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Clinical Pharmacology > 9.1 Opioids > Flashcards

9.1 Opioids Flashcards

1
Q

what is nociception?

A

non conscious neural traffic due to trauma or potential

trauma to tissue.

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2
Q

what is pain?

A

“complex, unpleasant awareness of sensation modified by experience, expectation, immediate context and culture

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3
Q

describe how we interpret pain from a pathological stimulus

A
  1. Nociceptors stimulated
  2. Release of Substance P and
    Glutamate
  3. Afferent nerve stimulated
  4. projects onto 2nd sensory fibre in the dorsal horn at the level the 1st order sensory fibre enters the spinal cord.
  5. Fibres decussate and Action potential ascends in the spinothalamic tract
  6. Synapse in thalamus on third order sensory neurone
  7. Project to Post central gyrus
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4
Q

how are nociceptors stimulated during tissue damage?

A

As tissue damage occurs, cells break down and release bradykinin/serotonin/prostagladins within the tissue. Stimulate the nociceptors

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5
Q

what is the function of substance P?

A

agonises local inflammatory response

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6
Q

what is the function of glutamate?

A

to stimulate afferent nerve fibres. major excitatory neurotransmitter.

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7
Q

pain can be detected by 2 different types of afferent nerve fibres. what are they and how do they differ?

A

Afferent nerve fibres can be A-delta or C fibres
A-delta = transmits sharp pain
C fibres = unmyelinated and transmit dull pain. Unmyelinated so dull pain travels slower and needs a lot more stimulation in order to generate the same response.

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8
Q

what are the peripheral pain modulators?

A

substantia gelatinosa

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9
Q

what are the central pain modulators

A

peri aqueductal grey

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10
Q

where is the substantia gelatinosa?

A

within the dorsal horn of the spinal cord

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11
Q

describe how pain can be modulated peripherally.

A

tissue damage is detected by nociceptors and first order A-delta and c fibres carry the pain signal to stimulate the secondary order sensory neurones in the dorsal horn and inhibit the substantia gelatinosa, preventing the modulation of pain.
rubbing the affected are stimulates mechanoceptors. This sensation is carried by A-Beta fibres which stimulate the inhibitory encephalinergic interneurones in the substantia gelatinosa. The interneurones inhibit the pain signals from ascending up the dorsal horn and therefore decreasing the signals received by the thalamus.

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12
Q

describe how pain can be modulated centrally.

A

Both the thalamus and cortex act of the periaqueductal grey matter and stimulate it. Periaqueductal grey matter sends inhibitory signals down to the dorsal horn, and reduces the amount of pain sent up throught the dorsal horn to the thalamus. Does this via endogenous opioids and 5-HT
Periaqueductal grey matter forms Mickey mouses nose/mouth.

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13
Q

give some examples of endogenous opioids?

A

enkephalins
dynorphins
B-endorphins

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14
Q

what are G protein receptors?

A

opioid receptors

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15
Q

what are the three opioid receptor subtypes?

A

MOP
DOP
KOP

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16
Q

where are MOP receptors predominantly found?

A

in the brainstem and thalamus

spinal cord and GI tract

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17
Q

what type of receptor is the MOP receptor?

A

GPCR

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18
Q

What is the mechanism of action of the MOP receptor?

A
  • Agonist binds leading to the release of the Gi alpha subunit
  • Leads to decrease in cAMP
  • Efflux of potassium
  • Hyperpolarisation of membrane
  • Decreases substance P and GABA release
  • Increases dopamine release
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19
Q

what are the 2 mechanisms of opioid tolerance?

A

phosphorylation and uncoupling

cAMP production

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20
Q

describe the phosphorylation and uncoupling mechanism of opioid tolerance

A

Intracellular kinases within the cells modulates and changes the MOD receptors. Allowing arrestin to bind and displace the G protein. Or opioid may not be able to bind as effectively. Means that when opioid binds there isnt the same decrease in cyclic AMP and therefore there is not the same decrease in pain perception.

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21
Q

describe the cAMP production mechanism of opioid tolerance?

A

cAMP levels can be paradoxically elevated with sustained opioid use.
This results in a state where more opioid is required to overcome an increased basal cAMP activity via inhibition of adenylyl cyclase.
The increased cAMP levels results in neuronal excitability causing sweating, cramping, diarrhoea, vomiting and extreme agitation. It is a common cause of death amongst opioid users. Results in withdrawal symptoms

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22
Q

what receptors do opioids act upon to cause their main therapeutic affect?

A

MOP receptors

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23
Q

what are the main indications of opioids?

A

pain
cough
diarrhoea
palliation

24
Q

give examples of strong opioid agonists

A

morphine

fentanyl

25
Q

give an example of a moderate opioid agonist

A

codeine

26
Q

give an example of a mixed agonist-antagonist of opioid receptors

A

buprenorphine

27
Q

give an example of an opioid antagonist

A

naloxone

28
Q

describe the pharmacokinetics of morphine

A

• Absorption
PO, IV, IM, SC, PR
Gut absorption erratic Significant first pass effect- 40% oral bioavailability
• Distribution
Rapidly enters all tissues including foetal
Struggles to cross blood- brain barrier
• Metabolism
Morphine + glucuronic acid -> M6G (therapeutic effect) +M3G (neuroexcitability effect)
• Elimination
Renally

29
Q

what are the actions of morphine?

A

analgesia
euphoria
- complete activation of mew receptors / MOP

30
Q

what are the side effects of morphine?

A
  • Respiratory Depression
  • Emesis
  • GI tract - increase sphincter tone and decreased gut motility result in constipation
  • Cardiovascular
  • Miosis - contraction of the pupils
  • Histamine release by activation of mast cells - caution in asthmatics
31
Q

how does morphine cause respiratory depression

A

decreased sensitivity of the medullary respiratory centre, resulting in respiratory depression and increased risk of carbon dioxide toxicity

32
Q

describe the pharmacokinetics of fentanyl

A 
• Absorption 
IV, Epidural, Intrathecal, Nasal 80-100% bioavailability
• Distribution
Highly lipophilic, highly protein bound 
High level of CNS crossing
• Metabolism
Hepatic via CYP3A4 
 • Elimination
Half life 6 minutes 
Renally excreted
33
Q

both fentanyl and morphine are strong opioid agoinsts. how do they differ?

A

fentanyl is 100x more potent than morphine and has a higher affinity for the MOP receptor. It also cause less histamine release, sedation and constipation. Fentanyl has a very short half life and therefore is good for induction and anaesthesia.

34
Q

what are the pharmacokinetics of codeine?

A 
• Absorption 
PO, SC administration
• Metabolism
Codeine -> Morphine via CYP2D6 
CYP2D6 inhibited by Fluoxetine  
Variable expression
• Elimination
Glucoronidation of morphine and renal excretion
35
Q

why might codeine not be effect in some people?

A

As codeine is metabolised to morphine by the CYP2D6 enzyme.
CYP2D6 has variable expression and if it has very low expression that morphine levels might be too low to exhibit a therapeutic effect

36
Q

what are the actions of codeine?

A

mild-moderate analgesia

cough depressant

37
Q

what are the side effects of codeine?

A

constipation

respiratory depression - worse in children

38
Q

why should codeine be avoided in children under 12?

A

as more likely to cause respiratory depression.

39
Q

describe the pharmacokinetics of buprenorphine?

A

• Absorption
Transdermal, Buccal, sublingual - often given in patches
• Distribution
Very lipophilic. Distributes well into lots of different tissues.
• Metabolism
Hepatic via CYP3A4. Then glucoronidation before biliary excretion
• Elimination
Biliary > Renal
Safe in renal impairment
Half life 37 hours

40
Q

what are the indications of buprenorphine?

A

moderate to severe pain

opioid addiction treatment

41
Q

what are the side effects of buprenorphine?

A

respiratory depression
Low BP
nausea
dizziness

42
Q

both morphine and buprenorphine bind to opioid receptors. how do their affects vary?

A

Buprenorphine has a very high affinity for μ receptor (Low Kd). Buprenorphine has a longer duration of action than morphine. Morphine can be displaced by opioid antagonists while buprenorphine cannot. Buprenorphine has a Lower E(max) as partial agonist, lower efficacy. Buprenorphine is a mixed agonist-antagonist whereas morphine is a strong agonist. Buprenorphine is an agonist at MOP receptors but an antagonist at KOP receptors (dont produce euphoric affect).

43
Q

describe the pharmacokinetics of naloxone?

A 
• Absorption
IV, IM, Intranasal, PO 
Very low oral bioavailabilty as extensive first pass effect 
Rapid onset of action
• Distribution 
Rapid distribution as very lipophilic
• Metabolism
Hepatic 
Renally excreted
• Elimination
Duration of action 30-60mins
44
Q

how does the affinity of naloxone compare to other opioid receptor binding drugs?

A

greater affinity than morphine

less affinity than buprenorphine

45
Q

what is the action of naloxone?

A

competitive antagonism of opioid

46
Q

how is naloxone administered and why?

A

Naloxone is administered as a slow infusion as the half life is very short and if given as a bolus bolus, the bolus would ware off and the opioid would still remain and the patient would get respiratory distress again

47
Q

what receptor causes opioid overdose?

A

MOP receptor (mew)

48
Q

what are the effects of opioid overdose?

A 
dependence
vomiting
constipation
hypotension
bradycardia 
decreased sex drive 
histamine release 
miosis 
drowsiness 
respiratory depression -> apnoea
49
Q

what patient groups should receive special considerations before commencing opioids?

A 
manual labourers/drivers
elderly
bedbound
asthmatics
biliary tract obstruction 
respiratory diseases 
renal impairment 
pregnancy
50
Q

what are the contraindications of opioids?

A
  • Hepatic failure
  • Acute respiratory Distress
  • Comatose
  • Head injuries
  • Raised ICP
51
Q

what is the aim of palliative prescribing?

A

to help symptom control in the last year of life. cover the holistic side of medicine and improve the quality of life of the patient

52
Q

what opioids might be given in palliative treatment? what are there indications?

A 
Buprenorphine
diamorphine
fentanyl
morphine
oxycodone 
indications: pain, shortness of breath
53
Q

what side effects need to managed in the palliative prescribing of opioids?

A

nausea

constipation

54
Q

how do we prescribe opioids in palliative prescribing for months to weeks?

A

oral

  • long acting background level of pain control
  • short acting top up doses as needed
55
Q

how do we prescribe opioids in palliative prescribing for days to hours?

A

continuous subcutaneous infusion

top up doses if needed

56
Q

what are the aims of controlling drugs?

A

aim to prevent:
misuse
illegal obtainment
harm being caused

57
Q

Opioids are controlled drugs under the misuse of drugs legislation. What information must be included when prescribing opioids to a patient?

A
  • Date and prescribers address and Full name
  • Patients address and name
  • Form of the drug- tablets, syrup, capsules, patches, ampoules etc
  • Units- mgs, mls etc
  • Total volume- in words and figures
  • Clearly defined dose

Clinical Pharmacology (26 decks)

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