Analgesics: Opioids Flashcards
1
Q
what are endogenous opioids ?
A
neurotransmitters in specialised CNS tracts
sometimes in periphery e.g. GI tract but not as common
2
Q
where are the cell bodies of endogenous opioids and where do they synapse?
A
RVM, PAG, and synapse in spinal cord laminae I-II
RVM - rostral ventromedial medulla
3
Q
where do the axons on endogenous opiod systems project/signal to ?
A
- to or within the PAG
- LC/Raphe
- spinal cord
4
Q
PAG in top down control
A
drives activation of LC and Raphe neurons, leads to disinhibition of internuerons for pain modulation in the descending pathway
disinhibition = inhibition of inhibitory interneurons
5
Q
what do opioids do to neurons in the PAG ?
A
reduce inhibition of PAG (excite/disinhibition) neurons, which activate inhibitory internurons in SC, reducing pain signal
6
Q
where do we mostly see the action of endogenous opioids ?
A
areas relating to processing or modulation of pain/nociception
higher centres rather than nociceptors themselves
7
Q
what is the opioid ascending pathway ?
A
A and C nociceptive fibres sending information into spinal cord at lamine I and II that projects to PAG and into the cortex (somatosensory/cingulate)
8
Q
descending opioid pathway
A
from PAG and recruits cells from Locus Coeruleus (NE) and Raphe Nuclei (5HT), synapses again in the spinal cord to dampen pain signal from second order neurons
9
Q
where is the site of endogenous opioid induced analgesia ?
A
PAG and spinal cord
10
Q
what are endogenous opioids in terms of composition ?
A
- peptide proteins
- high AA homology (similar structures)
suggests they have similar effects at similar receptors
11
Q
what are 3 endogenous opioids ?
A
- endorphins
- enkephalins
- dynorphins
12
Q
when are endogenous opioids release ?
A
- in response to pain
- during sport (‘runners high’)
accupuncture too - no clinical evidence
13
Q
what are the 3 receptors that recognise opioid peptides ?
A
- Mu opioid receptor (MOPr)
- Delta opioid receptor (DOPr)
- Kappa opioid receptor (KOPr)
14
Q
what is special about NOPr ?
other related (opioid like) receptors (NOPr)
A
shows a high AA sequence homology but doesn’t recognise opioid peptides but recognises similar peptide nociceptin
15
Q
Mu opioid receptor (MOPr) (5 points)
A
- 3 subtypes (MOPr1-3)
- opens K+ channels (hyperpolarisation in inhibitory interneuron)
- GIRK2 (G-protein activated inwardly rectifying K+ channel subunit)
- hyperpolarisation reduces neuronal activity, inhibiting the release of neurotransmitters due to Ca2+ actions beind reduced e.g. ACh, Glu, SP
- targets inhibitory neurons controlling PAG output (disinhibition - inhibits inhibitory interneurons that prevent PAG output from reducing pain signalling (they can now signal))
16
Q
what opioid receptor do we see most (not all) analgesic effects through ?
A
MOPr
17
Q
what are some side effects of MOPr acivation ?
A
- respiratory depression (peripheral)
- constipation (peripheral)
- euphoria
- sedation
- dependence
18
Q
what do we know about the delta opioid receptor ?
5 points
A
- DOPr 1-2 (2 subunits)
- 7 TMDs (GPCRs)
- acts similar to MOPr
- produces analgesia
- can be ‘proconvulsant’
19
Q
how is DOPr a ‘proconvulsant’ ?
A
reduced inhibition can lead to a generalised increase in excitation
disinhibiting neurons can lead to convulsive state due to overactivity of neuronal circuits
20
Q
what do we know about the Kappa opioid receptor ?
5 points
A
- KOPr1-3 (3 subunits)
- acts by reducing Ca2+ channel activity in presynaptic membrane
- less depolarisation; less neurotransmitter release
- analgesia at spinal level
- potential activation in the brain
21
Q
what suggests Kappa opioid receptors are linked to having phenotypes activated in the brain ?
A
sedative effects, hallucination and dysphoria
22
Q
what is the main mechanism of all opioid receptors ?
6 points
A
- GPCRs
- opioid binds, G protein negatively linked to adenylate cyclase
- AC decrease reduces Ca2+ entry (due to dephosphorylation of presynaptic Ca2+ channels)
- decreases neurotransmitter release
- increased potassium conductance via cell membrane
- cell becomes more hyperpolarised
23
Q
opioid vs opiate
A
- An opioid a drug that acts at the opioid receptors
- An opiate is an opioid derived from opium poppies
24
Q
what are the three main opitaes from opium poppies ?
A
- morphine
- codeine
- thebaine
25
what is heroin and how is it made ?
- it is a synthetic opioid
- produced by chemically modifying moorphine that has been purified from opium poppies
26
what are one of the major sites of pain management ?
dorsal horn of spinal cord
## Footnote
allow transmission of noiciceptive signals and modulation of signal
27
wher are opioid receptors present in pain management ?
- PAG
- LC
- Raphe
- Ascending tracts (projection neurons)
28
what are the three main ways that opioids are involved in pain management and acting as analgesics ?
## Footnote
(damped down pain signal)
- block release of Glu and SP reducing signal onto projection neuron
- mimic Enk+ interneurons (add inhibition onto projection neurons)
- enhance descending control of PAG
## Footnote
these 3 things are convering actions, all decrease pain signal, decreasing perception of pain through different mechanisms
29
how do opioids affect nociceptor circuity / pain management ?
- morphine (opioid/agonist) causes activation of K+ channels, causing efflux, reducing membrane potential
- reduces neurotransmitter release, dampening down projection neuron output (reduced firing/response)
30
what do we get with sensory input + opiate vs control ?
- control shows depolarisation of membrane and signal going out from projection neuron
- adding opiate (morphine or enkephalin) dampens down response and signal sent to the brain is weaker
31
32
What are the two types of opioids discussed?
Endogenous and exogenous opioids
## Footnote
Endogenous opioids are produced within the body, while exogenous opioids are introduced from outside sources, such as medications.
33
What is a major site of pain management within the body?
Dorsal horn of the spinal cord
## Footnote
The dorsal horn is where nociceptive signals are transmitted and modulated.
34
What are the primary afferents that sense nociceptive signals?
C fibers and A delta fibers
## Footnote
These fibers become activated during tissue damage and transmit pain signals.
35
What substances potentiate the nociceptive signal?
Substance P and glutamate
## Footnote
Both substances enhance the transmission of pain signals in the nervous system.
36
How do opiates affect the release of certain neurotransmitters?
They reduce the release of glutamate and substance P
## Footnote
This reduction helps to decrease the transmission of nociceptive signals.
37
What role do enkephalin-containing interneurons play in pain transmission?
They inhibit secondary projection neurons
## Footnote
This inhibition reduces the transmission of nociceptive signals to the brain.
38
What is the pain gate theory?
It describes how non-nociceptive A beta fibers can inhibit nociceptive signals
## Footnote
This theory explains how certain stimuli can dampen the perception of pain.
39
What areas of the brain are involved in descending control of pain?
Periaqueductal gray (PAG), locus coeruleus, and nucleus raphe magnus
## Footnote
These areas are involved in modulating pain signals descending from the brain.
40
What are the three main actions of opioids in pain modulation?
* Block release of glutamate and substance P
* Mimic enkephalin action
* Enhance descending control from the PAG
## Footnote
These actions converge to decrease the perception of pain.
41
What happens to the output of projection neurons when opioids are administered?
The output signal is dampened
## Footnote
This results in a weaker transmission of pain signals to the brain.
42
what are the dual actions of opiates ?
at both the pre and post synaptic terminals
43
why is the reduction in calcium important presynaptically ?
prevents release of neurotransmitters from vesicles as calcium dependent enzymes are important for this
44
what are some other parts of the body that may produce endogenous opioids outside of neurons?
- adrenal medulla
- activated immune cells
45
What are the two classes of opioid drugs?
Opiates and synthetic opioids
## Footnote
Opiates are derived from poppy seeds, while synthetic opioids are chemically manufactured.
46
what are the 3 commonly used groups of opioids ?
- agonists
- antagonists
- 'mixed' action compounds
47
Name a few classical opioid agonists.
* Morphine
* Codeine
## Footnote
These are commonly used for pain management.
48
What are opioid antagonists?
* Naloxone
* Naltrexone
## Footnote
These drugs block opioid receptors and can reverse the effects of opioids.
49
What is an example of a mixed action opioid?
Buprenorphine
| (also pentazocine)
## Footnote
This drug has complex actions at opioid receptors, affecting analgesia and side effects.
50
What effect do opioids have on potassium channels?
They activate potassium channels
## Footnote
This leads to hyperpolarization of neurons, reducing excitability.
51
what is a full agonist ?
a drug that produces maximum response possible from a receptor
52
what is a partial agonist ?
a drug that produces a submaximal response from a receptor, even when it occupies all the receptor
53
what is an antagonist ?
a drug that blocks the effects of agonists and inverse agonists
54
what is an inverse agonist ?
a drug that produces an effect oposite to that of an agonist
55
receptor response diagram for full agonist, partial agonist, antagonist and inverse agonist
56
what is the classical opioid agonist ?
morphine
57
what are the effects of central action from opioid agonists (morphine-like) ?
- analgesia, sedation, anti-tussive cough suppression)
- euphoria
- respiratory depression, nausea, itch
58
what are the effects of peripheral action from opioid agonists (morphine-like) ?
- reduced inflammation, increased threshold for pain
- acts on GI tract (MOPr, DOPr) e.g. loperamine (immodium)
59
what is loperamine ?
## Footnote
morphine-like actions
(immodium)
- Mu agonist, can't cross BB (not analgesic)
- reduced gut motility
- opiate addicts have constipation
60
at what level do opioid agonists work ?
- supraspinal (above spine): MOPr1, DOPr1, DOPr2, KOPr3
- spinal (dorsal horn): MOPr2, DOPr2 (KOPr1?)
61
what are the effects of opioid agonists in general ?
- increase pain threshold
- decrease pain tolerance
62
what kind of pain do opioid agonists work better for ?
dull pain (C fibres)
63
where is morphine an agonist at ?
Mu receptor (MOPr)
64
what are some additional side effects of morphine ?
- nausea, vomiting, consitpation, pupillary constriction, bronchoconstriction, hypotension, respiratory depression
## Footnote
pupillary constriction is different to many drugs
65
what is the active metabolite of morphine and why is this potentially better for new drug development ?
- morphine-6-glucuronide (M6G)
- lessened nausea
- retains strong MOPr agonism
66
what is diamorphoine ?
(diacetly morphine)
heroin
67
order for analgesic efficacy of opioid agonists
diamorphine > morphine > codeine
## Footnote
modulate central perception of pain signal on different levels/ start with codeine and work up if need higher analgesic efficacy
68
order for absorption/ onset of action for opioid agonists
diamorphine > morphine
## Footnote
concerns lipid solubility, diamorphine has high and therefore absorbed into CNS across BBB faster
69
how does absorption of opioid agonists related to duration ?
diamorphine > morphine as more lipid soluble
70
what side effect is codeine highly associated with ?
nausea
71
what side effect is pethidine (opioid agonist) highly associated with ?
convulsions
72
fentanyl as an opioid agonist
- rapid onset
- morphine-like actions
- chronic cancer pain management
- post-surgical analgesia
- can be by 'patch'
- abused
73
methadone as an opioid agonist
- much longer duration (24hrs)
- less withdrawl than morphine
- can 'wean' dependents from opioid addicition
74
oxycodone as an opioid agonist
- used for acute and chronic pain
- abused; particularly in the US with perscription for chronic pain
75
in what kind of cases are opioid agonists often given ?
- distressed patients/shock/acute pain
## Footnote
vs chronic pain
76
what is an example of a partial opioid agonist ?
buprenorphine
77
what is buprenorphine ?
- partial MOPr agonist
78
what are the effects of buprenorphine ?
- analgesia, other opioid effects
- sedative, nausea, vomitting, respiratory depression, complex side effects
- reduced abuse potenial
- less intense withdrawl compared to morphine
- can be used to treat opioid dependence (similar to methadone)
79
why can we get complex side effects with buprenorphine ?
it can act as an antagonist as KOP receptors
80
what is the result of the ceiling effect of buprenorphine ?
- limits respiratory depression
- limit euphoric effects so reduced abuse potential
81
what is nalorphine ?
- mixed action opioid compound
- DOPr and KOPr partial agonist
82
what are the effects of nalorphine ?
- SOME analgesia (lower): lower abuse potential
- dysphoria (depressive like symptoms): not used clinically
83
what is pentazocine ?
(talwin)
('mixed effect' compound)
- MOPr antagonism
- KOPr agonism
84
what is the result of pentazocine MOPr antagonism and KOPr agonism?
MOPr antagonism:
- reduced euphoria
- reduced abuse potential
- limited respiratory depression
KOPr agonism
- analgesia
- ceiling effects
- potential effects on DA system
85
what can pentazozine be used for clincally and why ?
- reducing manic symptoms in bipolar
- as it effect DA system at the KOP receptors
86
what is tramadol and what does it do?
- 'mixed effect'
- (ultram for brand name)
- MOPr agonist (weak, analgesic for moderate-severe pain)
- weakly inhibits monoamine reuptake
- inhibits GABA-A/NMDAR at high doses
87
what is a similar drug to tramadol and what is it used for theraputically ?
- tepentadol (TAP)(same mechanisms)
- neuropathic pain
## Footnote
used therputically as inhibits break down and reuptake of monoamine affecting system through which neurotransmitters are relased and taken back up
88
a labeled diagram for the effects of tramadol
89
what are the 3 main categories of non-analgesic effects of opioids ?
- cough suppression
- nausea & vomiting
- tolerance & dependence
90
what is another name for cough suppression ?
anti-tussive
91
how can we chemically modify morphine to only get the anti-tussive effects ?
- add large subsituent at position 3 on morphine to produce codeine and dextromethorphan
- action via MOPr/DOPr
- likely though 'cough centre' in medulla
## Footnote
cough reflex
92
where do we get nausea and vomiting from ?
- activation of the chemoreceptive trigger zone (CTZ) in the medulla oblongata which feeds into vomit reflex
- this region contains opioid receptors, so can be activated by drugs/toxins/opioids
- can also be activated peripherally by motion sickness which is sense by vestibular nuclei, which activates CTZ
- vomite centre can also be activated by sensory input from cerebral cortex (pain, smell)
- leads to vomit reflex
93
how can tolerance be demonstrated ?
in vivo (e.g. animal models)
## Footnote
important in pharamcological and behavioural study
94
how can we perform an in vivo treatment of a mouse with morphine for studying tolerance of opioids ?
- 1st morphine treatment to mouse (subcutaneous)
- 2nd morphine tretament given after delay: how much morphine do we need to get to give same analgesic effect ?
- amount of morphine needed increases over time for the same analgesic effect: measured in amount of time taken for mice to withdraw feet from hotplate
- shows system becomes tolerant, which can lead to dependance
95
how is tolerance and dependence demonstrated on a molecular level in terms of opioids?
- (morphine) inhibit cAMP production
- system responds by increasing adenylyl cycalse expression (tolerance) in an attempt to restore cAMP formation
- remove morphine: less inhibition and so large spike of cAMP production (dependence)
- this produces some of the effects of physical dependence
## Footnote
AC leads to cAMP production with ATP
96
how are opioid antagonists synthesised ?
through modification of morphine structure
97
what is an example of an opioid antagonist and how is this formed?
naloxone
- (on morphine) substitution of large groups of N atom (plus other small changes)
98
what is naloxone ?
- first opioid antagonist to be discovered
- competitive anatagonist at all 3 opioid receptors (MOPr,DOPr,KOPr)
- most active at MOPr
99
what are the effects if we use naloxone (opioid antagonist) alone ?
- very little effect
- respiratory depression in drug addicts
- respiratory depression in newborns when opioid analgesics are given during delivery
100
what are the effects if we use naloxone (opioid antagonist) after an agonist ?
- reverses all effects of full agonists
- reverses action of mixed action compounds but requires large dose
- used to treat respiratory depression
- short action and metabolised in the liver
101
what are the effects of using naloxone (opioid antagonist) in opioid-dependent patients ?
- precipitae (trigger) withdrawl syndome (rapidly, severely)
- used to treat opioid overdose in dependent px
- titrate carefully to reverse respiratory depression, without withdrawl
- potential to be used in treatment of dependence ?
102
What major health crisis has emerged in the United States since 2000?
An explosion in opioid use and opioid-related deaths
## Footnote
This crisis has led to thousands of lives lost and has affected life expectancy.
103
What two drugs are primarily driving the opioid crisis?
* Fentanyl
* Oxycontin
104
What is oxycodone?
A synthetic opioid (similar to heroin and twice as powerful as morphine)
## Footnote
active ingrediant in oxycontin
105
When was the extended release formulation of oxycodone?
oxycontin
- Purdue Pharma produced Oxycontin, marketed as effective for 12 hours with minimal risk of addicition
106
What was the actual effectiveness duration of Oxycontin as reported by patients?
4-6 hours
## Footnote
This discrepancy led to increased dependency on the drug.
107
What marketing strategy did Purdue Pharma use regarding Oxycontin prescriptions?
- Encouraged larger doses every 12 hours instead of switching to an 8-hour schedule
- also encourage use of oxycontin for types of pain which opioids would not normally be a first line treatment for
## Footnote
resulted in pateients becoming dependent on oxycontin
108
Define 'pill mill'.
A clinic that specializes in prescribing opioids to patients who do not need them
## Footnote
These clinics often facilitate drug abuse.
109
why was oxycontin a favourite in pill mills ?
- the tablets do not produce an intense 'high' but if they chewed or crushed and snorted they can have similar effects to heroin
110
What nickname has Oxycontin earned due to its abuse in poor white communities in the US?
'Hillbilly Heroin'
## Footnote
This reflects the socio-economic factors surrounding its misuse.
111
What is Fentanyl?
A synthetic opioid with 50-100 times the potency of morphine
## Footnote
It has legitimate medical uses but is often misused.
112
What is a significant risk associated with street fentanyl?
Variability in strength, leading to accidental overdoses
## Footnote
Most fentanyl sold is diluted and passed off as other opioids.
113
who owned the Purdue Pharma Company ?
the Sackler family
114
which drug produces cough suppression without analgesia?
pholcodine
- A large substituent at the 3 position on morphine
## Footnote
(not codeine as is metabolised to morphine, and so analgesic)
115
Which drug is a partial agonist of mu opioid receptors?
buprenorphine
116
what kind of opioid is methadone ?
full agonist but lower affinity than morphine
117
what is codeine ?
a prodrug for morphine
## Footnote
meaning it is metabolised to morphine
118
Which drug is a kappa agonist, but a mu antagonist?
Pentazocine
## Footnote
sometimes used for analgesia
119
what is naltrexzone ?
mu antagonist
## Footnote
similar to naloxone
120
Which opioid receptor does morphine bind to with the highest affinity?
mu
121
Which brain area contains cell bodies of neurons that release endogenous opioids?
the PAG contains the cell bodies of neurons that release endogenous opioids. These project to other brain areas but also form synapses within the PAG itself.
## Footnote
Other CNS regions that contain opioidergic neurons include the rostral ventral medulla and the spinal cord
122
in addition to acting on mu receptors as an agonist, what is the other site of action of tramadol that is thought to contribute to its analgesic properties?
blockade of monoamine reuptake
## Footnote
also block SERT and NET (partyl explain analgesic actions), and antagonist at 5HT2C receptors and M3 muscarinic receptors
