Opioids - Review, General info Flashcards
firing of a neuron that is not indicative of of physical damage, but is a pathalogical firing
Neuropathic pain
Pain out of proportion to noxious stimuli
Hyperalgesia
Pain evoked by a non-noxious stumuli
Allodynia
pain with no apparent stimuli - it is NERVE pain
spontaneous pain
Peripheral nociceptive neuron activated by intense noxious stimimuli (tissue damage) via
* Mechanical * thermal * chemical
slow conduction, dull, burning, diffuse
non-mylinated C fibers
fast conduction - sharp and well localized
A-delta fibers
nociceptiv impulse depends on the balance between
excitatory and inhibatory receptors
excitatory cation channel activated by: * Protons * heat * capsaisin * Endovanilloids
TRIP1
hyperpolarization related to opioid receptor activation
cells will need a stronger stimulus to fire
promotes depolarization and stimulates pain
Bradykinin and Prostaglandins
Area of dorsal horn that is very rich in opioid peptides and receptors
substantia geletinosa
Lamina for A delta fibers
Lamina I and V
Lamina for C fibers
Lamina II and III (substantia gelatinosa)
Located in lamina II and III
Substantia gelatinosa
where do opioids act at the brain level
pre and post synaptically to activate descending inhibatory pathways
where do opioids act at the spinal cord level
work directly on the dorsal horn of the spinal cord
where do opioids act at the periphery level
act on peripheral teminals of nociceptive neurons
why is the perception of noxious stimuli not the same as pain?
it is lacking the emotional component
Opioids can change patients ___ without necessarily changing the patients ability to _____ noxious stimuli
* tolerance of pain * perceive ie- they can still tell you where the wound is
The main use of opioids on anestehsia
Attenuate the SNS response to noxious stimuli- Laryngoscopy
opoids and inhaled anesthetics
act as an adjunct allowing for less use of inhaled agent
natrurally occuring drugs derrived from opium from the poppy plant
Opiate * Morphine * Codeine
Opioids produce analgesia without loss of
* Touch * Propioception * Conciousness
naturally occuring opioids
Morphine
semisynthetic: analogs of morphine
heroine dihydromorhone codeine
Synthetic Opioids
* Exogenous Has 4 classifications * agonist * partial aginist * mixed agonist/antagonist * antagonist
Synthetic antagonist
Narcan
can reach maximum eficacy on dose response curve their potency is what varries
Synthetic agonists (full)
will have a ceiling effect cannot reach maximum effect on dose response curve
Synthetic partial agnosts
Synthetic opioid agonist / antagonist
agonist at kappa receptors antagonist and mu receptors
if their is any potential you will need to switch to a full agonist you want to start with
a parial agonist and NOT an agonist / antagonist
Opioids - Mechanism of action
Activate stereo-specific G-protein coupled receptors and act post-synaptically to directly decrease neurotransmission by: increase K conductance (hyperpolarization) and Ca++ channnel inactivation (decreased NT release), inhabition of adenylate cyclase (decreased cAMP) Modulation of phospinositide- signaling cascade for phospholipase C increase MAP kinase which affects gene expression and increases phospholipase A2 (increase in leukotriens) and act Pre synaptically Decrease ACh, dopamine, norepi and Substance p release *anytime you hyperpolarize a membrane you decrease NT release*
anytime you hyperpolarize a cell you
decrease neurotransmitter release
Opioids PRE-synaptic mechanism of action
inhibits the release of excitatory neurotransmitters * ACh * Dopamine * Norepi * Substance P
Opioid receptors
* Mu (agnoist binding site) * Kappa (antagonist binding site) * Delta
All endogenous and exogenous opiois agonists work at these receptors
Mu-1 and Mu-2
May actually cause immunosupression and accelerate some types of cancer
Mu-3
Mu receptors location
* brain- supraspinal * spinalcord * periphery
Mu 1 site of analgesia
Supraspinal is thought to be the principal site of action but also works at spinal cord in a lesser degree (and periphery)
Mu-1 receptor activation causes
cardio - bradycardia no respiratory effects CNS effects: euphoria, sedation, prolactin release, hypothermia, catalepsy, indifference to environmental stimuli Pupil - miosis no Gi effects GU - urinary retention no pruritus low abuse potential
Mu-2 receptor activation effects
cardio - bradycardia respiratory - depression ->hypoventilation CNS: euphoria, pruritus, dopamine turnover, possible growth hormone release pupils - miosis GI - inhibition of peristalsis (constipation), nausea, vomiting GU - urinary retention Physical dependence
Mu 2 analgesia
principal site of action is the spinal cord (but also has some supruaspinal action as well)
kappa receptor analgesia
supraspinal, spinal
kappa receptor endogenous agonists
dynorphins
Kappa receptor activation effects
no cardio effects respiratory - possible depression ->hypoventilation CNS: sedation, dysphoria, hallucinations, delirium pupils - miosis GU - diuresis (inhibition of vasopressin release) Low physical dependence (low potential abuse)
Delta receptor endogenouas ligand
enkephalin
delta receptor analgesia
supraspinal, spinal modulates mu receptor activity
Delta receptor activation
no cardio respiratory - depression ->hypoventilation no CNS effects GI - minimal inhibition of peristalsis (some constipation) GU - urinary retention Pruritus Physical dependence
Located on Chromosome 6q24-q25
Mu opoid receptor
aspartated in place of asparagine 10-20% of the population
* Nucleotide 118 polymorphism * Gene Effects agonist binding to Mu receptor
valine in place of alanine 1-10% of population
* Nucleotide 17 polymorphism * Gene Effects agonist binding to Mu opioid receptor
Codine has unpredictable pharmacokinetics and half lives due to
CYP2D6 gene polymorphisms
Opioid least likely to be impacted by genetic variability. Predictable pharmacokinetics.
Fentanyl
side effect rate can be influenced by ….
The rate of metabolism
Ultra-rapid metabolizers are at risk for
PONV
Opioids and Perioperative cardiovasucular effects (4)
Minimal impairment of CV function but has additive effect with other analgesics profound vasodilation/ decrease SVR- most evident in patients with hypovolemia Dose dependant bradycardia- via vagal stimulation (nuclei in medula) and Direct SA/AV nodal depression Impairmennt of SNS response and baseline tone orthostatic hypotension that is pronounced with hypovolemia
morphine and meperedine and cardiovascular effects
Have a dose dependant histamine release * risk more vasodilation - decreased BP and SVR * risk bronchospasm
Why is meperidine an exception to the CV effects of opioids
It will cause tachycardia - due to its atropine like structure
When a large dose of opioids are given and the BP drops what is it likely due to?
Hypovolemia with vasodilation it is NOT likely a contractility isusse, Opioids are pretty cardiac stable
Opioids and HR
Dose dependant bradycardia * Central vagal stimulation * act directly on SA/AV nodal depression
Opioids and vasculature
Vasodilation/ Decreased SVR * decreased SNS response and baseline tone decreased CO and venous pooling = orthostatic hypotension * Pronounced effect on vasculature
What opiods do we want to avoid in astmatics? Why?
Morphine and meperidiene- dose and infusion rate dependant histamine release causes more vasodilation and BRONCHOSPASM
Do opioids produce amnesia
No
Opioids and patients with increased ICP
*minimal decrease in ICP * Must have ventilations controlled prior to giving opioids * Hypoventilation and Increased CO2 will cause cerebral vasodilation and increased ICP
Opioids and urination
Increased Uregency and reduced ability to void * Increased tone and peristaltic activity of ureter * incresed tone of detrusor
Why do opioids cause nausea and vomiting
* decreased gastric emptying * stimulation of chemoreceptor zone of the 4th ventricle * balanced depression of medulary vomiting center
Puritis and Opioids
cause is unknown, could be the histamine release with morphine and meperidine, but fentanyl it is unknown (fentanyl nose itch)
drugs that cause adverse affect: muscle rigidity in chest, abdomen, jaw and extremeties
* Fentanyl * Sufentanyl * Hydromorphone (Dilaudid)
issues with adverse affect: muscle rigidity from opioids
High airway pressures from increased intrathoracic pressure and decreased veonus return difficult/impossible to ventilate only releived my non-depolarizing muscle relaxant glottic rigidity and closure reported
Smaller dose of opioids - respiratory effects
Increased Tidal voume and decreased RR Increased CO2 and decrease O2
Larger dose of opioids
Decreased TV and Decreased RR
ventilatory effects of opioids
Dose dependant respiratory depression Decreased chest wall compliance constriction of pharyngeal and laryngeal muscles cough suppression Dramatically decreased response to hypercarbia and hypoxia
Factors that increase the magnitude and duration of opioid induced respiratory depression
higher doses Intermittent boluses have higher degree of respiratory depression than contiuous infusion Speed of injection Concurrent admin with other anesthetics Decreased clearance (active metabolites build up) Age - older and younger alkalosis - opioid are weak bases secondary peaks in plasma levels from reuptake from muscle, fat, lung and intestines
Morphine active metablolite
morphine-6-glucuroninde
prodrug- active form is morphine
Codeine (3-methylpmorphine)
Long plasma half life 8-59 hours or 13-100, sources vary * High variability among individuals
Methadone
How long does it take to develop tolerance to opioids?
48 hours - need to taper
effects of tolerance
reduction of adverse effects (less respiratory, nausea and CNS side effects) shorter duration of analgesia decrease in effectiveness does not work
What side effect dies NOT go away with tolerance
Constipation - a stimulant laxative w/ or without stool softener should be started early in treatment
Neuralaxial analgesia (diffusion)
Cross the dura onto mu receptors to the substantia geletinosa difuses into the vasculature to get systemic effect
given neuroaxial: very lipid soluable
fentanyl
Given neuroaxial: very water soluable - will circulate with CSF
Morphine
Opioids in the epeidural space may diffuse into * _______ * _______ * _______
* fat * systemic absorbtion (vasculature) * CSF
Cephalad movemnt of opioid in CSF depends on ____________.
Lipid solubility
lipid solubility and migration of neuroaxial opioids
more lipid soluble = limited migration, penetrates the dura more readily and has quicker peak in CSF/systemic concentration; resp depression seen immediately or early on Less lipid soluble = will remain in CSF for transfer to cephalad location; resp depression not seen until hrs later
Why is the dose for an epidural 5x higher than that for a spinal?
Because the spinal is directly at the site
side effects with neuraxial opioids
ventilatory depression pruritus N/V urinary retention
This can be given to treat muscle rigidity from opioids
NDMRs
What should you do if you see a localized reaction at the site of morphine injection?
DON’T PANIC Morphine causes histamine release, so this is a common reaction
These meds can be used to relieve sphincter of oddi spasm
Glucagon, nubain, and NTG
Opioids are weak (acids/bases)
Bases
Vd is related to
Lipid solubility and protein binding
A large Vd will equate to a long or short DOA?
Long
Do opioids produce amnesia?
NO
How do opioids produce bradycardia?
Vagal stimulation and inhibition of the SA node
The bradycardia and ventilatory depression caused by opioids are
dose dependent
Where do agonists/antogonists work?
They are Mu antagonists and full or partial kappa agonists
