Opioids from this lecture Flashcards
1
Q
Opioids are unique in producing analgesia without….
A
loss of touch, proprioception or consciousness
2
Q
Two classes of opioids
A
- Phenanthrene
- Benzylisoquinoline
3
Q
Structure of phenanthrene opioids
A
- 3 rings of 14 carbon atoms
- 4th ring is a piperidine ring with a tertiary amine nitrogen that is highly ionized at physiologic pH (7.4)
4
Q
Phenylpiperidine derrivitives
A
- Fentanyl
- Meperidine
5
Q
Major pharmacologic differences between fentanyl, alfenanyl, sufentanyl and remifentanyl are their…
A
- Differences in potency
- Differences in rate of equilibriation between the plasma and the site of drug effect (biophase)
6
Q
Opioids Postsynaptic MOA
A
- increase K conductance (hyperpolarization)
-
Ca++ channel inactivation (decreases NT release)
- Substance P
- Modulation of phosphinositide- signaling cascade for phospholipase C
- Inhabition of adenlyate cyclase (decrese cAMP)
7
Q
Opioids Presynamptic MOA
A
- inhibits the release of excitatory neurotransmitters
- ACh
- Dopamine
- Norepi
- Substance P
8
Q
Mu-1 receptor activation causes
A
- euphoria
- miosis pupil constriction
- Bradycardia
- Urinary retention
- hypothermia- impairment of thermal regulation
9
Q
Mu-2 receptor activation causes
A
- Most of the bad effects
- Hypoventilation
- physical dependence
- constipation
10
Q
Kappa receptor activation effects
A
- Dysphoria
- sedation
- Miosis- pupillary constriction
- Diuresis
11
Q
Where are opioid receptors in the brain and spinal cord?
A
-
Brain
- periaquaductal grey
- amygdala
- corpus striatum
- hypothalamus
-
Spinal Cord
- substantia geletinosa
12
Q
How do endorphins work?
A
they inhibit the release of excitatory neurotransmitters (substance P, Bradykinin) from nerve terminals of nerve carrying nociceptive impulses (afferent - A-delta and C fibers)
13
Q
Neuroaxial opioids in contrast to Local anesthetics
A
- Are NOT associated with SNS denervation (sympathectomy)
- Are NOT associated with skeletal muscle weakness
- Do NOT cause a loss pf proprioception
14
Q
What is the difference in dosages of the epidural and subarachnoid dose?
A
Epidural dose is 5-10x higher than subarachnoid
15
Q
Lipophilic an non-lipophilic neuroaxial anesthetics
A
- Lipophilic = fentanyl and sufentanyl
- Non-lipophilic = morphine = (water soluble)
- Fentanyl and sufentanyl will have a much faster onset than morphine.
- Morphine however will have a longer duration of action than the lipophilic fentanyl and sufentanyl
16
Q
Time to peak CSF concentration of epidural opioids
A
Lipid soluble = FAST
- Fentanyl = 20 minutes
- Sufentanil = 6 minutes
H2O Soluble = SLOW
- Morphine = 1-4 hours
- Only 3% of epidural morphince crosses to CSF
17
Q
Time to peak BLOOD concentrations of epidural opioids
A
Lipid soluble = FAST
- Fentanyl = 5-10 minutes
- Sufentanil = even faster
H2O Soluble = SLOW
- Morphine = 10-15 minutes
18
Q
Epinephrine in Epidural space
A
- decreases the rate of systemic absorbtion, but has NO EFFECT on the diffusion of the opioid into the CSF.
- Facilitates CSF absorbtion over systemic absorbtion
19
Q
What primarily influences cephalad movement of neuroaxial opioids and why?
A
- Lipid solubility
- More lipid soulble agents are less likely to have cephelad movement d/t rapid uptake by the spinal cord (Fentanyl,Sufentanil)
- Water soluble agents however remain in the CSF and are subject to bulk flow migration of CSF prior to uptake (Morphine)
20
Q
What are the four classic side effects of neuroaxial opioids?
A
-
Pruritis (MOST common)
- more likely in obstetric patients
- N/V
-
urinary retention
- young males
-
depression of ventilation
- (delayed 6-12 hours with morphine)
These side effects like all opioids are dose dependent
21
Q
Which has the highest risk for respiratory depression IV, IM or Neuroaxial opioids?
A
They all posess equal risk of respiratory depression
22
Q
Explain early and late depression of neuraxial administration of opioids
A
-
Early = <2 hours usually involves fentanyl and sufentanil
- likely from systemic absorbtion of opioid
- Possibly CSF migration
-
Late = >2 hours usually involves morphine
- Likely from CSF migration
- Usually 6-12 hours after administration
23
Q
What may speed the cephelad migration of CSF and increase the likelyhood of late onset respiratory depression?
A
Coughing
24
Q
What population is at less likely to have neuroaxial opioid respiratory depression?
A
Obstetrics- likely form the interaction of estrogen with with opioid receptors
25
Opioids with active metabolites
1. Morphine - **morpine-6-glucuronide** - greater potency than morphine
2. Meperidiene (demorol) - **normeperedine** - causes seizures
26
Metabolism of morphine
Hepatic an extrahepatic
1. Conjugation with glucuronic acid in both sites
2. Kidneys can actually compensate for cirrhosis, or during liver trasplantation (time without the liver)
3. Avoid in renal failure
4. Prolonged DOA with MAOIs
27
How mych morphine will gain access to the CNS? Why?
1. **\<0.1%** of the dose given
2. Reasons for poor penetration:
1. Poor lipid solubility
2. High amt of ionization at physiologic pH (**77%**)
3. Protein binding (**35%**)
4. Rapid conjugation with glucuronic acid
28
Morphine and alkalinizaton of blood
1. Increased non ionized fraction of morphine and increase passage to CNS
2. Morphines pKA = **7.9**
3. **Alkalosis** **increasese** the **non-ionized** percentage of morphine
29
Mechanism of opioid induced bradycardia
1. **direct** stimualtion of the **vagal** **nerve** in the **medulla**
2. **Direct** **depressant** effect on **SA node** that slows conduction of impulses through the AV node
3. Note: these mechanisma also reflect decreased vulnerability to v-fib in the presence of opioids
30
Hypotension caused by morphine and demerol is likely due to \_\_\_\_\_\_\_\_\_\_.
Histamine release
31
Clinical significance of using opioids and N2O together
1. the combination can result in cadiovascular depression which does not occur with each drug administerd alone (**synergistic effect**)
2. Skeletal muscle rigidity can be enhanced??
32
Dose-dependend depression of respiration is due to the __________ effect at ____________ receptors leding to a direct depressant effect on the \_\_\_\_\_\_\_\_\_\_.
* agoinist
* Mu2
* brainstem ventalatory centers
33
Ventilatory effects of low and high dose opioids.
1. **Low dose** = decreased RR and **increased** TV
2. **High dose** = decreased RR and decrease TV
34
Opioid induced respiratory depression is characterized by two things + one from the notes
1. Decreased responsiveness of the ventalation center on carbon dioxide reflected by an increased resting PaCO2
2. CO2 Dose resonese cuve is shifted sown and to the right (meaning it takes a higher CO2 to initiate breathing)
3. decreased HYPOXIC ventilatory drive
35
Respiratory depression with fentanyl compared to morphine
1. Respiratory depression will be immediate with fentanyl while it will take 10-15 miniutes for morphine
2. the respiratory depression from morphine will last longer d/t longer DOA
36
Opioid administration with increased ICP
**MAKE SURE** ventilations are controlled - increased CO2 caused by hypoventilation increases CBF and therefore ICP (opioids alone SLIGHTLY decrease ICP)
37
Explain the geeralizer hypertonus of skeletal muscles (ridgidity) with opioid administration
1. Thoracic and **abdominal rigidity** that is suffiecient to interfere with ventilation
2. Increased airway pressures result in a **decreased venous return**
3. there is a **closure of vocal cords** releved with NMB (SChs 20-40 mg)
4. Incidence depends on:
* the opioid
* the dose
* and the rate of administration
5. Most common with fentanyl and sufentanyl
6. Proposed mechanisms include
7. Inhibition of GABA and icreased dopamine production
8.
38
How is **miosis** from opioids produced?
1. excitatory action of opioids on the **etinger** **westfall** **nucleus** of the Occulomotor nerve (CN III)
2. Tolerance to this does not occur
3. Miosis can be antagonized by **atropine**
39
1. What is the dose of glucagon to reverse Sphincter of Oddi Spasm?
2. What other drugs releive it?
3. What drug is most likely to cause it?
1. 2mg IV glucagon
2. Also reversed by narcan and NTG
3. Fentanyl (99%) is the most likely then morphine (59%) - with equipotent doses
40
Opioids can increases preistaltic activity an tone of the ureters, they can also increase the tone and billiary tree pressure with the contraction of the gall bladder. What is the difference in the treatment of both?
The perestaltic activity and increased tone of the ureters can be reversed byy atropin while the sphincterof oddi spasm and increased billiar pressure cannont, it needs to be treated with glucagon, NTG.
Narcan will reverse both???
41
Atropine and physostigmine effects on opioid analgesia
Atropine antagonizes analgesia while physostigmine enhances analgesia
42
Two effects of opioids that are NOT susseptable to tolerance
Meiosis and Constipation (reduced bowel motility)
43
In the opioids class of drugs which ones can cause phisical dependence and whic ones do not?
Agonists cause dependance. Antagonists and agonist/antagonists are not associated with dependence
44
Opioid Tolerance
1. Tolerance can occur without physical dependence (but not the other way)
2. Can develop in 48 hours
3. Tolerance develops to all effects except constipation and meiosis
45
Opioid withdrwal timeline
1. Initailly, yawning, diaphoresis, acrimation and coryza (stuffy nose)
2. Insomnia and restlessness
3. cramps, N/V, diarrhea reach their peak in 72 hours and decline over the next 7-10 days
4. tolerance is rapidly lost and these symptoms can be treated with a very small dose of opioids- the farther out, the smaller the dose
46
Two proposed mechanisms of opioid tolerance
1. tolerance is a result of **opioid receptor desensitization and down regulation** of opioid receptors
2. **there is an up-regulation of cAMP system**
* opioids acutely inhibit cAMP pathways by blocking adenlylyl cyclace
* upregulation has ben demonstrated in the locus ceruleus
* this is demonstrated in that opioid withdrawl can be treated with clonidine a centrally acting alpha-2 agonist that decreases cAMP production and at the brainstem can cause analgesia and sedation
47
what is thought to be the mechanism of long term tolerance of opioids?
1. Opioid insensitivity form nomths to yeas
2. NMDA receptors are activated by prolonged exposure to opioids via second messanges which also down-regulates spinal glutamate transporters. High amtsof glutamate and NMDA activation contributes to abnormal pain sensitivity and opioid tolerence
48
Meperidine (demerol to morphine)
1/10th as potent as morphine, 80-100mg = 10 mg morphine
Meperidine (demerol to morphine)
49
DOA = 2-4 hours
meperidine
50
Urine acidification increases renal excretion
If urinary pH is \<5 as musch as 25% of this drug is excreted unchanged
Meperidine
51
How long can normeperedine be detected in the urine?
3 days
52
1. Increased tolerance ot opioids by alcolholics is reflected as \_\_\_\_\_\_\_\_\_\_
2. Having to reduce the dose of opioids is a result of \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_.
1. Increased volume of distribution
2. Decreased protein binding
53
Principal uses of Meperidine
1. OB
2. after surgery for pain
3. interthecally durring surgery
54
Three mechanisms that decrease shivering with Meperedine
1. mediated at kappa receptor
2. decreased shivering threshold
3. alph 2 receptor agonist
55
Three cardiac effects of meperidine that are different form other opioids
1. Negative ionotropic effect
2. Histamine release - decreased SVR
3. atropine like structure = increased HR
56
May induce serotonin syndrome with MAOI's and fluoxetine
Meparidine (demerol)
57
Which opioid causes mydriasis?
**Meperedine** - due to its **atropine** like structure
58
Pharmakoinetics of fentanyl
1. effect site equilbration time = **6.8 minutes**
2. **high lipid solubility** = higher **potency** and **rapid** **onset** of action
3. **75%** initial dose unergoes first pass **pumonary** **uptake** (inactive resevoir)
59
Continuous infusion of fentanyl causes \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_. As a result the plasma concentration of fentanyl does not decrease rapidly and the durtation of anealgesia and _____________ may be prolonged.
1. Progressive saturation of inactive tissues
2. ventilatory supression
60
Why does fentanyl have a shrt DOA and an E1/2 longer than morphine?
The short DOA is due to lipid solubillity, however, its E1/2 is longer due to a larger volume of distribution and uptake into inactive tissues. Plasma concentration is maintained from an infusion because fentanyl goes from the inactive tissues to the plasma to maintain the palsma concentration.
61
Explain the **prolonged E1/2** time with fentanyl in the elderly.
It is related to the **decreased clearance** of the opioid. Vd is unchanged in the elderly. Decreased clearance reflects **dereased hepatic blood flow,** **decreased hepatic enzyme activity and decreased protein binding** (fentanyl is highly protien bound - **84%**)
62
Explain the **context sensitive half time** for fentanyl
1. As the duration of a continuous infusion increases **\>2hours** the context sensitive half time of fentanyl becomes \> than sufentanil.
2. it is due to the **saturation of inactive tissues** with prolonged infusion and the return of fentanyl from the peripheral compartment to the plasma
3. this **slows the rate of decrease in plasma concentration** of fentanyl (do to fentanyl only being hepatic metabolism and as it is metabloized it tis replaced from the inactive reservoir)
4. After a **four hour infusion** the context sensitive half time of fentanyl is **260 minutes**
63
When giving fentanyl to blunt surgical stimulation what needs to be consitered?
* the **equilibration time at the effect site**.
* **Fentanyl** it is **6.8 minutes** while for **alfentanil** (**1.4 min**) so alfentanil it may be given closer to the time of the stimulation.
* **sufentanil** (**6.2 min**) is very close to fentanyl
64
What is a possible explaination for the **secondary peak** of fentanyl
**washout** of **opioid** from the **lungs** as ventilation and perfusion ralationshipps are re-established in the postopertive period
65
These opioids may actually **increase** **ICP**. What is the presumed mechanism?
1. **Fentanyl** and **Sufentanyl**
2. If MAP is not maintained there may be **autoregulatory** **vasodilation** to compensate for **hypotension** which **increases ICP**
66
Analgesic conentrations of fentany greatly potentiate the effects of _\_\_\_\_\_\_\_\_\_\_\_\__and decreased the dose requrements for _\_\_\_\_\_\_\_\_\_\_\_\__
**midazolam** (synergism)
## Footnote
**propofol**
67
Sufentanil potency
**10x fentanyl** and **1000x** morphine which parralles sufentanil's **greater affinity for opioid receptors** compared to fentanyl
68
Volume of distribution of sufentanyl compared to fentanyl
Sufentanyl has a lower Vd (only 123L)due to its increased amount of protein binding (92%) compared to that of fentanyl (Vd = **335L;** PB = **84%**)
69
Sufentanyl context sensitive halftime. Why is it unique?
1. Context sensitive halftime is **30 minutes**
2. It is unique because of its high **protein binding and small volume of distribution** - after the gtt is turned off, the drug will continue to **redistribute** into the **tissue reservoir** and be **metabolized** making the plasma concentration continue to go **down.**
70
Compared to large doses of ____________ or \_\_\_\_\_\_\_\_\_\_\_\_\_, _____________ produces more rapid induction of anesthesa, earlier emergence and earlier tracheal extubation.
1. Morphine
2. Fentanyl
3. **Sufentanil**
71
Two drugs with a 2nd peak
Fentalnyl and Sufentanil
72
Alfentanyl is _________ as potent as fentanyl and DOA is \_\_\_\_\_\_\_\_\_\_\_.
* 1/5
* 1/3 shorter
73
Cirrhosis of the liver prolongs the **E1/2t** of this opioid and renal failure **does not** alter clearance or elimination
Alfentanil
74
How is the rapid effect site equilibration of Alfentanil explained?
1. Alfentanil has a LOW pKa (**6.5**) which accounts for **89% nonionized** in the plasma
2. Non-ionized protion readily crosses the BBB
3. It has a **rapid equilibration at the effect site** of only **1.4 minutes**.
75
Why does **alfentanyl** have a **faster onset than fentanyl** when it is highly protein bound (**89%** compared to **8.5%**) and has a lower lipid solubility and its **6x** smaller Vd (**27L** compared to **335L**)?
Because **Alfentanil** has a **pK of 6.5** and is **89% non-ionized** in the plasma it can **readily cross the BBB** and equiliberate at the effect site in **1.4 minutes**!
76
How long does it take hepatic metabolism to clear **95%** of Alfentanyl?
**60 minutes** - this is also its context sensitive half time
77
Alfentanyl **context sensitive half time**
* **60 minutes**
* it is longer than Sufentanyl for infusions lasting up to 8 hours
* because of alfentanils low Vd drug does not go into peripheral compartments, but rather it depends on metabolism for elimination
78
Opioid to be avoided in Parkinsons disease
**Alfentinil** - have been cases of **dytonia** possibly due to the decrease in central dopaminergic transmission
79
Distinguishing feature of remifentanil and its effect on the drug
1. **Ester linkage**
2. **rapid hydrolysis** by nonspecific tissue and plasma esterases
3. **very fast on and very fast off** (must be on a pump)
4. Effect site equilibration **= 1.1 min**
80
Drug that is the best to use in a case where a patient needs to wake up fast (neuro, outpatient) and is rapidly titratable to effect
Remifentanil
81
1. Pharmacokinetics characterized by low interindividual variability, rapid clearance and a small Vd
2. What does this mean for the drug?
1. Remifentinil
2. Clearence = 4000 mL/min
3. Vd = 30L
4. Because of the high clearence and low Vd remifentanil will accumulate much LESS than other opioids and will have predictable termination of drug effect.
82
Dosing should be based on Lean body mass
Remifentanil
83
**Context sensitive half time** of remifentanil
**4 minutes** - it is **INDEPENDENT** of the length of the infusion d/t its rapid metabolism
84
How long does it take remifentinil to reach steady state in the plasma?
1. **10 minutes** - d/t rapid effect site equilibration
2. Also important to note that infusion changes will paralleled prompt effect of the drug
85
Does a **cholinesterase deficiency** or adminitration **anticholinergics** effect the metabolism of **remifentanil**
**NO** - it is metabolized by NONSPECIFIC tissue and plasma cholinesterases
86
Drug with rapid elimination and redistribution
**Derrivitive** of morphine that is **5x** more potent with a slightly **shorter DOA**- dosed q4 hours
Dilaudid (**Hydromorphone**)
87
Hydromorphone effects compared to morphine (receptor effects)
Hydromorphone has more sedation and less euphoria than morphine
88
Equal analgesic to morphine, works at the kappa and sigma receptors
Nalbuphine (nubain)
89
Due to the kappa receptor stimualtion agonits/antagonist may cause \_\_\_\_\_\_\_\_\_\_
dysphoria
90
Where do agonist/antagonist opioids work?
1. they are either agonists, or parial agonists and the **mu** receptors
2. are partial agonists at **kappa** receptors
91
Why may we use agonist/antagonist drugs?
1. analgesia with limited ventalatory depression
2. low probability of dependence
92
1. antagonizes opioid induced respiratory depression while maintianing analgesic effect
2. Reverses sphincter of oddi spasm
Nalbuphine (Nubain)
93
1. acts as an agonist at **kappa** and a weak antagonist/parial agonist at **mu** receeptors
2. comes in a **nasal spray** for migranes
1. **5x** more potent than morphine
Butorphanol (Stadol)
94
1. Pure opioid antagonist
2. Compeditive antagonist equally at mu, kappa and delta
Naloxone (Narcan)
95
Onset and DOA of Naloxone
1. Onset = **1-2** minutes (titrate)
2. DOA = shorter than most agonists and may ened to redose
96
Naloxone sie effects
1. Tachycardia, HTN, vetricular dysrhythmias
2. severe pain
3. **pulmonary edema** ****in people with severe CV disease d/t **vasoconstriction**
4. **pulmonary edema** in healthy patients due to catecholamaine release **and** vasoconstriction
97
Location of pain modulating systmes
1. periaquaductal gray
2. hypothalamus
3. substantia gelatinosa
98
Opioids act at both _____ and _______ sites
Pre and Post synaptic
99
Binding at the Opioid receptor causes
1. \_\_\_\_\_\_\_\_\_\_
2. \_\_\_\_\_\_\_\_\_\_
3. \_\_\_\_\_\_\_\_\_\_
4. \_\_\_\_\_\_\_\_\_\_
1. **decreased** neurotransmission
2. increased K conductance (**hyperpolarization**)
3. Ca++ channel **inactivation**- to a certain degree
4. **Immediate** decrease in neurotransmitter release
100
Opioid prototype
Morphine
101
Fentanyl Potency
100x morphine
102
Sufentanyl potency
1000x Morphine
103
Opioids ar cardiac stable and will not effect \_\_\_\_\_\_\_
SVR
104
Opioids and versed
Have a synergistic effect
