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APEX Pharmacology > PHARMACOLOGY-Opioids & non-opioid analgesics > Flashcards

PHARMACOLOGY-Opioids & non-opioid analgesics Flashcards

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1
Q

What 4 types of injury do nociceptors respond to

A

Mechanical
Chemical
Electrical
Thermal

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2
Q

List the nerve types that perceive pain

A 
Free nerve endings
Merkel's disks
Ruffini endings
Meissner's corpuscles
Pacinian corpuscles
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3
Q

Where are nociceptors located

A

Skin
Muscle
Connective tissue
Viscera

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4
Q

Define transduction

A

When a noxious stimulus is turned into an action potential

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5
Q

What mediators illicit transduction

A 
Substance P
PGs
Serotonin
Acetylcholine
Histamine
Glutamate
Adenosine
H+
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6
Q

How does a local inflammatory response affect pain perception

A

It causes peripheral sensitization which decreases threshold for pain stimulus and increases the frequency and rate of depolarization of nociceptors

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7
Q

How does a local inflammatory response affect pain perception

A

It causes peripheral sensitization which decreases threshold for pain stimulus and increases the frequency and rate of depolarization of nociceptors

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8
Q

What types of peripheral nerve fibers transmit are associated with the following

  • Free nerve endings
  • Specialized receptors
A

Free nerve endings = C fibers

Specialized receptors = A-delta fibers

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9
Q

What are 2 excitatory neurotransmitters in the dorsal horn

A

Glutamate

Substance P

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10
Q

How is pain in the face transmitted

A

The trigeminal nerve (CN V) bypasses the spinal cord conducting brain stimuli directly to the brain

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11
Q

What are the 4 steps of pain pathway

A
  1. Transduction
  2. Transmission
  3. Modulation
  4. Perception
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12
Q

What type of pain is transduced via A-Delta fibers

A

Fast pain that is sharp
Well-localized pain
Specialized receptors

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13
Q

What type of pain is transduced via C-fibers

A

Slow pain that is dull
Poorly localized pain
Free nerve endings

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14
Q

Define allodynia

A

Reduced threshold of pain stimulus

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15
Q

Define hyperalgesia

A

Increased response to pain stimulus

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16
Q

Name 5 drug classes that target pain during transduction

A
  1. NSAIDs
  2. Local anesthetic creams
  3. Steroids
  4. Antihistamines
  5. Opioids
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17
Q

Define transmission

A

The action potential that is relayed through the 3-neuron afferent pain pathway

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18
Q

How is pain transmission relayed

A

Via the spinothalamic tract:
First-order neuron = periphery to dorsal horn
Second-order neuron = dorsal horn to thalamus
Third-order neuron = thalamus to cerebral cortex

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19
Q

Which drug class targets pain during transmission

A

Local anesthetics

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20
Q

Define pain modulation

A

The pain signal is modified (inhibited or augmented) as it advances to the cerebral cortex

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21
Q

What is the most important site of pain modulation

A

Substantia gelatinosa in the dorsal horn (lamina 2 and 3)

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22
Q

Where does the descending inhibitory pain pathway begin and end

A

Begins: Periaqueductal gray and rostroventral medulla

Ends: substantia gelatinosa

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23
Q

What 2 mechanisms inhibit pain during modulation

A
  1. Spinal neurons releasing GABA and glycine

2. The descending pain pathway releasing norepinephrine, serotonin, and endorphins

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24
Q

What 2 mechanisms augment pain during modulation

A
  1. Central sensitization

2. Wind-up

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25
What 6 drug classes target pain during modulation
1. Neuraxial opioids 2. NMDA antagonists 3. Alpha-2 agonists 4. AchE inhibitors 5. SSRIs 6. SNRIs
26
Define pain perception
Processing of pain signals in the cerebral cortex and limbic system
27
What drug classes target pain perception
1. General anesthetics 2. Opioids 3. Alpha-2 agonists
28
What actions occur with the agonism of an opioid receptor
Agonism of the receptor instructs the G protein to "turn off" adenylate cyclase which decreases cAMP. The reduced cAMP alters ionic currents, reducing neuronal function
29
What type of receptor are opioid receptors
G protein
30
What is the ultimate ionic effect of opioid receptor agonism
1. Ca++ conductance is decreased (prevents NT release from nerve terminal) 2. K+ conductance is increase (prevents AP propagation)
31
What are the 4 types of opioid receptors
1. mu 2. delta 3. kappa 4. ORL-1
32
Where are opioid receptors located
1. Brain 2. Spinal cord 3. Sensory neurons 4. Immune cells
33
Where are opioid receptors located in the brain
1. Periaqueductal gray 2. Locus coeruleus 3. Rostral ventral medulla
34
Where are opioid receptors in the spinal cord located
1. Primary afferent neurons in dorsal horn | 2. Interneurons
35
``` What are the endogenous opioid ligand for each opioid receptor mu delta kappa ORL-1 ```
``` mu = endorphins delta = enkephalins kappa = dynorphins ORL-1 = nociceptin ```
36
What are the precursors for the endogenous opioids
Pre-proopiomelanocortin => endorphins Pre-enkephalin => enkephalins Pre-dynorphin => dynorphins
37
Which opioid receptor mediates bradycardia
Mu
38
What CNS effects result from mu opioid receptor agonism
Sedation Euphoria Prolactin release Mild hypothermia
39
What CNS effects result from kappa opioid receptor agonism
Sedation Dysphoria Hallucinations Delirium
40
Which opioid receptors result in miosis
Mu and Kappa
41
Which opioid receptors cause urinary retention
Mu and delta
42
How does kappa receptor agonism affect the GU tract
causes diuresis
43
Which opioid receptors cause n/v
Mu
44
Which opioid receptor affects shivering
Kappa
45
Which opioid receptors can illicit pruritus
Mu | Delta
46
What effects are associated with Mu-3 receptor
immune suppression
47
What effects are associated with Mu-1 receptor
1. Analgesia 2. Bradycardia 3. Euphoria 4. Low abuse potential 5. Miosis 6. Hypothermia 7. Urinary retention
48
What effects are associated with Mu-2 receptors
1. Analgesia (spinal only) 2. Respiratory depression 3. Constipation 4. Physical dependence
49
Which receptor can increase biliary pressure and by what mechanism
Mu | D/t contraction of the sphincter of Oddi
50
How do opioids affect ventilation centrally (3)
1. Shifts the CO2 response curve to the right, reducing ventilatory response to CO2 (depression) 2. Decrease RR 3. Increase Vt
51
How is the CO2 response curve affected by opioids
It shifts right, reducing ventilatory response to CO2 (takes increased CO2 to stimulate ventilation)
52
How do opioids affect pupil diameter | Which opioid receptor mediates this
Miosis (constrict) Mu and Kappa
53
What is the mechanism by which opioids produce miosis
Edinger Westphal nucleus stimulation leads to increased parasympathetic stimulation of ciliary ganglion and oculomotor nerve (CN 3)
54
How does opioid tolerance affect pupil diameter
Tolerance does not develop miosis
55
How do opioids elicit nausea and vomiting
1. Chemoreceptor trigger zone stimulation in medulla is stimulated 2. Interacts with vestibular apparatus
56
How is SSEP affected by opioids
No effect on evoked-potentials
57
What is the likely cause of HoTN from morphine or meperidine
Histamine release
58
What effect do opioids have on HR | Which opioid receptor mediates this
HR = bradycardia Mu
59
What effect do opioids have on BP
Minimal effect Decreased BP may be due to histamine release Dose-dependent vasodilation
60
What effect do opioids have on the baroreceptor reflex
No affect
61
What effect do opioids have on myocardial function
Contractility is not affected by opioids
62
How can increased biliary pressure caused by opioids be reversed?
Administration of naloxone or glucagon
63
What effect do opioids have on gastric emptying | Which receptor
Prolonged | Mu
64
What effect do opioids have on urination
1. Detrusor relaxation (contraction passes urine) | 2. Urinary sphincter contraction
65
Which opioids can produce histamine release
Morphine Meperidine Codeine
66
What immunologic effects come with opioid administration
1. Histamine release 2. Inhibition of cellular and humoral immune function 3. Suppression of natural killer cell function
67
What effect do opioids have on thermoregulation
Resets hypothalamic temperature set point, decreasing core body temperature
68
``` Compare the potency of the following opioids from greatest to least morphine meperidine sufentanil hydromorphone fentanyl alfentanil remifentanil ```
Sufentanil > fentanyl = remifentanil > alfentanil > hydromorphone > morphine > meperidine
69
``` What is the class of naturally occurring opioids Examples ```
Phenanthrene derivatives Example=morphine, codeine
70
What are 2 classes of semisynthetic opioids | Example for each
Morphine derivative Ex=hydromorphone, heroin, naloxone, naltrexone Thebaine derivative Ex=oxycodone
71
What are 3 classes of synthetic opioids | Example for each
Piperdines Ex=meperidine Phenylpiperdines Ex=Fentanyl, sufenta, remi, alfenta Diphenylpropylamines Ex=methadone
72
100 mcg of fentanyl is equivalent to how much morphine
10 mg
73
``` How much (dose) of the following drugs compare to 10 mg of morphine: Meperidine Hydromorphone alfentanil Remifentanil Fentanyl Sufentanil ```
``` Meperidine = 100 mg Hydromorphone = 1.4 mg alfentanil = 1000 mcg Remifentanil = 100 mcg Fentanyl = 100 mcg Sufentanil = 10 mcg ```
74
Define dependence
When a person taking a drug experiences withdrawal upon discontinuation of that drug
75
Define tolerance
When a person requires higher doses of a drug to achieve a given effect
76
Define cross-tolerance
When tolerance to one drug produces tolerance to another drug that has similar function or effect
77
Define addiction
It is a disease | Inability of a person to stop using a drug despite negative consequences from that drug
78
What is the most likely cause of tolerance and physical dependence
Receptor desensitization | Increased synthesis of cAMP
79
What are early vs late signs and symptoms of withdrawal
Early = diaphoresis, insomnia, restlessness Late = abdominal cramping, N/V
80
When/How does withdrawal from opioids occur
It is a function of the drug's half-life
81
When can withdrawal s/sx be expected to occur with the following (onset, peak, duration): Fentanyl and meperidine Morphine and heroin Methadone
Fentanyl and meperidine Onset=2-6 hrs Peak= 6-12 hrs Duration= 4-5 d Morphine and heroin Onset=6-18 hrs Peak=36-73 hrs Duration=7-10 d Methadone Onset=24-48 hrs Peak=3-21 d Duration=6-7 wks
82
Which opioid dose not undergo hepatic biotransformation
Remifentanil
83
Which opioids have active metabolites
Morphine Meperidine Hydromorphone
84
What is the active and inactive metabolite of morphine
Active = morphine-6-glucuronide Inactive = morphine-3-glucuronide
85
How does the active metabolite for morphine compare to morphine's solubility
M6G is more water-soluble so it tends not to cross the BBB at normal concentrations
86
How are dialysis patients affected by morphine
They are unable to excrete the M6G metabolite, so they are prone to accumulation Since the concentration of M6G is greater in the blood, M6G can cross the BBB entering the CNS for effect
87
Why are renal failure patients at increased risk for respiratory depression with morphine
D/t accumulation of the M6G active metabolite, which can cross the BBB inflicting greater CNS effects (i.e. depressed ventilatory drive)
88
What is the active metabolite for meperidine and how is it transformed
Normeperidine Meperidine is demethylated in liver
89
What effect does the active metabolite normeperidine have
Reduces the seizure threshold and increases CNS excitability -muscle twitches, tremors, sz
90
How does normeperidine potency compare to its parent compound
It is half as potent
91
Which patients should meperidine use be avoided
Dialysis | Elderly
92
How is remifentanil metabolized
In the plasma by erythrocyte and tissue esterases
93
Is remifentanil metabolism affected by pseudocholinesterase deficiency
No b/c it is not metabolized by pseudocholinesterase | It is metabolized by erythrocyte and tissue esterases
94
How does meperidine affect serotonin
It is a weak serotonin reuptake inhibitor
95
Co-administration of meperidine with MAOi's can lead to what complication
Serotonin syndrome
96
What are s/sx of serotonin syndrome
``` hyperthermia mental status changes hyperreflexia seizures death ```
97
What drug is meperidine structurally related? | How does this relation exhibited in meperidine's side effects?
Atropine Tachycardia Mydriasis Dry mouth
98
How does meperidine reduce shivering
Stimulation of the kappa receptor
99
Which opioid receptors are stimulated by meperidine
Mu | Kappa
100
What are 2 significant side effects of meperidine's active metabolite
Myoclonus | Seizures
101
What factors lead to rapid onset of alfentanil
pKa < physiologic pH pKa = 6.5 90% of alfentanil is non-ionized allowing it to diffuse the BBB
102
Which protein does alfentanil bind
Alpha-1-acid glycoprotein
103
``` Alfentanil: pKa = non-ionized % = Protein binding = Vd = ```
pKa = 6.5 non-ionized % = 90% protein binding = 92% alpha-1-acid glycoprotein Vd = l
104
``` Remifentanil: pKa = non-ionized % = Protein binding = Vd = ```
pKa = 7.2 non-ionized % = 58% Protein binding = 93% Vd = 0.39
105
``` Morphine: pKa = non-ionized % = Protein binding = Vd = ```
pKa = 7.9 non-ionized % = 23% Protein binding = 35% Vd = 2.8
106
``` Sufentanil: pKa = non-ionized % = Protein binding = Vd = ```
pKa = 8.0 non-ionized % = 20% Protein binding = 93% Vd = 2
107
``` Fentanyl: pKa = non-ionized % = Protein binding = Vd = ```
pKa = 8.4 non-ionized % = 8.5% Protein binding = 84% Vd = 4
108
``` Meperidine: pKa = non-ionized % = Protein binding = Vd = ```
pKa = 8.5 non-ionized % = 7% Protein binding = 70% Vd = 2.6
109
Which opioids have the highest and lowest pKa? | What does this mean for the non-ionized percent
Highest = Meperidine 8.5 -Very low 7% Lowest = alfentanil 6.5 -Very high 89%
110
Which opioids have the highest and lowest non-ionized percent
Highest = Alfentanil 89% Lowest = meperidine 7%
111
Which opioids have the greatest and least protein binding percent
Highest = Remifentanil and sufentanil 93% Lowest = Morphine 35%
112
Which opioids have the highest and lowest Vd
Highest = fentanyl 4 L/kg Lowest = Remifentanil 0.39 L/kg
113
What is the effect-site equilibration time for alfentanil? | How does this compare to fentanyl and sufentanil?
Alfentanil = 1.4 minutes Much quicker than fentanyl and sufentanil ``` Fentanyl = 6.8 minutes Sufentanil = 6.2 minutes ```
114
Compare the effect-site equilibration time for sufentanil, fentanyl, and alfentanil from quickest to slowest
Alfentanil 1.4 min < Sufentanil 6.2 min < fentanyl 6.8 min
115
What type of metabolism does alfentanil undergo
Hepatic cytochrome P450 via CYP3A4 - N-dealkylation - O-demethylation
116
How is the metabolism of alfentanil affected by erythromycin
It causes inhibition of alfentanil metabolism prolonging respiratory depressant effects
117
How is alfentanil clearance affected by renal failure
It is not altered
118
How does remifentanil potency compare to fentanyl and morphine 10 mg
It has equivalent potency to fentanyl 100 mcg of remi = 10 mg of morphine
119
What is the context-sensitive half-time fore remifentanil and why
4 minutes regardless of duration Because it is metabolized in the plasma by erythrocyte and tissue esterase
120
Despite remifentanil being highly lipophilic, why does it have a small Vd
Due to the fast rate of clearance via metabolism in plasma
121
How is remifentanil metabolism affect by the following: Hepatic dz Renal dz Pseudocholinesterase deficiency
Hepatic dz = no effect Renal dz = no effect Pseudocholinesterase deficiency = no effect
122
What phenomenon can occur following remifentanil discontinuation
Opioid-induced hyperalgesia | They require more postop opioids
123
How can opioid-induced hyperalgesia be mediated in patients receiving remifentanil infusions
Ketamine (blocks NMDA receptor) Magnesium sulfate (limits NMDA receptor activation by increasing Mg++ at the receptor site)
124
Can remifentanil be used intrathecally?
No, it should be avoided because remi powder is mixed with glycine, which is an inhibitory neurotransmitter in the spinal cord. This would cause skeletal muscle weakness
125
Which opioid receptor does remifentanil target
Mu
126
What 3 distinct mechanisms or action differentiate methadone from other opioids
1. Mu receptor agonism 2. NMDA receptor antagonism 3. Monoamine reuptake inhibition
127
What 3 circumstances is methadone useful
1. Chronic treatment of opioid abuse (to prevent withdrawal) 2. Chronic pain syndromes 3. Cancer pain
128
Structurally, how does methadone affect NMDA receptor
Dextrorotatory isomer from racemic mixture provides NMDA receptor antagonism
129
``` Methadone: Oral bioavailability= Duration= Metabolism= Metabolite= ```
Oral bioavailability= 80% Duration= 3 - 6 hrs Metabolism= liver P450 Metabolite= no active metabolite
130
What rare EKG event can occur with methadone use and why
QT prolongation leading to Torsades de pointes D/t inhibition of delayed rectifier potassium ion channel
131
What causes skeletal muscle rigidity with opioid use
Rapid IV administration
132
Which opioids more commonly cause skeletal muscle rigidity
More lipophilic compounds | -Sufentanil, fentanyl, remifentanil, alfentanil
133
What is the mechanism of skeletal muscle rigidity with opioid administration
Mu receptor stimulation in the CNS ultimately influencing dopamine and GABA motor pathways
134
What is the best treatment for opioid-induced skeletal muscle rigidity
Paralysis and intubation | Naloxone
135
What are 7 respiratory complications of opioid-induced muscle rigidity
1. Hypoxia 2. Hypercapnia 3. Increased O2 consumption 4. Decreased SvO2 5. Decreased Thoracic compliance 6. Decreased FRC 7. Decreased minute ventilation
136
What are 3 cardiovascular complications of opioid-induced muscle rigidity
1. increased CVP 2. Increased PAP 3. Increased PVR
137
What are GI/CNS complications of opioid-induced muscle rigidity
1. Increased ICP | 2. Increased gastric pressure w/ mask ventilation
138
In the patient with opioid-induced muscle rigidity, where is the greatest resistance to ventilation
Larynx
139
What are 3 benefits of partial opioid agonists
1. Produce analgesia w/ less risk for respiratory depression 2. Low risk of dependence 3. Use in patients who cannot tolerate a full opioid agonist
140
What are 4 drawbacks of partial opioid agonists
1. Have a ceiling effect 2. Reduce efficacy of previously administered opioids 3. Can cause opioid withdrawal in opioid dependent patient 4. Can cause dysphoric reactions
141
Buprenorphine: Mechanism= Analgesia compared to morphine= Naloxone reversal?=
Mechanism= partial mu agonist Analgesia compared to morphine= GREATER Naloxone reversal?= difficult d/t high affinity for mu receptor
142
Nalbuphine: Mechanism= Analgesia compared to morphine= Naloxone reversal?=
Mechanism= Kappa agonist, Mu antagonist Analgesia compared to morphine= similar Naloxone reversal?= yes
143
Butorphanol: Mechanism= Analgesia compared to morphine= Naloxone reversal?=
Mechanism= Kappa agonist, mu antagonist (weak) Analgesia compared to morphine= GREATER Naloxone reversal?= Yes
144
Why is buprenorphine resistant to naloxone reversal
Because buprenorphine has a very high affinity for mu receptors, much greater than naloxone
145
What is the duration of buprenorphine
8 hrs
146
What beneficial CV effects does nalbuphine have
Doesn't increase BP, PAP, HR, or RAP | Useful in pts w/ heart dz
147
Which partial opioid agonist is useful in postop shivering
Butorphanol
148
Which partial opioid agonists can be administered intranasally
Butorphanol | Buprenorphine
149
What type of drug is naloxone
Opioid antagonist
150
What is the mechanism of action of naloxone
Competitively antagonizes the mu, kappa, and delta opioid receptors. Greatest affinity is to mu receptor
151
``` Naloxone: Dose= Duration= Metabolism= Repeat dosing= ```
Dose= 1 - 4 mcg/kg (20 - 40 mcg at a time) Duration= 30 - 45 min Metabolism= Liver Repeat dosing= depends on the duration of the opioid being reversed
152
When should a naloxone infusion be considered
When the opioid being reversed is long-acting
153
What s/sx are associated with opioid reversal in patients with pain
SNS activation causing - Neurogenic pulmonary edema - tachycardia - cardiac dysrhythmias - sudden death
154
How are SNS effect minimized with naloxone administration
Slow titration to minimize SNS effects (20 - 40 mcg at a time)
155
What effect does naloxone have in the neonate
It crosses the placenta, so it can precipitate acute opioid withdrawal in the neonate
156
How can patients receiving neuraxial opioids obtain relief from pruritis
Naloxone infusion
157
What are the benefits of methylnaltrexone
It does not cross the BBB d/t its quaternary amino group | It is useful in relieving peripheral effects of opioids like constipation
158
what is the dose and duration of nalmefene
``` Dose = 0.1-0.5 mcg/kg Duration= 10 hrs ```
159
How does naltrexone differ from naloxone in duration and metabolism
``` Duration = 24 hrs when given orally Metabolism= doesn't undergo first-pass metabolism like naloxone ```
160
Which opioid antagonist does NOT reverse opioid-induced respiratory depression
Methylnaltrexone
161
What are 2 benefits of IV PCA vs PRN IV analgesia
1. Better postop analgesia | 2. Improved patient satisfaction
162
How does the incidence of respiratory depression with IV PCA compare to PRN analgesia
The incidence is not higher
163
What factors can increase the risk of respiratory depression in the patient receiving IV PCA
1. Basal infusion rate 2. Administration of other sedatives 3. Old age 4. Pulmonary dz 5. OSA
164
What is the lockout interval for IV PCA based on
The time it take for the demand dose to reach an effective plasma concentration
165
How do scheduled NSAIDs affect IV PCA opioid requirements
reduces requirements
166
What is the most sensitive measure of respiratory depression in patients receiving IV PCA
Monitoring EtCO2

APEX Pharmacology (8 decks)

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