Opioids Flashcards
1
Q
What is an opiate
A
An alkaloid derived from the poppy, Papaver somniferum
2
Q
What is an opioid
A
Opioids are anything that behaves like an opiate (natural or synthetic)
3
Q
Re opiate structure, what is important for the analgesic effect?
A
Tertiary nitrogen
4
Q
What part of an opioid binds to receptor
A
Tertiary nitrogen
5
Q
How to turn an opioid into an antagonist?
A
Extend tertiary nitrogen side chain by 3 carbons
6
Q
What is the second most important part of an opioid for it to bind to a receptor
A
Hydroxyl group at position 3
7
Q
Intravenous bioavailability of opioids?
A
100%
8
Q
Opioids pKa? Implication for GI absorption?
A
More than 8, weak bases. So, poorly absorbed in stomach
9
Q
Ionised or unionised in blood? Implication for tissue absorption? Opioids
A
Ionised, so not readily absorbed
10
Q
How does lipid solubility effect potency, generally?
A
More lipid soluble, faster into brain, more powerful effect
11
Q
What makes morphine the least lipid soluble?
A
The OH groups
12
Q
how active are metabolites of morphine?
A
Active
13
Q
Why are people who metabolize morphine poorly more likely to see negative side-effects
A
Because Morphine seems more likely to cause negative side-effects than the active metabolites
14
Q
Which opioids are basically prodrugs? What are they metabolised into?
A
Heroine and codeine. Metabolised into morphine
15
Q
Where is heroine metabolised into morphine?
A
In the brain
16
Q
Active metabolite of morphine?
A
Morphine 6 glucoronide
17
Q
Speed of metabolism and clearance of fentanyl? Impact on its effect
A
metabolized quickly and cleared, so it has a fast but short-lasting effect
18
Q
Speed of metabolism and clearance of methadone? Impact on its effect
A
is metabolized slowly, so it accumulates in blood and fat, so it has a long-lasting effect (one of the reasons it’s used to ween people off of heroin)
19
Q
Where is codeine metabolised into morphine?
A
liver
20
Q
What metabolises codeine
A
2 cytochrome p450s
21
Q
What is codeine metabolised into, %’s of each metabolite?
A
Norcodeine (90-95%, inactive) and morphine (active, 5-10%)
22
Q
Why are some people good/some people bad metabolisers of codeine
A
common polymorphisms in the 2DY enzyme - People can be good or bad metabolizers of codeine
23
Q
What receptors do opioids target
A
Opioid receptors
24
Q
Endogenous opioids? (3/4)
A
- Endorphins
- Enkephalins
- Dynorphins/neoendorphins
25
What function do endorphins regulate?
Pain/sensorimotor
26
What function do Enkephalins regulate?
Motor/cognitive function
27
What function do dynorphins regulate?
Neuroendocrin
28
What receptors do dynorphins activate?
Kappa
29
What receptors do Enkephalins activate?
Delta
30
What receptors do endorphins activate?
Mu or Delta and Mu again
31
How do opioids slow cellular activity? (3)
1. Hyperpolarizing cells (increasing K+ efflux) – so nerves affected can’t fire again till the effect wears off
2. Reducing the inward calcium current (impacts exocytosis and release of neurotransmitters
3. Decreasing adenylate cyclase activity
32
Positive effects of opioids? (3)
- Analgesia
- Euphoria
- Depression of cough centre (anti-tussive)
33
Negative effects of opioids?
- Depression of respiration (medulla)
- Stimulation of chemoreceptor trigger zone (nausea/vomiting)
- Pupillary Constriction
- G.I. Effects
34
How does pain reach the thalamus (start from pain reception)
- Pain is usually sensed peripherally by sensory neurons
- These relay information to the spinal cord (dorsal horn)
- This information is then relayed along spino-thalamic neurons to the brain
- The first place it reaches is the thalamus, which decides where to direct the information
35
What is the role of the PAG - PERIAQUEDUCTAL GRAY in the pain tolerance pathway
PAG region is the integrating centre for the PTP – it receives all the information and determines output
36
What does PAG stand for
PERIAQUEDUCTAL GRAY
37
Where does the thalamus send its pain sensory information
cortex and PAG
38
What does NRPG stand for
NUCLEUS RETICULARIS PARAGIGANTOCELLULARIS
39
Where does the dorsal horn send its pain information, and along what
along the spinothalamic tract to the NRPG (NUCLEUS RETICULARIS PARAGIGANTOCELLULARIS ) and thalamus
40
Where does the cortex send its pain sensory information
PAG
41
Where does the PAG send its information
TO the NRM
42
What does NRM stand for
Nucleus raphe magnus
43
What is the role of the NRM - nucleus raphe Magnus - in the pain tolerance pathway
which is the effector arm of the PTP. From there, the descending neurons try to depress the feelings of pain in the spinal cord
44
What is the role of the hypothalamus in the pain tolerance pathway
constantly relaying information on your general state of health and can also activate the PAG The hypothalamus reduces pain tolerance if someone is in a lot of pain (so they still feel a lot of pain) in order to stop the body from wasting resources on doing anything other than healing i.e. moving around or being active
45
What is the role of the locus conealeus in the pain tolerance pathway
the SNS effector, which is largely independent of the PTP It signals to the dorsal horn of the spinal cord to dampen the pain (think about when you’re playing sport – the LC is active and you feel little pain until after you finish when the SNS switches off releasing its inhibition on the spinothalamic nuclei),
46
What is the role of the substantia gelatinosa in the pain tolerance pathway
which can process the information from the LC and modify the signal, to determine how much inhibition of the pain you actually get
47
Where is the substantial gelatinosa found
in the dorsal horn
48
Where does the thalamus put it signals out to in the PTP?
Cortex and PAG
49
Where does the cortex put it signals out to?
PAG
50
Where does the hypothalamus put it signals out to?
PAG
51
Where does the PAG put it signals out to?
NRM
52
Where does the NRM put it signals out to?
dorsal horn
53
Where does the NRPG put it signals out to?
NRM
54
Where does the LC put it signals out to?
Dorsal horn
55
Are signals from the NRPG excitatory/inhibitory/both?
excitatory
56
Are signals from the thalamus excitatory/inhibitory/both?
excitatory
57
Are signals from the cortex excitatory/inhibitory/both?
both
58
Are signals from the PAG excitatory/inhibitory/both?
excitatory
59
Are signals from the NRM excitatory/inhibitory/both?
inhibitory
60
Are signals from the hypothalamus excitatory/inhibitory/both?
both
61
Are signals from the LC excitatory/inhibitory/both?
inhibitory
62
Are signals from the dorsal horn excitatory/inhibitory/both?
excitatory
63
Are signals from the substantia gelatinosa excitatory/inhibitory/both?
inhibitory
64
What does LC stand for
locus coeruleus
65
Where does the PAG receive signals from
Thalamus, cortex and hypothalamus
66
Where does the dorsal horn receive signals from
LC, NRM and substantia gelatinosa
67
Where do opioids act in the PTP
PAG, NRPG, Dorsal horn and periphery
68
What receptors do opioids act on
Mew and opioid receptors
69
How do opioids cause analgesia
Disinhibition - it switches off GABA in the PAG and NRPG which fires on NRM which suppresses pain
70
How do opioids cause euphoria
- Opiates enter the brain and bind to opioid receptors
- They depress the firing rate of GABA neurons - DISINHIBITION
- Remember GABA suppresses reward neurons
- This means that the dopaminergic neurons increase their firing rate and euphoria is experienced
71
Neurologically why do we cough? (what fibres, NT and nerve)
- Ach/neurokinin (NK) C-fibres relay cough information via the vagus nerve to the cough centre
72
Anti-cough NT?
Serotonin
73
What receptors are found on the vomiting centre
5HT
74
How are opioids anti-tussive? (3)
- Opioids decrease the firing rate of C-fibres - Decreased sensory relay
- They also have a direct depressant effect on the cough centre itself
- They also inhibit the 5HT1A receptors, so you have more serotonin in the cough centre, which is anti-cough
75
What senses blood CO2
Chemoreceptors
76
Where is the resp control centre
Medulla
77
what coordinates respiratory rhythm generation (determines respiratory rate)
PRE-BOTZINGER COMPLEX
78
How do opioids REDUCE RESPIRATORY RATE significantly (2)
- Opioids inhibit the central chemoreceptors (reduce information relay to the medulla)
- They also reduce rhythm generation in the pre-Botzinger complex
79
how do opioids stimulate nausea/vomiting
- Opiates cause disinhibition (of GABA) of the chemoreceptor trigger zone
- The chemoreceptor trigger zone sends a signal of nausea to the medullary vomiting centre which leads to nausea and vomiting
- There are also signals from the higher centres and the gut to the chemoreceptor trigger zone
80
Where do opioids act to stimulate nausea/vomiting
chemoreceptor trigger zone
81
How do opioids stimulate miosis
- Opioids switch on the parasympathetic nerve which starts in the Edinger-Westphal nucleus
- The parasympathetic nerve causes constriction of the pupils
- The effect is disinhibition again by switching off GABA
82
What is a good sign of heroine OD
Pinpoint pupils
83
What effect do opioids have on the GI system
- They inhibit secretions and gut contraction by effecting motor actions
- Cause heavy constipation
84
What is urticaria
- Histamine release in a non-allergic response to opioids
- Some kind of direct interaction of opioids with mast cells which causes histamine release
- Seems to involve PKA
- Doesn’t seem to need opioid receptors
- Opioids needs to have an OH group on C6
85
What does an opioid need to stimulate urticaria
Opioids needs to have an OH group on C6
86
Key mechanism for opioid tolerance?
receptor internalization
87
What proteins drive receptor internalisation
Arrestins
88
High opioid exposure leads to ... (arrestin conc.)
If opioids are constantly suppressing cells, the cell tries to desensitise itself to opioids
- Arrestin concentration increases and more receptors are internalized
89
Explain the physical withdrawal effects of opioids
rebound effect of cells - They respond to opioids decreasing cellular activity by increasing adenylate cyclase – if you remove the opioid you then have cells with overactive adenylate cyclase – this causes a lot of the side-effects seen with withdrawal
90
How do you combat the physical withdrawal effects of opioids
You need cellular adenylate cyclase to return to normal before withdrawal symptoms disappear and use methadone to ween people off it
91
Why is opioid OD common
users who try to come off of the drugs, and then go back to them and have the same dose as before (even though their tolerance has decreased)
92
Signs of opioid OD? (4)
- Coma
- Respiratory depression The major problem – difficult to reverse
- Pin-point pupils
- Hypotension Excessive histamine release
93
Main problem of opioid OD
Respiratory depression The major problem – difficult to reverse
94
treatment of opioid OD?
NALOXONE (opioid antagonist)
95
What about naloxone makes it an opioid antagonist
3 carbon++ side chain on the tertiary nitrogen
96
What is naloxone
NALOXONE (opioid antagonist)
