Unit 5 - Opioids & Non-Opioid Analgesics Flashcards
(169 cards)
1
Q
what is transduction
pain reponse
A
Injured tissues release chemicals that activate peripheral nerves and/or cause immune cells to release proinflammatory compounds
chemical, mechanical, or thermal stimulus sensed by nociceptor and conve
2
Q
nerve fibers that transmit “fast pain”
A
A-delta fibers
sharp, well-localized pain
3
Q
nerve fibers that transmit “slow pain”
A
c fibers
dull, poorly localized pain
4
Q
drugs that target transduction of pain
A
- NSAIDS
- LAs (infiltration at surgical site)
- steroids
- antihistamines
- opioids
5
Q
how does inflammation contribute to pain transduction
A
- ↓ threshold to pain stimulus (allodynia)
- ↑ response to pain stimulus (hyperalgesia)
6
Q
how is pain transmitted
A
Pain signal relayed through 3-neuron afferent pain pathway along spinothalamic
* 1st order neuron: periphery to dorsal horn (cell body in DRG)
* 2nd order: dorsal horn to thalamus (cell body in dorsal horn)
* 3rd order: thalamus to cerebral cortex (cell body in thalamus)
7
Q
drugs that target pain transmission
A
LA for PNB
8
Q
what is pain modulation
A
Pain signal modified (inhibited or augmented) as it advances to cerebral cortex
9
Q
most important site of pain modulation
A
substantia gelatinosa in dorsal horn (Rexed lamina 2 & 3)
10
Q
where does the descending inhibitory pain pathway begin
A
begins in periaqueductal gray & rostroventral medulla
projects to substantia gelatinosa
11
Q
how is pain inhibited via the descending pain pathway
A
- Spinal neurons release GABA and glycine (inhibitor NTs)
- Descending pain pathway releases NE, serotonin, endorphins
12
Q
how is pain modulation augmented
A
- central sensitization
- wind-up
13
Q
drugs that target pain modulation
A
- neuraxial opioids
- NMDA antagonists
- a2 agonists
- AChE inhibitors
- SSRIs
- SNRIs
14
Q
what is pain perception
A
Describes process of afferent pain signals in cerebral cortex & limbic system
15
Q
drugs that target pain perception
A
general anesthetics, opioids, a2 agonists (sedation)
16
Q
MOA of opioid receptors
A
- opioid binds to receptor
- GPCR activated (Gi)
- AC inhibited
- decreased intracellular cAMP
- Ca2+ conductance decreased
- K+ conductance increased
17
Q
4 types of opioid receptors
A
mu, delta, kappa, ORL-1
18
Q
where are opioid receptors located in the brain
A
periaqueductal gray, locus coeruleus, rostral ventral medulla
19
Q
where are opioid receptors located in the spinal cord
A
primary afferent neurons in dorsal horn & interneurons
20
Q
where are opioid receptors located in the periphery
A
sensory neurons and immune cells
21
Q
precursors to endogenous opioids
A
- Pre-proopiomelanocortin = endorphins (mu receptor)
- Pre-enkephalin = enkephalins (delta receptor)
- Pre-dynorphin = dynorphins (kappa receptor)
22
Q
endogenous ligand of mu opioid receptor
A
endorphin
23
Q
endogenous ligand of delta opioid receptors
A
enkephalin
24
Q
endogenous ligand of kappa opioid receptor
A
dynorphin
25
agonism of which opioid receptor can cause bradycardia
mu
26
CNS effects of mu agonism
* Sedation
* Euphoria
* Prolactin release
* Mild hypothermia
27
CNS effects of kappa agonism
* Sedation
* Dysphoria
* Hallucinations
* Delirium
28
how are pupils affected by opioid receptor agonism
Mu & kappa = miosis
29
GU effects of opioid receptors
* mu & delta = retention
* kappa = diuresis
30
GI effects of mu receptor agonism
| N/V
↑ biliary pressure
↓ peristalsis
31
GI effects of mu receptor agonism
N/V
↑ biliary pressure
↓ peristalsis
32
which opioid receptors are assoc. with itching
mu, delta
33
which opioid receptor(s) is assoc. with antishivering effect
kappa
34
where is analgesia provided by mu receptors
* mu 1 = spinal and supraspinal
* mu 2 = spinal only
35
which mu receptor subtype is assoc. with respiratory depression, constipation, and physical dependence
mu-2
36
which mu receptor is assoc. with immune suppression
M3
37
effects of Mu-1 agonism
* Analgesia (supraspinal/spinal)
* Bradycardia
* Euphoria
* Low abuse potential
* Miosis
* Hypothermia
* Urinary retention
38
how do opioids affect CO2 response curve
shift to the right
| decreased ventilatory response to CO2
dec. RR, increased Vt
39
how do opioids affect pupils
Stim of Edinger Westphal nucleus = PNS stim. of ciliary ganglion & CN 3 = pupil constriction
| pts do not develop tolerance to this (miosis)
40
how do opioids affect pupils
Stim of Edinger Westphal nucleus = PNS stim. of ciliary ganglion & CN 3 = pupil constriction
| pts do not develop tolerance to this (miosis)
41
how do opioids cause N/V
* CTZ stim (area postrema of medulla)
* Possible interaction with vestibular apparatus
42
respiratory effects of opioid overdose
centrally-mediated respiratory depression
* Net effect: ↓ Vm that can produce resp. acidosis
* ↑ PaCO2 = ↑ ICP if ventilation uncontrolled
43
how do opioids affect BP
* Minimal effect in healthy pts
* ↓ with morphine & meperidine likely r/t histamine release
* Dose-dependent vasodilation
44
opioids can cause myocardial depression if combined with:
N2O
45
how do opioids affect biliary pressure
increased (sphincter of oddi contraction)
46
GU effects of opioids
* Detrusor relaxation (contraction needed to pass urine into urethra)
* Urinary sphincter contraction
| urinary retention
47
opioids assoc with histamine release
morphine, meperidine, codeine
48
immunologic effects of opioids
* Inhibition of cellular & humoral immune function
* Suppression of natural killer cell function
49
how do opioids affect thermoregulation
Resets hypothalamic temp set point = decreased core body temp
50
naturally-occuring phenanthrene derivative opioids
morphine
codeine
51
drugs that are morphine derivatives
hydromorphone, heroin, naloxone, naltrexone
52
opioids in phenylperidine class
fentanyl, sufentanil, remifentanil, alfentanil
53
opioid potency
sufentanil > fentanyl > remifentanil > alfentanil > hydromorphone > morphine > meperidine
54
10 mg morphine =
__ meperidine
__ hydromorphone
__ alfentanil
__ remifentanil
__ fentanyl
__ sufentanil
* 100 mg meperidine
* 1.4 mg hydromorphone
* 1000 mcg alfentanil
* 100 mcg remifentanil
* 100 mcg fentanyl
* 10 mcg sufentanil
55
2 factors that determine IV dose and relative ptoency of methadone
depends on patient’s daily opioid requirements & duration of therapy
56
what causes opioid dependence
occurs when a person taking a drug goes through withdrawal when discontinued
57
what causes opioid tolerance
occurs when patient requires higher dose to achieve given effect
58
what is opioid cross-tolerance
occurs when tolerance to 1 drug produces tolerance to another with similar effects
59
what is opioid addiction
a disease when a person can’t stop using a drug despite negative consequences
60
most likely causes of opioid tolerance and physical dependence
most likely d/t receptor desensitization, ↑ cAMP synthesis (Not d/t enzyme induction)
61
tolernace to nearly all side effects of opioids can be developed, except
mioisis, constipation
62
early s/s opioid withdrawal
diaphoresis, insomnia, restlessness
63
later s/s opioid withdrawal
abdominal cramping, N/V
64
onset, peak, and duration of withdrawal from fentanyl or meperidine
* onset = 2-6 hours
* peak = 6-12 hours
* duration = 4-5 days
65
which opioid agonists produce active metabolites
"M drugs"
morphine, meperidine (?hydromorphone)
66
metabolism of opioid agonists
All undergo hepatic biotransformation except remifentanil
67
onset, peak, & duration of morphine & heroin withdrawal
* onset = 6-18 hours
* peak = 36- 72 hours
* duration = 7-10 days
68
onset, peak, & duration of methadone withdrawal
* onset = 24-48 hours
* peak = 3-21 days
* duration = 6-7 weeks
69
effect-site equilibration of alfentanil, fentanyl, and sufentanil
alfentanil = 1.4 min
fentanyl = 6.8 min
sufentanil = 6.2 min
70
opioid agonist with the lowest pka
alfentanil (6.5)
71
opioid agonist with the greatest degree of protein binding
remifentanil & sufentanil (93%)
72
opioid agonist with the smallest Vd
remifentanil (0.39 L/kg)
73
morphine metabolism
conjugated to M3G (inactive) & M6G (active)
74
effects of M3G
hyperalgesia, agitation, myoclonus, delirium (some say inactive)
75
effects of M6G
respiratory depression, drowsiness, N/V, coma
76
patients prone to M6G accumulation
patients on dialysis (can't excrete)
77
pts more likely to experience resp depression & toxicity with morphine
renal failure
## Footnote
chronic admin can also cause accumulation & toxicity
78
hydromorphone metabolite
hydromorphone-3-glucoronide excreted by kidneys
## Footnote
some say no active metabolites
79
s/s hydromorphone metabolite accumulation
prolonged respiratory depression, myoclonus
80
MOA of meperidine
stimulates mu & kappa
81
opioid agonist with lowest non-ionized fraction at physiologic pH
meperidine (7%)
82
metabolism of meperidine
demethylated to **normeperidine** via CYP450 in liver (1/2 as potent0
83
elimination 1/2 time of normeperidine
15 hours
## Footnote
can exceed 35 hours in renal failure
84
elimination 1/2 time of normeperidine
15 hours
## Footnote
can exceed 35 hours in renal failure
85
SEs assoc. with normeperidine accumulation
Decreases seizure threshold, increases CNS excitability = twitches, tremors, seizures
86
drug class that should be avoided with meperidine
MAOIs (co-admin. could cause serotonin syndrome)
87
s/s serotonin syndrome
hyperthermia, AMS, hyperreflexia, seizures, death
88
opioid agonist structurally related to atropine
meperidine
| reason for increased HR, mydriasis, dry mouth
89
MOA of decreased postop shivering with meperidine
kappa receptor agonism
90
why does alfentanil have the fastest onset despite lower pKa
more molecules available to enter the brain because it’s 90% non-ionized at physiologic pH
91
Vd & protein binding of alfentanil
low Vd, high protein binding (alpha-1 acid glycoprotein)
92
alfentanil metabolism
N-dealkylation and O-demethylation by hepatic CYP450 (specifically CYP3A4)
93
why is alfentanil more susceptible to alterations in hepatic CYP450
Comparatively lower hepatic ER
| specifically CYP3A4
94
med that inhibits alfentanil metabolism
erythromycin
95
does renal failure alter alfentanil clearance
nope
96
uses of alfentanil
Useful for blunting HD response to short, intense periods of stimulation (tracheal intubation, retrobulbar block)
97
MOA of remifentanil
mu agonist
98
maintenance infusion rate of remifentanil
0.1-1 mcg/kg/min
99
CSHT of remifentanil
~4 min regardless of infusion duration
100
is remifentanil based on TBW or LBW
LBW
101
remifentanil metabolism
ester linkage = hydrolysis via erythrocyte and tissue esterases
102
which opioid is assoc. with hyperalgesia when drip d/c'd
remifentanil
103
methods to prevent remifentanil-induced hyperalgesia
ketamine, mag sulfate
104
how is remifentanil prepared
powder mixed with free base & glycine to provide buffered solution
## Footnote
glycine = inhibitory NT
105
how is remifentanil prepared
powder mixed with free base & glycine to provide buffered solution
## Footnote
glycine = inhibitory NT
106
why shouldn't remifentanil be given in epidural or intrathecal space
can cause skeletal muscle weakness
107
uses of methadone
Useful for treating chronic opioid abuse (prevent withdrawal), chronic pain, cancer pain
108
3 mechanisms which methadone decreases pain
1. Mu receptor agonism
2. NMDA receptor antagonism (dextrorotatory isomer)
3. Inhibits reuptake of monoamines in synaptic cleft
109
methadone metabolism
P450 system in liver
## Footnote
80% oral bioavailability
110
duration of methadone
3-6 hours
111
rare complication of methadone admin
prolonged QTc
can lead to Torsades
| Inhibits delayed rectifier potassium ion channel (IKr)
112
MOA of oliceridine
primarily mu agonism
113
indications for oliceridine
adults with acute pain when other opioids and alternative treatments fail
114
oliceridine dosing
* bolus: 1-2 mg loading, 1-3 mg Q1-3 hours PRN
* PCA: 1.5 mg loading, demand 0.35-0.5 mg, lockout 6 min
## Footnote
max 27 mg/day
115
pts who may require a dose reductiuon of oliceridine
pts on strong CYP2D6 & CYP3A4 inhibitors
116
is dose adjustment of oliceridine required for renal or hepatic impairment
yes
117
oliceridine contraindications
* Significant respiratory depression
* Acute or severe asthma in an unmonitored setting without resuscitative equipment
* GI obstruction (including ileus)
118
AEs of oliceridine
* Can cause mild QTc prolongation
* ↑ risk seizures in pts with seizure disorder
* ↑ risk serotonin syndrome in pts on serotonergic drugs
119
when is chest wall rigidity from opioids most common
with more lipophilic (potent) compounds
sufentanil, fentanyl, remifentanil, alfentanil
120
where is the greatest resistance to ventilation with chest wall rigidity from opioids
larynx
121
best treatment for opioid induced chest wall rigidity
* paralysis
* intubation
* naloxone can reverse
122
respiratory complications of chest wall rigidity
hypoxia, hypercapnia, ↑ O2 consumption, ↓ SvO2, ↓ thoracic compliance, ↓ FRC, ↓ minute ventilation
123
CV complications from chest wall rigidity
↑ CVP, ↑ PAP, ↑ PVR
124
what causes chest wall rigidity with opioids
Believed to result from mu receptor stimulation in CNS (ultimately influencing dopamine & GABA motor pathways)
125
advantages of partial opioid agonists
* Analgesia with reduced risk of respiratory depression
* Low risk of dependence
126
4 disadvantages of partial opioid agonists
* Ceiling effect on analgesia
* Reduce efficacy of previously administered opioids
* Can cause acute opioid withdrawal in opioid-depednent patient
* Can cause dysphoric reactions
127
4 disadvantages of partial opioid agonists
* Ceiling effect on analgesia
* Reduce efficacy of previously administered opioids
* Can cause acute opioid withdrawal in opioid-depednent patient
* Can cause dysphoric reactions
128
MOA of bureprenorphine
partial mu agonist
129
MOA of nalbuphine
kappa agonist
mu antagonist
130
MOA of butorphanol
kappa agonist
weak mu antagonist
131
partial opioid agonist that's difficult to reverse with naloxone
buprenorphine
132
duration of buprenorphine
8 hours
133
partial opioid agonist useful in pts with heart disease
nalbuphine
| Does not ↑ BP, PAP, HR, or RAP
134
partial opioid agonist useful in pts with heart disease
nalbuphine
| Does not ↑ BP, PAP, HR, or RAP
135
partial opioid agonist useful forr postop shivering
butorphanol
136
partial opioid agonist useful forr postop shivering
butorphanol
137
moa of naloxone
Competitively antagonizes mu, kappa, and delta opioids receptors
| greatest affinity at mu
138
naloxone dosing
1-4 mcg/kg (better to give 20-40 mcg at a time)
139
metabolism of naloxone
liver (significant 1st pass metabolism)
140
use of naloxone infusion
relieve severe pruritis from neuraxial opioids
141
can naloxone precipitate acute opioid withdrawal in neonate of abusing mother
yes - crosses BBB
142
can naloxone precipitate acute opioid withdrawal in neonate of abusing mother
yes - crosses BBB
143
AEs of naloxone
* Activates SNS in patient with pain & can cause neurogenic pulmonary edema, tachycardia, dysrhythmias, sudden death
* Other SEs: N/V
| (minimize with slow titration)
144
what is Methylnaltrexone
Quarternary amino group, prohibits BBB passage
| does not reverse respiratory depression
145
what is Methylnaltrexone
Quarternary amino group, prohibits BBB passage
| does not reverse respiratory depression
146
use of Methylnaltrexone
Useful for mitigating peripheral effects of opioids (opioid-induced constipation)
147
dosing, duration, use of nalmfene
* 0.1-0.5 mcg/kg
* Duration: ~ 10 hours
* Can be used to maintain recovering opioid abusers
148
duration of PO naltrexone admin
up to 24 hours
149
uses of naltrexone
* Extended-release may be used for alcohol withdrawal treatment
* Can also be used to maintain recovering opioid abusers
150
factors that increase risk respiratory depression with PCAs
Increased risk of respiratory depression (incidence not higher than with PRN analgesics/neuraxial)
151
demand dose, lockout interval, and basal infusion for morphine PCA
* demand dose = 0.5-2.5 mg
* lockout = 5-10 min
* basal = 0.5-2.5 mg/hr
152
demand dose, lockout interval, and basal infusion for hydromorphone PCA
* demand = 0.05-0.25
* lockout = 5-10 min
* basal = 0.05 - 0.25 mg/hr
153
demand dose, lockout interval, and basal infusion for fentanyl PCA
* demand = 10-20 mcg
* lockout = 4-10 min
* basal - 20-100 mcg/hr
154
demand dose, lockout interval, and basal infusion for sufentanil PCA
* demand = 2-5 mcg
* lockout = 4-10 mcg
* basal = 2-5 mcg/hr
155
demand dose, lockout interval, and basal infusion for remifentanil PCA
* demand = 0.2-0.7 mcg/kg
* lockout = 1-3 min
* basal = 0.025-0.1 mcg/kg/min
156
demand dose, lockout interval, and basal infusion for methadone PCA
* demand = 0.5-2.5 mg
* lockout = 8-20 min
* basal = 0.5-2.5 mg/hr
157
demand dose & lockout interval for nalbuphine PCA
* demand = 1-5 mg
* lockout = 5=15 min
158
demand dose & lockout interval for buprenorphine PCA
* demand = 0.03-0.1 mg
* lockout = 8-20 min
159
goal of PCA demand dose
provide analgesia without toxicity
160
what is PCA lockout interval based on
time it takes for demand dose to reach effective plasma conc.
161
is basal rate for PCA recommended?
nah - doesn’t provide superior pain relief & increases risk of resp. depression
162
drug class that decreases IV PCA opioid requirements
scheduled NSAIDs
163
which opioid may produce the least N/V, pruritis, and urinary retention with PCA
fentanyl
164
opioid useful for PCA when short burst of pain such as labor
remifentanil
165
why can rmifentanil cause skeletal muscle weakness
has glycine in the vial
| glycine = inhibitory NT
166
which opioid inhibits nerve conduction
meperidine
| structural resemblence to LAs (& atropine) - inhibits Na channels in axo
167
where does the endogenous pain modulation pathway terminate
substantia gelatinosa
168
which opioid is assoc. with the greatet amount of rostral spread when injected into intrathecal space
morphine
169
route of morphine admin assoc. with reactivation. of HSV
epidural
