Analgesics Flashcards
1
Q
What is somatosensation?
A
Our sense of touch, pressure and vibration against the skin
2
Q
What is propriosensation?
A
Our sense of where our body parts are (a subtype of somatosensation)
3
Q
What is nociception?
A
Our sense of tissue damage and the neural processes of encoding and processing noxious stimuli
4
Q
What is pain?
A
Our perception of nociception that is in the brain (the sensory input)
5
Q
Is pain made up of peripheral or central elements?
A
BOTH
Pain is the result of damaging processes and our interpretation of them
6
Q
What are the four types of nocicpetor?
A
- Thermal
- Mechanical
- Polymodal
- Silent
7
Q
What do thermal nocicpetors detect?
A
- 45 degree (painful heat)
- 10-15 degree (painful cold)
8
Q
What do mechanical nociceptors detect?
A
- Squeezing, streching or penetrating the skin
- Sharp, intense pain
9
Q
What do polymodal nocicpetors detect?
A
Dull, diffuse burning pain type
10
Q
Where are silent nocicpetors found and what do they detect?
A
- Found in the viscera
- Respond to (over) distension/swelling
- Intense poorly localised pain
11
Q
What do mechanical alpha delta fibres respond to?
A
- Do not respond to strong pressure from a blunt probe
- If equal pressure is applied all over a small area (pin prick, causing damage) they show a robust response
- Increased by pinching (damaging) a larger area
12
Q
What is the nociceptor receptor family called?
A
TRP
13
Q
How many heat sensing alpha delta TRP’s are there?
A
6 that cover a range of temperature sensing thermal nociception
14
Q
Which two thermal TRP’s are activated at normal temperatures (more somatosensory than nocicpetive)?
A
- TRPv3
-TRPv4
15
Q
What TRP is activated by chemicals such as garlic and radish?
A
TRPA1
16
Q
Which TRP is active to menthol?
A
TRPM8
17
Q
Which TRP is active to camphor?
A
TRPV3
18
Q
Which TRP is active to capsaicin (chilli)?
A
TRPV1
19
Q
Which chemical causes the spreading of local projections away from the site of injury?
A
Histamine
20
Q
Which two chemicals are involved in exacerbating the nocicpetive response locally?
A
- Bradykinin
- Prostaglandin
21
Q
What does substance P do?
A
- Dilates the blood vessel
- Can cause histamine release to potentiate the response
22
Q
What is mechanical hyperaglesia?
A
The hyper-sensing of pain due to the spreading effect
23
Q
What are prostaglandins produced by?
A
COX enzymes
24
Q
What are the two neurotransmitters which project up the spinal cord?
A
- Glutamate
co-localised with - Substance P
25
Where are glutamate and substance P stored in the spinal cord?
In vesicles in dorsal route ganglion cells
26
How does Substance P act on glutamate?
- Causes depolarisation as it slows and prolongs the action of glutamate
- As it is not easily broken down, it can also act on neighbouring neurons (paracrine)
27
Why does substance P make it hard to localise some pain?
- Because it activates neighbouring synapses (paracrine)
- Regions in the spinal cord are being activated so the damage seems to spread out as there are other inputs and over estimation
28
Which type of nociceptive fibre causes a wind up effect?
Repetative activation of C but NOT alpha delta
29
What is the wind-up effect (steps)?
1. Activation which projects to neurons in the spinal cord
2. Second order neurons
3. Input from C fibres and alpha delta fibres
4. As alpha delta fibres are myelinated, the signal jumps across the nodes
5. Because C fibres are un-myelinated, the signal has to be regenerated
6. The initial reaction is the A volley because the AD fiibres get the information the quickest
7. The A volley remains steady throughout
8. Later on, the C volley starts earlier and lasts longer on every stimulus because there is priming input from the AD fibre
9. When the C input comes along, there is plasticity from the C fibre and this increases the response of the neuron to the C fibre
30
What are the two second order neurons in the dorsal horn called?
- A-Volley from alpha delta
- C-Volley from C fibre
31
What receptors do glutamate and substance P bind to?
NK1, NMDA and AMPA
32
Why is AMPA the primary glutamate receptor in nocicpetive transmission?
The A fibre alone is not enough to release the Mg molecule from the NMDA receptor
33
How does the wind-up from the C fibre increase the firing at the synapse?
- The increased input the receptor receives means there is enough depolarisation for the NMDA to displace the Mg molecule
- Lots of calcium then enters
- This can cause the post-synaptic ion channels more likely to fire
- This then causes more C fibre response
34
Which axons make up most of the spinothalamic tract?
- Alpha delta fibres
- C fibres
- Alpha beta fibre (mechanoreceptor)
35
What layers of the spinal cord do the alpha delta and c fibres project into?
Layers 1 and 5
36
How does gating pain at the spinal cord level work?
- If drive the alpha beta mechanoreceptors by rubbing the area, they drive interneurons to become more active
- This increases the inhibition and reduces the excitability of the inhibitory neurons
- This reduces the projection neuron action the the C fibre
37
What is the cause of referred pain?
Due to poor localisation, particularly in the viscera
37
What is an example of referred pain?
Pain from a myocardial infarction can be felt away from the heart such as in the jaw
38
Where does the nocicpetive tract synapse at the supraspinal level?
- Thalamic level
- Then project to the other cortices
39
When does nociceptive decussation occur?
As soon as information enters te spine
40
What is the spinoreticular transmission system?
- Runs to the reticular formation from the spinal cord
- Then into the medulla and PONS
- Next into the thalamus and the cortex
- Lastly into the periaqueductal grey
41
Which regions of the brain project into the periaqueductal grey (PAG)?
- Insula
- Hypothalamus
- Amygdala
42
What are three bits of evidence that there is top-down modulation of pain?
- Electrical stimulation of the PAG
- Effect of opioids
- PAG through locus coereleus and raphe
43
What neurotransmitters do the locus coerleus and the Raphe use?
Noradrenaline (second order projection) and serotonin (projection neurons)
44
How do the pontine and 5HT neurons top-down regulate?
- They drive the interneuron which contains an endogenous opioid
- This decreases the excitability by reducing calcium entry and reduces activity
- This will turn off the synapse, reducing the nocicpetive information flowing into the brain
45
Which centre drives the LC and Raphe?
PAG
46
What mutations cause insensitivity to pain?
Autosomal recessive mutations
47
What can individuals with congenital pain sensitivity not detect?
Severe damage such as broken bones, burns, or even self inflicted injuries such as biting off the tip of their tongue
48
What does the gene SCN9A code for?
Voltage gated socium channel Nav1.7
49
What does the sodium channel Nav1.7 do?
Plays an important role in the dorsal route ganglion nociceptive neurons
50
What is the gene FAAH-OUT associated with?
The endocannabinoid system
51
What can long-term uncontrolled diabetes lead to?
Neuropahthy (nerve damage) with the legs and feet often the first tissues affected
52
What is parasthesia?
Pins and needles sensation
53
What are the steps to prostaglandin synthesis?
- Tissue damage to the cell membranes
- Arachidonic acid is converted to prostaglandin
- Leaves prostaglandin H2 and G2
- These are converted into a various group of compounds (icodomoids) such as prostaglandin E2
54
Where do the NSAID drugs act on prostaglandin synthesis?
When arachidonic acid is converted to prostaglandin G2 and H2 by targetting cyclooxygenases
55
What are three types of cyclooxygenases and when are they expressed?
- COX-1: constitutively expressed
- COX-2: Induced in damaged/infected cells
- COX-3: (splice varient of COX-1)
56
Which COX is the best target for the NSAIDs?
COX-2
57
What are the main therpeutic roles of NSAIDS (3)?
1. Antipyretic (lower body temp)
2. Analgesic (reduce pain)
3. Anti-inflammatory
58
What does NSAIDS stand for
Non-steroidal anti-inflammatory drugs
59
What needs to happen when the core temperature is too low?
1. Increase heat conservation- vasoconstriction (piloerection)
2. Increase heat production- shivering, exercise
60
What needs to happen when the core temperature is too high?
1. Increase heat loss- vasodilation, sweating
2. Decrease heat production
61
Outline pyresis (fever)
CAUSE
Body thermostat is raised (hypothalamus is too high because of inflammatory response)
Core temp is sensed as too low
EFFECT
Increase heat gain/conservation
SYMPTOMS
Feel cold
WHY
Because prostaglandin E2 has been released in the periphery and this has an effect on increasing the set point of the thermostat
62
What is hyperthermia?
- Thermostat is not increased
- Too much heat production
- Feel hot
63
What is the area in the hypothalamus involves with heat?
Preoptic area hypothalamus
64
Where do TRP thermoreceptor channels run to?
- Run through the peripheral nervous system into the POA in the hypothalamus (central thermostat site)
65
How does the hypothalamus cause the production of prostaglandin E2?
Generates in response to interleukin-1 and released by macrophages
or
Via the blood
66
How do NSAIDs reduce fever (pyrexia)?
- Inflammatory mediators (PGE2, IL-1) raise the preoptic areas set point (thermostat)
- NSAIDs reduce the set point back down to a normal level
67
Will NSAIDs reduce core temperature in hyperthermia?
No, because there is no raised thermostat
68
How does bradykinn work?
- It is potentiated by prostaglandin E2 and released by damaged or infected tissue
- The effect of the PGE2 is to sensitise the C fibre to bradykinin
69
Which NSAID is selective for COX2?
Celecoxib
70
Which NSAID us used more as an anti-platelet drug?
Aspirin
71
Name five NSAID drugs
- Aspirin
- Ibuprofen
- Diclofenac
- Naproxen
- Celecoxib
72
How does aspirin function at COX?
Irreversible on both COX1 and 2
73
How does Ibuprofen act at COX?
Is reversible, non-competative and weakly selective at COX1
74
What are some common NSAID side-effects?
- GI upsets (dyspepsia, nausea, ulcers)
- Aspirin inhibits platelet aggregation, prolongs clotting time
- Skin reactions
- Renal damage
- Bronchospasm in aspirin sensitive asthmatics
75
What is aspirin and reyes syndrome?
Rare disorder occuring in children- hepatic encephalopathy with 20-40% mortality (aspirin is no longer given to under 16s)
76
What is salicylism?
Salicylate overdose (non-fatal) produces symptoms of 8th cranial nerve damage- tinnitus, vertigo, nausea and vomiting
77
What is an uncommon heart side effect of NSAIDs?
Cardiovascular effects including MI and stroke
78
How does paracetamol act?
- Potentially onlt central action
- Antipyretic analgesic, not anti-inflammatory (not a classic NSAID)
- Reversably competative at COX3, splice variant of COX1
79
What are the side-effects of paracetamol?
- None at therpeutic doses
- Toxic at high doses, may be hepatotoxic if taken at max
- In overdose, it is metabolised to a toxic metabolite which causes liver necrosis
80
What is neuropathic pain?
- Damage to neural tissue
- Signals nociceptive reaction inappropriately as there is no local damage
- Cannot be treated with NSAIDs
81
What are the treatments for neuropathic pain?
- May respond to opioids
- Generally managed with tricyclic antidepressant or anti-epileptics
- Capsaicin cream is licensed for the symptomatic relief of postherepetic neuralgia or pain in diabetic neuropathy
- Lidocaine can be used for localised pain
82
How does ketamine act as an analgesic?
- Is an NMDA antagonist/dissociative anaesthetic at higher doses
- Can be used for brief painful procedures
83
How is Nitrous oxide used as an analgesic?
- Not anaesthetic in hmans- is a powerful analgesic which can be used alone or to augment anaesthetics
- May be an NMDA antagonist but hard to identify the precise pharmacology
84
What are three types of neuropathic pain?
- Ongoing
- Allodynia
- Hyperaglasia
85
What is allodynia?
Where a normally non painful stimulus such as light touch produces pain
86
What is hyperaglasia?
Where pain sensations aree heightened
87
What can trigger neuropathic pain?
- Viral infections (shingles)
- Autoimmine disease (MS)
- Strokes
- Diabetes
- Cancer
- Etc
88
What is trigeminal neuraglia?
- Common form of neuropathic pain that is caused by the compression of the trigeminal nerve
- Results in excruciating face pain
- Sometimes attacks of pain can be triggered by even the slightest pressure on the face
89
Why are peptide toxins attractive candidates for drugs?
Because, unlike small molecule inhibitors of ion channels, they are highly selective
90
What kinds of molecules do cone snails release?
Peptide toxins
91
What toxins does the conus magus produce?
- Peptide toxins that target nicotinic ACh receptors
- Voltage gated sodium channels
- Calcium channels
- Possibly potassium channels
92
What is the name of the conus magus's toxin?
Nicotinic selective toxin a-conotoxin M1
93
What is the C magus toxin omega-conotoxin MVIIA selective for?
N-type calcium channels
94
What is a synthetic version of What is the C magus toxin omega-conotoxin MVIIA?
Ziconotide (prialt)
95
How is ziconotide administered?
- Intrathecally (directly into the CSF) becasue it is a peptide and cannot cross the BBB
96
How does ziconotide act?
- Inhibiting neurotransmitter released by nociceptive neurons at the level of the spinal cord
- Shows relatively good efficacy against neuropathic pain
97
What are some side effects of ziconotide?
- Dizzines
- Nausea
- Anxiety
- Insomnia
- Psychosis
- Suicide
- Depression
- Seizures
98
What are Endogenous Opioids?
Neurotransmitters in specialised CNS tracts
99
Where are endogenous opioid cell bodies found?
- Rostral ventral medulla
- PAG
- Spinal cord laminae 1 and 2
100
Where so the endogenous opioids axons project to?
- To/within the PAG
- LC
- Raphe
- Within the spinal cord
101
How do the endogenous opioids work?
- Through the descending pathway
- From PAG, it recruits seretonergic and dopiminergic neurons to reduce the activity of second order neurons in the laminae
102
What are three opioid peptides?
- Endorphins
- Enkephalins
- Dynorphins
103
What is the role of the opioid peptides?
- Released in the prescence of pain (endogenous system)
- Released in accupuncture/sport
104
What are the three traditional opioid receptors?
- Mu
- Delta
- Kappa
105
What are the re-classified, new opioid receptors?
- MOPr (Mu opioid receptor)
- DOPr
- KOPr
- NOPr
106
What are Mu Opioid receptor subtypes?
1, 2 and 3
107
What are Mu Opioid receptor mechanisms?
- Open up K channels in the membrane
- Causes hyperpolarisation
- Reduces neuronal activity
- Inhibit neurotransmitter release (especially ACh, glutamate and substance P)
- Produces analgesia
108
What are Mu Opioid receptor side effects?
- Respiratory depression
- Constipation
- Euphoria
- Sedation
- Dependence
109
What are Delta Opioid receptor subtypes?
1 and 2
110
How do Delta Opioid receptors act?
- Similarly to Mu receptors
- Produces analgesia
- Can be proconvulsant (too much excitation)
111
What are Kappa Opioid receptor subtypes?
1, 2 and 3
112
How do Kappa Opioid receptors work?
- Reduce calcium channel activity presynaptically
- Means less depolarisation because they inhibit neurotransmitter release
- Analgesia at the spinal level
113
What are side effects of Kappa opioid receptors?
- Sedation
- Dysphoria/hallucinations
114
What type of receptors are opioid receptors linked with?
- GPCR family
- Often negatively linked to adenylyl cyclase (decrease cAMP)
115
How much homology do the opioid receptors show?
65%
116
Where is pain management located?
In the dorsal horm of the spinal cord
117
How do analgesias act to manage pain?
- Enhance the transmission from the PAG to the other sites (LC, Raphe)
- This inhibits the projection neurons by increasing inhibition and increasing the response
- There is then lots of converging responses of opioids in increasing sensitivity and directly inhibiting the potentiation of the descending pathways
118
What are three groups of opioid receptor targetting compounds with examples?
1. Agonists (morphine and codeine)
2. Antagonists (naloxone and naltrxone)
3. Mixed action compounds (buprenorphine and pentazocine)
119
What are some central morphine like side effects?
- Analgesia
- Sedation
- Cough- suppression (anti-tussive)
- Euphoria
- Respiratory depression
- Nausea
- Itch
120
What is peripheral and what does it do?
- Morphine like analgesia
- Reduces inflammation
- Increases the threshold for pain
- Action on the GI tract (Mu and Delta receptors)
121
What is Ioperamide?
- Morphine-like drug
- Mu agonist, cannot cross the BBB (not analgesic)
- Causes constipation (imodium)
122
Where do opioid agonists act?
- Spinal level (dorsal horn) Mu2. delta2, Kappa1
- At the supraspinal level (brain) Mu1, Delta 1&2, Kappa3
123
What do opioid agonists do?
- Raise the pain threshold
- Increase the pain tolerance
- Are better against dull, constant pain than sharp, stinging pain
124
What is the 'classic opiate' and how does it act?
- Morphine
- Mu agonist
125
What are some side-effects of morphine?
- Analgesia
- Euphoria
- Anti-tussive
- Sedative
- Nausea
- Constipation
- Pupillary constriction
- Bronchoconstriction
- Hypotension
- Respiratory depression
126
What is a potential new synthetic morphine-like drug with fewer side effects?
Morphine 6 glucuronide
127
What 4 areas do opioid agonists vary in?
- Analgesic efficacy
- Absorption/distribution
- Duration of effect
- Side effects
128
What is diamorphine
- Heroin
- Pre-cursor to morphine (de-acetlyated)
- Is faster and more potent than morphine
129
What is Fentanyl
- An agonist with similar actions to morphine
- Rapid onset
- Used in chronic cancer pain and post-surgical analgesia
- Can be given by patch
130
What is Methodone?
- Used to 'wean' dependents away from opioid addiction
- Longer duration of action and lessened withdrawal symptoms than morphine
131
What is Oxycodone?
- Used for acure/chronic pain
- Now widely abused
132
What is an opioid?
A drug that acts at opioid receptors
133
What is an opiate?
- Is an opioid derved from opium poppies
- Such as morphine, codeine and thebaine
134
What is Heroin?
A semisynthetic opioid produced by chemically modifying morphine that has been purified from opium poppies
135
What is Buprenorphine?
A partial Mu agonist
136
What are side-effects of buprenorphine?
- Analgesia
- Sedation
- Nausea
- Respiratory depression not fully reversed by naloxone
137
What is Buprenorphine used to treat?
- Opioid dependence
- As reduced abuse potential and less intense withdrawal than morphine
138
What is Nalorphine?
- A mixed action compound as it was initially regarded as a Mu antagonist but is now seen to be: delta, kappa partial agonist
139
What are side-effects of nalorphine?
- Some Analgesia (lower abuse potential)
- Dysphoria (depression)
140
What is Pentazocine?
- A mixed action compound which combines:
- Mu antagonism and Kappa agonist
- Reduces euphoria, abuse potential and limits respiratory depression, however Kappa agonist means analgesia
141
What is Tramadol?
- A mixed action compound that combines:
- Weak Mu agonist and weak inhibition of monoamine reuptake
- Is used therapeutically as analgesic for moderate to severe pain
142
What are some side-effects of Tramadol?
- Anti-tussive
- Nausea
- Tolerance/dependence
143
How do many of the Opioid drugs have cough suppressive effects?
Action at cough centres in the CNS via Mu or delta receptors
144
How can we seperate the anti-tussive elements from the analgesic ones in opioid drugs?
- Quantitatively, by adding a large subsituent at position 3 on the morphine molecule
145
What is Dextromethorphan?
A cough suppressant without the analgesia
146
How do opioids trigger nausea?
- Endogenous toxins trigger the opioid receptors in the **chemoreceptor trigger zone**
- This is located the medulla oblongata
- Crosses the BBB
- Triggers the vomit reflex
147
How are motion sickness and opioid nausea related?
- Motion sickness in detected by the vestibular nuclei signals to the chemoreceptor trigger zone
- Opioid receptors in the medulla oblongata trigger the chemoreceptor trigger zone
- Both then cause the vomit reflex
148
What is a study done on mice into tolerance of opioids?
- Give mouse a treatment of morphine
- Then wait a period of time and give a second treatment whilst it is on a hot plate
- Mouse will not sense the hot plate
- Continue to dose the mouse and measure how much morphine is needed to give the same analgesic effect for it not to feel the hot plate
- Need to increase the dosage each time to cause the same effect
149
How does tolerance to morphine lead to dependence?
- Morphine inhibits cAMP production
- System responds by increasing Adenylate cyclase expression (tolerance)
- When remove the morphine, there is a spike in cAMP production (dependence)
150
How are narcotic antagonists formed?
- Synthesised by modification of the structure of morphine and other agonists
- Usually by substitution of large groups on the N atom at position 17 in morphine
151
What is an example of a narcotic antagonist?
Naloxone
152
How does Naloxone act?
Competative antagonist at all 3 opioid receptors but particularly Mu
153
What are three potential therapeutic ways to use naloxone?
1. Alone
2. After an agonist
3. Used in a patient dependent on opioids
154
What occurs when naloxone is given alone?
- Very little effect
BUT
- Respiratory depression in drug addicts
- Respiratory depression in newborns
155
What occurs when naloxone is given after an agonist?
- Reverses all effects of full agonists
- Reverses agonist actions of mixed action compounds (need lagrer dose)
- Used to treat respiratory depression (in opioid overdose)
- Short action (longer than agonist), metabolized in the liver
156
What occurs when naloxone is given to dependent patients?
- Precipitate withdrawal syndrome
- Used to treat overdose in dependent patients but have to titrate carefully to do this without precipitating withdrawal
- Used in 'treatment' of dependence?
157
What is Oxycontin?
A synthetic opioid
158
How long did Purdue marketer state that oxycontin was effective for compared to reality?
- Claimed to be a '12 hour drug'
- Actually 4-6 hours
159
What is a pill mill?
- A clinic that specialises in prescribing opioids to patients that do not need them
- Patients are bought in by drug dealers where they buy medication for them or exchange other drugs
160
What is Oxycontin's nickname?
Hillbilly heroin
161
What is Fentanyl?
A synthetic opioid with 50-100 times the potency of morphine
