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180 Cards in this Set
- Front
- Back
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What is an opioid?
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Exogenous natural and synthetic substances that bind specifically to opioid receptors and produce morphine-like effects
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What kind of sensation is fast pain?
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Well localized
Sharp Stabbing |
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What nerve fibers are involved with fast pain?
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Myelinated A-delta nerve fibers
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What is the conduction velocity of fast pain?
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12-30 m/s
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What kind of sensation is slow pain?
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Throbbing
Burning Aching |
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What nerve fibers are involved with slow pain?
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Unmyelinated type C nerve fibers
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What is the conduction velocity of slow pain?
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0.5-2 m/s
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What is Rexed's Laminae?
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Architectural scheme used to classify the structure of the spinal cord based on features of the neurons in different regions of gray matter
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How many laminae are in Rexed's Laminae?
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10 laminae
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What laminae involve the dorsal horn?
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Laminae I-VI
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What is in laminae II-III?
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Substantia gelatinosa
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What laminae involve the ventral horn?
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Laminae VII-IX
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What lamina involves the central canal?
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Lamina X
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What is activated in the periphery when their nerve endings are damaged?
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A-delta and C fibers
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Pain impulses travel to cell bodies located where?
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Dorsal root ganglion
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Where do pain impulses (fast and slow) enter and where do they go in the spinal cord?
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Enter the dorsal horn of the spinal cord:
-A-delta fibers to laminae I and V -C fibers to lamina II (substantia gelatinosa) |
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What do pain impulses synapse with and where?
What is their pathway after synapsing? |
Second order neurons (interneurons) synapse with A-delta and C fibers
Cross to the contralateral spinothalamic tract and ascend to the brain |
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What is the spinothalamic tract for fast pain?
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A-delta: neospinothalamic tract
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What is the spinothalamic tract for slow pain?
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C fibers: paleospinothalamic tract
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What is the neurotransmitter for C fibers (slow pain)?
When is this released? |
Substance P
Released in the substantia gelatinosa where type C nerves synapse with second order neurons |
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What is the neurotransmitter for A-delta fibers (fast pain)?
Where is this released? |
Glutamate
In laminae I and V |
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What do enkephalin releasing interneurons release?
Where does this occur? |
Substance P
In the substantia gelatinosa |
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What does enkephalin act on?
What does this cause? |
Acts on the primary pain afferent nerve
Decreases the release of Substance P |
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What does the effect of enkephalin cause?
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Decreased substance P release limits the number of action potentials traveling the spinothalamic tract
Decreases the perception of pain |
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Impulses from the spinothalamic tracts arrive where?
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Ventroposteriolateral nucleus (VPL) in the thalamus
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From the ventroposteriolateral nucleus in the thalamus, where do pain impulses travel to next? Via what?
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To the periaqueductal grey (PAG) area via the spinomesencephalic tract
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From the periaqueductal grey (PAG) area, where are pain impulses transmitted to?
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To the nucleus raphe magnus in the medulla
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From the rap he magnus in the medulla, where does the pain impulse travel to next? Via what?
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The substantia gelatinosa via the descending dorsolateral tract
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Impulses arriving from the descending dorsolateral tract to the substantia gelatinosa activate what?
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Enkephalin releasing interneurons
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What do enkephalin releasing interneurons do?
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Decrease the release of substance P by the primary pain afferent
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What is spinal analgesia?
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Modulation of pain in the dorsal horn by decreasing the release of substance P
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What is supraspinal analgesia?
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Results from opioid action in the limbic system, thalamus, and hypothalamus:
-The response to pain is altered -"I can feel the pain, but I don't care" |
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What are the 4 opioid receptors?
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Mu-1
Mu-2 Kappa Delta |
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What superfamily do opioid receptors belong to?
What % of all receptors do they occupy? |
Guanine (G) protein receptors
Constitute 80% of all known receptors |
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Where are opioid receptors located?
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Brain: PAG, hypothalamus, thalamus
Spinal cord: substantia gelatinosa |
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What does activation of opioid receptors cause?
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Spinal and supraspinal analgesia and undesirable side effects
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What 2 chemical classes are opium alkaloids divided into?
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Phenanthrenes
Benzylisoquinolines |
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What are 2 examples of phenanthrenenes?
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Morphine
Codeine |
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What are 2 examples of benzylisoquinolines?
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Papaverine
Noscapine |
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What do semisynthetic opioids result from?
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Single modifications of the morphine molecule
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What are 2 examples of semisynthetic opioids?
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1. Substitution of methyl group for the hydroxyl group on carbon-3 = methyl morphine (codeine)
2. Substitution of acetyl group on carbons-3,6 result in diacetylmorphine (heroin) |
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What is the composition of synthetic opioids?
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Contain the phenanthrene nucleus of morphine but are manufactured by synthesis instead of chemical modification of morphine
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What are 4 examples of synthetic opioids?
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1. Morphine derivatives (levorphanol)
2. Methadone derivaties 3. Benzomorphan derivatives (pentazocine) 4. Phenylpiperidine derivatives (fentanyl) |
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What is the prototype agonist all other opioids are compared to?
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Morphine
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What 4 effects dose morphine cause?
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1. Analgesia
2. Euphoria 3. Sedation 4. Diminished ability to concentrate? |
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What are 2 common side effect of morphine?
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1. Nausea
2. Pruritis |
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IV and IM dosing of morphine?
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IV: 0.1-0.15 mg/kg
IM: 0.5-1.0 mg/kg |
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IV morphine:
-Onset -Peak effect -Duration |
Onset: 1-3 minutes
Peak effect: 30 minutes Duration: 2-4 hours |
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IM morphine:
-Onset -Peak effect -Duration |
Onset: 15-30 minutes
Peak effect: 45-90 minutes Duration: 4 hours |
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Does morphine cross the blood-brain-barrier?
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No: poorly penetrates the CNS
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How much morphine enters the CNS at time of peak plasma concentrations?
4 reasons why: |
< 0.1% in CNS
1. Poorly lipid soluble 2. High ionization at physiologic pH 3. Protein binding 4. Rapid conjugation with glucuronic acid |
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What kind of metabolism does morphine undergo?
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Conjugation with glucuronic acid in hepatic and extra-hepatic sites
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What are the 2 metabolites of morphine?
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Morphine-3-glucuronide
Morphine-6-glucuronide |
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How much of a dose appears as morphine-3-glucuronide? Active or inactive?
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75%: inactive
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How much of a dose appears as morphine-6-glucuronide? Active or inactive?
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10%: active
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What is the effect of morphine-6-glucuronide compared to morphine?
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Produces analgesia and respiratory depression
Potency and duration of action greater than morphine |
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How is morphine eliminated?
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Kidneys (90%)
Bile (10%) |
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What is the effect of renal failure on clearance of morphine?
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May cause accumulation of morphine glucuronide metabolites with increased or prolonged ventilatory depression
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What is the potency of meperidine?
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1/10th as potent as morphine
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IV and IM dosing of meperidine?
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IV: 0.2-0.5 mg/kg
IM: 0.5-1.0 mg/kg |
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Meperidine:
-Peak effect (IV, IM) -Duration of action |
Peak effect (IV): 5-20 minutes
Peak effect (IM): 30-50 minutes Duration of action: 2-4 hours |
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What % of meperidine is bound to plasma proteins?
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60%
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What kind of metabolism does meperidine undergo?
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Extensive hepatic metabolism
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What is the metabolite of meperidine?
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Normeperidine
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What % of a dose of meperidine undergoes demethylation to normeperidine?
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90%
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How is normeperidine eliminated?
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Hydrolyzed and excreted in urine
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How potent is normeperidine compared to meperidine?
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1/2 as potent
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What kind of stimulant is normeperidine?
What 3 things does this cause? |
CNS stimulant:
-Myoclonus -Seizures -Delirium |
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What is meperidine's elimination half-time?
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15 hours
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How is meperidine affected by renal failure?
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Elimination half-time increased to 35 hours (from 15 hours)
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What is a potential consequence of meperidine given to patients on antidepressants?
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Serotonin syndrome
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What antidepressants are associated with serotonin syndrome with meperidine?
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-Monoamine oxidase inhibitors (MAOI)
-Fluoxetine |
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What does serotonin syndrome result in?
What are 4 manifestations of this? |
Severe autonomic instability:
-HTN -Tachycardia -Diaphoresis -Hyperthermia |
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What are 3 severe consequences of serotonin syndrome?
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1. Coma
2. Metabolic acidosis 3. Coagulopathy |
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How potent is fentanyl?
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75-125x more potent than morphine
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What is the IV and intranasal dosing for fentanyl?
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IV: 2-150 mcg/kg
Intranasal: 1-2 mcg/kg |
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Compare the onset and duration of fentanyl and morphine.
What does this reflect? |
Fentanyl has a more rapid onset and shorter duration of action
Reflects greater lipid solubility of fentanyl -Passage across blood brain barrier -Short duration of action reflects rapid distribution to inactive tissue depots |
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What occurs to fentanyl in the lungs?
What does this result in? |
75% of dose undergoes first-pass pulmonary uptake
Progressive saturation of the lungs results in prolonged anesthesia and respiratory depression |
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How is fentanyl metabolized?
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Extensively metabolized in the liver
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What is the metabolite of fentanyl? Active or inactive?
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Norfentanyl: inactive
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How is norfentanyl excreted?
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Kidneys
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What % of a dose of fentanyl is excreted unchanged in the urine?
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10%
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What is the elimination half-time of fentanyl?
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3-7 hours
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What has a longer elimination half-time: fentanyl or morphine?
What does this represent? |
Fentanyl has a longer elimination half-time than morphine:
-Represents a larger Vd Longer T1/2B in patients with decreased plasma proteins |
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What is context-sensitive half-time?
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Reflects elimination half-time relative to the duration of infusion
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What is the potency of sufentanil?
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5-10x more potent than fentanyl
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Dosing of sufentanil?
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Bolus: 1 mcg/kg
Infusion: 0.1-1.0 mcg/kg/hr |
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What is the most potent opioid agonist?
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Sufentanil
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Sufentanil has a rapid onset comparable to which other drug?
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Fentanyl
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What occurs to 60% of sufentanil in the lungs?
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Pulmonary first-pass uptake
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Which is more protein bound: sufentanil or fentanyl?
What does this result in? |
Sufentanil has a greater fraction of protein bound drug
Produces a smaller Vd |
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How is sufentanil metabolized?
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Rapidly metabolized in the liver
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Does sufentanil have active or inactive metabolites?
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Weakly active
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How is sufentanil eliminated?
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Excreted equally in the urine and feces
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What has a longer context-sensitive half-time? Sufentanil or alfentanil?
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Sufentanil has a lesser context-sensitive half-time (for infusions up to 8 hours)
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What is the potency of alfentanil?
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1/5 to 1/10 as potent as fentanyl
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What is the duration of alfentanil's action?
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1/3 the duration of fentanyl
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High or low pKa of alfentanil and what does this result in?
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Low pKa: allows for >90% of drug to be nonionized at physiologic pH
Very fast onset of action |
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What is the Vd of alfentanil compared to fentanyl?
Why does this occur? |
Alfentanil's Vd is 4-6x smaller than fentanyl:
-Lower lipid solubility -Greater protein binding |
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How is alfentanil metabolized?
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Extensive hepatic metabolism
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What is the metabolite of alfentanil? Active or inactive?
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Noralfentanil: inactive
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How much of alfentanil is cleared from plasma within 60 minutes?
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>96% cleared within 60 minutes of administration
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How is noralfentanil excreted?
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Urine
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What is the context-sensitive half-time of alfentanil compared to sufentanil?
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Longer context-sensitive half-time of sufentanil due to smaller Vd
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What kind of agonist is remifentanil?
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Selective mu agonist
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What is the potency of remifentanil?
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Similar to fentanyl
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What is the onset of remifentanil?
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Fast: similar to fentanyl
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Dosing of remifentanil:
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Loading dose: 1 mcg/kg
Infusion: 0.1-1.0 mcg/kg/min |
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What is the Vd of remifentanil compared to alfentanil?
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Similar: small
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What is the clearance of remifentanil compared to alfentanil?
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Clearance of remifentanil is 8x more rapid than alfentanil
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How fast does remifentanil equilibrate with the brain?
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1 minute: reaches plasma steady state within 10 minutes
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How is remifentanil metabolized?
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Hydrolyzed by nonspecific tissue and plasma esterase's
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Does remifentanil have active or inactive metabolites?
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Inactive metabolites
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How is remifentanil excreted?
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Urine
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What is remifentanil not susceptible to (in terms of metabolism)?
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Hydrolysis by plasma pseudocholinesterase
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What is the context-sensitive half-time of remifentanil?
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Independent of infusion duration:
4-8 minutes |
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Do opioids cause hemodynamic changes in the presence and absence of noxious stimuli?
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Opioids promote stable hemodynamics:
-Decreased release of catecholamines -Decreased SNS response |
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What blood pressure effect do opioids have? What does this augment?
Why does this occur? |
Hypotension: augment cardiodepressive effects of potent inhaled anesthetics or propofol
Inhibits SNS compensation |
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Does morphine cause histamine release?
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Yes
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What does morphine's histamine release cause?
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Vagal-mediated bradycardia
Venodilation |
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Does meperidine cause histamine release?
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Yes
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What does meperidine due to contractility?
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Negative inotropic effect
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What is meperidine structurally similar to and what can this cause?
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Atropine: increased HR
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What do all opioids do to respiratory function? Why does this occur?
Results in a decreased response to what 2 things? |
Dose-dependent respiratory depression: brainstem respiratory center depression
PaCO2 and hypoxemia |
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What effect do opioids have that provides for better toleration of ETT?
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Antitussive
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What effect do morphine and meperidine have on bronchomotor tone and why?
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May help avoid increases in bronchomotor done due to histamine release
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What 4 neurologic effects do opioids have?
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1. Drowsiness
2. Lethargy 3. Sleep 4. Euphoria |
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What do opioids do to CMRO2?
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Modest decrease: 10-25%
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What do opioids do to CBF? What may this be offset by?
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Small reduction in CBF:
May be offset cerebral vasodilation due to hypoventilation and increased PaCO2 if ventilation not controlled |
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Do opioids affect somatosensory or motor evoked potentials?
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Do not appreciably affect
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What can opioids cause in regards to muscle tone? Where?
When does this occur more? |
Can cause an increase in muscle tone and severe muscle rigidity:
thoracic and abdominal musculature Occurs more with large, rapid boluses |
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What threshold do meperidine and sufentanil decrease?
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Shivering threshold
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What is meperidine's effect on the shivering threshold?
Why does this occur? |
Terminate or attenuate shivering in 80% of patients
Likely due to kappa receptor stimulation |
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What is the a prominent side effect of opioids?
What is this most often seen with? Where on the body? |
Pruritis
Most often seen with neuroaxial administration: face, neck, upper thorax |
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What side effect results from direct stimulation of the chemoreceptor trigger zone in the brainstem?
What may this result from? What else may play a role? |
Nausea
May result from dopaminergic agonism: also, increased GI secretions and decreased GI emptying |
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What do opioids do to gastric emptying?
What is an implication of this? |
Decrease gastric emptying
Consider patients on chronic opioid therapy a full stomach |
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What do opioids do to biliary duct pressure? Affect what sphincter?
What does this mimic? Treatment? |
Increase biliary duct pressure and sphincter of Oddi tone
Mimic cholecystic disease on cholangiogram Treat: glucagon, naloxone, NTG |
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What knowledge is the basis for placing opioids in the epidural or subarachnoid space?
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Opioid receptors are located in the substantia gelatinosa of the spinal cord
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How do opioids work in neuroaxial blockade?
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Opioid diffuses into the substantia gelatinosa and binds to the opioid receptor on the primary pain afferent
This decreases release of substance P |
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What is a secondary mechanism of action of neuroaxial blockade with opioids?
What is this more prominent with? SAB or epidural? Why? |
Analgesia also results from systemic absorption of drug (similar to IV administration)
More prominent with epidurals due to vasculature |
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How do opioids and local anesthetics used in regional anesthesia differ?
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Analgesia is not associated with:
-Nervous system denervation (sympatectomy) -Skeletal muscle weakness -Loss of proprioception |
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What is the onset and duration of hydrophilic opioids in epidural placement?
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Slow onset
Prolonged duration of action |
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Why does early depression of ventilation occur with hydrophilic opioids in epidural placement?
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Due to absorption of drug by epidural venous plexuses
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Why does late depression of ventilation occur with hydrophilic opioids in epidural placement?
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Due to cephalad spread of drug via CSF to brainstem respiratory centers
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What is the onset and duration of hydrophilic opioids in subarachnoid placement?
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Slow onset
Prolonged duration of action |
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Does early ventilatory depression occur with hydrophilic opioids with subarachnoid placement?
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Does not occur: minimal systemic absorption
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Why does late ventilatory depression occur with hydrophilic opioids in subarachnoid placement?
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Due to cephalad spread of drug via CSF
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What is the onset and duration of lipophilic opioids in epidural placement?
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Rapid onset
Short duration of action |
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Why does early ventilatory depression occur with lipophilic opioids in epidural placement?
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Due to significant systemic absorption
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Does late ventilatory depression occur with lipophilic opioids with epidural placement?
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Does not occur: diffusion of drug out of epidural space is rapid and substantial
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What is the onset and duration of lipophilic opioids in subarachnoid placement?
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Fast onset
Short duration of action |
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Why does early ventilatory depression occur with lipophilic opioids with subarachnoid placement?
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Due to systemic absorption
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Does late ventilatory depression occur with lipophilic opioids in subarachnoid placement?
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Does not occur
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What 4 factors influence spread of drug in CSF?
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1. Lipid solubility
2. CSF bulk flow 3. Coughing, straining 4. Body position |
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What drugs are limited in cephalad spread by CSF?
What drugs remain in the CSF for cephalad spread? |
Lipophilic drugs limited in cephalad spread due to absorption by the spinal cord or epidural venous plexuses
Hydrophilic drugs remain in CSF for transfer in cephalad direction |
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When does CSF reach the 4th and lateral ventricle post-lumbar injection
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By 3-6 hours
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Morphine dosing:
Subarachnoid and Epidural |
Subarachnoid: 0.1-0.2 mg
(preservative free) Epidural: 5-10 mg |
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Fentanyl dosing:
Subarachnoid and Epidural |
Subarachnoid: 20-50 mcg
Epidural: 50-100 mcg |
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Sufentanil dosing:
Subarachnoid and Epidural |
Subarachnoid: 2-5 mcg
Epidural: 10 mcg |
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What 2 ways can increase your level of neuraxial block?
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1. Increased volume injected
2. Increased rate of injection |
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What are 4 side effects of neuroaxial opioid administration?
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1. Pruritis
2. Nausea and vomiting 3. Urinary retention 4. Ventilatory depression |
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What is the most common side effect of neuroaxial opioid administration?
Where is there a high incidence? |
Pruritis
Obstetric patients |
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Why does pruritis occur with neuroaxial opioid administration?
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Likely due to cephalad spread of drug in CSF and interaction with trigeminal nucleus
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What 2 drugs are used to attenuate the side effect of pruritis with neuroaxial opioid administration?
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1. Nalbuphine
2. Naloxone |
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What is the incidence of nausea and vomiting with neuroaxial opioid administration similar to?
What does this result from? |
Similar to IV use of opioids
Results from stimulation of the chemoreceptor trigger zone (CTZ) |
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What population is urinary retention common in after opioid administration in neuroaxial blocks?
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Young males
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Why does urinary retention occur after neuroaxial opioid administration?
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Results from the interaction of opioid and opioid receptors in the sacral spinal cord
Inhibits sacral parasympathetic outflow resulting in detrussor muscle relaxation and increased bladder capacity |
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What is the incidence of respiratory depression requiring intervention after administration of neuroaxial opioids?
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1%
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What increases the risk of ventilatory depression with neuroaxial opioid administration?
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Use of IV opioids or sedatives
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What kind of drug is nalbuphine?
|
Opioid agonist-antagonist
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How do opioid agonist-antagonists work?
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Bind to mu receptors:
-Limited response (partial agonist) -No effect (competitive antagonist) |
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Where do opioid agonist-antagonists have partial agonist activity?
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Delta and kappa receptors
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What are opioid agonist-antagonist's effects on analgesia and ventilation
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-Produce analgesia
-Limited to no ventilatory depression Can reverse opioid induced ventilatory depression without reversing analgesia |
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What is the analgesic potency of nalbuphine comparable to?
|
Morphine
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What is the dose of nalbuphine to reverse postoperative respiratory depression?
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5-20 mg IV
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What kind of drug is naloxone?
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Opioid antagonist
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How do opioid antagonists exert an effect at the receptor? Which receptor?
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Pure mu receptor antagonist (no agonist activity)
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What class of drugs has the highest affinity for mu receptors?
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Opioid antagonists
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What is the dose of naloxone?
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20-40 mcg IV
"Titrate to effect" |
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What is the duration of naloxone?
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30-60 minutes
(may necessitate repeat dose) |
