SS25 Opioids Agonists (Exam 2) Flashcards
(118 cards)
1
Q
What are opioids effects on the CO₂ medullary center?
A
- Opioids inhibit the CO₂ medullary center.
2
Q
Differentiate opioids from narcotics.
A
- Opioids = all exogenous substances that bind to endogenous opioid receptors.
- Narcotic = any substance that can produce dependence (stupor)
3
Q
What two types of opioid chemical structures are there?
A
- Phenanthrenes
- Benzylisoquinolines
4
Q
What types of drugs are Phenanthrenes?
What types of drugs are benzylisoquinolines?
A
- Phenanthrenes: Morphine, Codeine, Thebaine
- Benzylisoquinoline: Papaverine, Noscapine
5
Q
What is papaverine mostly used for?
A
Vasodilator; Treating intra-arterial barbiturate administration (dilates the highly constricted artery)
6
Q
What portions of the brain are the source of descending inhibitory signals?
A
- Thalamus
- PAG
- Locus Coeruleus
- Opioid receptors are located here
7
Q
What endogenous substances have the same effect as opioids?
A
Endorphins, Enkephalins, and Dynorphines.
8
Q
Presynaptic inhibition of what neurotransmitters occurs with opioid administration?
A
- ACh
- Dopamine
- NE
- Substance P
9
Q
How do opioids modulate pain at the cellular level?
A
- ↑plasma K⁺ conductance (hyperpolarization)
- Ca⁺⁺ channel inactivation (decreased neurotransmission)
10
Q
Where are opioid receptors located in the brain?
A
- Periaqueductal Gray (PAG)
- Locus Ceruleus
- Rostral Ventral Medulla (RVM)
- Hypothalamus
11
Q
Where is the primary site of opioid receptors in the spinal cord?
A
- Substantia gelatinosa (Lamina II)
- Slow afferent C-fibers
12
Q
Where is/are opioid receptors found outside the CNS?
A
- Sensory neurons & immune cells
- Ex: Intraarticular Morphine after joint sx (make sure not injected intravascularly)
13
Q
What are the four (most important) types of opioid receptors?
A
- Μu1 (μ₁)
- Μu2 (μ₂)
- Κappa (κ)
- Delta (δ)
14
Q
Which opioid receptor(s) is/are responsible for respiratory depression & physical dependence?
A
- Μu2 and δ
15
Q
Which receptors are responsible for constipation?
A
- Μu2 primarily
- δ (minimal)
16
Q
Which receptors can cause urinary retention?
Are there any receptors that cause diuresis when bound?
A
- Retention: Μu1 and δ
- Diuresis: κ
17
Q
All opioid receptors induce analgesia at both the brain and the spinal cord. T/F?
A
- False. Μu2 receptors only cause at analgesia at the spinal cord level.
18
Q
What opioid receptors have low abuse potential when bound?
A
Μu1 and κ
19
Q
Which opioid receptor is responsible for analgesia, euphoria, bradycardia, hypothermia, urinary retention, miosis and has low abuse potential when bound?
A
Mu1
20
Q
Which opioid receptors cause miosis?
A
- mu1
- k
21
Q
which opioid receptor(s) cause sedation and dysphoria?
A
- k
22
Q
What agonists bind to the four opioid receptors?
A
- Mu1 & Mu2 = endorphins, morphine, & synthetics.
- κ = dynorphins.
- δ = enkephalins.
23
Q
Which opioid receptors can cause physical dependance?
A
- mu2
- delta
24
Q
Describe the adverse side effects of opioids on the cardiovascular system.
A
- ↓SNS tone = ↓ VR, CO, BP (csn lead to orthostatic hypotension and sycope)
- ↓HR + histamine release = ↓BP
Initiate @ low doses and maintain BP within 20% of baseline. (ie: SBP 156: 20% ~ 30 mmHG up/down)
25
What possible cardiovascular benefits do opioids provide?
- Myocardial ischemia protection (won't cause myocardial depression)
26
What are the respiratory effects of opioids?
What would symptoms of overdose be?
- Decreased response of ventilation centers to CO₂ = ↑ resting PaCO₂ (shift **Right**)
- ventilation depression (mu2 & δ): ↓RR and compensatory ↑ in tidal volme
- Overdose = **APNEA**: miosis, hypoventilation, coma.
- Cough suppression: Codeine, Dextromethorphan (no analgesic effect)
27
What drug would treat opioid ventilatory depression but **not** reverse analgesia?
How?
- **Physostigmine**
- **Increases CNS levels of Ach**
- Not pure antagonist so doesn't reverse analgesia
- Crosses BBB (low doses)
## Footnote
- Also used for benzo ODs
28
- What is normal PaO₂?
- What shift in PaO₂ would be seen with opiates?
- What shift in PaO₂ would be seen with metabolic acidosis?
- What shift in PaO₂ would be seen with general anesthesia?
- What shift in PaO₂ would be seen with sleep?
- Normal PaO₂ is 80 mmHg
- **Opiates**, **General anesthesia**, and **Sleep** = shift to **right**
- **Metabolic acidosis** = shift to **left**
29
Why should caution be used when administering opioids to head trauma patients?
- Opioids ↓CBF and possibly ICP
- wakefulness, miosis, increased PaCO2, BBB
30
What other CNS effects occur with opioid administration?
- Myoclonus with large doses
- Sedation (60% with titr for postop)
- Skeletal chest wall and abdominal muscle **rigidity**.
31
What makes opioid-induced skeletal rigidity worse?
How is it treated?
- Mechanical ventilation
- Treatment = **Muscle relaxants or Naloxone**
32
Opioid GI SE
**- Sphincter of Oddi Spasms**
-Delayed gastric emptying = **constipation**
**- N/V** d/t direct stimulation of CTZ, increased GI secretions, & Delayed gastric emptying
## Footnote
Contraindicated in ERCP/ MRCP
33
What are sphincter of Oddi spasms?
Which drugs can cause this?
- Biliary smooth muscle spasm
- **Fentanyl** (99%), Morphine (53%), and Meperidine (61%).
## Footnote
*I think maybe all opioids can cause this but these are the primary culprits*
34
What drugs should be used for ERCP cases?
- Non-opioids (multimodal approach w/ NSAIDs, gabapentin, etc.)
35
How are opioid-induced sphincter of Oddi spasm's treated?
- **Glucagon** ( 2mg IV max given incrementally) and causes no opioid antagonism.
- induces gastric emptying = decrease spams
Others:
- Naloxone 40 mcg IV
- Atropine 0.2 mg IV
- Nalbuphine 10 mg IV
- NTG 50 mcg IV
36
Other Opioid SE:
- GU
- Cutaneous (Integumentary)
- Placenta
- urinary urgency
- Histamine release = flushed face, neck, & upper chest
- Neonate depression/dependence (chronic)
37
How long does it take to develop tolerance to opioids?
What causes tolerance?
-Usually 2-3 weeks (morphine = 25 days)
- Downregulation
38
What is downregulation?
- Opioid receptors on cell wall gradually desensitize by reduced transcription --> **reduced opioid receptors**
- requires increase dosing
## Footnote
Cross-tolerance can occur between all opioids
39
Opioid WDL (withdrawal):
Initials symptoms?
72 hr symptoms?
- yawning, diaphoresis, lacrimation, coryza (rhinits), insomnia, restlessness
- 72 hrs: N/V/D, abd. cramps
40
What is the time course of **Meperidine** & **Fentanyl** WDL?
- Onset: 2 - 6 hrs
- Peak Intensity: 6-12 hrs
- Duration: 4 - 5 days
41
What is the time course of **Morphine** & **Heroin** WDL?
- Onset: 6 -18 hrs
- Peak Intensity: 36 - 72 hrs
- Duration: 7 - 10 days
42
What is the time course of **Methadone** WDL?
- Onset: 24 - 48 hrs
- Peak Intensity: 3 -21 days
- Duration: 6 -7 wks
43
What is the intraop & postop dosage of morphine?
IV/IM Onset?
When does it IV/IM peak?
How long does it last?
- IntraOp: 1 - 10 mg IV
- PostOp: 5 - 20 mg IV
- Onset: 10 - 20 mins
- Peak: IV: 15 - 30 mins; IM: 45 - 90 mins
- Duration: 4 - 5 hours
44
How is morphine metabolized?
- Glucoronic Acid Conjugation in hepatic and extrahepatic sites
45
What is the active metabolite of Morphine and its significance?
- **Morphine-6-glucuronide** = comprises only 5-25% of morphine metabolites but is an **active analgesic causing late resp depression** via mu receptors; x650-fold to Morphine
46
Interpret the data b/w morphine and it's active metabolite.
The ventilatory response to CO2 is impacted similarly by Morphine and Morphine-6-glucuronide
47
What is the inactive metabolite of Morphine and its significance?
- **Morphine-3-glucuronide** = comprises only 75-95% of morphine metabolites. **Prolonged E1/2 causing renal dysfunction**
48
What would occur with morphine overdose in a renal failure patient?
- Prolonged ventilatory depression.
49
What receptors does meperidine agonize?
- Synthetic opioid agonist at **μ and κ receptors**
- potent agonist at α2 receptors as well
50
What are the analogues of meperidine?
- Fentanyl
- Sufentanil
- Alfentanil
- Remifentanil
51
What other drugs does meperidine have a similar organic structure to?
- Lidocaine: Tertiary amine, ester, & lipophilic phenyl
- Atropine
52
What is the primary indication for meperidine?
- Post-operative shivering
53
What does shivering put you at risk for?
**MI**
- causes increased O2 consumption x500-fold, decreasing O2 supply to vital organs (ie: brain, kidney, etc)
54
Meperidine (Demerol):
Dose?
Onset?
Duration?
- Dose 12.5 mg IV
- Onset 5 -15 mins
- Duration: 2 - 4 hours
55
Meperidine:
Metabolism?
Active Metabolite?
Clinical significance?
Metabolism: 90% Hepatic
- Demethylation to **Normeperidine**
- 1/2 analgesic effects as Meperidine
- **Accumulation Normeperidine can lead to delirium and seizures**
- Hydrolysis Normeperidine to Meperidinic acid
56
Which patient population may have increased sensitivity to Meperidine and require lower doses?
- elderly
57
Which patient population may have increased tolerance to Meperidine?
- alcoholics
58
What is the E1/2 for Meperidine?
What if renal failure is present?
- 3 - 5 hrs
- 35 hrs
59
Prolonged use (> 3 days) can lead to ______ and _______.
seizures and delirium
(ie: PCA)
60
What organ eliminates Meperidine?
What can speed up elimination?
- Kidney (pH dependent elimination)
- Acidic urine
61
When should meperidine not be used?
- Bronchoscopy
- Coughing
- Diarrhea
62
- Side effects of Meperidine?
- Drug interactions with ___ & _____ can lead to ______ syndrome.
- **Tachycardia**, mydriasis with dry mouth, **decreased contractility**
- MAOIs & TCAs; Serotonin Syndrome
## Footnote
similar structure to atropine
63
What other drugs can be used to treat postop shivering?
- Clonidine (more effective than Meperidine)
- Metoprolol
- Physostigmine
64
How potent is fentanyl?
- 75 - 125 x morphine.
65
What is the blood-brain equilibration of fentanyl?
What does this mean?
- 6.4 minutes (quick)
- Rapid onset but lag b/w peak plasma and peak EEG slowing
- Greater potency and more rapid onset = ↑ lipid solubility than morphine and facilitates passage to BBB
66
How is the rapid onset of fentanyl related to redistribution?
- Rapid distribution into inactive tissues (ie: fat and skeletal muscles) = decrease plasma concentrations
of drug
67
What percent of fentanyl is subject to lung first-pass effect?
What does this mean?
- **75%**
- Drug is taken up into lung (reservoir) and gets retained, removed, cleared, and **metabolized**
- Lung uptake and **extraction** can occur removing endogenous substances via pulmonary arterial blood
68
Where is another organ that metabolizes fentanyl?
What is its principal metabolite?
- Liver via CYP4503A
- **Norfentanyl** via de-methylation
69
Is Fentanyl's Vd large or small?
Why?
- **Large Vd**
_ D/t high lipid solubility
IV bolus: < 5 mins = 80% gone (into high vascular tissue
70
How does fentanyl dosing change for the elderly or liver patients?
- Prolonged E1/2 in elderly and cirrhotic liver patients however **No change in elderly or cirrhotic patients** per book
## Footnote
Per Castillo, recommends lower dosing
71
Describe what the graph below is showing.
- Fentanyl has the greatest context-sensitive half-time of any of the fentanyl derivatives (ie: **sufentanil**)
- This reflects saturation of inactive tissue sites with fentanyl during prolonged infusions & return of the opiod from periphery to plasma
72
Fentanyl:
Analgesia dosage?
IntraOp dose?
Onset?
Duration?
- Analgesia: 1 - 2 μg/kg IV
- Induction/IntraOp: 1.5 - 3 μg/kg IV 5 mins prior
- Onset: 30- 60 sec
- Duration: 1 - 1.5 hr
73
Fentanyl Dosage for **adjunct use with inhaled anesthetics**?
- What are two examples of adjunct use?
- **2 - 20 mcg/kg IV**
- Direct laryngoscope intubation
- Sudden change in surgical stimulation level
74
What is the **intrathecal dosage** of fentanyl?
- Can it be used adjunctly with Local A?
- 25 mcg
- Yes (ie: Bupivacaine or Lido)
75
What is the adult **transmucosal (oral)** dose of fentanyl?
- Adult: 5 - 20 mcg/kg PO lozenge
76
Fentanyl: surgical anesthesia (solo) dose?
- 50 - 150 mcg/kg IV
77
- What is the pediatric (2 - 8 y/o) transmucosal (oral) dose of fentanyl?
- What is the oral pediatric form?
- Peds: **15 - 20 mcg/kg PO 45 mins prior**
- Rapid dissolving film or lozenge
78
1 **mg** of PO fentanyl = ____ mg of IV morphine
5 **mg** of IV Morphine
79
What is the adult transdermal dose of fentanyl?
- 75 - 100 μg
- steady state = 18 hrs
80
Fentanyl SE:
- CV?
-CNS?
- CV: **↓BP & ↓CO** (esp. neonates); No significant bradycardia (**NO histamine release**)
- CNS: seizures (**SSEP & EEG > 30 μg /kg IV**) & modest **increase ICP** (**6 - 9 mmHg**)
81
Explain graph:
Similar HR but lower SBP
- this is based on neonates but Dr. Castillo explains in general for all ages
82
**T/F**: All opioids show a increase in plasma concentration with initiation of cardiopulmonary bypass?
- **FALSE**
- all opioIds show an **DECREASE**
83
What is the clinical significance of Fentanyl given during CABG?
- What derivative shows similar effects?
- Fentanyl has the **greatest decrease of plasma concentration** b/c significant amount of the **drug adheres to the surface of the bypass circuit**
- Alfentanil
84
Which fentanyl derivatives are recommended for CABG?
- Why?
- **Sufentanil**
- smaller Vd ?
85
How much of sufentanil is subject to first pass effects?
- 60% lung first-pass
86
How much of sufentanil is protein bound?
What protein is it bound to?
- **92.5%**
- α-1 acid glycoprotein
87
Sufentanil clinical dosages:
- Analgesia?
- Induction?
- IntraOp?
- Infusion?
- Analgesia: 0.1 - 0.4 μg/kg IV
- **Induction: 18.9 μg/kg IV**
- IntraOp: 0.3 - 1 μg/kg IV
- Infusion: 0.5 - 1 μg/kg/hr IV
88
List side effect(s) of Sufentanil.
- **Bradycardia** (decreased CO)
- Skeletal muscle **rigidity** of chest wall and abdominal muscles
89
- The rapid onset is due to a low or high pKa?
- How is the clinically significant?
- Low pKa
- About 90% **nonionized** at physiologic pH (7.40) - **Nonionized form of drug readily crosses BBB**
90
Metabolite of Alfentanil:
Noralfentanil (via CYP450 3A4)
91
Alfentanil Dosages:
- Induction:
- Induction laryngoscopy:
- Maintenance:
- Induction: **150 - 300 mcg /kg** IV
- Induction Laryngoscopy: **15 - 30 mcg/kg** IV (90 secs prior)
- Maintenance: 25 - 150 mcg/kg/hr with inhaled anesthetics
92
What drug can cause acute dystonia when given to a Parkinson's patient?
Alfentanil
- Contraindication
93
What receptor affinity does Remifentanil (Remi) have?
How potent is it?
- **Selective** μ opioid agonist
- 15 - 20 times more potent than Alfentanil (same as Fentanyl)
94
What is remifentanil's structure?
- Why is it important?
**Ester Structure** = hydrolyzed by plasma & tissue esterases.
- Rapid onset & recovery (15 mins)
- Very titratable
- No accumulation
- Typically used adjunctly during emergence
95
What drug was said to be a great choice for carotid endarterectomy during lecture?
Remifentanil d/t rapid onset and offset
96
Characteristics of remifentanil below:
- Clearance:
- Peak effect:
- Steady state:
- E1/2:
- Excretion:
- Clearance: 3 L/min (8x faster than Alfentanil)
- Peak: 30 - 60 secs (**fastest fentanyl derivative**)
- Steady state: 10 mins (infusion)
- E1/2: 6.3 mins (99.8% gone from system)
- Excretion: Kidney (unchanged by kidney/liver failure)
97
Remifentanil dosages:
- Induction:
- Maintenance:
- How do you calculate dosages?
- Induction: **0.5 - 1 mcg/kg IV over 30 - 60 secs**
- Maintenance: 0.25 - 1 mcg/kg or 0.005 - 2 mcg/kg/min IV
- Use IBW
98
Remi SE:
- Sz
- N/V
- Ventilation depression
- Decreased BP/ HR
- **Hyperalgesia** d/t **previous acute exposure to large opioid doses)** = tolerance b/c attacks same receptors
99
Before discontinuation of Remi, what should you do to ensure adequate analgesia upon emergence?
- Administer a longer acting opioid
100
Why is spinal or epidural administration of "Remi" not recommended?
- Per book, **safety of Glycine & opioid undetermined** for the neuraxial route
101
**Place Meperdine analogues in order from fastest to slowest site equillibration (onset).**
1. Remifentanil
2. Alfentanil
3. Sufentanil
4. Fentanyl
102
Hydromorphone:
- Potency
- Dose and max
- 5x more potent than morphine
- **0.5mg q 4 hrs (max 1-4 mg total)**
- No histamine release
103
Hydromorphone is ____ hydrophilic than morphine?
- Less
- Leading to faster onset
104
Does Hydromorphone induce Histamine release?
- Per slide, no
105
Large doses on Hydromorphone has been found to cause _____ & ______.
- agitation & myoclonus
106
Codeine SE:
- Physical dependence
- Minimal sedation
- N/V/ constipation
-dizzy
107
Why is codeine not given IV?
- **Histamine - Induced Hypotension**
- Only given PO or IM
108
Codeine clinical dosing:
- Analgesia
- Cough suppression
- Analgesia: 60 mg (120 mg = 10 mg of morphine)
- **Cough**: 15 mg
109
Which opioid is most cleared?
- Remifentanil (3 L/min)
- 8x more rapid than Alfentanil
110
Which opioid(s) is/are the most protein bound?
Which is the least?
- Sufentanil (92.5%), alfentanil (basically same 92%), & remifentanil (66 -93%)
- Least = morphine
111
Which opioid is the highest percent non-ionized?
- Alfentanil (~ 90%)
- rapidly crosses BBB
112
What opioid can cause synergistic ventilation depression with Propofol?
Remifentanil
113
Morphine tends to relieve _____ type pain more than _____ type pain.
Dull: sharp
114
Which oral opioid agonist is used for wdl & chronic pain?
- Which receptor does this drug antagonize?
- Methadone
- NMDA antagonism
115
Tramadol:
- receptors?
- PO Dose?
- What drug interaction do you have to consider?
- mu receptor; weak k & delta activity
- Interacts with Coumadin
116
**Know this table**:
- Lecture Q: Based off table, which category **best** describes onset of action?
- Effect - site (Blood/Brain) Equilibration Time (mins)
117
Opioid Agonist are weak acids or weak bases?
- Weak **bases**
118
What does a high nonionized percentage indicate?
- Rapidly crosses BBB
