analgesics

Question 1

why is pain a drug target

Answer 1

has both sensory and psychological component, impinges on other physiological processes such as;
sleep, mood, appetite and motivation

Question 2

what are main types of pain

Answer 2

inflammatory, headache (migraine) and neuropathic pain

Question 3

how is inflammatory pain mediated

Answer 3

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

Question 4

how can acute inflammatory pain be managed

Answer 4

if pain is acute and localised then local anaesthetics can be used

Question 5

what is used in treatment of inflammatory pain

Answer 5

aspirin and ibuprofen etc (NSAIDs) block synthesis of prostaglandins by inhibiting enzyme COX (COX1 is always present, COX2 induced at site of injury)

Question 6

how are migraines treated

Answer 6

drugs such as sumatriptan are agonists of 5HT1 receptors, work well in migraine

Question 7

how is neuropathic pain generated

Answer 7

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

Question 8

what is mechanism of some drugs used to treat neuropathic pain

Answer 8

gabapentin blocks calcium channels

carbamazepine and lignocaine block sodium channels

Question 9

what specific neurotransmission is involved in pain

Answer 9

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

Question 10

how does ketamine block pain

Answer 10

blocks neuropathic pain by blocking NMDA receptor mediated neurotransmission of c fibres

Question 11

how are opioids used in pain treatment, give examples

Answer 11

used in moderate (codeine) to severe pain (morphine etc)

Question 12

how does heroin stimulate opioid receptors

Answer 12

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

Question 13

what are the different opioid receptors, given examples of endogenous and exogenous agonists, what is effect of stimulating these on ion channels

Answer 13

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

Question 14

what are physiological effects of opioid receptors

Answer 14

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

Question 15

what opioid receptors are drug targets

Answer 15

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

Question 16

what do all endogenous opioids have in common

Answer 16

all peptide transmitters, inhibitory

Question 17

how do opioids compare in terms of drug action

Answer 17

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

Question 18

what is an antagonist for opioid receptors

Answer 18

naloxone is antagonist for all opioid receptors except ORL-1

Question 19

what determines efficacy of opioid dosage

Answer 19

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

Question 20

what are spinal mechanisms of opioid analgesia

Answer 20

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

Question 21

how does nerve injury effect opioid dosage

Answer 21

after nerve injury there is loss of opioid receptors and spinal cord may be hyper excitable so doses are higher after nerve injury

Question 22

what are supralspinal effects of opioid analgesia

Answer 22

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

Question 23

what are side effects of opioids and what site are these mechanisms mediated

Answer 23

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

Question 24

how are the side effects of opioids used therapeutically

Answer 24

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

Question 25

how do opioids cause dependence

Answer 25

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