Opioids Flashcards
What is the path of the sense of pain?
Nociceptor (type A or C) is activated
Travels to dorsal root of spinal cord
Interneurones from substantia gelatinosa stop pain getting through from mechanoreceptors
Travels to thalamus and primary sensory cortex (they can also inhibit pain)
What are the different endogenous opioids, their precursors and different types in each category?
Proenkephaplin -> enkephalins
- > metenkephalin
- > leu-enkephalin
POMC -> endorphins
->β-endorphin
Prodynorphin -> dynorphins
Which type one of type A and C pain fibres is myelinated?
Type A
What are the different classes of opioid receptors?
μ - mu - MOP
δ - delta - DOP
κ - kappa - KOP
What type of receptor are opioid receptors?
GPCRs
Which receptor appears to mediate the majority of therapeutic effects of exogenous opioids?
Mu/MOP
What is the signalling pathway begun when an opioid binds to receptor?
They are all Gi GPCRs
Inhibition of adenylyl cyclase and reduction in cAMP levels
Activates K+ channels allowing K+ efflux
Causes hyperpolarisation of membrane so less excitable
Decreased influx of Ca
Reduced release of glutamate and substance P from vesicles (requires Ca)
What are the different types of opiates?
Agonists eg morphine
Partial agonists eg buprenorphine
Agonists/antagonists eg nalbuphine
Antagonists eg naloxone
Morphine
- half life?
- oral bioavailability?
- lipid soluble?
Half life: 1.3-6.7 hours
Oral bioavailability: 25% (low)
Not lipid soluble
What is the metabolite of morphine? Half life?
Morphine-6-glucuronide
4-5 hours
What are slow release preparations of morphine used for?
Chronic pain control
Half life of diamophine?
0.08 hours
Methadone
- half life?
- oral bioavailability?
- protein binding?
Half life: 15-30 hours
Oral bioavailability: 90%
90% of oral bioavailability is bound to protein, reducing direct availability for receptor binding
Codeine
- half-life?
- bioavailability?
Half life: 1.9-3.9 hours (quite short)
Bioavailability: 90%
Benefits of administering opiates IV?
Most rapid response
Avoids hepatic first pass metabolism
Good for severe pain
Patient can control the level of analgesia directly
What is a risk factor for ADRs/overdose with opiates?
Hepatic and renal failure
- can increase half-life by up to 50 hours
- careful with palliative care patients who could be suffering from terminal organ failure
Uses of morphine?
Analgesic
Diarrhoea
Metabolism of morphine?
Conjugated with glucuronide to produce morphine-6-glucuronide and morphine-3-glucuronide
Metabolites can be measured in the urine for screening
Metabolism of diapmorphine?
Prodrug - metabolised to morphine
Can cross blood brain barrier
What is diamorphine used for?
Analgesic in terminal illness
Use if methadone?
Maintenance in dependence
Uses of tramadol?
Analgesic
Also has serotonin and NA effects
Effects of tapentadol?
Analgesic
- specific μ agonist
- NA re-uptake inhibitor
Why does codeine not have an effect in some people?
Metabolised to morphine by CYP2D6
Some people do not express this enzyme
(Chinese and Caucasians)
Which opiates are used in anaesthetics? Why are they suitable for this?
Fentanyl - 100 times more potent than morphine
Alfentanil - 1000 times more potent than morphine
Remifentanil
Rapid onset and short half-life
ADR of alfentanil and remifentanil?
Can cause histamine release
Problem with pethidine?
Its metabolite, norpethidine, can build up with frequent repeated doses - dangerous so don’t give lots of doses
Name some opioid agonists-antagonists
Pentazoxine Nalbuphine Butorphanol Buprenorphine Meptazinol
Why can agonists-antagonists be better than full agonists?
Full agonists have a higher affinity for μ receptors
Partial opioid agonists-antagonists have mixed effects at the three sites
E.g. Nalbuphine
-antagonises μ
-partial agonist at κ
-weak agonist at δ
Good analgesia without euphoria
What are the uses of opioid antagonists? Name some and their half-lives
Opioid toxicity
Reverse respiratory depression
Treatment of dependence
Naloxone - 1-1.5 hours
Naltrexone - 4 hours
What are ADRs of agonising μ and κ receptors?
μ: nausea, vomiting, constipation, drowsiness, miosis, respiratory depression, hypotension
κ: dysphoria
What increases the risk of respiratory depression with opiates?
When combined with a pulmonary deficit
When combined with other depressant drugs eg anaesthetics, alcohol or sedatives
How do opiates cause respiratory depression?
Via μ receptor - action of CO2 sensitivity
What are other general ADRs of opiates?
Neurological effects such as euphoria, confusion, miosis, psychosis and coma
Constipation
Immunosuppresion with long term use (rare)
Anaphylaxis - non-opiate receptor effects on mast cells causing release of histamine
How does naloxone manage an opiate overdose?
It is an antagonist
Highly competitive with opiates
Rapidly reverses respiratory depression
-short half-life so need continued dosing over time
