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
2
Q
define pain
A
is the neural processes of encoding and processing noxious stimuli.
3
Q
outline pain pathway
A
- Damaged tissue release bradykinin and prostaglandins etc
- Nociceptors stimulated
- Release of Substance P (agonises local inflammatory response) and Glutamate
- Glutamate stimulates Adelta fibres (sharp pain) or C fibres (unmyelinated and transmit dull pain)
- Afferent nerve stimulated enter spinal cord in the dorsal horn and synapse with second order neurone
- Fibres decussate at the same level of entry
- Action potential ascends (spinothalamic)
- Synapse in thalamus
- Project to Post central gyrus (primary somatosensory cortex)
4
Q
where can we modulate pain
A
peripherally and centrally
5
Q
where is pain modulate peripherally and centrally
A
- Peripherally: Substantia Gelatinosa
- Centrally: Peri aqueductal grey
different mechanisms used
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
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)
8
Q
Endogenous opioids
A
Enkephalins, Endorphins and Dynorphins
9
Q
opioid receptor
A
- Opioid receptors= G protein receptors
- Three receptor subtypes
- MOP/μ – most important clinically
- DOP/δ
- KOP/Κ
10
Q
MOP receptor (u)
A
- Found predominantly brainstem and thalamus
- Also in spinal cord and GI tract
- Responsible for therapeutic and adverse effects
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
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
13
Q
Opioid tolerance
A
- Many mechanisms
- Can start to develop after a single dose
- 2 main proposed mechanisms
14
Q
opioid tolerace mechanisms
A
- Phosphorylation and uncoupling
- cAMP production
15
Q
Phosphorylation and uncoupling
A
- Opioid binds to MOP receptor and activates G protein
- Causes decreased cAMP within cell
- Decreased pain in the body
- 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
- Modulation means that proteins like Arrestin can bind and displaces G protein…
- Or it means the opioid may not have the same effect on the MOP receptor…
- Therefore don’t get decrease cAMP
- Therefore don’t get decrease in pain
16
Q
cAMP production
A
- Opioid binds causing decreased cAMP and decreased pain
-
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
- Can cause neuronal excitability which causes withdrawal symptoms
- Therefore… have to give higher and higher dose of opioid in order to achieve same decrease in cAMP and pain
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
18
Q
simple analgeisa
A
paracetamol, NSAIDS
19
Q
weak opiod
A
codeine
20
Q
strong opioid
A
tramadol, buprenorphine, methadone, diamorphine, fentanyl, hydromorphone, morphine
21
Q
opioids do not work for …
A
Nerve pain: Neuropathic drugs used e.g. shingles
- Anticonvulsants
- Tricyclics
- Serotonin/NA reuptake inhibitors
22
Q
name 2 strong MOP(u) receptor agonists
A
morphine and fentanyl
23
Q
name a moderate MOP receptor agonisrs
A
codeine
24
Q
name a mixed agonist-antagonist of MOP receptor
A
buprenorphine
25
name an MOP receptor antagonists
naloxone
26
uses of morphine (oral/IV/IM/PR)
* Analgesia – severe pain
* Long-standing pain when weaker painkillers no longer work
27
**Pharmacokinetics of morphine**
* 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
**Mode of action of morphine**
* Strong agonist of U (MOP) receptor
* Complete activation of U
* Decrease in cAMP
* Decrease in pain
29
**Adverse drug response of morphine**
* Resp depression
* Emesis
* GI tract
* Increases sphincter tone
* Reduces GI motility
* CVD
* arrhythmias
* Miosis
* Histamine release- caution in asthmatics
* Euphoric effect
* Dizziness
30
**Contraindication of morphine**
* Renal impairment
* Head injury
* Acute resp depression
* Heart failure secondary to chronic lung disease
* Raised ICP
* Risk of paralytic ileus
* **Pregnancy**
31
**Drug-drug interactions** (many) of morphine
Alcohol- both depressant effects on CNS
32
uses of fentanyl (IV, epidural, interthecal and nasal)
* Analgesia
* Anaesthetic
33
Compared to morphine…fentanyl is
* 100x potency
* Higher affinity for U (MOP) receptor
* Less histamine release, sedation and constipation
34
**Pharmacokinetics fentanyl**
* 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
**Mode of action fentanyl**
* Strong agonist of U (MOP) receptor
* Complete activation of U
* Decrease in cAMP
* Decrease in pain
36
**Adverse drug response fentanyl**
* Respiratory depression
* Constipation
* vomiting
37
38
**Contraindication fentanyl**
* head injury
* raised ICP
* acute resp depression
39
**Drug-drug interactions** (many) fentanyl
* alcohol
* st john’s wart
40
uses of codein (oral, SC)
* Mild- moderate analgesia
* Cough depressant
41
**Pharmacokinetics codeine**
* 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
**Mode of action codeine**
* Moderate agonist to MOP receptor
* Decrease in cAMP
* Decrease in pain
43
**Adverse drug response** codeine
* Constipation (very bad)
* Prescribe laxative alongside
* Respiratory depression (worse in children)
44
**Contraindication codeine**
* Head injury
* Acute resp depression
* ICP
* UC
* Known ultra-rapid codeine metabolisers
45
**Drug-drug interactions** (many)
* Alcohol
* CYP2D6 inhibitors
* Fluxetine
* Buprenorphine
46
buprenoprhine uses
* Moderate- severe pain
* Opioid addiction treatment
47
**Pharmacokinetics buprenorphine**
* 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
**Mode of action buprenorphine**
* 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
**Adverse drug response buprenorphine**
* Respiratory depression
* Low BP
* Nausea
* Dizziness
50
**Contraindication buprenorphine**
* Hepatitis
* Liver problems
* Alcohol intoxication
* Biliary and gall bladder problems
51
**Drug-drug interactions** (many) buprenorphine
* Amiodarone
* amlodipine
52
naloxone uses
* Rapidly reverse opioid overdose
53
**Pharmacokinetics naloxone**
* **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
**Mode of action naloxone**
* 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
naloxone compared to morphine:
* Affinity μ\>δ\>κ
* Greater affinity than morphine
* Affinity less than buprenorphine
56
**Adverse drug response**
* 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
**Contraindication naloxone**
* Pts known to be hypersensitive
* Cardiac problems- caution
58
**Drug-drug interactions nalxoone**
* Codeine
* Tramadol
* Opium
* Morphine (good)
59
overdose epidemic
* 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
**How is overdose mediated**
* 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
62
**Special considerations**
* Manual labourers/Drivers
* Elderly
* Bedbound
* Asthmatics
* Biliary tract obstruction
* Respiratory Diseases
* Renal impairment
* Pregnancy
63
**Contraindications**
* Hepatic failure
* Acute respiratory Distress
* Comatose
* Head injuries
* Raised ICP
64
which opioids are used for palliative prescriving
* Buprenorphine, diamorphine, fentanyl, morphine and oxycodone
* Difficult area of prescribing
* **Tend to ignore special considerations**
65
palliative prescribing of opioids
* 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
**Opioids as controlled drugs**
* Controlled under Misuse of Drugs Legislation
* Aim to prevent
* Misuse
* Illegal obtainment
* Harm being caused
* Benefit of medical use vs Risk of harm
67
**How to prescribe opioids**
* 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
