What is an opiate?
An alkaloid derived form the poppy, Papaver somniferum
What are the four most commonly occurring opiates?
Morphine Codeine Papaverine Thebaine
What is the significance of the tertiary nitrogen in the structure of morphine?
It is crucial for receptor anchoring and the analgesic effects of opioids
How can the structure of morphine be altered to turn it into anopioid receptor antagonist?
The side chain that the tertiary nitrogen is on can be extended by 3+ carbons to turn it into an opioid receptor antagonist
What is the importance of the hydroxyl group in position 3 inmorphine?
Required for binding
How is the structure of codeine different to morphine?
Codeine is methyl morphine (methyl group instead of hydroxyl group in position 3)
How is the structure of heroin different to morphine?
Heroin is diacetyl morphine
How does this structural difference affect the properties ofheroin?
This means that heroin is much more lipid soluble than morphine so it has much more profound effects on the brain
What is a very important feature of methadone and fentanyl?
They are extremely lipid soluble
Given that opioids are all WEAK BASES (pKa 8), in what state are they likely to be in: a. The stomach b. The small intestine
a. The stomach IONISED – relatively little is absorbed b. The small intestine UNIONISED – more readily absorbed
In what state will most opioids be in in the blood?
Blood has a pH of around 7.4 so the majority of opioids will be ionised in the blood - <20% of opioids will be unionised, and this is thecomponent that can access tissues
List morphine, fentanyl, methadone and heroin in order of decreasing lipid solubility.
Methadone/fentanyl Heroin Morphine
How is the metabolism of morphine different to the metabolism of other opioids?
Morphine is metabolised in the liver and then excreted in the BILE
What is the main, active metabolite that is produced from the metabolism of morphine?
What happens to this metabolite once it is excreted into the small intestine in the bile?
It undergoes enterohepatic cycling and returns to the blood where it can exert its effects
Describe the rate of metabolism of fentanyl and methadone.
Fentanyl is metabolised rapidly (it can be broken down by cholinesterases in the blood) Methadone is metabolised slowly so remains in the blood for longer
What is a use of methadone that is based on its metabolism?
It is used to wean people off heroin and morphine – as methadone remains in the blood for longer, it can reduce cravings
What percentage of codeine gets converted to morphine?
What are the two enzymes that are involved in codeine metabolism? State their relative rates of action.
CYP2D6 – activates codeine to morphine (O-dealkylation) - SLOW CYP3A4 – deactivates codeine - FAST
List some endogenous opioid peptides.
Endorphins Enkephalins Dynorphins/Neoendorphins
Which opioid receptors do the following act on: a. Endorphins b. Enkephalins c. Dynorphins
a. Endorphins Mu or Delta b. Enkephalins Delta c. Dynorphins Kappa
What are endorphins and enkephalins involved in regulating?
What are dynorphins involved in regulating?
Where in the brain are high concentrations of mu receptors found?
Amygdala Nucleus Accumbens Thalamus Periaqueductal Grey matter Cerebellum Caudate nucleus
All opiates are depressants. What are the THREE main mechanisms by which opiates have a depressive effect?
Hyperpolarisation (increased K+ efflux) Reduce Ca2+ influx (affects neurotransmitter exocytosis) Reduce adenylate cyclase activity (general reduction in cellular activity)
What are the main effects of opioids?
Analgesia Euphoria Depression of cough centre Depression of respiratory centre Nausea/Vomiting Pupillary constriction GI effects
Broadly speaking, what are the main methods of analgesia?
Increase pain tolerance Decrease pain perception
Describe the passage of pain information from the stimulus to the thalamus.
The painful stimulus is detected by a sensory neurone This then synapses with a spinothalamic neurone in the dorsal horn, which then passes the information to the thalamus
What happens as the pain information reaches the thalamus?
The thalamus immediately activates the PAG (central pain coordinatingregion of the brain) The thalamus also sends the pain information to the cortex, which processes the pain and modulates the firing of PAG The way in which the cortex affects PAG firing is based on previous experiences, memories etc.
What does the PAG do once it has received the input from the thalamus?
The PAG activates the nucleus raphe magnus