Unit 5 Pharmacology: Opioid Agonists & Antagonists Flashcards
(128 cards)
1
Q
what are the 4 steps of pain transmission?
A
Transduction
Transmission
Modulation
Perception
2
Q
Describe transduction
A
Inquired tissues release a variety of chemicals that activate peripheral nerves and/or cause immune cells to release pro inflammatory compounds. The peripheral nerves transduce this chemical soup into an action potential, so that the extent of tissue injury can ultimately be interpreted by the brain.
3
Q
What nerve fibers transmit pain? Which type of pain?
A
A-delta fibers transmit fast pain that is sharp and well localized
C fibers transmit slow pain that is dull and poorly localized
4
Q
What is the role of inflammation in pain transduction?
A
It contributes to:
Reduced threshold to pain stimulus - allodynia
Increased response to pain stimulus - hyperalgesia
5
Q
Describe pain transmission:
A
The pain signal is relayed through the 3-neuron afferent pain pathway along the spinothalmic tract:
1st order neuron: periphery to dorsal horn (cell body in the dorsal root ganglion)
2nd order neuron: dorsal horn to thalamus (cell body in dorsal horn)
3rd order neuron: thalamus to cerebral cortex (cell body in thalamus)
6
Q
Discuss the process of pain modulation:
A
The pain signal is modified (inhibited to augmented) as it advances towards the cerebral cortex.
The most important site of modulation is the substantia gelatinosa in the dorsal horn (Rexed lamina II & III).
Pain is inhibited when:
-spinal neurons release GABA and glycine (inhibitory neurotransmitters)
-the descending pain pathway releases NE, 5-HT, and endorphins
Pain is augmented by:
-central sensitization
- wind-up
7
Q
Discuss the process of pain perception:
A
Describes the processing of afferent pain signals in the cerebral cortex and limbic system (how we “feel” about pain)
8
Q
List the 4 types of opioid receptors:
A
Mu (MOP)
Delta (DOP)
Kappa (KOP)
ORL1 (NOP)
9
Q
What is the mechanism of action of opioids?
A
Each opioid receptor is linked to a G protein, and agonism of the receptor instructs the G protein to “turn off” adenylate cyclase. This reduces the intracellular concentration of cAMP (second messenger), which alters ionic currents and reduces neuronal function.
10
Q
6 steps of opioid MOA
A
- Opioid binds to receptor
- G protein is activated
- Adenylate cyclase is inhibited
- Less cAMP is produced
- Ca+2 conductance is decreased
- K+ conductance is increased
11
Q
What occurs due to the Ca+2 conductance decrease that occurs with opioids?
A
It reduces neurotransmitter release from presynaptic neuron
12
Q
What occurs due to the increase in K+ conductance that occurs with opioids?
A
Hyperpolarizes the postsynaptic neuron
TP further RMP
More resistant to stimulation
13
Q
What opioid receptor contributes to most of the classic signs of opioids?
A
Mu receptor
14
Q
Where are opioid receptors located?
A
Brain: periaqueductal gray, locus coeruleus, and rostrum ventral medulla
Spinal cord: primary afferent neurons in the dorsal horn and the interneurons
Peripheral: sensory neurons and immune cells
15
Q
What are the precursors of the endogenous opioids?
A
Pre-proopiomelanocortin -> endorphins (Mu receptor)
Pre-enkephalin -> enkephalins (Delta receptor)
Pre-dynorphins -> dynorphins (Kappa receptor)
16
Q
What are the endogenous ligand(s) of the Mu receptor?
A
Endorphin
- Beta-endorphin
- Endomorphin
17
Q
What are the endogenous ligand of the Delta receptor?
A
Enkephalin
- Leu-enkephalin
- Met-enkephalin
18
Q
What are the endogenous ligand of the kappa receptor?
A
Dynorphin
- dynorphin A
- dynorphin B
- neodynorphin
19
Q
Where do the opioid receptors produce analgesia?
A
Supraspinal and spinal
20
Q
Which opioid receptors are responsible for respiratory depression?
A
Mu
Delta
Kappa ??
21
Q
What opioid receptors are responsible for Bradycardia?
A
Mu
22
Q
What opioid receptors are responsible for sedation?
A
Mu
Kappa
23
Q
What opioid receptors are responsible for euphoria?
A
Mu
24
Q
What opioid receptors are responsible for Dysphoria
A
Kappa
25
What opioid receptors are responsible for Prolactin release?
Mu
26
What opioid receptors are responsible for Hallucinations?
Kappa
27
What opioid receptors are responsible for mild hypothermia?
Mu
28
What opioid receptors are responsible for delirium?
Kappa
29
What CNS effects are the delta receptors responsible for?
None
30
What opioid receptors are responsible for miosis?
Mu and kappa
31
What opioid receptors are responsible for urinary retention?
Mu and Delta
32
What opioid receptors are responsible for diuresis?
Kappa
33
What opioid receptors are responsible for N/V?
Mu
34
What opioid receptors are responsible for increase biliary pressure?
Mu
35
What opioid receptors are responsible for decreased peristalsis?
Mu
36
What opioid receptors are responsible for pruritus?
Mu and Delta
37
What opioid receptors are responsible for antishivering?
Kappa
38
List opioid side effects caused by Mu-1: (7)
```
Analgesia (supraspinal and spinal)
Bradycardia
Euphoria
Low abuse potential
Miosis
Hypothermia
Urinary retention
```
39
List opioid side effects caused by Mu-2: (4)
Analgesia (spinal only)
Respiratory depression
Constipation
Physical dependence
40
List opioid side effects caused by Mu-3
Immune suppression
41
What are the unique effects of kappa stimulation? (5)
```
Antishivering effect
Diuresis
Dysphoria
Delirium
Hallucinations
```
42
How do opioids affect heart rate?
Bradycardia is the result of mu stimulation (mu-2)
43
Which opioid can produce increased HR? How?
Meperidine can increase HR: atropine like ring in chemical structure produces anticholinergic effects: tachycardia, mydriasis, and dry mouth
44
How do opioids affect blood pressure?
There in a minimal effect on BP in healthy patients
Hypotension with morphine or meperidine is likely the result of histamine release
Dose dependent vasodilation
Baroreceptor reflex is not affected
45
How do opioids affect myocardial function?
Contractility is not affected
| Myocardial depression can occur if combined with N2O
46
How do opioids affect ventilation?
Opioids stimulate the mu and delta receptors (and possibly kappa) to produce their ventilatory effects:
Decreased ventilatory response to CO2 (CO2 response curve shifted to the right)
Decreased RR and compensatory increase in Vt (partial compensation)
Increased PaCO2 -> increased ICP if ventilation is not maintained
47
How do opioids affect the pupil?
Edinger Westphal nucleus stimulation -> increased PNS stimulation of ciliary ganglion and oculomotor nerve (CN III) -> pupil constriction
Tolerance does not develop to miosis
48
How do opioids produce nausea and vomiting?
Mu receptor stimulation:
Chemoreceptor trigger zone stimulation (area postrema of medulla)
Possible interaction with the vestibular apparatus
49
Do opioids affect SSEPs?
Minimal effects on evoked-potentials
50
How do opioids affect biliary pressure?
GI effects through mu receptor stimulation
Contraction of sphincter of Oddi -> increased biliary pressure
Reversed by naloxone or glucagon
Meperidine causes the lowest incidence
51
How do opioids affect gastric emptying?
GI effects through mu receptor stimulation
| Gastric emptying is prolonged
52
How do opioids affect peristalsis?
GI effects through mu receptor stimulation
| Peristalsis is slowed -> constipation
53
How do opioid contribute to urinary retention?
```
Mu and delta receptor stimulation
Detrusor relaxation (contraction is needed to pass urine into the urethra)
Urinary sphincter contraction (relaxation is needed to void)
```
54
What are the immunologic effects of opioids?
```
Histamine release (morphine, meperidine, codeine)
Inhibition of cellular and humoral immune function
Suppression of natural killer cell function
```
55
How do opioids affect thermoregulation?
Opioids reset the hypothalamic temperature set point -> decreased core body temperature
56
What are the gender differences in opioids?
```
In women morphine is associated with a:
Greater analgesic potency
Slower onset of action
Longer duration of action
Lower post op opioid consumption
```
57
Rank the IV opioids in terms of potency:
Sufentanil > Fentanyl = Remifentanil > Alfentanil > Hydromorphone > Morphine > Meperidine
58
```
Compare the equianalgesic opioid doses relative to 10 mg of morphine; relative potency:
Meperidine
Morphine
Hydromorphone
Alfentanil
Fentanyl
Remifentanil
Sufentanil
```
```
Meperidine 100 mg ; 0.1
Morphine: 10 mg; 1
Hydromorphone: 1.4 mg; 7
Alfentanil: 1000 mcg; 10
Fentanyl: 100 mcg; 100
Remifentanil: 100 mcg; 100
Sufentanil: 10 mcg; 1000
```
59
What about the relative potency of methadone?
It is variable and based on the patient’s daily opioid requirements and duration of therapy.
60
Tolerance and physical dependence are most likely due to:
Receptor desensitization and increased synthesis of cAMP. These phenomena are not due to enzyme induction.
61
Tolerance develops to nearly all of the side affects associated with opioids, what 2 exceptions are there?
Miosis
| Constipation
62
Early s/sx of opioid withdrawal: (3)
Diaphoresis
Insomnia
Restlessness
63
Late s/sx of opioid withdrawal: (2)
Abdominal cramping
| N/V
64
Time course of withdrawal is a function of the drug’s half-life:
Fentanyl and meperidine
Morphine and heroin
Methadone
Fentanyl and meperidine: onset 2 - 6 hours, peak 6 - 12 hours, duration 4 - 5 days
Morphine and heroin: onset 6 - 18 hours, peak 36 - 72 hours, duration 7 - 10 days
Methadone: onset 24 - 48 hours, peak 3 - 21 days, duration 6 - 7 weeks
65
What metabolism do opioids undergo?
All under hepatic biotransformation except for Remifentanil
66
What opioids have an active metabolite?
Morphine
| Meperidine
67
What is the active metabolite of morphine, and why is it a problem?
Morphine is conjugated to morphine-3-glucuronide (inactive) and morphine-6-glucuronide (active).
Impaired renal function -> decreased MP6 excretion -> increased accumulation -> respiratory depression
68
What is the active metabolite of meperidine, and why is it a problem?
Meperidine is demethylated in the liver to normeperidine:
Normeperidine is one half as potent as its parent compound.
It reduces the seizure threshold and increases CNS excitability.
Impaired renal function -> decreased normeperidine excretion -> increased accumulation -> seizures
69
Meperidine should maybe be avoided in what patient population?
Those on dialysis and the elderly
70
How is Remifentanil metabolized?
It is hydrolyzes in the plasma by erythrocyte and tissue esterases.
71
How is Remifentanil dosed?
Always at lean body weight
72
Meperidine is what type of opioid, and stimulates what receptors?
Synthetic phenylpiperidine
| Mu and kappa receptor
73
How is meperidine metabolized?
Demethylated to normeperidine by the CYP450 system in the liver
74
Normeperidine is what potency compared to the parent compound?
1/2 the potency
75
What is the elimination 1/2 life of meperidine?
15 hours, but it can exceed 35 hours in the patient with renal failure
76
Discuss the co-administration of meperidine and MAO inhibitors
Meperidine is a weak serotonin reuptake inhibitor
Since MAO delaminates serotonin in the synaptic cleft, co-admin of meperidine and an MAO inhibitor can cause serotonin syndrome
S/SX: hyperthermia, mental status change, hyperreflexia, seizures, death
MAO inhibitors: phenelzine, isocarboxazid, tranylcypromine
77
Meperidine has anticholinergic effects, why?
Structurally related to atropine
| Tachycardia, mydriasis, dry mouth
78
Why does meperidine have an antishivering effect?
It stimulated the kappa receptor
79
What opioids cause histamine release from mast cells?
Meperidine
Morphine
Codeine
Oxycodone
80
What opioid has the fastest onset of action? Why?
Alfentanil.
pKa is 6.5 which is less than physiologic pH
It is ~90% unionized and 10% ionized (unionized is what crosses BBB)
It has a low Vd and high degree of protein binding (alpha-1-acid glycoprotein)
Since it’s highly unionized and it doesn’t have a large Vd, more of the drug is available to enter the brain
81
Which opioid has the largest Vd? Which has the smallest?
Largest: Fentanyl 4 L/kg
Smallest: Remifentanil 0.39 L/kg
Remifentanil doesn’t distribute to the fat, because it’s metabolized so quickly in the plasma.
82
```
Alfentanil:
pKa
Unionized %
Protein binding %
Vd L/kg
```
pKa: 6.5
Unionized %: 89
Protein binding %: 92
Vd L/kg: 0.6
83
```
Remifentanil:
pKa
Unionized %
Protein binding %
Vd L/kg
```
pKa: 7.2
Unionized %: 58
Protein binding %: 93
Vd L/kg: 0.39
84
```
Morphine:
pKa
Unionized %
Protein binding %
Vd L/kg
```
pKa: 7.9
Unionized %: 23
Protein binding %: 35
Vd L/kg: 2.8
85
```
Sufentanil:
pKa
Unionized %
Protein binding %
Vd L/kg
```
pKa: 8.0
Unionized %: 20
Protein binding %: 93
Vd L/kg: 2
86
```
Fentanyl:
pKa
Unionized %
Protein binding %
Vd L/kg
```
pKa: 8.4
Unionized %: 8.5
Protein binding %: 84
Vd L/kg: 4
87
```
Meperidine:
pKa
Unionized %
Protein binding %
Vd L/kg
```
pKa: 8.5
Unionized %: 7
Protein binding %: 70
Vd L/kg: 2.6
88
Which opioid has the highest pKa? The lowest?
Highest: meperidine - 8.5
Lowest: alfentanil - 6.5
89
Which opioid has the highest unionized %? The lowest?
Highest: alfentanil - 89
Lowest: meperidine - 7
90
Which opioid has the highest protein binding? The lowest?
Highest: Remifentanil and Sufentanil- 93%
Lowest: morphine - 35%
91
Which opioid has the highest Vd? Lowest?
Highest: fentanyl - 4 L/kg
Lowest: Remifentanil - 0.39 L/kg
92
Alfentanil’s effect side equilibration is ~____ minutes. Fentanyl? Sufentanil?
Alfentanil: 1.4 min
Fentanyl: 6.8 min
Sufentanil: 6.2 min
93
Alfentanil undergoes what type of metabolism?
N-dealkylation and O-demthylation by the hepatic cytochrome P450 system, specifically CYP3A4
94
What drug inhibits alfentanil’s metabolism and can result in prolonged respiratory depression?
Erythromycin
95
Does renal failure alter alfentanil clearance?
No
96
Remifentanil is a ___ agonist
Mu
97
Maintenance infusion for Remifentanil:
0.1 - 1.0 mcg/kg/min
98
Context-sensitive half time is about ____ regardless of infusion duration of Remifentanil
4 minutes
99
Remifentanil is highly lipophilic, but behaves as though it has a small Vd, why?
Very fast rate of clearance in the plasma
100
How is Remifentanil ALWAYS dosed?
Calculated with lean body weight because it does not distribute into fat
101
What is the significance of Remifentanil’s ester linkage?
This makes it susceptible to hydrolysis by erythrocyte and tissue esterases.
102
Remifentanil causes acute opioid induced hyperalgesia following discontinuation, what is the significant post op? How can this be prevented?
Post op opioid consumption is high in these patients.
| Can be prevented with ketamine or magnesium sulfate
103
Can Remifentanil be used for neuraxial anesthesia? Why or why not?
Remifentanil powder is mixed with a free base glycine to provide a buffered solution following reconstitution.
Glycine is an inhibitory neurotransmitter
It can cause skeletal muscle weakness, so it should no be administered in the epidural or intrathecal space
104
How does methadone reduce pain?
By 3 mechanisms:
Mu receptor agonist
NMDA receptor antagonist (only opioid that has this effect)
Inhibits reuptake of monoamines in the synaptic cleft
105
Methadone is a racemic mixture. T/F
True
106
When administered orally methadone has a bioavailability of ___%
80%
107
DOA of methadone?
3 - 6 hours, however chronic administration prolongs its elimination half-life as well as its duration of analgesia
108
How is methadone metabolized? Does it have an active metabolite?
In the liver by CYP450 system
| No active metabolite
109
Which opioid is most likely to cause QT prolongation?
although a rare event, methadone can potentially increase the QT interval. This can lead to Torsades de pointes
110
What is the etiology of opioid induced skeletal muscle rigidity?
Rapid IV administration of the potent IV opioids can cause skeletal muscle rigidity (mu receptor stimulation in the CNS ultimately influencing dopamine and GABA motor pathways). Historically, this compilation has been described as chest wall rigidity or stiff chest syndrome, however current evidence suggests that the greatest resistance to ventilation occurs at the larynx. Opioids do not directly affect motor nerve conduction, the neuromuscular junction, or skeletal muscle.
111
What opioids are more likely to produce skeletal muscle rigidity?
The potent (lipophilic) compounds such as sufentanil, fentanyl, Remifentanil, and Alfentanil
112
What is the treatment for opioid induced skeletal muscle rigidity?
Best treatment is paralysis and intubation
| Naloxone can also reverse rigidity (counterproductive just before surgery)
113
Respiratory complications of opioid induced muscle rigidity: (7)
```
Hypoxia
Hypercapnia
Increased oxygen consumption
Decreased SVO2
Decreased thoracic compliance
Decreased FRC
Decreased minute ventilation
```
114
Cardiovascular complications of opioid induced muscle rigidity: (3)
Increased CVP
Increased PAP
Increased PVR
115
Neuro complications of opioid induced muscle rigidity:
Increased ICP
116
GI complications of opioid induced muscle rigidity:
Increased gastric pressure with mask ventilation
117
Opioid partial agonists (agonist-antagonist) common characteristics:
Analgesia with a reduced risk of respiratory depression
Have a ceiling effect
Reduce the efficacy of previously administered opioids
Can cause acute withdrawal in opioid dependent patients
Cause cause Dysphoria reactions
Carry low risk of dependence
Are used in patients who cannot tolerate a full opioid agonist
118
```
Buprenorphine:
Mechanism
Analgesia compared to morphine
Reversed by Naloxone
Key Features
```
Mechanism: Mu partial agonist
Analgesia compared to morphine: greater
Reversed by Naloxone: difficult due to high affinity for mu receptor
Key Features: long duration - 8hr; available via transdermal
119
```
Nalbuphine:
Mechanism
Analgesia compared to morphine
Reversed by Naloxone
Key Features
```
Mechanism: Kappa agonist, mu antagonist
Analgesia compared to morphine: similar
Reversed by Naloxone: yes
Key Features: does not increase BP, PAP, HR, or RAP; useful with hx of heart dz
120
```
Butorphanol:
Mechanism
Analgesia compared to morphine
Reversed by Naloxone
Key Features
```
Mechanism: kappa agonist, mu antagonist (weak)
Analgesia compared to morphine: greater
Reversed by Naloxone: yes
Key Features: useful for post op shivering, available in intranasal
121
Naloxone is the prototype opioid antagonist, what receptor(s) does it antagonize?
Mu, kappa, and delta
| it has the greatest affinity for the mu receptor
122
Naloxone dose, duration?
Dose: 1 - 4 mcg/kg - it is best to give 20 - 40 mcg at a time to prevent overshooting
Duration: 30 - 45 minutes - this may be shorter than the opioid
123
Naloxone metabolism?
Liver with significant first pass metabolism
124
In a patient with pain, analgesic reversal actives the SNS, what are the implications of this? How can these effects be minimized?
This is the mechanism by which naloxone causes neurogenic pulmonary edema, tachycardia, cardiac dysrhythmias, and sudden death.
Slow titration minimizes these effects.
It can also cause N/V, slow titration over 2 - 3 minutes causes less N/V.
125
Can naloxone cross the placenta?
Yes. So giving to an opioid abusing mother, it can precipitate acute opioid withdrawal in the neonate.
126
Methylnatrexone is an antagonist that has a quaternary amino group, what is the significance of this?
It cannot cross the BBB, therefore can not be used to reverse respiratory depression.
It is useful for mitigating the peripheral effects of opioids, such as bowel dysfunction
127
Nalmefene has a similar profile to naloxone, except for what? Dose?
Duration of action is about 10 hours.
| Dose: 0.1 - 0.5 mcg/kg
128
What opioid antagonist has the longest duration of action?
Naltrexone - up to 24 hours.
It does not undergo significant first pass metabolism.
An extended release formulation may be used for alcohol withdrawal treatment.
Can also be used to maintain recovering opioid abusers.
