Opioid agonists - test 2 Flashcards
What do opioids decrease in the brain?
CBF (cerebral blood flow) and possibly also ICP (intracranial pressure).
Why should you proceed with caution with opioids and head injury?
Opioids have some of the same effects a brain injury can cause, such as affecting wakefulness, causing miosis, increase PaCO2 levels and cross the BBB
What is a common side effect of opioids that they share with induction agents?
Myoclonus (with large doses)
What is a severe side effect of opioids involving the chest and abdominal walls?
How do you treat this?
Skeletal muscle rigidity
Treat with Naloxone or muscle relaxer.
What common GI side effect of opioids and how do you treat it?
Spasm of the Sphincter of Oddi
To treat the spasm, give Naloxone or incremental doses of Glucagon up to 2mg IV.
Other than spasm of the Sphincter of Oddi, what are other GI side effects of opioids?
Delayed gastric emptying, nausea/vomiting, increased GI secretions, and constipation.
What are some miscellaneous side effects of opioids?
Urinary urgency, flushing from histamine release, neonatal depression and dependence
What is it called when a patient requires increased drug doses after chronic opioid use?
Tolerance (or physical dependence)
Opioid receptors become desensitized and decrease in number simultaneously. What is this called?
Downregulation
True or false: Cross-tolerance can develop between all opioids
True
How do opioids hyperpolarize neurons in the ascending tract of pain to make it less likely for them to fire an action potential?
How do they work on presynaptic neurons to inhibit release of NTMs?
Opioids promote K+ conductance on second order neurons.
Inhibit Ca++ conductance
What area in the brainstem has heavy opioid receptors that can inhibit pain signaling vie the medulla to the spinal cord?
PAG (periaqueductal gray)
Which brain region do opioids act on to reduce the emotional impact of pain?
Anterior Cingulate Cortex - increases dopamine levels in areas like the nucleus accumbens
Which has a greater context-sensitive half-time, Fentanyl or Sufentanil?
Fentanyl
What is the analgesia dose for fentanyl?
1-2 mcg/kg IV
What is the induction dose for fentanyl?
1.5-3 mcg/kg IV 5 mins prior to induction
What dose of fentanyl is given as an adjunct with inhaled anesthetics?
2-20 mcg/kg IV
What dose of fentanyl is given for surgical anesthesia (solo)?
50-150 mcg/kg IV
In what form can kids have fentanyl?
A lollipop with the dose of 5 to 20 mcg/kg
What is the steady delivery time for a fentanyl patch dose of 75 to 100 mcg?
18 hours
1 mg of PO Fentanyl is equal to how many mgs of Morphine?
5 mg
True or False: Fentanyl releases histamine.
False - It does not
What reflex does Fentanyl depress, leading to bradycardia and decreased CO?
Carotid Sinus Baroreceptor
Fentanyl has synergistic effects with which two drugs?
Benzos and propofol
How much does Fentanyl increase ICP?
6 to 9 mmHg
At which dose of fentanyl would you maybe get an EEG?
> 30 mcg/kg IV
Sufentanil is how many times more potent than fentanyl?
5 to 12 times
Where are the opioid receptors found in the brain and spinal cord?
Periaqueductal gray (PAG), Locus ceruleus, Rostral ventral medulla (RVM), Hypothalamus, Substantia Gelatinosa
Sufentanil is 92.5% bound to which protein?
alpha-1-acid glycoprotein
Where are the opioid receptors found in the spinal cord?
Interneurons and primary afferent neurons in the dorsal horn (substantia gelatinosa).
Which has a larger volume of distribution, Alfentanil or Sufentanil?
Sufentanil
Where are the opioid receptors found outside of the CNS?
Sensory neurons and immune cells.
How is Sufentanil metabolized?
Hepatic enzymes
What medications can be used on opioid receptors outside of the CNS?
Morphine and Ketorolac
What other medications can be used on opioid receptors outside of the CNS?
Local anesthetics - They are directly applied due to intense analgesia
With L&D, some places use sufentanil
What are the effects of Mu 1 opioid receptors?
Analgesia (supraspinal, spinal), Euphoria, Low abuse potential, Miosis, Bradycardia, Hypothermia, Urinary retention.
What are examples of Mu 1 agonists?
Endorphins, Morphine, synthetic opioids
What are examples of Mu 1 antagonists?
Naloxone, naltrexone, nalmefene
What are the effects of Mu 2 opioid receptors?
Analgesia (spinal), Depression of ventilation, Constipation (marked).
What are examples of Mu 2 agonists?
Endorphins, morphine, synthetic opioids
What are examples of Mu 2 antagonists?
Naloxone, naltrexone, nalmefene
What are the effects of Kappa opioid receptors?
Analgesia (supraspinal, spinal), Dysphoria, Sedation, Low abuse potential, Miosis, Diuresis.
What are examples of Kappa agonists?
Dynorphins
What are examples of Kappa antagonists?
Naloxone, naltrexone, nalmefene
What are effects of delta opioid receptors?
Analgesia (supraspinal, spinal), Depression of ventilation, Physical dependence, constipation, urinary retention
What is an example of a delta agonist?
Enkephalins
What are examples of delta antagonists?
Naloxone, naltrexone, nalmefene
Which opioid receptor produces physical dependence?
Mu 2
What are the side effects of opioids on the cardiovascular system?
Decreased SNS tone in peripheral veins:
- Decrease in venous return, CO, & BP
- Orthostatic hypotension & syncope
Decreased BP
- Due to Bradycardia or Histamine release
- Bradycardia is also due to direct inhibition of the SA node
- Morphine displaces histamine
True or False: Opioids + N20 or benzo = CV depression (CO & BP).
True
What are the benefits we get from the side effects on the cardiovascular system caused by opioids?
Cardioprotective from myocardial ischemia
If your patient is being sewn up, would you give a 10 mg bolus of morphine or give it in increments? Why?
Increments -
A bolus will displace a lot of histamine, especially if they are predisposed to it.
Giving the morphine in increments will allow you to have better control of BP and reduce the risk of a large histamine release causing hypotension. Also you will have a happy patient and a happy PACU nurse.
You accidentally give your patient a large bolus of morphine while they are stitching him up towards the end of the case. You notice your patient is now bradycardic and hypotensive, what drugs would you want to give and in what order?
To counteract the bradycardia from narcotics you first give atropine;
If atropine doesn’t work then you can give them Epi, just a smaller dose. You can dilute the 1 mg dose in a 10 or 20 mL syringe and give it 1 cc at a time!
Vasopressin (40 units) would be up next - Same thing, dilute it with 10 mL and give it 0.5 to 1 cc at a time. Depending on how bad the hypotension is!
What are the side effects of opioids with ventilation?
Decreased responsiveness of ventilation centers to CO2!
- Increase in resting PaCO2 (Shift to the right)! End tidal will need to be higher than 35-45 [~50] for the patient to start breathing!
- Going up to 60 PaCO2 will cause CO2 narcosis and the patient will be in a deeper sleep and be harder to wake up!
- Effects on mu2 receptors will cause a change in rhythm (decreased rate with compensatory increase in tidal volume), pauses, & periodic breathing!
What are signs of opioid overdose?
Apnea, Miosis, Hypoventilation & Coma
How does Physostigmine help a patient that is overdosed with opioids during a case?
It increases CNS levels of Acetylcholine (Ach) which antagonizes ventilatory depression but not analgesia! You give it in increments.
If you overdose a patient with a volatile anesthetic, how can giving a narcotic be beneficial?
Volatile anesthetics cause fast and shallow breaths. Narcotics decrease rate with compensatory increase in tidal volume.
The increase in tidal volume can help blow out volatile anesthetics.
What two drugs presented in class cause cough suppression and do not provoke the cough reflex?
Codeine (Opioid)
Dextromethorphan: no analgesia (It is a non-opioid derivative of morphine)
What should you be concerned with when giving a pre-induction dose of narcotics?
Reflex coughing
(Make sure you have your suction! You do not have to get ready if you stay ready!)
What causes the elimination half-time of Morphine to be longer? And what organ dysfunction contributes to this?
Longer with morphine-3-glucuronide metabolites
Renal dysfunction
Does Morphine exhibit a greater analgesic potency and slower speed of offset more in women or men?
Women
Which 4 patient populations should we be more careful in administering Morphine due to its increased effects?
- women
- neonates
- elderly (due to decreased kidney function and protein levels)
- renal dysfunction patients
Prolonged depression of ventilation (>7 days) has been observed in patients with renal failure after the administration of what medication?
Morphine
Morphine causes hypoxic sensitivity decrease in women or men more?
Women - morphine decreases the slope of the ventilatory response to carbon dioxide in women, whereas in men there wa no significant effect
Meperidine (AKA pethidine) is an agonist at what 2 opioid receptors?
agonist at µ and κ opioid receptors
What are the 4 analogues of Meperidine?
Fentanyl
Sufentanil
Alfentanil
Remifentanil
What 2 drugs and groups is Meperidine structurally similar?
- Lidocaine: tertiary amine, ester group, & lipophilic phenyl group
- Atropine
Meperidine administered intrathecally blocks what electrolyte channels to a degree? AND due to this, is comparable with what medication?
- Sodium channels
- Lidocaine
Structurally, Meperidine is similar to WHAT medication causing antispasmodic effect on smooth muscle?
Atropine
Meperidine (AKA pethidine) was discovered in what year?
1939
Compared to Morphine, Meperidine is what fraction as potent?
1/10th as potent as morphine - making it a shorter acting opioid agonist than morphine
For Meperidine, what is the: Dose, Uses, Effects, Duration, Elimination half-time?
Dose: 12.5mg
Duration: 2-4 hrs
Uses: Intrathecal, IM for postop analgesia/ post-op shivering (κ receptors; potent agonist at α2 receptors)
Effects: cause sedation, euphoria, N/V, depression of ventilation.
E 1/2 time: 3-5 hrs (35hrs with renal failure)
For Meperidine, what is the: Hepatic 1st pass, Metabolism, Protein Bound %, Elimination?
- 80%
- 90% Hepatic –> into normeperidine (metabolite)
- 60% (elderly considerations)
- Renal elimination (urinary excretion)
In elimination for Meperidine, what can speed up this process?
acidic urine
In equianalgesic doses, does Meperidine produce equivalent sedation, euphoria, nausea, vomiting, and depression of ventilation as to Morphine?
Yes
WHAT medication is the only opioid considered adequate for surgery when administered intrathecally, owing to its ability to block WHAT type of electrolyte channels?
Meperidine
Sodium
Evidence for the role of κ receptors in the antishivering effects of Meperidine post-op, contributes to the failure of WHAT drugs ability to completely inhibit this effect?
Naloxone
Meperidine Toxicity can cause what effects?
delirium (confusion, hallucinations) myoclonus & seizures
What are the major side effects of Meperidine?
tachycardia & mydriasis with dry mouth, (-) inotropy, serotonin syndrome (MAOIs & TCAs), impaired ventilation, crosses placenta,
Withdrawal symptoms develop more rapidly than Morphine
(meperidine is not used in high doses because of significant negative cardiac inotropic effects plus due to its histamine release)
What are 2 other medications that have a greater effect than Meperidine for post-op shivering?
- Clonidine (also agonist at α2 receptors)
- Butorphanol (a κ receptor agonist-antagonist)
What is Meperidine’s active metabolite?
Normeperidine
Meperidine (in comparison to Morphine) is NOT useful in the treatment of what 3 conditions?
-diarrhea
-as a cough suppressant
-during a bronchoscopy (r/t its lack of antitussive activity)
Per Dr. Castillo, is it better to give more or less of Meperidine?
Less
Fentanyl is what range x more potent than morphine?
75-125 times more potent than morphine
In 1960’s what was Fentanyl’s trade name?
Sublimaze
How long is the Blood:Brain Effect-site Equilibration of Fentanyl? What’s its distribution qualities?
6.4 min
Potent, rapid onset, very lipid soluble (more lipid soluble than morphine)
What’s Fentanyl’s Lung first-pass %?
75%
(slide 32)
What’s Fentanyl’s metabolism?
Hepatic P450 enzymes (CYP3A)
What is Fentanyl’s principal metabolite?
Norfentanyl
How is Fentanyl excreted?
Kidneys
What is the volume of distribution (Vd) of Fentanyl?
Large
How quickly is Fentanyl eliminated after IV administration?
IV (<5 mins 80% is gone)
(slide 78)
What are the side effects of Remifentanil?
- Seizure like activity,
- N/V,
- depression of ventilation,
- decreased BP and HR,
- hyperalgesia due to previous acute exposure to large opioid doses and tolerance (due to mu1 receptors)
How does Hydromorphone compare to morphine in terms of potency and hydrophilicity?
5X more potent and less hydrophilic
(less hydrophilicity leads to faster onset of analgesia) (slide 80)
What is the dosage for Hydromorphone?
0.5mg IV up to 1 - 4 mgs total. Re-dose q4hrs.
What are the uses and side effects of Hydromorphone?
Similar to morphine but no histamine release and has active metabolite. It evokes more sedation and less euphoria than morphine.
How is codeine administered?
PO or IM but no IV
What is the elimination half-time of codeine and where does metabolism occur?
3 to 3.5 hours elimination half-time and metabolism occurs in liver.
What is the dosage of codeine for cough suppressant and analgesia?
Cough suppressant: 15 mg, Analgesia: 60mg (120mg = 10 mg of morphine)
What are the side effects of codeine?
Physical dependence, minimal sedation, N/V, constipation, dizziness, and histamine induced hypotension.
What are the other opioids listed?
Oxymorphone, oxycodone, methadone, propoxyphene, tramadol, heroin.
(methadone is used in opioid withdrawal and chronic pain)
How does Tramadol compare to morphine in terms of potency?
What does tramadol interact with?
5-10x less potent than morphine
Coumadin
What are the receptor sites and dosages of Tramadol?
Receptor site: mu with weak k and delta, PO: 3mg/kg
Which opioid was said to have no addiction when it came out?
Heroin
(Great potential for dependency, less N/V, more rapid onset–> we do not use in clinical practice)
Which pharmacokinetic category best describes onset of action?
A. effect site equillibration
B. Protein binding
C. Elimination half time
D. pK
A. Effect site equilibration
Fentanyl has effect-site equilibrium time of 6.8 min and remifentanil has effect site equilibrium of 1.1, which opioid has a quick onset and offset?
Remifentanil is quick on and quick off.
What is considered the mainstay of modern perioperative care and pain management?
Opiates
What movie popularized the poppy plant?
Wizard of Oz
What is the Greek definition of ‘Narcotic’?
Stupor; which has the potential to produce physical dependence
What are opioids?
ALL Exogenous substances
Should you be concerned about withdrawal symptoms if a patient last used heroin 6 hours ago?
Yes! The onset of withdrawal for heroin can start 6 hrs from last dose.
What are the opioid agonists from Table 7-1?
Morphine; Morphine-6-glucuronide; Merperidine; Sufentanil; Fentanyl; Alfentanil; Remifentanil; Codeine; Hydromorphone; Oxymorphone; Oxycodone; Hydrocodone; Propoxyphene; Methadone; Tramadol; Heroin
Is it possible for a patient to start withdrawing from fentanyl 2 hours after last dose?
Yes! The onset of fentanyl withdrawal is 2 - 6 hrs (same for meperidine)
Which medications are included in Phenanthrenes?
Thebaine, Codeine, and Morphine
What effect do higher doses of intra-op opioids have on post-op pain?
Higher doses of intra-op opioids cause greater post-op pain.
What is the gold standard of opioids?
Morphine.
What are the effects of morphine?
Analgesia, euphoria, sedation, diminished ability to concentrate, nausea, feeling of body warmth, heaviness of extremities, dryness of mouth, pruritis.
Is morphine better for treating dull pain or sharp pain?
What other types of pain is morphine ideal for?
Morphine is better for treating dull pain.
Can also treat visceral, skeletal muscle, joint, integumental, and intermittent pain
What are the peak times, dose, onset, and duration for Morphine IV vs IM?
Morphine IV and IM have the same dose, onset and duration
- Dose: 1 - 10 mg,
- Onset: 10 - 20 min,
- Duration: 4 - 5 hrs.
- IV Peak: 15 - 30 min,
- IM Peak: 45 - 90 min.
What is Papaverine used for?
Direct vasodilator
This drug is the response drug given in the event of sodium thiopental, aka pentathol, accidentally injected into artery
Papaverine
What is the bioavailability of oral morphine?
Bioavailability = 75%.
25% is metabolized in the liver on first pass.
How is morphine metabolized?
Conjugation with glucuronic acid in hepatic and extrahepatic sites.
What are the two metabolites of morphine, and which is active and inactive?
Morphine 3 glucuronide = inactive metabolite,
Morphine 6 glucuronide = active metabolite, can contribute to respiratory depression.
What effect occurs when morphine is given to a patient in renal failure?
Prolonged respiratory depressive effects.
What 3 centers in the brain are opioid receptors located?
These brain centers are originations of what type of pathway?
Thalamus, Periaqueductal gray, Locus coeruleus
Descending inhibitory
Mu receptors are responsible for including but not limited to:
analgesia, euphoria, sedation, respiratory depression, decreased peristalsis in the gut –> constipation
Delta receptors in the brain may have ______________ effect and are also located in the ___ and cause decreased __ secretions
hallucinogenic; gut; gastrointestinal
Kappa receptors mediate _________ by reducing ________ release
dysphoria; dopamine
Pain signals are transmitted from the periphery to the CNS by way of light myelinated _-_____ fibers and/or non-myelinated _ fibers which make up the _______ neuron in the __________ __________ of the spinal cord. The _______ neuron synapses with a _________ neuron that carries the pain signal to the brain.
A-delta; C; primary; substantia gelatinosa; primary; secondary
Activation of ____’s by _______ in the membrane of the axon terminal cause closure of __++ channels leading to ____ release of excitatory neurotransmitters like Substance P and Glutamate from the axon of the ________ neuron.
GPCR’s; opioids; Ca; less; primary
Decreased release of excitatory neurotransmitters from the primary neuron (r/t opioids) leads to what effects?
reduction in release of excitatory NT’s –> less excitation of secondary neuron; hyperpolarization and a decrease in the AP frequency –> decreasing pain signals sent to the brain
opioids bind to opioid __ receptors in the membrane of the _________ (aka cell body) of secondary neurons and cause _______ of _+ channels causing hyperpolarization of the secondary neuron, which decreases pain AP frequency causing ____ pain signals to be sent to the brain.
Mu; dendrite; opening; K; less
Which of the following is NOT an opioid receptor?
A. Mu
B. Sigma
C. Delta
D. Kappa
B. Sigma
Which of the following locations for opioid receptors is NOT in the brain?
A. Periaqueductal gray
B. Locus coeruleus
C. Substantia gelatinosa
C - (it’s in the spinal cord)
Which of the following is NOT a therapeutic effect or side effect of opioids?
A. analgesia
B. diarrhea
C. respiratory depression
D. pupillary constriction
E. antidiuresis
B
Name the 3 “endogenous opioids” our body produces.
Enkephalins, Endorphins, and Dynorphines
*Presynaptic inhibition of ACh, dopamine, norepi, and substance P causes what?
- Increased K+ conductance (hyperpolarization);
- Ca++ channel inactivation;
- decreased neurotransmission;
- pain modulators or anti-nociceptive
Why is a combo of spinal LA with opioids beneficial?
Spinal LA STOPS neurotransmission up to the duration of the LA, while Opioids only decrease neurotransmission
What is the analgesia dose and the induction dose of Sufentanil?
Analgesia: 0.1 - 0.4 mcg/kg IV; Induction: 18.9 mcg/kg IV
Alfentanil is _________ potent than fentanyl and the onset is _______ than Fentanyl and Sufentanil.
1/5th less; 1.4 minutes; less
Alfentanil doses for:
Induction laryngoscopy:
Induction alone:
Maintenance:
Induction laryngoscopy: 15 - 30mcg/kg IV; Induction alone: 150 - 300mcg/kg IV; Maintenance: 25 - 150 mcg/kg/hour IV with inhaled anesthetics
What is different about Remifentanil? (think propofol, etomidate, Succ)
It is hydrolyzed by nonspecific plasma and tissue esterases due to its ester structure. Rapid onset and offset; Lack of accumulation
Is Remifentanil dosed with ABW or IBW?
IBW
Remifentanil:
Peak Effect:
Clearance:
Plasma Steady State:
Elimination 1/2 time:
Peak Effect: 1.1 minutes;
Clearance: 3L/min;
Plasma Steady State: @ 10 minutes; Elimination 1/2 time: 6.3 minutes
Remifentanil
Clinical doses:
Induction:
Maintenance:
Induction: 0.5 - 1mcg/kg IV over 30-60 seconds;
Maintenance: 0.25 - 1mcg/kg IV or 0.005 - 2mcg/kg/min IV
What is important to remember when stopping a dose of Remifentanil?
Very short action so we need to give a longer acting pain medication before stopping to keep our patients pain under control.
You’re pre-op evaluating a pt and prepping your care plan. Your pt admits to significant use of opioid abuse. What are some alternative pain management therapies mentioned by Castillo?
ERAS (Enhanced Recovery After Surgery) multimodal analgesia; effort to avoid opioids as much as possible
