9.2 opioids Flashcards
how is pain detected?
1) tissue damage = cells release prostaglandins, bradykinin and serotonin into tissue
2) nociceptors stimulated (pain receptors in tissue)
3) Release of substance P (acts locally for inflammation) and glutamate (stimulates afferent nerves for action potential in dorsal horn)
4) afferent nerve stimulated. get
- Sharp pain via A delta fibres = felt quickly as mylinated. will pull hand away from stimulus quickly
- Dull pain/ throbbing via unmylinated C fibres = have reached AP threshold to stimulate. slower conducting.
5) first order project onto second order fibres which decussate
6) action potentials ascends up spinothalamic tract
7) synapse in thalamus
8) project to post central gyrus
how can we modulate pain peripherally and how can ‘rubbing it better’ modulate pain?
via the substantia gelatinosa in dorsal horn
tissue damage = stimulates afferent fibres of Alpha delta and C fibres. However also has inhibitory fibres that can help modulate pain.
Pain can also be modulated by ‘rubbing it better’ as it stimulates A beta fibres which stimulate the substantia gelatinosa = inhibit lamina = decrease pain signals going up to thalamus
how can we modulate pain centrally?
via the periaqueductal grey matter
Tissue damage occours
transmitted up to thalamus via spinothalamic tract
goes to periaqueductal grey matter which is usually inhibited via the cortex, however when we get a pain response the pain detected by cortex and thalamus can stimulate it
Periaqueductal grey matter then sends inhibitory endogenous signals down spinal cord which is mediated by 5HT and endogenous opioids (enkephalins, dynorphins and B endorphins)
this reduces the signal that reaches the thalamus and reduces the pain we are feeling.
where are MOP, DOP AND KOP receptors found and what kind of receptors are they?
MOP = suprispinal/GI tract
DOP = wide distribution
KOP = spinal cord/brain/periphery
they are GPCR
what endogenous opioids are released through stimulation of MOP(u) , DOP(a) AND KOP(k)?
MOP = enkephalins and B endorphins
DOP = enkephalins
KOPS = dynorphins
what is the mechanism of stimulation of MOP (u) , DOP (a) and KOP (k) receptors?
They are GPCRs
so stimulation =
- reduced cAMP
- MOP = outflow K
- DOP = Ca influx
- KOP = both
Result = hyper polarisation and decreased substance P release
result = analgesia
what effects does MOP(u) stimulation have?
MOP = enkephalins and B endorphins
result = analgesia, depression, euphoria, dependence, respiratory sedation
what effect does DOP(a) stimulation have?
DOP = enkephalins
result = analgesia, inhibit dopamine
what effect does KOP(k) stimulation?
KOP = dynorphins
result = analgesia, diuresis, dysphoria
what are the components of the WHO analgesic ladder?
simple analgesic e.g Paracetamol, NSAIDS
weak opioid e.g codine
strong opiid e.g morphine, fentanyl
what type of pain do strong opioids work best with?
malignant/ non malignant pain
chronic pain
acute chronic pain
what medication work best of neuropathic pain e.g diabetic feet pain due to damaged nerve?
- anticonvulsants/ anti epileptics
- tricyclic antidepressants
- serotonin/ noradrenaline reuptake inhibitors
what are the general principles of opiods?
Generally act on MOP(u) (most ADR via stimulation of other receptor)
aim to modulate pain but can also be used in cough and diarrhoea and palliation
how is morphine
- absorbed
- distributed
- eliminated
A STRONG OPIOID AGONIST
absorbed
- PO, IV, IM, SC, PR
- gut absorption erratic
- significant first pass effect = 40% oral bioavailability
Distributed
- rapidly enters all tissue including foetal
- struggles to cross blood brain barrier
eliminated
- renally
why should you give morphine to pregnant ladies?
can get respiratory distress in the new born
what are the actions and side effects of morphine?
has strong affinity for MOP (u) receptors
actions
- analgesia
- europhia
ADR
- resp depression as medulla res centre less responsive to CO2 (which drives breathing - won’t be able be to increase breathing rate to compensate)
- emesis as stimulates chemoreceptor trigger zone
- Decreased GI motility and increased sphincter tone
- histamine release via mast cells = caution in asthmatics
how is fentanyl
- absorbed
- distributed
- metabolised
- eliminated
A STRONG OPIOID AGONIST
Absorbed
- IV, epidural, intrathecal, nasal
- 80-100% bioavailability
Distribution
- highly lipophilic, highly protein bound
- high level of CNS crossing
metabolism
- hepatic
Elimination
- 6 minute half life
- renally excreted
how is fentanyl different to morphine in its action?
higher potency
higher affinity for u MOP receptors
less histamine release, sedation and constipation
what are the actions and the ADR of fentanyl?
action
- analgesia
- anaesthetic
side effects
- respiratory depression
- constipation
- vomiting
how is codeine
- absorbed
- metabolised
- elimination
absorption
- PO, SC administration
metabolism
- codine to morphine via CYP2D6 (if you don’t have much of this enzyme naturally, won’t have any affect as won’t have any circulating morphine)
- CYP2D6 can be inhibited by fluoxetine
Elimination
- glucoronidation of morphine and renal excretion
what is codeines potency compared to morphine?
approx 1/10th potency
what are the actions and side effects of codeine?
actions
- mild to moderate analgesia
- cough depressant
side effects
- constipation
- respiratory depression (worse in children under 12)
how is buprenorphine
- absorbed
- distributed
- metabolised
- eliminated
A MIXED AGONIST ANTAGONIST
Absorbed
- transdermal, buccal, sublingual
distribution
- very lipophilic
metabolism
- hepatic
- then glucoronidation before biliary excretion
elimination
- biliary over renal
- safe in renal impairment
- half life 37hrs
how does buprenorphine compare to morphine?
high affinity for MOP u receptors, low kD
long duration of action
not easily displaced
low Emax as partial agonist = less analgesia but less side effects
lower efficacy
what are the actions and side effects of buprenorphine?
action
- moderate to severe pain
- opioid addiction treatment (titrate down dose slowly)
side effects
- resp depressio
- low BP
- nausea
- dizziness
how is naloxone
- absorbed
- distributed
- metabolised
- eliminated
A MIXED AGONIST ANTAGONIST
Absorbed
- IV, IM, intranasal, PO
- very low oral bioavailability as extensive first pass effect
- rapid onset of action
Distribution
- rapid as very lipophilic
metabolism
- hepatic
- renally excreted
elimination
- duration of action 30-60mins
what is the action of naloxone compared to morphine?
- affinity for MOP>DOP>KOP
- greater affinity than morphine, less than buprenorphie
what are the actions and side effects of naloxone?
action
- competitive antagonism of opioid
side effects
- short half life
- slow infusion
how do synthetic opioids effect the amount of receptors and how can this cause withdrawal symptoms?
cells insert more MOP u opioid receptors as a result
more receptors = higher doses needed to fill at least 80% of receptors for a response of analgesia/euphoria.
need to gradually reduce intake and use something like methadone = reduced Emax and side effects e.g resp distress
what is the most common cause of death in opioid overdose and how do you treat?
resp depression
treat with nalaxone
what are the side effects of opioid addiction?
dependence vomiting constipation hypotension and bradycardia decreased sex drive resp distress => apnoea histamine release
who would you avoid giving opioids to?
manual labourers/drivers elderly bed bound asthmatics resp disease renal impairment pregnant
Ignore in palliative prescribing
what dosages can you get cocodamol in?
8/500mg = over the counter
30/500mg = prescription only
