Opioids Flashcards
What is an opiate?
anything that comes from the opium poppy. An opiate is an alkaloid derived from the poppy, Papaver somniferum
What are common natural opiates?
- morphine
- codeine
- thebaine
- papaverine
What role does the tertiary nitrogen on morphine play?
The tertiary nitrogen seems to be incredibly important for the analgesic effect of morphine. If you extend the nitrogen side chain, you go from agonist -> antagonist
How are heroine and codeine activated?
hydroxyl groups associated with morphine are needed for activity. As a result, heroine and codeine have to be converted to morphine to exert an effect
*For heroine, this conversion can happen in the brain. This is not the case for codeine (codeine à morphine conversion must take place outside the brain)
Describe the structures of some synthetic opioids
Methadone looks very similar to morphine (tertiary nitrogen, along with phenolic groups).
Fentanyl is less like morphine, but it still possesses the tertiary nitrogen (incredibly important for receptor binding).
How are opioids administered?
For therapeutic uses, this is often oral – for abusive uses, this is often intravenous (heroine is injected)
- Intravenous injection provides 100% bioavailability
How are opioids absorbed and metabolised?
Opioids are weak bases – pKa >8 – so they won’t be very unionised in the stomach (-> poor absorption)
once they enter the small intestines, they are well absorbed (alkaline environment)
Opioids are heavily metabolised in the liver (first pass) – this impacts their bioavailability
Because the pH of the blood is around 7.4, opioids are largely ionised in the blood (80%)
How does lipid solubility relate to potency?
the more lipid soluble, the more potent (exception: codeine - more lipid soluble than morphine but less potent)
How does metabolism of morphine affect the likelihood of experiencing negative side effects?
Morphine seems more likely to cause the negative side effects (e.g. respiratory depression)
The active metabolites (morphine 3-glucuronide and morphine 6-glucuronide) are less likely to do this
- individuals who don’t metabolise morphine very well are more likely to have negative side effects
Compare the rate of metabolism of fentanyl to morphine. What is the significance of this?
fentanyl - fast - metabolised by cytochrome 3A4 quickly, and is cleared equally fast
morphine - slow - metabolised by several enzymes and drug isn’t cleared well from the body
- both very lipid soluble but morphine cleared slowly -> accumulation in fatty tissue - often used as heroine replacement
Describe the metabolism of codeine
metabolised by two cytochrome P450 enzymes:
- One enzyme activates codeine (CYP2D6) to morphine – 5-10% of the codeine is converted via this route
- The other enzyme (CYP3A4) deactivates codeine – all conversion takes place in the liver
- people may have good metabolism of codeine -> more powerful effect (more morphine)
What are the man types of opiate receptors?
- Endorphins act on Mu (μ) receptors OR delta (δ) receptors
- Located in the cerebellum, caudate nucleus, nucleus accumbens and PAG
- Important in pain and sensation - Enkephalins act on delta (δ) receptors
- Located in the nucleus accumbens, cerebral cortex, hippocampus and putamen
- Important in motor and cognitive function - Dynorphins act on kappa (κ) receptors
- Located in the hypothalamus, putamen and caudate
- Important neuroendocrine role (via the hypothalamus)
What are endogenous agonists of opiates?
- endorphins
- enkephalins
- dynorphins/ neoendorphins
What is the cellular MoA of opioid receptors?
Opioids are depressant – they tend to slow cellular activity
They can hyperpolarise cells -> (increase K+ efflux)
They can reduce the Ca2+ inward current – this massively impacts exocytosis and NT release
- Within the cell, they can decrease adenylate cyclase activity
What are the effects of opioids?
positive:
- Analgesia
- Euphoria
- Depression of cough centre (anti-tussive)
negative:
- Depression of respiration (medulla)
- Stimulation of chemoreceptor trigger zone (nausea/vomiting)
- Pupillary Constriction
- G.I. Effects
What is the mechanism of analgesia caused by opioids?
- Sensory from the periphery into the thalamus via the spinothalamic tract.
- Thalamus and extra-cortical and cortical inputs activate the PAG (co-ordinates pain).
- PAG activates the NRM (Nucleus Raphe Magnus).
- NRM sends inhibitory descending signals to the dorsal horn – NRM increases pain tolerance
What does the NPRG do?
Nucleus Reticularis Paragigantocellularis
automatically suppresses pain before the brain processes it - independent of thalamus
- negative-feedback centre of the brain
How are the hypothalamus and locus coeruleus involved in the analgesic effects of opioids?
Hypothalamus:
- Constantly signals PAG independent of pain sensation
- In a poorer state of health, you are likely to be more sensitive to pain
LC (Locus Coeruleus) – major SNS outflow:
- Activated during a stress response
- During fight/flight, you do NOT want the pain response interfering with fight/flight
- Pain worse after an accident than during!
How is pain transmission modulated?
Spinal cord can modulate pain tolerance
descending inhibition from NRM:
- Some go directly into decreasing pain transmission in the spinothalamic tract.
- Some project into the Substantia Gelatinosa (can modulate/determine level of inhibition necessary on the sensory neurones from the NRM)
How do opioids cause analgesia?
Opioids act in the dorsal horn to prevent information relay from periphery to the spinothalamic tract (DEPRESSANT)
They also suppress the normal inhibitory signal (GABA) in the NRPG and PAG -> more pain toleranc
How do opiates cause euphoria?
bind to Mu receptors and decrease GABA exocytosis -> reduces inhibition of VTA -> more dopamine released
How do opioids cause an anti-tussive effect?
Central:
- 5HT1A-receptor antagonist:
> 5HT1A-receptor is a negative feedback receptor for serotonin and firing leads to suppression of serotonin and activation of the cough reflex - inhibition -> increased serotonin -> less cough
- Medulla direct depression
Peripheral:
- ACh and NK (Neurokinin) release inhibition so less transmission down the sensory nerves to the vagus afferents
How do opioids cause respiratory depression?
Depression of the Pre-Botzinger complex in the ventrolateral medulla – this generates respiratory rhythm so less rhythm with depression.
Central chemoreceptors are also inhibited by opioids and so depress the firing rate of the central chemoreceptors
How do opioids cause vomiting/ nausea?
can be seen at therapeutic dose via direct effect at chemoreceptor trigger zone (Mu receptors)
GABA keeps the CTZ suppressed – opioids switch this inhibition off. The CTZ signals to the medullary vomiting centre, and you feel nauseous
