1. Tissue damage releases mediators e.g. serotonin, bradykinin and prostaglandins 2. Nociceptors are stimulated 3. Substance P, glutamate and bradykinin is released which agonises the local inflammatory response 4. Afferent nerve is stimulated which projects to the dorsal horn (lamina 1 and 5) 5. Fibres decussate at the ventral white commissure 6. Fibres ascend via the 2nd order neurone in the lateral spinothalamic tract 7. Synapses in the thalamus 8. Projects to the post central gyrus (primary sensory cortex)

The cortex normally inhibits the periaqueductal grey matter - when pain is overwhelming, the cortex stimulates the periaqueductal grey matter - stimulates the release of endogenous opioids i.e. enkephalins, dynorphins and beta endorphins which act on endogenous opioid receptors - inhibits signals to the dorsal horn - reduces pain

Mu GPCR Location: supraspinal and GI tract cAMP: decreases Effect: K+ efflux Causes: - hyperpolarisation - decrease in substance P release - less local inflammation and agonisation - increases dopamine release Endogenous opioids: - enkephalins - Beta - endorphins Uses: - analgesia - depression - euphoria - dependence - respiratory sedation

Delta GPCR Location : wide distribution cAMP: decreases Effect: inhibits influx of Ca2+ Causes: - hyperpolarisation - decreased release of substance P - increases dopamine release (as less GABA released so less inhibition) Endogenous Opioid: - enkephalins Use: - analgesia

Kappa GPCR Location: spinal cord/ brain and periphery cAMP: decreased Effects: - K+ efflux - inhibits Ca2+ influx Causes: - hyperpolarisation - decreased substance P - increases dopamine release Endogenous Opioid: - dynorphins Uses: - Analgesia - diuresis - dysphoria

Strong agonist of MOP Absorption: - gut absorption can be erratic as motility is slower - significant first pass effect - 40% bioavailability Distribution: - lipophilic so enters all tissues - passes through placenta - babies can get morphine withdrawal - doesn’t pass blood brain barrier Metabolism: - glucoronication in liver to active metabolites M3G and M6G Elimination: - renal Action: Analgesia and euphoria

L14 - Opiods Flashcards by Anmol Landa

Nociception

Non conscious neuronal activity due to trauma or potential trauma to tissue

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Pain

Complex awareness of sensation modified by experience, expectation, immediate context and culture involving the somatosensory cortex interpreting pain

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Pain pathway

Tissue damage releases mediators e.g. serotonin, bradykinin and prostaglandins
Nociceptors are stimulated
Substance P, glutamate and bradykinin is released which agonises the local inflammatory response
Afferent nerve is stimulated which projects to the dorsal horn (lamina 1 and 5)
Fibres decussate at the ventral white commissure
Fibres ascend via the 2nd order neurone in the lateral spinothalamic tract
Synapses in the thalamus
Projects to the post central gyrus (primary sensory cortex)

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A fibres

Myelinated

Sharp pain transmission

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C fibres

Unmyelinated
Dull ache pain
Requires more stimulation
Slower in transmission

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What modulates pain?

Centrally - periaqueductal grey

Peripherally - substantia gelatinosa

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Substantia gelatinosa

Tissue damage inhibits the substantia gelatinosa so pain is felt

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Rub wound

Rubbing the wound stimulates the substantia gelatinosa which inhibits lamina 1 and 5

Therefore reduced pain

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Periaqueductal grey

The cortex normally inhibits the periaqueductal grey matter

when pain is overwhelming, the cortex stimulates the periaqueductal grey matter
stimulates the release of endogenous opioids i.e. enkephalins, dynorphins and beta endorphins which act on endogenous opioid receptors
inhibits signals to the dorsal horn
reduces pain

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MOP receptors

Mu GPCR

Location: supraspinal and GI tract

cAMP: decreases

Effect: K+ efflux

Causes:

hyperpolarisation
decrease in substance P release - less local inflammation and agonisation
increases dopamine release

Endogenous opioids:

enkephalins
Beta - endorphins

Uses:

analgesia
depression
euphoria
dependence
respiratory sedation

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DOP receptors

Delta GPCR

Location : wide distribution

cAMP: decreases

Effect: inhibits influx of Ca2+

Causes:

hyperpolarisation
decreased release of substance P
increases dopamine release (as less GABA released so less inhibition)

Endogenous Opioid:
- enkephalins

Use:
- analgesia

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KOP receptors

Kappa GPCR

Location: spinal cord/ brain and periphery

cAMP: decreased

Effects:

K+ efflux
inhibits Ca2+ influx

Causes:

hyperpolarisation
decreased substance P
increases dopamine release

Endogenous Opioid:
- dynorphins

Uses:

Analgesia
diuresis
dysphoria

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WHO analgesic ladder

Simple analgesia: paracetamol, NSAIDs

Weak opioid: codeine - very addictive with many side effects

Strong opioid: morphine and fentanyl
- used in acute severe or malignant pain

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Other effects of opioids

Used in:

Cough
Diarrhoea - particularly chemotherapy induced
Palliation

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Morphine

Strong agonist of MOP

Absorption:

gut absorption can be erratic as motility is slower
significant first pass effect - 40% bioavailability

Distribution:

lipophilic so enters all tissues
passes through placenta - babies can get morphine withdrawal
doesn’t pass blood brain barrier

Metabolism:
- glucoronication in liver to active metabolites M3G and M6G

Elimination:
- renal

Action:
Analgesia and euphoria

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M6G and M3G

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M6G - Analgesic effect

M3G - neuroexcitatory and euphoria

Side effects of morphine

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Respiratory distress - medullary resp centres are less responsive to CO2
Emissions - stimulates the chemoreceptor trigger zone
GI- decreases motility and increases sphincter tone - constipation
Cardiovascular - lowers BP and causes vasodilation - syncope
Miosis - constriction of pupils
Histamine release - caution in asthmatics - itchy and can trigger asthma attack

Fentanyl

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Administration:

IV, intrathecal (in CSF space), epidural or nasal
80-100% bioavailability

Distribution

highly lipophilic therefore wide distribution
highly protein bound
passes blood brain barrier

Metabolism
- hepatic CYP3A4

Elimination

renal - less than morphine therefore better for renal patients
short half life (6mins)

Use:
- pre operative analgesia and anaesthetic

Fentanyl compared with morphine

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100x more potent
Higher affinity for MOP - shifts morphine off

Less side effects of:

constipation
histamine release
sedation

Fentanyl side effects

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Respiratory distress
Vomiting
constipation

Codeine

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Administration: oral or subcutaneous injection

Metabolism:
Codeine is metabolised to morphine via CYP2D6

Elimination:
Glucoronidation of morphine by the liver (second pass) and really excreted

Use:
Analgesia
Cough depressant

CYP2D6

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Inhibited by fluoxetine and other SRRIs

Variably expressed - Caucasians have a higher prevalence of 2 null alleles therefore codeine is not metabolised to morphine so no effect.

Codeine potency

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1/10th of morphine potency

Side effects of codeine

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Constipation - give laxative

Respiratory distress - worse in under 12s

Buprenorphine

Mixed agonist and antagonist (partial agonist) Administration: - transdermal patch - buccal - sublingual Distribution: - very lipophilic - highly distributed - passes blood brain barrier Metabolism: - hepatic CYP3A4 - glucoronidation before biliary excretion (good for renal patients) Elimination: - biliary excretion - safe in really impaired - long half life Use: - used in moderate to sever pain - chronic pain in elderly - opioid addiction treatment

Buprenorphine compared to morphine

High affinity for MOP - not easily displaced Longer duration of action Partial agonist - Lower efficacy Antagonist at KOP

Side effects of buprenorphine

``` (Less severe) Respiratory distress Low BP Nausea Dizziness ```

Naloxone

Competitive antagonist of opioid Administration: - IV or IM injection - not very effective when given orally as low bioavailability (first pass) Distribution - lipophilic - rapid wide distribution Metabolism: - hepatic glucoronidation Excretion: - renally excreted - short half life - given as slow infusion - rapid onset and elimination (30-60mins) Use: - opioid overdose

Nalaxone compared to morphine

affinity for mu, then delta then kappa | Higher affinity than morphine but less than buprenorphine

Opioid tolerance mechanism

- Phosphorylation and uncoupling | - cAMP production

Phosphorylation and uncoupling

1. Repeated exposure of opioid causes intracellular phosphorylation mediated by PKC and Ca2+ dependent proteins within the cell 2. Arrestin proteins bind to MOP and uncouple the G protein 3. Opioid doesn’t bind as readily therefore sensitivity decreases and cAMP production doesn’t decrease

cAMP production

1. When opioids bind they decrease cAMP 2. When the opioid is not given, there is a rebound effects where the cell is flooded with cAMP 3. A higher dose is needed to reduce cAMP to reduce pain 4. More cAMP causes increased depolarisation 5. Increases neuronal excitability 6. Leads to withdrawal symptoms

Withdrawal symptoms of opioids

``` Nausea and vomiting Muscles cramps Abdominal pain Constipation and diarrhoea Sweating Agitated and anxious ```

Overdose

Can cause death due to respiratory depression - drowsy therefore not breathing as quickly - decreased medullary responsiveness to CO2 - acidosis Decreases effects of - DOP agonists and serotonin agonists Hypoxia - pulmonary oedema and vasodilation

Special considerations

- drivers - makes drowsy - elderly - distribution changes due to change in fat: muscle distribution - bedbound - asthmatics and respiratory disease - respiratory depression and histamine - biliary tract obstruction - renal impairments - give fentanyl or codeine - pregnancy - morphine withdrawals -

Contraindications

``` Hepatic failure Acute respiratory distress Comatose Head injuries Raised ICP - can mask symptoms ```

L14 - Opiods Flashcards

(36 cards)