analgesics Flashcards
why is pain a drug target
has both sensory and psychological component, impinges on other physiological processes such as;
sleep, mood, appetite and motivation
what are main types of pain
inflammatory, headache (migraine) and neuropathic pain
how is inflammatory pain mediated
transmission of acute pain involves activation of sensory receptors (nociceptors) on peripheral C fibres, nociceptors which respond to thermal and mechanical stimuli
after tissue damage and inflammation occurs actions of inflammatory mediators such as prostaglandins, substance P and bradykinin mediate pain by sensitising and stimulating C fibres
how can acute inflammatory pain be managed
if pain is acute and localised then local anaesthetics can be used
what is used in treatment of inflammatory pain
aspirin and ibuprofen etc (NSAIDs) block synthesis of prostaglandins by inhibiting enzyme COX (COX1 is always present, COX2 induced at site of injury)
how are migraines treated
drugs such as sumatriptan are agonists of 5HT1 receptors, work well in migraine
how is neuropathic pain generated
these pain states are generally generated in peripheral sensory neurones by events independent of nociceptors
clustering of sodium channels around areas of nerve damage set up ectopic activity that can spread to spinal cord and causes increase in sensitivity of spinal cord and brain
c fibres stimulate spinal neurones which project to thalamus and cortex where location and intensity of pain are perceived
drugs that block these sodium channels can be used to treat neuropathic pain e.g carbamazepine and gabapentin and lignocaine
examples of neuropathic pain; trauma, cancer
what is mechanism of some drugs used to treat neuropathic pain
gabapentin blocks calcium channels
carbamazepine and lignocaine block sodium channels
what specific neurotransmission is involved in pain
c fibre release of glutamate and peptides such as pain stimulates spinal receptors;
AMPA receptors are involved in very acute touch and pain
NMDA receptors are involved in rapidly enhanced pain
hypersensitivity after tissue and nerve damage can amplify pain (wind up and long term potentiation), can prolong and increase area of pain, this processes and mediated by C fibre inputs to spinal cord
how does ketamine block pain
blocks neuropathic pain by blocking NMDA receptor mediated neurotransmission of c fibres
how are opioids used in pain treatment, give examples
used in moderate (codeine) to severe pain (morphine etc)
how does heroin stimulate opioid receptors
heroin is diacetylmorphine, is highly lipophillic drug, and so penetrates CNS efficiently
itself is has no affinity for opioid receptors, however it crosses into CNS where it is converted into morphine, a mu receptor agonist
what are the different opioid receptors, given examples of endogenous and exogenous agonists, what is effect of stimulating these on ion channels
all opioid receptors are inhibitory and are GPCRs:
mu receptor:
endogenous agonists: endomorphins
exogenous agonists: morphine etc
activation of mu receptor opens potassium channels, causing inhibition
delta receptor:
endogenous agonists: enkephalins
exogenous agonist: DPDPE
activation of delta receptor causes opening of potassium channels,
kappa receptor:
endogenous agonist: dynorphin
exogenous agonist is U50488H
closes calcium channels when stimulated
ORL-1:
endogenous agonist is nociceptin
no exogenous agonists known
opens potassium channels
what are physiological effects of opioid receptors
mu: analgesia, anxiolysis, euphoria, respiratory depression, constipation
delta: similar to mu but to lesser extent
kappa: analgesia, aversion, diuresis
ORL-1 receptor: unknown, analgesia is suspected
kappa and delta agonists cause less respiratory depression than mu agonists
what opioid receptors are drug targets
mu: most clincally used drugs
although kappa has similar effects to mu no drugs are used for this
kappa drugs are usually not used since they have odd side effects, general effect is also effected by gender
what do all endogenous opioids have in common
all peptide transmitters, inhibitory
how do opioids compare in terms of drug action
morphine can be given orally or injected or via slow release iv
codeine is a weak pro drug for morphine (metabolised into morphine in liver)
fentanyl: has fast onset of action but also short length of action
pethidine is used in childbirth
heroin: strong morphine prodrug, has fast action
all clinically used opioids have same pharmacological effects in that they are all mu receptor agonists, they only differ in potency and pharmacokinetics
what is an antagonist for opioid receptors
naloxone is antagonist for all opioid receptors except ORL-1
what determines efficacy of opioid dosage
morphine: not to do with levels of pain
to do with genetics, possibly due to differences in mu receptor sequence
dosage ranges from 95to 150mg/day
codeine: some patients cannot metabolise codeine into morphine, others metabolise morphine slowly so increased effects
what are spinal mechanisms of opioid analgesia
involved in pre synaptic control of fibres via inhibition of release of glutamate and substance P from c fibres and Adelta fibres to spinal cord
in post synaptic response there is inhibition of spinal neuronal activity
pre synaptic effects predominate due to higher receptor density
how does nerve injury effect opioid dosage
after nerve injury there is loss of opioid receptors and spinal cord may be hyper excitable so doses are higher after nerve injury
what are supralspinal effects of opioid analgesia
opioid action sites are located in 5HT and noradrenergic nuclei of brainstem and midbrain including; raphe nuclei, periaqueductal grey matter and locus coeruleues
these sites are triggered by painful inputs, opioids have inhibitory actions here; when receptors are activated they alter level of activity in descending pathways from these zones to spinal cord
mechanism is poorly understood
antidepressants that alter levels of 5HT and noradrenaline are used in neuropathic pains where they are analgesics independent of mood changes
what are side effects of opioids and what site are these mechanisms mediated
respiratory depression; due to action at brainstem
anti-tussive due to action at brainstem
constipation is a peripheral side effect due to enteric inhibition
nausea and vomiting since it has receptors in the chemoreceptor trigger zone
dependence although rare in hospital patients
how are the side effects of opioids used therapeutically
anxiolysis: used pre-operatively, (and street use)
anti tussive: chest surgery; dextromethorphan is a non-opioid isomer of levorphanol
constipation: bowel surgery, loperamide use in diarrhoea diarrhoea
how do opioids cause dependence
opioids have effects on noradrenergic transmission in locus coeruleus and enhance dopamine release in ventral tegmental area, these pathways are reward pathways and so relate to dependence
psychological dependence does not occur in presence of pain
however:
prolonged actions of enkephalins via peptidase inhibitors does not cause dependence liability
lack of dependence is also seen with kappa agonists but is accompanied with aversive effects that limit therapeutic use
