Opioids Flashcards
Describe the pain signal transduction pathway
- Nociceptors stimulated
- Release of Substance P and Glutamate
- Afferent fibres stimulated (A-Delta and C fibres)
- Fibres decussate and ascend
- Synapse in thalamus
- Project to Sensory Cortex
Compare afferent C and A-Delta fibres
A-Delta fibres;
- Transmit sharp pain
C fibres;
- Transmit dull pain
- Unmyelinated (so need more stimulation to generate a response)
We can modulate pain via modulators in the PNS and CNS
State the modulators in the PNS and CNS
PNS: Substantia Gelatinosa
CNS: Peri-aqueductal grey
Describe the modulation of pain peripherally via the Substantia Gelatinosa
- Normally A-Delta and C fibres detect pain and inhibit the Substantia Gelatinosa
- Rubbing the site of pain sends impulses down A-Beta fibres, which stimulate the Substantia Gelatinosa
- SG acts to inhibit ascending sensation of pain in dorsal horn
List 3 Endogenous Opioids that act to modulate pain
Opioid receptors are G Protein receptors. What are the 3 types of Opioid receptor?
- Encephalins, Endorphins, Dynorphins
- MOP (main one that is clinically relevant)
- DOP
- KOP
Where are MOP receptors found?
Describe what happens when an agonist binds to a MOP receptor
- Mainly in Brainstem + Thalamus, but also in GI tract and Spinal cord
- Agonist binds-> Decreases in cAMP-> K+ efflux
- Leads to membrane hyperpolarisation
- Decreased release of Substance P and GABA
- Increased Dopamine release
What are 2 main mechanisms of Opioid tolerance (can start after 1 dose)
- Phosphorylation and uncoupling
- cAMP production
Describe how Phosphorylation & Uncoupling can lead to Opioid tolerance
(Normally, agonist binds to receptor-> Decreased cAMP-> Decreased pain)
- Intracellular phosphorylation occurs as Opioids bind
- Causes changes in MOP receptors
Leading to;
- Arrestins displacing the G Protein on the MOP receptors
- Opioid binds less effectively to MOP receptor
Thus, diminished decrease in cAMP-> Diminished decrease in pain
Describe the mechanism of how cAMP production can lead to Opioid tolerance
(Normally, agonist binds to receptor-> Decreased cAMP-> Decreased pain)
- As opioid is removed, cAMP inside cell starts to increase massively
Thus to get same level of pain reduction you either need to;
- Decrease time between doses
- Increase dose
How does cAMP production explain withdrawal symptoms
Increase in cAMP caused by opioid removal-> Neuronal excitability which is what causes withdrawal symptoms
Suggest 3 non-palliative uses of Opioids
- SOB control
- Cough
- Diarrhoea
Strong Opioids (Morphine, Fentanyl) aren’t usually used for alleviating nerve pain (Diabetes, Shingles etc)
What kind of drugs do we use for this?
Suggest 3 groups of these drugs
Neuropathic drugs
- Anticonvulsants
- Tricyclics
- Serotonin/ NA Reuptake Inhibitors
Name 2 Strong Agonists
- Morphine
- Fentanyl
Describe the Absorption and Distribution of Morphine
A;
- Oral, IV, IM, Rectal, Subcutaneous
- Significant 1st pass effect so only 40% oral bioavailability
D;
- Rapidly enters all tissues (including foetal)
- Struggles to cross Blood-Brain Barrier
Describe the Metabolism and Elimination of Morphine
M;
- Glucororonidation in liver-> M6G (main therapeutic effect) and M3G (neuroexcitability effect)
E;
- Renally
Describe the Absorption and Distribution of Fentanyl
A;
- IV, Epidural, Intrathecal, Nasal
- 80 to 100% oral bioavailability
D;
- Highly lipophilic AND protein bound (so to many tissues AND CNS)
- Strongly crosses BBB
Describe the Metabolism and Elimination of Fentanyl
M;
- Hepatic via CYP 3A4
E;
- Renally
- Short half life of 6 mins
Compare Fentanyl to Morphine
- 100x more potent
- Higher affinity for MOP receptor
- Less histamine release, sedation and constipation
Suggest 2 uses and 3 side effects of Fentanyl
- Anaesthesia
- Analgesia
- Respiratory depression
- Vomiting
- Constipation
State a Moderate Agonsist
Codeine
Describe the Absorption, Metabolism and Excretion of Codeine
A;
- Oral, Subcutaneous
M;
- Converted to Morphine via CYP 2D6 (Highly polymorphic)
- Glucoronidation of Morphine
E;
- Renally
Suggest a group of drugs that inhibits CYP 2D6, thus increasing plasma Codeine concentration
Certain SSRIs (such as Fluoxetine)
Compare Codeine to Morphine
List 2 actions and 2 side effects
- 10% of Morphine’s potency
Actions;
- Cough depressant
- Mild to moderate analgesia
Side effects;
- Constipation
- Respiratory depression (worse in children)
Name a Mixed Agonist-Antagonist
Buprenorphine
Describe the Absorption and Distribution of Buprenorphine
A;
- Transdermal, Buccal, Sublingual
D;
- Very lipophilic so gets into a lot of tissues
Describe the Metabolism and Excretion of Buprenorphine
M;
- Hepatic via CYP 3A4
- Glucoronidation
E;
- Biliary excretion more than renal (so safe in renal impairment)
- Half life of 37 hours (given via patches usually)
Compare Buprenorphine to Morphine
- Higher affinity for MOP receptor, so not easily displaced by morphine (In case of OD)
- Lower Efficacy, as a Partial Agonist
- Antagonist at KOP receptors
List 2 actions and 4 side effects of Buprenorphine
- Moderate to severe analgesia
- Opioid addiction treatment
- Respiratory depression
- Low BP
- Nausea
- Dizziness
Name an Antagonist
Describe its onset of action
How long does it action last?
Naloxone
Rapid OoA
Duration of action: 30-60 mins
Describe the Absorption and Distribution of Naloxone
A;
- IV, IM, Oral, Nasal
- Very low oral bioavailability (extensive 1st pass)
D;
- Very lipophilic (so gets into many tissues)
Describe the Metabolism and Excretion of Naloxone
M;
- Glucoronidation in liver-> Naloxone-3-glucoronide
E;
- Renally
Compare Naloxone to Morphine and Buprenorphine
- Greatest affinity for MOP, least for KOP receptors
- Can displace Morphine, but not Buprenorphine from MOP
List 1 action and Side effect of Naloxone
- Competitive antagonism for opioids
- Short half life (so need to give as slow infusion)
What’s the most common cause of death in opioid OD
What is the main treatment
Respiratory depression
Naloxone
Suggest 8 groups of people who you should be cautious to prescribe long-term opioid use to
- Manual labourers/ drivers
- Elderly
- Bedbound
- Asthmatics
- Biliary tract obstruction (Buprenorphine)
- Respiratory diseases
- Renal impairment
- Pregnancy
List 5 contraindications for Opioid use
- Hepatic failure
- Acute respiratory destress
- Comatose
- Head injuries
- Raised ICP
Morphine has a strong affinity for MOP receptors, completely activating them.
2 actions are Analgesia and Euphoria
List 6 side effects
- Respiratory depression
- Emesis
- GI Tract (Constipation as it increases sphincter tone)
- CVS
- Miosis
- Histamine release (caution in asthmatics)
