Opiates/Opioids Flashcards
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 an opioid receptor antagonist?
The side chain on the tertiary nitrogen 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 in morphine?
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) i.e. codeine has CH3O- and morphine has HO-
How is the structure of heroin different to morphine?
How does this structural difference affect the properties of heroin?
Heroin is diacetyl morphine i.e. heroin has H3COO- and morphine has HO- (both hydroxyl groups oxidised to give to acetyl groups)
This means that heroin is much more lipid soluble than morphine so it has much more profound effects on the brain
What three structures tend to be necessary for opioid activity? How do the drugs methadone and fentanyl fit with this statement?
Tertiary nitrogen, quarternary carbon, phenyl group (‘Morphine Rule’)
- Methadone conforms to this rule.
- Fentanyl has a tertiary carbon NOT a quarternary carbon
Both of the above drugs are extremely lipid soluble and potent.
Given that opioids are all WEAK BASES, in what state are they likely to be in:
a. The stomach
b. The small intestine
State the two common routes of administration for opioids.
a. The stomach
IONISED – relatively little is absorbed
b. The small intestine
UNIONISED – more readily absorbed
Oral or IV
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. How does this determine potency (any exception)?
Methadone/fentanyl
Heroin
Morphine
More lipid soluble = more potent (generally)
Exception = codeine is slightly more lipid soluble than morphine but is less potent
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? Any others?
Morphine-6-glucuronide (M6G)
Also M3G
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?
5-10%
What are the two enzymes that are involved in codeine metabolism? What do they each do and state their relative rates of action.
CYP2D6 – activates codeine to morphine* (O-dealkylation) - SLOW
CYP3A4 – deactivates codeine (i.e. converts it into norcodeine) - FAST
Codeine is a prodrug.
List some endogenous opioid peptides.
Endorphins
Enkephalins
Dynorphins/Neoendorphins
Which opioid receptors do the following act on:
a. Endorphins
b. Enkephalins
c. Dynorphins
Endorphins => Mu or Delta
Enkephalins => Delta
Dynorphins => Kappa
What are endorphins, enkephalins and dynorphins involved in regulating?
Endorphins = Pain/Sensorimotor Enkephalins = Motor/Cognitive function Dynorphins = Neuroendocrine (hypothalamus)
Where in the brain are high concentrations of mu receptors found?
Amygdala
Nucleus Accumbens
Thalamus
Periaqueductal Grey matter (PAG)
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 positive and negative effects of opioids?
Positive:
Analgesia
Euphoria
Depression of cough centre (anti-tussive)
Negative: Depression of respiratory centre Nausea/Vomiting Pupillary constriction GI effects Urticaria