset and duration of opioids?
Difference in onset and duration is related to lipophilicity.
What happens to lipophilic opioids after neuraxial administration?
Lipophilic opioids (fentanyl) move quickly into CNS and effects are terminated by redistribution.
What is the effect of rapid redistribution in lipophilic opioids?
It leads to a rapid onset of highly segmental block and rapid offset of effect.
What is the duration of effect for epidural or intrathecal morphine?
Long duration of effect.
How long does CSF take to circulate from the lumbar cistern to the brain for water soluble opioids?
6 or more hours.
What can rostral spread of epidural morphine lead to?
Delayed respiratory depression or thoracic analgesia after lumbar epidural.
How is morphine metabolized?
Extensive hepatic metabolism to polar metabolites that are excreted in urine.
What is unique about remifentanil’s metabolism?
It is uniquely hydrolyzed by esterases in plasma and peripheral tissues.
What are the active metabolites of morphine?
Morphine-3- and -6-glucuronide, which have prolonged effects especially in renal patients.
How do meperidine and fentanyl undergo metabolism?
They undergo oxidation by CYP450.
What is meperidine metabolized to?
Meperidine is n-demethylated to normerpidine, which has analgesic properties but also convulsive properties.
What precautions should be taken with normerpidine?
Care should be exercised in renal patients or others with compromised renal function (e.g., elderly).
What are the CNS clinical effects of opioids?
Sedation and sleep often accompany pain relief, but opioids are generally poor hypnotics.
What adverse effects can occur with opioids?
Agitation and dysphoria can occur, along with convulsant effects (generally only with high doses).
How do opioids affect intracranial pressure?
Opioids can increase intracranial pressure by causing hypercarbia.
What effect do opioids have on cerebral vasodilation?
Opioids cause modest direct cerebral vasodilation.
What is the CNS effect of opioids on ventilatory response?
Dose dependent depression of ventilatory response to hypercapnia and hypoxia; with increasing dose there is initial decreased ventilatory rate with increasing tidal volume, which can progress to apnea.
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.
What is a dangerous effect of fentanyl, sufentanil, and alfentanil?
They have caused ‘recurrent’ ventilatory depression—dangerous postoperative depression of breathing in patients who previously seemed to be breathing well.
What is the effect of opioids on cough suppression?
Opioids suppress cough through medullary cough centers.
Which substances are known for cough suppression?
Codeine, heroin, and dextromethorphan.
What are the CNS clinical effects of opioids?
Nausea and vomiting, miosis, and skeletal muscle rigidity.
What causes nausea and vomiting in opioids?
Direct effect at the chemoreceptor trigger zone in the area postrema.
Exacerbated by labyrinthic input (increased nausea with movement).
What is miosis and how is it affected by opioids?
Miosis is a direct effect on the autonomic nucleus of the oculomotor nerve with little or no tolerance to this effect.
Meperidine may actually cause mydriasis (atropine-like effect).
What is skeletal muscle rigidity in the context of opioids?
It is referred to as ‘truncal or chest wall rigidity’ and is actually generalized hypertonus of striated muscles throughout the body, most pronounced with potent opioids (e.g., fentanyl) when given rapidly.
Mechanism is thought to be inhibition of GABA with enhancement of dopaminergic tone.
What is skeletal muscle rigidity?
Skeletal muscle rigidity is seen during induction (rarely during emergence), making the patient difficult to ventilate due to pharyngeal and laryngeal hypertonus.
Treat with muscle relaxant or can be reversed with naloxone.
What causes bradycardia?
Bradycardia is a direct effect on the vagus and can be prevented by atropine, pancuronium, or other vagolytic drugs.
Less likely with merpidine due to weakly anticholinergic properties.
What is vasodilation in relation to the vagotonic effects of opioids?
Vasodilation is caused by vasomotor depression in the medulla and decreased sympathetic tone, leading to mild orthostatic hypotension.
Responsive to fluids and recumbency.
What is a good choice for critically ill patients with decreased cardiac reserve?
Opiate based anesthesia
It does not cause myocardial depression, does not pre-dispose to arrhythmias, and preserves cardiac response to circulating catecholamines.
What is true about allergies to opioids?
True allergy to opioids is extremely rare.
Hives and itching are most likely due to histamine release from mast cells.
Which opioids do not release histamine?
Fentanyl and congeners do not release histamine.
What are the effects of histamine release?
Histamine release leads to decreased systemic vascular resistance, hypotension, and tachycardia.
This may be prevented by pre-treating with H1 or H2 blockers.
What symptoms are associated with histamine release?
Itching and warmth over the neck and face.
What is a common side effect of epidural opioids?
Epidural opioids are notorious for generalized itching.
What is the effect of smooth muscle spasm on the enteric nervous system?
It stimulates tonic contraction while reducing normal propulsive activity.
What are the components of the plexus of bowel?
Sacral plexus, biliary tree, ureters, and bladder.
What is a consequence of decreased peristalsis?
It leads to constipation.
Little if any tolerance develops to this effect.
What is delayed gastric emptying associated with?
Post operative ileus.
What is the role of Methylnaltrexone?
It reverses or prevents the peripheral component since it is permanently ionically charged and cannot penetrate the CNS.
What happens with direct stimulation of the gall bladder and cystic duct?
It leads to contraction of the sphincter of Oddi, increasing intrabiliary pressure and causing biliary colic or false positive cholangiograms.
This effect can be reversed by naloxone, atropine, or nitroglycerin.
What is a clinical effect of smooth muscle spasm?
Urinary retention secondary to decreased tone of bladder detrusor muscle and increased tone of urinary sphincter.
What is decreased awareness of bladder distension?
Inhibition of urge to void.
When are urinary effects most likely to occur?
Urinary effects are most likely in epidural or intrathecal administration.
What is acute drug tolerance?
Occurs within hours usually after single high dose or rapid infusion.
What is chronic drug tolerance?
Decrease in duration of effect and decrease in intensity of effect.
Which effects develop tolerance most rapidly?
Tolerance is most rapid to analgesic and ventilatory depression; slower to constipation and miosis.
What is known about the mechanism of drug tolerance?
Unknown mechanism, but may involve NMDA activation and production of nitric oxide.
What is drug tolerance?
A reduced response to a drug after repeated use.
What is physical dependence?
A condition where the body adapts to a drug, leading to withdrawal symptoms when the drug is not taken.
What is opiate withdrawal syndrome?
A set of symptoms that occur upon the abrupt discontinuation of opiates.
What are common symptoms of opiate withdrawal?
Restlessness, mydriasis, goose flesh, runny nose, diarrhea, shaking chills.
What is drug seeking behavior?
Behavior exhibited by individuals to obtain drugs despite negative consequences.
What triggers the onset of withdrawal symptoms?
The elimination of opioids from the body.
What can opioid antagonists or mixed agonist/antagonists cause?
Immediate severe withdrawal symptoms.
What is a methadone taper?
A method of slowly reducing methadone dosage to manage withdrawal.
What is the approach to managing protracted withdrawal syndrome?
Slow dosage reduction.
What is the separation of physical and psychological dependence?
The distinction between physical dependence on a drug and psychological addiction.
What are Dave’s listed opioid agonists?
Morphine
Meperidine
Sufentanil
Fentanyl
Alfentanil
Remifentanil
Codeine
Dextromethorphan
Hydromorphone
Oxymorphone
Methadone
Heroin
Listed opioid agonist/antagonists?
Pentazocine
Butorphanol
Nalbuphine
Buprenorphine
Nalorphine
Bremazocine
Dezocine
Listed opioid antagonists
Naloxone
Naltrexone
Nalmefene
Methylnaltrexone
What are the two distinct chemical classes of alkaloids of opium?
Phenanthrenes and Benzylisoquinolines
What are the characteristics of Phenanthrenes?
They have 3 rings with 14 carbon atoms; they are tertiary amines that are highly ionized and water soluble at physiologic pH; levorotatory isomers tend to be most active.
Name three examples of Phenanthrenes.
Morphine, Codeine, Thebaine
Thebaine has insignificant analgesic activity but is a precursor for etophine, which is >1000 times more potent than morphine.
What are the characteristics of Benzylisoquinolines?
They lack opioid activity.
Name two examples of Benzylisoquinolines.
Papaverine, Noscapine
What are synthetic opioids?
They include Levorphanol, Methadone derivatives, Benzomorphan derivatives (like pentazocine), and Phenylpiperdine derivatives (like meperidine and fentanyl).
What is pruritis?
Generalized itching, most pronounced in the face, neck, and upper thorax.
More pronounced in obstetrical patients due to interaction of estrogen with opioid receptors.
What is the mechanism behind pruritis in neuraxial anesthesia?
Not histamine mediated; most likely mechanism is opioid receptors in the trigeminal nucleus.
How is pruritis treated in neuraxial anesthesia?
Naloxone is effective in treating pruritis; the effect of antihistamines on pruritis is secondary to sedative effects.
What causes nausea and vomiting in neuraxial anesthesia?
Activation of the chemoreceptor trigger zone and depression of the vomiting center.
What is the process behind nausea and vomiting in neuraxial anesthesia?
A dopaminergic process that responds well to anti-dopamine agents such as metoclopramide or promethazine.
What is urinary retention related to in neuraxial anesthesia?
Activation of opioid receptors in the sacral spinal cord; reduced parasympathetic outflow with detrusor muscle relaxation and increase in maximum bladder capacity.
What are the risk factors for ventilatory depression in neuraxial anesthesia?
High opioid dose, low lipid solubility, concomitant parenteral opioids or other sedatives, lack of opioid tolerance, advanced age, patient position, increased intrathoracic pressure.
When can delayed depression occur after morphine administration?
6-12 hours after morphine, but has never been described more than 24 hours after neuraxial administration.
What is the risk of ventilatory depression in obstetric patients in neuraxial anesthesia?
Obstetric patients have a lowered risk for depression secondary to ventilatory stimulation by progesterone.
What may develop despite a normal breathing rate in neuraxial anesthesia?
Arterial hypoxemia and hypercarbia; monitor with pulse oximetry and treat with supplemental oxygen.
What may be the best indicator of impending ventilatory depression in neuraxial anesthesia?
Decreased level of consciousness.
What is a common side effect of sufentanil?
Sedation is dose dependent but occurs most frequently with sufentanil.
What should be considered first with decreased level of consciousness?
Always think ventilatory depression first.
What can cause Central Nervous System Excitation?
-Large doses of IV opioids can cause seizure activity; rarely with neuraxial.
-It is due to cephalad spread with blockade of glycine and GABA.
What viral reactivation has been seen in obstetrical patients?
Herpes reactivation has been observed.
What causes herpes reactivation in obstetrical patients?
It is caused by cephalad spread with interaction at the trigeminal nucleus.
What is a concern regarding neonatal morbidity in neuraxial opioid administration?
Clinically important ventilatory depression in the newborn has been observed as the placenta has no real barrier to the transfer of opioids.
How do the effects of morphine compare to meperidine?
Effects of morphine are much more pronounced when compared with meperidine.
