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
Broadly speaking, what are the main methods of analgesia?
Increase pain tolerance
Decrease pain perception
Briefly 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 activates the PAG (central pain coordinating region of the brain) and also sends 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 and modulation from the cortex?
The PAG activates the nucleus raphe magnus (NRM)
What is the role of NRM?
It sends descending inhibitory neurones down to the dorsal horn
The NRM is responsible for reducing painful sensation (pain tolerance)
What is the NRPG, and what does it do?
NRPG – nucleus reticularis paragigantocellularis
It is independent of the thalamus
As soon as you sense pain, the NRPG is activated, which then activates NRM
You’re trying to suppress pain even before the brain has had a chance to think about it
Describe the role of the hypothalamus in this system.
The hypothalamus constantly inputs into the PAG informing about general health.
Describe the role of the Locus Coeruleus in this system. What will activate LC and is this important?
The locus coeruleus is the sympathetic outflow that has a negative effect on pain perception
A stress response will activate LC
Reason: at a time of stress, you wouldn’t want a painful stimulus to affect your fight or flight response
Describe the role of the Substantia gellatinosa in this system?
Some of the descending input from the NRM will be processed by the substantia gellatinosa, which then decides the level of inhibition necessary
What are the main targets of opioids within the pain transmission system?
- Increased inhibition at the dorsal horn
- Enhanced PAG firing
- Activates NRPG
Can also act at the periphery
How do opioids cause euphoria?
Opioids bind to mu receptors on GABA neurones and switch them off
This removes the inhibitory effect of GABA neurones on the dopaminergic neurones projecting from the ventral tegmental area to the nucleus accumbens –> increase in dopamine release at the nucleus accumbens
Describe the central anti-tussive effect of opioids.
The 5HT1A receptor in the Dorsal Raphe Nucleus (DRN) is the negative feedback receptor for serotonin – firing of this receptor leads to suppression of serotonin, which leads to activation of the cough centre
Opioids desensitise this receptor so serotonin levels rise in the cough centre, which inhibits the motor neurones that connect the cough centre to the larynx
What are the two main neurotransmitters released by sensory neurones going from the airways to activate the vagus? Which fibres? How do opioids affect this transmission?
Acetylcholine/Neurokinin C-fibres relay to vagus
Opioids stop the transmission of information from the sensory nerves to the vagus
Which part of the brain is responsible for rhythm generation?
Pre-Botzinger complex in the ventrolateral medulla
Describe how opioids affect respiration.
Opioids inhibit the pre-Botzinger complex
They also depress the firing rate of central chemoreceptors, which interferes with the ability of the brain to control respiration
How do opioids cause nausea/vomiting?
Opioids switch off GABA, which is normally suppressing the chemoreceptor trigger zone
This leads to activation of the chemoreceptor trigger zone, which then stimulates vomiting via the medullar vomiting centre
Why do opioids cause pinpoint pupils?
The preganglionic parasympathetic nerve to the eye is the oculomotor nerve (CN III)
This begins in the Edinger-Westphal nucleus
There are lots of GABA neurones with mu opioid receptors within the Edinger-Westphal nucleus
The removal of the inhibitory GABA input stimulates firing of the oculomotor nerve – MIOSIS
What are the effects of opioids on the GI tract?
Decrease gastric emptying Decrease GI motility Increase water reabsorption CONSTIPATION NOTE: this is due to the presence of opioid receptors on myenteric neurones
Explain how opioids can cause, what looks like, an allergic response?
Opioids bind to mast cells and promote histamine release (skin mast cells appear to be particularly sensitive) => urticaria (itchy red bumps on skin)
The combination of the N-methyl group and the 6-hydroxyl group (common to all opioids) induces the non IgE mediated histamine release; so not a mu receptor mediated response
What does opioid tolerance tend to be due to?
Receptor internalisation,
Which proteins are important in receptor internalisation?
Arrestins
Describe opioid withdrawal.
Psychological craving
Physical withdrawal
(resembling flu)
What is thought to be the cause of this powerful physical withdrawal?
One of the mechanisms of action of opioids is to reduce adenylate cyclase activity.
With long-term use of opioids, the body attempts to compensate by upregulating adenylate cyclase
Stopping opioids will result in increased adenylate cyclase activity in tissues –> shakes, headaches, sickness etc.
Summarise some of the features of opioid overdose?
Coma
Respiratory depression
Pinpoint pupils
Hypotension
What drug can be used to treat opioid overdose? How is it administered and what class of drug does it belong to? What is it about its structure that makes it so?
Naloxone
Intravenously
This is an opioid receptor antagonist
Similar structure to morphine but has an extended side chain on the nitrogen
