Opioids Flashcards
What is the important structural group in Opiates, and what function does it provide?
Tertiary nitrogen
Permits Receptor anchoring which allows it to have an analgesic effect
How does extending the side chain of Morphine to 3+ carbons change its effects?
Generates an antagonist
Why is Codine considered a Prodrug?
Opiates require a Hydroxyl group at 3’ to allow them to bind.
Codine does not have this and needs to be converted to morphine before it has any effects
Why is Heroin much stronger than Morphine?
Substituting the -OH groups at 3’ and 6’ with Acetyl groups made it much more lipid soluble allowing it to enter and have a more profound effect on the brain
What is the pH of Opioids?
How does this affect their absorption?
Weak Bases
Ionised in the stomach - poor absorption
Unionised in the small intestine - more readily absorbed
Compare the lipid solubilities of different opioids:
How does this relate to their potency?
Methadone/Fentanyl > Heroin > Morphine
More to less lipid-soluble
More lipid soluble = more potent
How is the metabolism of Morphine different from other Opioids?
It is metabolised to other active metabolites - Morphine-6 Glucuronide (10% of metabolites)
This is secreted into bile and then undergoes enterohepatic cycling having more of an effect
Where are most Opioids metabolised by?
CYPs
Morphine by Uridine-5-diphosphate glucuronosyltransferase
Why do some patients not respond well to Codine?
It is metabolised by CYP2D6
What is Methadone used for?
Why does the metabolism of Codeine make it not very potent?
CYP2D6 - performs O-dealkylation and ACTIVATES codeine (this is quite SLOW)
CYP3A4 - DEACTIVATES codeine (works quite FAST)
Vast majority is deavtivated
What are the main endogenous Opioid agonists?
Endorphins
Enkephalins
Dynorphins/Neoendorphins
What are the three main Opiate receptors?
Which endogenous opioids agonise them?
Mu & Delta - Endorphins
Delta - Enkephalins
Kappa - Dynorphins
What are the four main areas of the brain where Mu opioid receptors are expressed in abundance?
Thalamus
Amygdala
Nucleus Accumbens
Periaqueductal grey matter
How do Opioid receptors work?
Depressants - slow down cellular activity
Three main mechanisms:
Hyperpolarisation (increased potassium efflux)
Reduce Ca2+ influx (Reduces neurotransmitter exocytosis)
Reduced Adenylate cyclase activity (general reduction in cellular activity)
What are the three main effects of Opioids?
Analgesia
Euphoria
Anti-tussive (Depression of cough centre)
What are four side effects of Opioids?
Depression of respiration (medulla) - Most dangerous side-effect
Stimulation of Chemoreceptor trigger zone (nausea/vomiting)
Pupillary constriction
GI effects
What are the two main methods of analgesia?
Decrease pain perception
Increase pain tolerance
Describe how pain is sensed - what pathway does it take?
Stimulus @ sensory neurones in the periphery
Conducted via dorsal horn to spinothalamic tract
Thalamus receives the painful information and distributes it to different sites
It activates the PAG (Periaqueductal grey matter) which is the central pain coordinating region of the brain
How is Pain tolerance increased?
Signals from the thalamus and cortices converge on the PAG - causes it to active the nucleus raphe magnus (NRM)
This projects down the spinal cord sends inhibitory neurones to the dorsal horn which dampen further pain perception
