Opioida Flashcards
What is meant by an opioid
An alkaloid derived from the poppy, Papaver somniferum
Opiate- nautral product – alkaloids that come from poppy
Give some examples of opiates
Morphine
Codeine
Thebaine
Papaverine
What is meant by an opioid
Opiod- anything with opiate like activity- synthetic
Describe the importance of the tertiary nitrogen in the opiate structure-activity relatiobship
Tertiary nitrogen = analgesia Permits receptor anchoring Extend side chain to 3+ carbons and you generate antagonist
The tertiary form of the nitrogen appears to be crucial to the analgesia of morphine; making the nitrogen quaternary greatly decrease the analgesia, since it cannot pass into the central nervous system. Changes to the methyl group on the nitrogen will decrease analgesia as well, creating antagonists
Tertiary nitrogen- important for affinity
Extend this chain- determines whether its agonist or antagonist
Afiinity and efficaycy- need teriary niterogen and short side chain
Describe the importance of the hydroxyl groups at position 3 and 6 in morphine
Hydroxyl groups- sites for modification
Heroin- is di-acetyl morphine- hydroxyl groups replaced by acetyl groups
Hydroxyl group at position 3: Required for Binding i.e. codeine is a prodrug
What is important for the activity of morphine
Aromatic ring- all 3 parts of molecule interacting with receptor- vand der waals forces
Morphine best at bidnign to receptor- all 3 compnents, hydroxyl group, aromatic ring and 3 nitrogen
How is the structure of codeine different to morphine
Codeine is methyl morphine (methyl group instead of hydroxyl group in position 3)
Describe the hydroxyl group at position. 6 in morphine
Hydroxyl group at position 6: Oxidise the OH group and lipophilicity Increases 10-fold
Heroin most lipid soluble
Di-acetyle instead of two hydroxyl groups
Describe methadone and fentanyl
Methadone conforms to the ‘Morphine Rule’ – tertiary nitrogen, quarternary carbon, phenyl group.
Fentanyl – moving away from the morphine rule has generated even more potent opioids i.e. fentanyl has a tertiary carbon NOT a quarternary carbon.
Morphine rulep- gap between aromatic ring and teriary nitrogen, also quaternary cartbon
Need to look like morphine to have an effect
Rule has broken down
2 other similar drugs to morphine include – methadone and fentanyl.
o Methadone – tertiary nitrogen.
o Fentanyl – 2x tertiary nitrogen’s?
They are extremely lipid soluble
Describe the key pharmacokinetic properties of opiates
Opioids are weak bases and thus are likely to be ionised in the acidic stomach and poorly absorbed from this site.
In the small intestine, they will be unionised and more readily absorbed. However, first pass metabolism will decrease the bioavailability.
Blood pH = 7.4. Therefore most opioids will be largely ionised in the blood. Usually <20% unionised. This is the component that can access tissues.
S.I- 5-7
Opioids are weak bases – mostly pKa > 8
Why is the comparison of potency of the opiates complex
Comparison of potency is complex. What route are you comparing? E.g. oral vs i.v. vs i.m. etc. What effect are you comparing? E.g. euphoria vs analgesia vs respiratory depression.
How is the lipid solubility of the opiates determined
Comparison of potency is complex. What route are you comparing? E.g. oral vs i.v. vs i.m. etc. What effect are you comparing? E.g. euphoria vs analgesia vs respiratory depression.
Describe the lipid solubility of the different opiates
morphine - 1 heroin- 2.3 codeine- 1.2 methadone - 116 fentanyl - 816
Lipid Solubility: Methadone/Fentanyl»_space; Heroin > Morphine
General rule of thumb – More lipid soluble, more potent - except for codeine
potency: morphine 1:1 heroin 2:1 codeine 1:10 methadone 4:1 fentanyl: 100:1
Describe the active and inactive metabolites of the opioids
Morphine:
Inactive metabolite - normorphine
Active metabolites - Morphine 3-G glucuronide
Morphine 6-G glucuronide (10%)
Heroin:
Inactive metabolites- normprphine
Active metabolites- Morphine
Codeine:
Inactive metabolite- nor codeine
Active metabolite- codeine
Methadone
inactive - EDDP
Active- none
Fentanyl
inactive - norfentanyl
active- none
Describe the metabolism of morohine, methadone and fentanyl
Like morphine, M6G is a μ-opioid receptor agonist with potent analgesic activity. However, morphine has greater affinity than M6G for the μ2-opioid receptor thought to be responsible for many of the adverse effects of μ-receptor agonists
In some patients, the most effective and well-tolerated opioid will be one that undergoes CYP-mediated metabolism. For example, in a 2001 clinical trial, 50 patients with cancer who did not respond to morphine or were unable to tolerate it were switched to methadone, which undergoes complex metabolism involving up to 6 CYP enzymes.
Fentanyl is predominantly converted by CYP3A4-mediated N-dealkylation to norfentanyl, a nontoxic and inactive metabolite
EDDP = 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine
Active metabolites- cxaude euophori but not respiratory depression
Compare 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 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
Describe the metabolism of codeine
Metabolism 2: Codeine morphine – only 5-10% of codeine is metabolised to produce morphine as there are activating (slow) and inactivating enzymes found in the liver:
o Activation (slow) via CYP-2D6 (O-dealkylation) – can have a polymorphism so don’t respond to codeine.
o Deactivation via CYP-3A4.
Most opioids are metabolised by CYP-2D6 and CYP-3A4 in the liver.
Morphine is the major exception – metabolised by uridine 5 diphosphate glucoronosyltransferase.
Essentially, how do opioids work
They act via specific ‘opioid’ receptors
Endogenous opioid peptides:
Endorphins
Enkephalins
Dynorphins/neoendorphins
What do endorphins act on
Mu or delta receptors
Cerebellum Caudaute Nucleus accumbent PAG All mu-mediated
Pain/Sensorimotor
What do the enkephalins act on
Delta
Nucleus accumbens
Cerebral cortex
Hippocampus
Putamen
Motor/cognitive function
What do the dymorphins act on
Kappa
Hypothalamus
putamen
caudate
Neuroendocrine
Describe the cellular actions of opioids at the opiate receptors
Hyperpolarisation (increased K+ efflux)
Reduce Ca2+ influx (affects neurotransmitter exocytosis)
Reduce adenylate cyclase activity (general reduction in cellular activity)
What are the clinical effects of opioids
Analgesia
Euphoria
Depression of cough centre (anti-tussive)
What are the side effects of opioids
Depression of respiration (medulla)
Stimulation of chemoreceptor trigger zone (nausea/vomiting)
Pupillary Constriction
G.I. Effects
Summarise how opioid modify pain transmission
ANALGESIA
Decrease pain perception
Increase pain tolerance
Central pain perception?
Which type of nerve responds to painful stimuli
Noiciceptors
Responds to stimulus rleases by damaged tissue
Describe the passage of the painful stimulus from the periphery 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
mu receptors in thalamus and dorsal horn
kappa receptors also in dorsal horn
What happens as the painful stimulus reaches the thalamus
The thalamus immediately activates the PAG (central pain coordinating region 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.
for example, if twisted ankle in sports- cortex will know that the outcome is not bad- so will increase activity of PAG to increase painful tolerance
pain tolerance is important in preventing the brain from becoming overwhelmed by painful stimuli
What does the PAG activate
The PAG activates the nucleus raphe magnus
It sends descending inhibitory neurones down to the dorsal horn
The NRM is responsible for reducing painful sensation (pain tolerance)
PAG has mu and kappa receptors
NRM has delta receptors
What does the NRPG 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 feeds into the PAG about the general health of the organism
Hypothalamus- samples current state of health
Poor health- paoinful stimuli exacerabated
Describe the role of the locus coreuleus in this system
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
What structure in the spinal cord acts like a mini-brain
Substantia gellatinosa
Some of the descending input from the NRM will be processed by the substantia gellatinosa, which then decides the level of inhibition necessary
Where might opioids act to modulate pain transmission
Dorsal horn and noicieptors – increase inhibition
PAG – enhance PAG firing - inhibiting GABA interneurones
NRPG – activates this - inhibits GABA interneurones
Opioids are very good at switching OFF GABA.
o GABA has an inhibitory effect on many of the pain tolerance centres so blocking GABA activates the pain tolerance centres.
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
Outline the cough reflex
Stimulation of mechanical or chemoreceptors
(throat, respiratory passages, or stretch receptors in the lungs)
Affterent impulses to cough centre (medulla)
Efferent impulses via parasympathetic and motor nerves to diaphragm, intercostal muscles and lungs
Increased contraction of diaphragmatic, abdominal and intercostal muscles – noisy expiration (cough)
- What are the two main neurotransmitters released by sensory neurones going from the airways to activate the vagus?
Acetylcholine
Neurokinin
By c-fibres
Describe the peripheral anti-jussive effects of opioids
Peripheral:
o ACh and NK (Neurokinin) release inhibition so less transmission down the sensory nerves to the vagus afferents.
opioids inhibit both eNANC nerve activity and cholinergic contraction of smooth muscles.
Describe the central anti-jussive effects of opioids
Central:
o 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 of this receptor increases serotonin so less cough.
o Medulla direct depression
Reduced 5HT1A receptor function in the dorsal raphe nucleus leads to an increase in 5HT levels which may depress discharges from inspiratory motorneurones.
NTS is a strong candidate for the cough centre. Opioids may directly inhibit cough responses from this site.
Describe how opioids can lead to respiratory depression
The most opioid sensitive aspect of respiration is rhythm generation.
The pre-Bötzinger complex is a small area in the ventrolateral medulla that can generate a ‘respiratory’ rhythm. The pre-Bötzinger complex is active during inspiration and is inhibited by opioids.
Central chemoreceptors provide tonic drive to the respiratory motor output by sensing changes in pH and are inhibited by opioids.
HIGH DOSE
Urge to breath is impaired
mu 2 receptors on central chemoreceptors
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 medullary vomiting centre
Low doses of opioids can do this
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
Why are pinpoint pupils clinically diagnostic
Most overdoses exhibit dilated pupils (mydriasis) as the decreased brain function reduces the level of constriction but opiates cause “pin-prick” eyes.
So indicates opioid overdose
Summarise the function of the enteric nervous system
Sensory neurone connected to mucosal chemoreceptors and stretch receptors detect chemical substances in the gut lumen or tension in the gut wall caused by food.
Information relayed to submucosal and myenteric plexus via interneurons.
Motor neurones release acetylcholine or substance P to contract smooth muscle or vasoactive intestinal peptide or nitric oxide to relax smooth muscle
Describe how opioids can lead to G.I disturbances
Many opioid receptors (kappa and Mu) are found in the myenteric plexus.
o Motor neurones release Ach or substance P to contract SM.
o Motor neurones release VIP (vasoactive intestinal peptide) or NO to relax SM.
Opioids cause:
o Decrease in gastric emptying. Decreased GI motility.
o Increase in water reabsorption. CONSTIPATION.
Summarise how opioids cause urticaria
Not all opioids cause histamine release – it is the hydroxyl group found on some opioids that cause mast cell degranulation (non-IgE-mediated).
o You can switch people to different opioids if they display this response (one without the OH group).
This reaction is PKA mediated (not receptor-mediated).
Not an allergic response
Strucutre of opiod drives this- not receptor driven
Why do opioids cause urticaria
Opioids bind to mast cells in the skin and promote histamine release (skin mast cells appear to be particularly sensitive)
The hydroxyl group at position 6 appears to be vital to this
Not all opioids cause histamine release – in fact it is the combination of the N-methyl group and the 6-hydroxyl group that is common to all opioids that induce non IgE mediated histamine release.
Itching (pruritis)
Hives (urticarial)
Hypotension
Describe the mechanism of tolerance to opioids
Opioids upregulate levels of arrestin in the tissues.
Arrestin promotes receptor internalisation.
The over-internalisation of receptors means the tissue becomes less receptive to opioids and so becomes tissue tolerant.
Tissue tolerance
What is withdrawal from opioids associated with
Withdrawal associated with:
o Psychological craving.
o Physical withdrawal (resembling the flu):
Opioids normally depress cell activity by reducing AC activity and so the body responds by upregulating AC activity. When you remove the opioid drug, the body is overstimulating AC and so general cell activity is greatly increased for a few weeks after withdrawal.
may get increased muscle cramps
Stopping opioids will result in increased adenylate cyclase activity in tissues shakes, headaches, sickness etc.
Describe the features of opioid overdose and how it is treated
Coma
Respiratory depression
Pin-point pupils
Hypotension
Treatment: Naloxone (opioid antagonist) i.v
Explain the treatment for opioid overdose
Treatment – I.V. Naloxone (opioid antagonist).
o Naloxone also has a tertiary nitrogen and so can bind to the opioid receptors.
o Naloxone has a LONG side chain of carbons and so has ANTAGONISTIC properties once bound to the opioid receptors.