Pharmacology of Opioid Analgesics Flashcards
1
Q
Analgesia definition
A
block pain neurotransmission; antinociception
2
Q
Anesthesia definition
A
block sensory neurotransmission; pain, motor and autonomic pathways
3
Q
Nociception definition
A
pain sensation
4
Q
qd
A
once daily
5
Q
bid
A
twice a day
6
Q
Q12
A
every 12 hrs
7
Q
tid
A
three times a day
8
Q
qid
A
four times a day
9
Q
What happens when tissue is damaged
A
release of cytokines, chemical mediators
increase vascularization, sensitize somatosensory nervous system, promote recovery
10
Q
Types of pain
A
thermal, mechanical, and chemical
11
Q
Co-morbidities with chronic pain
A
anxiety, depression, insomnia/disrupted sleep, activation of glia, hyperalgesia, allodynia
12
Q
How are pain signals transmitted
A
pain signals are transmitted to the CNS where different aspects of the pain signal are processed by specific brain regions
13
Q
Assigns aversive or pleasurable qualities to pain
A
nucleus accumbens
14
Q
Involved with fear processing associated with pain expectation
A
amygdala
15
Q
important for determining what action should be taken to deal with pain (fight or flight)
A
frontal cortex
16
Q
Key brain regions expression opioid receptors
A
- periagueductal gray (PAG)
- rostral ventral medulla (RVM)
- dorsal root ganglion (drg)/dorsal horn
17
Q
Two types of alkaloids that opium contains
A
- Phenanthrenes
2. Benzylisoquinolines
18
Q
Mu opioid receptor structures can be divided into
A
phenanthrene and non-phenanthrene alkaloids
19
Q
Phenanthrene opioids primarily show differences where
A
at the 3 and 6 position
20
Q
How is antagonist of phenanthrene opioids conferred
A
conferred by bulky side groups indicated in the red circle
21
Q
Why is it worthwhile to switch between phenanthrene and non-phenanthrene opioids in patients that are not responsive/show strong side effects to one type
A
it is suggested that some patients respond better to phenanthrene than non-phenanthrene opioids and vice versa
22
Q
Phenanthrenes
A
morphine, hydrocodone, buprenorphine, naloxone
23
Q
Non-phenanthrenes
A
tramadol, meperidine, fentanyl, and methadone
24
Q
Metabolism of phenanthrene opioids occurs primarily by
A
glucorinidation at the 3 and 6 position
25
Activity of morphine-6-glucoronide
metabolite that is still pharmacologically active
26
Where is morphine/phenanthrenes metabolized
large hepatic (CYP2D6) and can be impaired by patients with liver disease or genetic difference in the make up of their liver enzymes
27
Where is morphine/phenanthrenes excreted?
excreted through the kidneys by glomerular filtration
28
Describe opioid receptors
G protein-coupled receptors
family A- peptide receptors
Gi/o - coupled (inhibition of cAMP production)
29
Three types of opioid receptors
Mu, Kappa, Delta, Nociceptin orphanin FQ receptor
30
Are there currently kappa or delta opioid-selective FDA approved drugs
No
31
Therapeutic targets for the mu opioid receptor
analgesia (not acute sharp localized pain, not neuropathic pain, cancer pain, peripheral, PCA)
sedation
antitussive (supress cough reflex)
32
Natural ligand for the mu opioid receptor?
beta-endorphine (endogenous morphine)
pro-opiomelanocortin (POMC)
"runners high"
33
Side effects from the mu opioid receptor
respiratory depression, constipation, pruritis, tolerance/dependent, urinary retention, nausea/vomiting, muscle rigidity, miosis
34
Kappa opioid receptor are involved in what type of feedback loop
negative feedback loop, inhibiting the release of dopamine
35
Describe the negative feedback loop with the kappa opioid receptor
initial release of dopamine causes transcription of dynorphin, the endogenous kappa opioid agonist; release of dynorphin will activate presynaptic Kappa receptors on dopaminergic terminals, inhibiting further release of dopamine
36
Endogenous kappa opioid agonist
dynorphin
37
Kappa opioid receptor has potential for use of treatment of
addiction
38
Salivinorin A
Kappa opioid receptor agonist, not an alkaloid
39
Delta opioid receptors are being considered as target for
anxiety, depressive and alcohol use disorders, preventing ischemic damage
40
Natural ligands for the delta opioid receptor
enkephalins
41
Endogenous peptides released during hibernation act on which receptors
delta receptors
42
When are delta opioid receptors upregulated
during chronic stimulation, such as during chronic inflammation and nerve damage, thus making it an interested target for treatment of chronic pain
43
Effect of Mu opioid receptor activation
analgesia, euphoria and mood effects, respiratory depression, miosis, neuroendocrine regulation, decreased GI motility, autonomic regulation, tolerance and withdrawal
44
Endogenous Mu opioid receptor peptide affinity
Endorphins
45
Effect of Kappa opioid receptor activation
analgesia, diuresis, sedation, dysphoria and psychotomimetic, less miosis, less respiratory depression, little dependence
46
Effect of Delta opioid receptor activation
analgesia, mood, hypoxia, chronic pain, alcohol addiction
47
Effect of Orphanin opioid-receptor-like sybtype 1 (ORL1), Nociceptin receptor activation
controversy actions, opposes classic mu effects, mediate pain
48
Endogenous ORL1, Nociceptin peptide affinity
Nociceptin/Orphanin FQ
49
Opioids bind to
opioid receptors which are G-protein coupled receptors
50
All opioid receptors are
Gi/o-coupled causing inhibition of adenylyl cyclase induced cAMP production
51
Opioid receptors also activate which channels (besides G-protein coupled)
GIRK channels (G-protein activated inwardly rectifying potassium channels) causing hyperpolarization, inhibiting neurotransmitter release
52
Where are opioid receptors located on the neuron
located both presynaptic and postsynaptic
53
Presynaptic inhibition of neurotransmitter release is mediated by
inhibition of calcium uptake
54
Postsynaptic inhibition of pain transmission is by
inducing hyperpolarization throgh activation of GIRK channels -> effux of K+
55
Clinically used opioid receptor agonists (strongest)
sufentanil, remifentanyl, fentanyl, hydromorphone (Dilaudid), morphine, hydrocodone, oxycodone
56
Opioid receptor agonists used most often in surgical settings
sufentanil, remifentanyl, fentanyl
57
Opioid receptor agonists used most often post-surgically
hydromorphone and morphine
58
Orally available opioid receptor agonists
hydrocodone (Lortab/Vicodin/Norco) and Oxycodone (oxycontin/percocet)
59
Clinical used opiod receptor agonists not as strong
Methadone, Meperidine (Demerol), Codeine, Tramadol (Ultram), Loperamide (Imodium), Propoxyphene (Darvon)
60
Meperidine (Demerol) used to treat
rigors
61
Tramadol (Ultram) used when
painkiller used when you don't want to prescribe a stronger opioid
62
Loperamide (Imodium) used as
an anti-diarrheal
63
Why is risk of dependence low with Loperamide (Imodium)
PgP substrate -> low BBB penetration -> doesn't get into the CNS with risk of dependence is lower
64
When is Propoxyphene (Darvon) used
withdrawn due to heart rhythm abnormalities
65
Non phenanthrene opioids
Tramadol (Ultram), Tapentadol (Nucynta), Meperidine (Demerol)
66
Tramadol (Ultram), Tapentadol (Nucynta) have what kind of properties
SNRI properties; 5HT/NE reuptake inhibitor, stimulate 5HT release
67
Activate metabolite of Meperidine (Normeperidine) can do what?
can accumulate and cuase CNS irritability and myoclonic seizures
68
When is Meperidine recommended?
not recommended without good justification; dangerous in patients with decreased renal function
69
Opioids with NMDA action
Methadone and Levorphanol
70
Methadone
primarily used for opioid dependence; NMDA antagonist; chronic pain; long duration of action
71
Levorphanol
analgesic half-life is shower than the serum half-life of drug; NMDA antagonist; neuropahtic pain
72
Why is antagonism at NMDA receptors useful?
NMDA receptors are upregulated in chronic pain
73
What is upregulated during chronic pain establishment
AMPA and NDMA receptors
74
Buprenorphine
partial mu agonist, weak K agonist and delta antagonist; long acting; low tolerance, dependence and addiction, used to treat opioid withdrawal in addiction therapy
75
Buprenorphine as a partial agonist can activate?
mu receptors and cause euphoria and analgesia to a lesser extent than a full agonist like morphine would
76
If a patient is already using a full agonist buprenorphine will work as a
antagonist and can thus induce some withdrawal signs
77
Partial mu antagonists
Naloxone (Narcan) and Naltrexone (Revia/vivitrol)
78
Which opioids are used for surgery and why?
fentanyl, sufentanil, remifentanil
| fast onset, short duration
79
Which opioids are used postop and for epidurals and why?
hydromorphone (dilaudid) and morphine
| 4-5X more potent than morphine, greater half life than fentanyl
80
Which opioids are used for management of pain and why?
oxycodone, hydrocodone, oxycontin, and zohydro
| oral bioavailability, greater half life than fentanil
81
Which opioid is used for terminal cancer pain and why?
morphine
| low cost, history of knowledge, risk of dependence not an issue in a terminal cancer patient
82
Which opioid is used for opioid intolerance and why?
Merperidine (Demerol)
constipation less common than with morphine; seizure, delirium, neurotoxic, metabolites not blocked by NTX; MAO inhibitors contraindicated
83
Administration routes of opioids
IV, intramuscular, intraaxial, intrathecal, epidural, oral, topical/transdermal/transmucosal
84
Why are opioids like remifentanyl, sufentanil useful for inducing and maintaining surgial analgesia/anesthesia?
they reach peak plasma level quickly and are quickly excreted
85
Rationales for opioid rotation
1. lack of initial efficacy, despite titration to acceptable levels
2. decreased efficacy over time (tolerance)
3. side effects that cannot be tolerated or adequately remedied
4. insurance coverage and cost constraints
86
How do you calculate an equianalgesic dose?
1. convert each opioid to equi-analgesic morphine dose
2. combine morphine equivalents to calculate total daily opioid dose
3. calculate daily equivalent dose of new opioid
87
At a low dose, opioids will cause
euphoria and pain relief
88
At a high dose of opioids, patients will experience
constipation, miosis, urinary retention, itch and respiratory depression
89
Major side effect of prolonged opioid use
constipation
90
Major strategy of dealing with opioid induced constipation (OIC)
peripherally restricted opioid antagonists
91
Preventive and acute management of ileus and constipation
senna, polyethylene glycol (Miralax) and dioctyl sodium sulfosuccinate/docusate
92
Senna
Irritates colon, causes fluid secretion/colonic contraction
93
Polyethylene glycol (Miralax)
stool softener; osmotic increase in GI water content
94
Dioctyl sodium sulfosuccinate/docusate
stool softener; peristalsis greater than 400 mg/day
95
Peripherally restricted my opioid antagonists
Methylnaltrexone (Relistor), Alvimopan (Entereg), Naloxegol (Movantik), and Naldemedine
96
Is opioid induced itch an allergic reaction?
No
97
What causes opioid induced pruritis?
heteromer of a mu opioid receptor splice variant and the gastrin releasing peptide receptor
98
Opioid tolerance
analgesic effects, nausea, urinary retention, respiratory depression, euphoria
99
Biggest risk of death with opioid tolerance in which people
biggest risk of death in withdrawn patients/users (addicts that relapse)
100
Changes seen with tolerance
increased dose required to produce equivalent effect
receptor adaptation
decreased receptor number
decreased coupling to effector
101
Changes seen with hyperalgesia
compensatory changes
| altered excitability of target neurons
102
Neurotransmitters involved with opioid induced hyperalgesia
NMDA, cholecystokinin, dynorphin, substance P
103
What causes persistent inhibition of adenylyl cyclase with opioid tolerance
activation of MORs by morphine and many other Mu opioid receptor agonists does not lead to strong phosphorylation and desensitization of the receptor
104
In response to maintain homeostasis in opioid tolerance, what does the cell do?
the cell upregulates adenylyl cyclase -> causes an increase in cAMP production leading to cellular tolerance to t he opioid effect
105
Honestly just go learn the opioid tolerance mechanism really well
It's too complicated to put into flashcards
106
Signs of opioid induced hypersensitivity
pain not relieved (exacerbated) by opioid
diffuse pain
cold pressor test (emerge arm in ice bath and check time to withdraw)
107
What to do with signs of OIH?
```
switch opioid class
phenanthrenes vs non-phenanthrenes
```
108
Opioid detox
switch to clonidine/diazepam
109
Use extreme caution when administering opioid to patients with
compromised respiratory function
| chronic bronchitis, asthma, emphysema
110
Opioids and seizure disorders
opioids may aggravate pre-exisint seizure problems
111
Opioid drug-drug interactions
```
Depressants (alcohol, benzos, barbituarates)
Antipsychotics
TCA antidepressants
Antihistamines
Meperidine (MAOs, SSRIs)
```
112
Symptoms of morphine and heroin overdose
coma, depressed respiration, pinpoint pupils (miosis), needle marks, mixed poisonings
113
Treatment for acute opioid overdose
restore respiration, maintain CV function, Naloxone (opioid antagonist)
114
FDA approved opioids to treat opioid abuse
methadone, buprenorphine, suboxone, zubsolv
115
Suboxone
buprenorphine + maloxone
116
The presence of naloxone in suboxone is used as
an abuse deterrent
117
What do some opioids for treating diarrhea contain as an abuse deterrent?
atropine
118
Agonist maintenance to treat opioid addiction
methadone maintenance therapy; cross tolerance to heroin can reduce illicit drug use
119
Partial agonist therapy for opioid addiction
buprenorphine; cross tolerance; pharmacologically blocks effects of opiate agonists
120
Antagonist therapy for opioid addiction
naltrexone; long-term treatment; does not alleviate cravings
121
Should you prescribe opioids?
Yes but with proper awareness, monitoring, communications with the patient
122
Opioids to treat alcohol use disorders
Naltrexone, Nalmefene
