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Clinical Pharmacology, Therapeutics & Intro to Prescribing > Lecture 17- Opioids > Flashcards

Lecture 17- Opioids Flashcards

1
Q

define nociception

A

Nociception – ‘non-conscious neural traffic due to trauma or potential trauma to tissue’

  • E.g. when we touch something hot
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2
Q

define pain

A

is the neural processes of encoding and processing noxious stimuli.

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3
Q

outline pain pathway

A
  1. Damaged tissue release bradykinin and prostaglandins etc
  2. Nociceptors stimulated
  3. Release of Substance P (agonises local inflammatory response) and Glutamate
    1. Glutamate stimulates Adelta fibres (sharp pain) or C fibres (unmyelinated and transmit dull pain)
  4. Afferent nerve stimulated enter spinal cord in the dorsal horn and synapse with second order neurone
  5. Fibres decussate at the same level of entry
  6. Action potential ascends (spinothalamic)
  7. Synapse in thalamus
  8. Project to Post central gyrus (primary somatosensory cortex)
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4
Q

where can we modulate pain

A

peripherally and centrally

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5
Q

where is pain modulate peripherally and centrally

A
  • Peripherally: Substantia Gelatinosa
  • Centrally: Peri aqueductal grey

different mechanisms used

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6
Q

Peripheral modulation

A
  • Within the substantia gelatinosa in the dorsal horn
    • Lamina 1 and 5 are where pain fibres transmit
  • E.g.
    • Stimulation of Adelta + C fibres due to tissue damage
    • Enters lamina 1 and 5
    • Ascends the spinal cord via the spinothalamic tract and projects to the thalamus
    • Receive pain sensation in the primary somatosensory cortex
  • The tissue damage also sends inhibitory signals to the substantia gelatinosa- technically would make it feel as painful as possible
  • How do we modulate this? By ‘rubbing it better’
    • Ab fibres are activated by rubbing the tissue and send stimulatory signals to the substantia gelatinosa
    • Send inhibitor signals to lamin 1 and 5, reducing amount of pain received by the thalamus
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7
Q

Central modulation

A
  • Pain received by the thalamus and then cortex (primary somatosensory cortex)
  • Both the thalamus and cortex can stimulate the periaqueductal grey matter
  • Which then sends inhibitory signals to the dorsal horn and reduce the amount of pain being send from the DH to the thalamus.
  • Via endogenous opioids and 5-HT (serotonin)
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8
Q

Endogenous opioids

A

Enkephalins, Endorphins and Dynorphins

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9
Q

opioid receptor

A
  • Opioid receptors= G protein receptors
  • Three receptor subtypes
    • MOP/μ – most important clinically
    • DOP/δ
    • KOP/Κ
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10
Q

MOP receptor (u)

A
  • Found predominantly brainstem and thalamus
    • Also in spinal cord and GI tract
  • Responsible for therapeutic and adverse effects
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11
Q

outline how opioid GPCR receptors decrease pai felt

A
  • Agonist (opioid) binds to GPCR e.g. MOP receptor
  • Leads to decrease in cAMP
  • Efflux of potassium
  • Hyperpolarisation of membrane
  • Decreases substance P and GABA release
  • Increases dopamine release
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12
Q

Opioids as a class

A
  • Use opioids to exploit natural opioid receptors either by agonising or antagonising them
  • Main therapeutic effect via u-receptors (MOP)
  • Aim to modulate pain
  • Also indicated in cough, diarrhoea and palliation
  • Many different examples
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13
Q

Opioid tolerance

A
  • Many mechanisms
  • Can start to develop after a single dose
  • 2 main proposed mechanisms
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14
Q

opioid tolerace mechanisms

A
  1. Phosphorylation and uncoupling
  2. cAMP production
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15
Q

Phosphorylation and uncoupling

A
  1. Opioid binds to MOP receptor and activates G protein
  2. Causes decreased cAMP within cell
  3. Decreased pain in the body
  4. However … as opioid starts to bind we get intracellular phosphorylation of MOP receptor by kinases within the cell and these start to modulate the MOP receptor
  5. Modulation means that proteins like Arrestin can bind and displaces G protein…
  6. Or it means the opioid may not have the same effect on the MOP receptor…
  7. Therefore don’t get decrease cAMP
  8. Therefore don’t get decrease in pain
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16
Q

cAMP production

A
  1. Opioid binds causing decreased cAMP and decreased pain
  2. However… over a period of time when opioid is removed we get rebound effect massively increasing amount of camp in the cell, therefore increased pain
    1. Can cause neuronal excitability which causes withdrawal symptoms
  3. Therefore… have to give higher and higher dose of opioid in order to achieve same decrease in cAMP and pain
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17
Q

WHO analgesic ladder

A
  • For chronic pain (not as useful for acute pain)
  • Want to aim to keep lowest dose and weaker opioid for as long as possible
    • Start with simple analgesia e.g. paracetamol and NSAIDS
    • Then use weak opioids e.g. codeine
    • Then move to strong opioids e.g. morphine, fentanyl
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18
Q

simple analgeisa

A

paracetamol, NSAIDS

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19
Q

weak opiod

A

codeine

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20
Q

strong opioid

A

tramadol, buprenorphine, methadone, diamorphine, fentanyl, hydromorphone, morphine

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21
Q

opioids do not work for …

A

Nerve pain: Neuropathic drugs used e.g. shingles

  • Anticonvulsants
  • Tricyclics
  • Serotonin/NA reuptake inhibitors
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22
Q

name 2 strong MOP(u) receptor agonists

A

morphine and fentanyl

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23
Q

name a moderate MOP receptor agonisrs

A

codeine

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24
Q

name a mixed agonist-antagonist of MOP receptor

A

buprenorphine

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25
Q

name an MOP receptor antagonists

A

naloxone

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26
Q

uses of morphine (oral/IV/IM/PR)

A
  • Analgesia – severe pain
  • Long-standing pain when weaker painkillers no longer work
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27
Q

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 (lipophilc) including foetal
    • Struggles to cross blood- brain barrier (no protein binding)
  • Metabolism
    • Morphine + glucuronic acid–> M6G +M3G
      • M6G- main analgesic effect
  • Elimination
    • Renally
28
Q

Mode of action of morphine

A
  • Strong agonist of U (MOP) receptor
  • Complete activation of U
  • Decrease in cAMP
  • Decrease in pain
29
Q

Adverse drug response of morphine

A
  • Resp depression
  • Emesis
  • GI tract
    • Increases sphincter tone
    • Reduces GI motility
  • CVD
    • arrhythmias
  • Miosis
  • Histamine release- caution in asthmatics
  • Euphoric effect
  • Dizziness
30
Q

Contraindication of morphine

A
  • Renal impairment
  • Head injury
  • Acute resp depression
  • Heart failure secondary to chronic lung disease
  • Raised ICP
  • Risk of paralytic ileus
  • Pregnancy
31
Q

Drug-drug interactions (many) of morphine

A

Alcohol- both depressant effects on CNS

32
Q

uses of fentanyl (IV, epidural, interthecal and nasal)

A
  • Analgesia
  • Anaesthetic
33
Q

Compared to morphine…fentanyl is

A
  • 100x potency
  • Higher affinity for U (MOP) receptor
  • Less histamine release, sedation and constipation
34
Q

Pharmacokinetics 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
35
Q

Mode of action fentanyl

A
  • Strong agonist of U (MOP) receptor
  • Complete activation of U
  • Decrease in cAMP
  • Decrease in pain
36
Q

Adverse drug response fentanyl

A
  • Respiratory depression
  • Constipation
  • vomiting
37
Q
A
38
Q

Contraindication fentanyl

A
  • head injury
  • raised ICP
  • acute resp depression
39
Q

Drug-drug interactions (many) fentanyl

A
  • alcohol
  • st john’s wart
40
Q

uses of codein (oral, SC)

A
  • Mild- moderate analgesia
  • Cough depressant
41
Q

Pharmacokinetics codeine

A
  • Absorption
    • PO, SC administration
  • Metabolism
    • Codeine–> Morphine via CYP2D6
    • CYP2D6 inhibited by some drugs
    • Variable expression
      • Either not enough (no effect) or too much (toxicity)
  • Elimination
    • Glucoronidation of morphine and renal excretion
42
Q

Mode of action codeine

A
  • Moderate agonist to MOP receptor
  • Decrease in cAMP
  • Decrease in pain
43
Q

Adverse drug response codeine

A
  • Constipation (very bad)
    • Prescribe laxative alongside
  • Respiratory depression (worse in children)
44
Q

Contraindication codeine

A
  • Head injury
  • Acute resp depression
  • ICP
  • UC
  • Known ultra-rapid codeine metabolisers
45
Q

Drug-drug interactions (many)

A
  • Alcohol
  • CYP2D6 inhibitors
    • Fluxetine
    • Buprenorphine
46
Q

buprenoprhine uses

A
  • Moderate- severe pain
  • Opioid addiction treatment
47
Q

Pharmacokinetics buprenorphine

A
  • Absorption
    • Transdermal, Buccal, sublingual
  • Distribution
    • Very lipophilic
  • Metabolism
    • Hepatic via CYP3A4
    • Then glucoronidation before biliary excretion
  • Elimination
    • Biliary > Renal
    • Safe in renal impairment
    • Half life 37 hours – give patches
48
Q

Mode of action buprenorphine

A
  • Partial agonists to mu (MOP) receptor, meaning it only partially activates opiate receptors
  • Also weak kapp receptor antagonist and delta receptor agonists
  • Compared to morphine:
    • Very high affinity for μ receptor
    • Low Kd
    • Long duration of action
    • Not easily displaced
      • Difficult to reverse effect
    • Lower E(max) as partial agonist, lower efficacy à less side effect
  • Antagonistic κ receptors
49
Q

Adverse drug response buprenorphine

A
  • Respiratory depression
  • Low BP
  • Nausea
  • Dizziness
50
Q

Contraindication buprenorphine

A
  • Hepatitis
  • Liver problems
  • Alcohol intoxication
  • Biliary and gall bladder problems
51
Q

Drug-drug interactions (many) buprenorphine

A
  • Amiodarone
  • amlodipine
52
Q

naloxone uses

A
  • Rapidly reverse opioid overdose
53
Q

Pharmacokinetics 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–> naloxone-3- glucuronide
    • Renally excreted
  • Elimination
    • Duration of action 30-60mins
54
Q

Mode of action naloxone

A
  • Competitive antagonism of opioid – MU or MOP receptor
  • Blocks effect of other opioids e.g. morphine
  • Therefore increase in cAMP, increase pain, less of a high
55
Q

naloxone compared to morphine:

A
  • Affinity μ>δ>κ
  • Greater affinity than morphine
  • Affinity less than buprenorphine
56
Q

Adverse drug response

A
  • Short half life
    • Must give as slow infusion (gradual displacement of morphine)
    • If given in a rapid bolus will rapidly wear off the effect of morphine, however then the effects of morphine may become toxic again rapidly because its not been metabolised/excreted yet
57
Q

Contraindication naloxone

A
  • Pts known to be hypersensitive
  • Cardiac problems- caution
58
Q

Drug-drug interactions nalxoone

A
  • Codeine
  • Tramadol
  • Opium
  • Morphine (good)
59
Q

overdose epidemic

A
  • Growing problem
  • Large number of iatrogenic addicts
  • 1 in 4 will develop addiction
  • 9.6% rise in drug related deaths 2016à2017
  • 67.8% caused by opiates
60
Q

How is overdose mediated

A
  • U (MOP) receptor
  • As you take more and more you need to take more to get relief
  • Variable effects of doses
  • Main cause of death is resp depression- acidosis
  • Naloxone= treatment
  • Be a vigilant prescriber
61
Q
A
62
Q

Special considerations

A
  • Manual labourers/Drivers
  • Elderly
  • Bedbound
  • Asthmatics
  • Biliary tract obstruction
  • Respiratory Diseases
  • Renal impairment
  • Pregnancy
63
Q

Contraindications

A
  • Hepatic failure
  • Acute respiratory Distress
  • Comatose
  • Head injuries
  • Raised ICP
64
Q

which opioids are used for palliative prescriving

A
  • Buprenorphine, diamorphine, fentanyl, morphine and oxycodone
  • Difficult area of prescribing
  • Tend to ignore special considerations
65
Q

palliative prescribing of opioids

A
  • Difficult area of prescribing
  • Tend to ignore special considerations
  • Indications: Pain, Shortness of breath
  • Manage side effects: nausea, constipation
  • Last Months to Weeks of life
    • Long acting background level of pain control
    • Short acting top up doses for extra
  • Last Days to Hours of life
    • Continuous subcutaneous infusion
    • Top up doses as needed
66
Q

Opioids as controlled drugs

A
  • Controlled under Misuse of Drugs Legislation
  • Aim to prevent
    • Misuse
    • Illegal obtainment
    • Harm being caused
  • Benefit of medical use vs Risk of harm
67
Q

How to prescribe opioids

A
  • Start low and titrate up
  • Remember paracetamol element
  • Must include:
    • 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, Therapeutics & Intro to Prescribing (39 decks)

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